[{"handle":{"url":"https://hdl.handle.net/2434/1240156"},"title":"THE GOVERNANCE OF OUTCOME ACCOUNTABILITY IN SOCIAL IMPACT BONDS","internalauthor":"SCHMALZ, JULIA NATASCHA","type":"Tesi di dottorato","year":"2026","abstract":"Social Impact Bonds (SIBs) are an advanced form of outcomes-based contracting that facilitate private investment in public service delivery. Their contractual form establishes accountability between stakeholders primarily through measurable outcomes rather than through relational processes. Concerns about how this financing structure reshapes the governance of delivery processes have motivated engagement with how relational and diverse value considerations can and should be re-embedded into the instrument.    This thesis examines who assumes responsibility for maintaining outcome accountability in SIBs, in particular who contributes to and governs the coordination and valuation work that SIB contracts do not price or allocate. The research is based on a systematic review of peer-reviewed studies on SIB governance, an analysis of the same literature through the lens of residual value risk, and a qualitative document analysis of international guidance on SIB governance and the Finnish Kotouttamisen (KOTO) Social Impact Bond.    The findings show that contractual and financial mechanisms in the design of SIBs accommodate the adjustment of governance primarily within the framework of outcome accountability. Process-based mechanisms, especially in the context of contractual learning, tend to test how far stakeholders within a particular institutional system can sustain relational and adaptive processes externalized by the outcomes-based design, rather than structurally integrating them.    The research highlights the patterns in how governance efforts required to sustain outcome accountability are distributed among stakeholders: providers internalizing the translation between evidence and impact, intermediaries mediating between stakeholders, and public commissioners supporting them through administrative procedures. The findings indicate that maintaining outcome accountability depends less on the particular outcome arrangement than on the institutional and organizational capacity to manage the governance work it externalizes. Interpreted through the lens of residual value risk, this externalization reveals how the contractual and financial arrangements of SIBs require governance capacity to sustain outcomes without structurally securing it.    The thesis contributes to the scholarship on SIBs by conceptualizing outcome accountability as a governance object whose stabilization produces residual value risk. It argues that SIBs face a structural trap: they rely on governance capacity that they do not structurally secure, while learning processes tend to stabilize rather than transform this trap. Practitioners and policymakers considering SIBs as financing public service provision may benefit from viewing outcome accountability itself as an object of governance that needs to be actively designed and institutionally supported, rather than a result of the SIB structure.","language":"eng","citation":"THE GOVERNANCE OF OUTCOME ACCOUNTABILITY IN SOCIAL IMPACT BONDS / J.n. Schmalz ; tutor: N.von Jacobi ;  co-tutor: V. Cecchini Manara, Giulio Peroni ;  coordinators: L. Sacconi , D. U.Galetta. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2026 Jun 25. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13338.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 29-OTT-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1193735"},"title":"UNVEILING THE ADVERSE EFFECTS OF POLYSTYRENE NANOPLASTICS IN THE HUMAN-DERIVED HEPG2-OA STEATOTIC-LIKE MODEL, VALIDATING DYSFUNCTIONAL HUMAN-DERIVED SW872 ADIPOCYTE IN VITRO MODELS FOR THE STUDY OF CARDIOMETABOLIC DISEASES, AND ASSESSING TRIMETHYLAMINE N-OXIDE IN A PLIC STUDY SUB-COHORT","internalauthor":"GIGLIONE, CLAUDIA","type":"Tesi di dottorato","year":"2025","abstract":"Background and aims. Cardiometabolic (CM) and cardiovascular (CV) diseases currently represent the leading cause of mortality worldwide. In recent years, research advances have shed light on novel potential risk factors, involved in both CMDs and CVDs, including polystyrene nanoplastics (PSNPs), a widespread contaminant in the environment and living organism, and Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite. PSNPs were found to accumulate in different tissues and organs, including vascular walls, liver, adipose tissue, kidneys and pancreas, exerting potential adverse effects as they accumulate over time. Particularly, PSNPs were found to induce liver steatosis by altering lipid metabolism, based on animal studies, suggesting a role for PSNPs in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). On the other hand, TMAO was found to contribute to atherosclerotic CVD (ASCVD) pathogenesis and development based on in vitro and in vivo models, as it accumulates either in presence of gut dysbiosis and renal impairments or based on certain food consumption. Association studies have also shown strong correlations between high circulating TMAO levels and increased CVD risk. To this aim, TMAO has been quantified exploiting different technological platforms, including proton nuclear magnetic resonance (1H NMR) and mass spectrometry (MS) coupled to high performance liquid chromatography (HPLC). Notwithstanding the robustness of a wide spectrum of analytical methods to measure TMAO from human- derived plasma or serum samples, there is still the need of standardized approach to improve clinical data variability. Moreover, under the light of the strikingly interconnection between CMDs and CVDs and the central role of the adipose tissue in the occurrence of such disorders, modeling dysfunctional adipose tissue recapitulating key features of CMDs has been of considerable interest. Currently, most research relied on the use of animal models, either in vivo or in vitro to model pathological mechanism and driving drug discovery addressing novel therapeutical approaches. However, interspecies-related differences could limit translatability of pre-clinical research into clinical settings. Therefore, the present doctoral thesis aimed at (1) investigating cytotoxic and dysmetabolic effects induced by PSNPs in a human-derived steatotic-like model of hepatocytes, (2) modelling human-derived dysfunctional model of adipocytes recapitulating key CMD traits, and ultimately (3) to develop and validate a robust HPLC-MS/MS analytical method to quantify TMAO from plasma or serum samples. The same method was used to quantify TMAO in a sub-cohort of the PLIC study, encompasses patients in CVD primary prevention. Clinical and anthropometric data, coupled to TMAO quantification were integrated within a machine-learning (ML)-based model to generate personalized CVD risk profiles.  Materials and methods. For aim 1: fluorescent and non-fluorescent 500-200-100-20 nm PSNPs were tested at 200-100-10 μg/mL concentrations for 24 and 48 hours in the human- derived hepatoma cell line, HepG2, and in a steatotic-like model of HepG2 cells induced by 100 μM oleic acid for 7 days (HepG2-OA cells). PSNPs-mediated cytotoxic effects were assessed with MTT assay. PSNP uptake and inhibition (only for 500 nm PSNPs) of intracellular internalization via chemical and physical agents were addressed by cytofluorimetric analysis, as well as for dysmetabolic changes, including glucose uptake, and oxidative stress. Moreover, lipid accumulation was explored by light microscopy, and mitochondrial membrane damage with spectrophotometric analysis.  For aim 2: human-derived liposarcoma SW872 cell line was selected to obtain 2 distinct dysfunctional models of adipocytes, one induced by 100 μM oleic acid for 7 days (SW872- OA) and the other one via spontaneous differentiation in culture for 17 continuous days (SW872-AUTO). Both models and the control cell line, SW872, were explored by looking at the expression of pharmacologically relevant target genes (qRT-PCR) and glucose transporters at the protein level (immunofluorescence), and by evaluating mitochondrial activity (Seahorse). SW872 and SW872-OA were further investigated via metabolomics analyses (1H NMR) exploiting cell pellets and cell culture media.  For aim 3: a stable isotope dilution HPLC-MS/MS analytical method was developed and validated in collaboration with B.S.N. srl, to measure TMAO from either plasma or serum samples. TMAO was specifically measured from plasma samples of a sub-cohort of the PLIC study. Supervised ML-based approach was thereby applied to integrate multiple variables from the PLIC cohort data set, including TMAO quantification, into a modular pipeline using Konstanz Information Miner (KNIME) platform.  Results. For aim 1: PSNPs were found to reduce overall HepG2 and HepG2-OA cell viability by 20%. Intracellular internalization of PSNPs occurred in a dose-dependent manner for all the tested sizes, and in a time-dependent manner both cell models, except in HepG2-OA cells after 48 hours of exposure. Cold exposure and nystatin significantly inhibited 500 nm PSNP uptake in HepG2 and HepG2-OA after 3 hours of exposure. PSNP exposure led to impair glucose uptake and mitochondrial membrane potential in both HepG2 and HepG2-OA cells. Oxidative stress production induced by PSNPs was found to increase in a dose- and size- dependent fashion in both cell models. 20 nm PSNPs were observed to induced higher oxidative stress compared to biggest PSNPs in both cell models. Moreover, PSNPs promoted increase accumulation of lipid droplets in HepG2 and HepG2-OA cells.  For aim 2: SW872-OA and SW872-AUTO cells showed increased expression of glucose transporters (isoform 1 and 4) both at the gene and protein levels, but reduced translocation to the plasma membrane compared to SW872 cells. Both cell models did not show expression of GLP1R and specular expression of SLC5A2. In addition, SW872-OA and SW872-AUTO cells showed a distinct mitochondrial activity; SW872-AUTO mitochondrial activity diverged the most against control SW872 cells with significant increase of coupling efficiency and spare respiratory capacity. 1H NMR metabolomics revealed altered lipid metabolism in SW872-OA compared to SW872 cells, coupled to inflammatory and adipocyte differentiation-related signatures.  For aim 3: Calibration curve of HPLC-MS/MS analytical method to measure TMAO showed high linearity (r2: 0,99997). Coefficient of variation (%CV) for intra-/inter-assay precision resulted below 10%. TMAO measured concentrations from the lowest point of the calibration curve showed a %CV below 12%. Chromatographic run-time was optimized up to 6 minutes. cTMAO median (Q1-Q3) value was 258 (176-417) (ng/mL) in the sub- cohort of the PLIC study. cTMAO weakly contributed to the CVD risk prediction (accuracy: 0.687) in the ML-based predictive model, compared to LDL-C and common carotid intima media thickness (CC-IMT), which were revealed among stronger predictors (accuracy: 0.724; area under the curve: 0.743; CI lower-upper: 0.689-0.79).  Conclusions. (1) PSNPs showed to induce cytotoxic and dysmetabolic alterations in a dose- and size-dependent fashion particularly in HepG2-OA cells, suggesting a relevant role for PSNPs in the exacerbation of pathological mechanisms linked to liver diseases, including MASLD.  (2) Metabolomic analysis of SW872-OA and SW872-AUTO cells has revealed distinct dysmetabolic signatures and impaired translocation of glucose transporters to the plasma membrane, further valuing these models for their potential applications in CMD and CVD studies, in line with previous assessments.  (3) Stable isotope dilution HPLC-MS/MS analytical method to quantify TMAO revealed robustness, precision and high reproducibility following validation and advantageous turnaround time for the analysis, making it suitable for large-scale applications in clinics. ML predictive model revealed TMAO as a weaker CVD risk predictor in the sub-cohort of PLIC patients in CVD primary prevention. Further evaluations in subjects with more severe CVD risk/disease will extend these observations.","language":"eng","citation":"UNVEILING THE ADVERSE EFFECTS OF POLYSTYRENE NANOPLASTICS IN THE HUMAN-DERIVED HEPG2-OA STEATOTIC-LIKE MODEL, VALIDATING DYSFUNCTIONAL HUMAN-DERIVED SW872 ADIPOCYTE IN VITRO MODELS FOR THE STUDY OF CARDIOMETABOLIC DISEASES, AND ASSESSING TRIMETHYLAMINE N-OXIDE IN A PLIC STUDY SUB-COHORT / C. Giglione ; tutor: P. Magni ;  co-tutor: G. Guercilena ;  coordinatore: G. Danilo Norata. - MILANO. Dipartimento di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti, 2025 Dec. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14015.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 07-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/821354"},"title":"POTENTIAL ROLE OF LIN28/LET-7 AXIS IN SEZARY SYNDROME","internalauthor":"FANONI, DANIELE","type":"Tesi di dottorato","year":"2021","abstract":"Sézary Syndrome (SS) is a rare leukemic cutaneous T-cell lymphoma (CTCL) with an aggressive clinical course and a survival of 1-5 years.  It is characterized by erythroderma, generalized lymphadenopathy and the presence of neoplastic CD4+ lymphocytes (Sézary cells) in the skin, lymph nodes and peripheral blood. It is well known that deregulation in STAT3 signaling is one of the molecular mechanism involved in CTCL pathogenesis and cancer progression and many studies demonstrated the efficacy of JAK/STAT inhibitors to induce apoptosis in Sézary cells. However the cause of SS is still unknown and until now, no specific therapy is available for this disease. Recently, microRNA (miRNA) profiling analysis in SS revealed a possible role of miRNAs in the pathogenesis of the disease and identified specific miRNAs as possible new targets in SS treatment. Particularly miR-21, miR-486 and miR-214 were found upregulated in SS while let-7 family members were found downregulated. miRNAs are small non-coding RNAs that regulate gene expression via post transcriptional silencing of target genes. They have important roles in fundamental biological processes such as cell development, differentiation, proliferation and apoptosis.  Let-7 family members are widely viewed as tumor suppressor miRNAs and they are strongly downregulated in many cancers. Particularly let-7a is known to target many oncogenes including c-Myc and its upregulation inhibits cell proliferation by reducing the expression of c-Myc. Another target of let-7a is c-MET and its downstream signaling pathways such as RAS, PI3K, STAT3 and β-catenin pathways. Let-7b has several oncogenes as targets such as HMGA1, HMGA2, CCND2 and KRAS, and loss of expression of let-7b has been demonstrated in many cancers comprising acute lymphoblastic leukemia. Many studies demonstrated that downregulation of let-7 is due to its direct interaction with LIN28A or LIN28B. LIN28 depletion resulted in specific increases in all let-7 family members. On contrast Nishi et al demonstrated that let-7b is downregulated in leukemic cells via DNA hypermethylation of its regulatory region. Moreover in pancreatic cancer cell lines let-7 downregulation has been reported to be linked to a constitutively-active STAT3.   In two independent studies (Narducci et al. and Corti et al.) a downregulation of some members of let-7 family, particularly let-7a and let-7b, was demonstrated in SS by using microRNA microarrays.   Particularly, in a previous unpublished study from our group we found a clear split in miRNA expression between SS patients and controls. Of particular interest let-7b was the most downregulated in our patients series and comparison of miRNA profile and CGH data showed that all patients with gains in 8q (MYC) have also let-7b downregulation. We found 24 miRNA differentially expressed between SS patients and healthy controls, including miR-214, miR-486 and miR-21 yet described and validated by Narducci et al. and Qin et al. Expression of let-7 members is controlled by MYC binding to their promoters and levels of let-7 have been reported to decrease in models of MYC-mediated tumorigenesis. Amplification of 8q (MYC) found on the same patients with let-7b downregulation and LIN28/let-7b link with STAT3/miR21 activation suggest a possible key role of let-7 family members (particularly let-7b) in SS. Finally, let-7 family members expression lead to apoptosis by Bcl-XL repression. In a recent study, Adams et al demonstrates that, in a wide group of haematologic malignancies, Let-7b downregulation lead to apoptosis blockage and that restoring let-7 normal expression downregulates Bcl-XL with a consequent upregulation of caspase-3 and apoptotic activity in neoplastic cells.  26 patients affected by SS and 15 healthy donors were recruited at Dermatology Department of Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico of Milan. Each group (patients and controls) released their informed consent according to the Declaration of Helsinki Principles.  Heparinized (or EDTA) blood were drawn from patients and controls, and mononuclear cells were isolated by Ficoll density centrifugation. Subsequently, CD4+ T-cells were isolated by using magnetic-beads conjugated antibodies (CD14 negative selection and CD4 positive selection). Depending on material availability CD4+ lymphocytes from patients and HD were used for RNA and/or protein extraction.  Total RNA samples will be converted into complementary DNA (cDNA) and used to asses expression levels of let-7b, let-7c, Lin28A, Lin28B, c-Myc, CCND1, HMGA1 and HMGA2 by quantitative reverse transcriptase PCR (qRT-PCR). The expression levels were standardized using RNA18S gene as housekeeping.   Apoptosis molecules were evaluated by means of protein array experiment. Protein array is a glass slide based array in which is possible to investigate expression levels of different proteins at the same time. The goal was to demonstrate whether let-7s downregulation could be related to a diminished apoptosis activity in SS. This hypothesis would allow targeting let-7s to restore apoptosis in neoplastic cells.  By q-RT PCR both let-7 miRNAs (let-7b and let-7c) showed differential expression with greater downregulation in SS than in healthy donors.  Let-7b resulted downregulated in 8/18 (44%) patients and in 0/9 (0%) controls while let-7c was shown downregulated in 7/18 (39%) patients and 0/9 (0%) HD. 2 patients showed a downregulation of both let-7b and let-7c miRNAs (11%). Globally, 13/18 (72%) patients had a downregulation in at least one let-7.  Analyzing expression levels of Lin28A and Lin28B both resulted unexpressed in HD. In SS patients Lin28B was found unexpressed while Lin28A was found only in a 7 out 18 SS patients.   However, 5 out of 7 patients with Lin28A overexpression had a let-7c downregulation. Let-7c downregulation could be considered a consequence of direct repression by Lin28A.  Moreover, in order to investigate whether let-7 expression influenced response to therapy all SS patients were divided in two groups. “responders” and “non responders” to therapy.  Let-7 downregulation seemed to be linked to response to therapy. In fact, number of “non responder” patients in let-7 downregulated group was much higher than those in let-7 normal expressed group.  Among the 43 protein studied by means of apoptosis array 11 proteins showed a statistically significative difference between SS and HD.  Among these pro-apoptotic factors bad, bax, bcl-w and BID and cyclin-dependent kinase inhibitors p21, p27 and p53 resulted less expressed in SS than in normal controls. Particularly, p53 showed very low levels in patients with let-7 downregulation.   On the other hand inhibitors of apoptosis family members cIAP-2 and XIAP and heat shock protein 60 (HSP60) showed a higher expression in SS than in HD.  qRT-PCR experiments confirmed let-7b and let-7c downregulation in more than 70% of SS patients versus 0% of HD.  In the present study a significant linear correlation was found between Lin28A expression and let-7c downregulation. This suggest that let-7c downregulation in SS is due to a Lin28A reactivation.  Finally, about apoptosis pathways, some apoptosis related molecules were found differentially expressed in SS than in HD. Although no evidences were found for a direct role of let-7s in regulating apoptosis in SS, some de-regulated proteins could collaborate to chemoresistance in SS.  Taken together these data suggest the existence of complex mechanisms regulating apoptosis and drug resistance in SS. Further studies, including functional studies, are needed to better understand the role of each molecule in this complex network.","language":"eng","citation":"POTENTIAL ROLE OF LIN28/LET-7 AXIS IN SEZARY SYNDROME / D. Fanoni ; tutor: E. Berti ; coordinatore: E. Berti. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2021 Mar 26. 33. ciclo, Anno Accademico 2020. [10.13130/fanoni-daniele_phd2021-03-26].","filename":"phd_unimi_R11910.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/821354/1725045/phd_unimi_R11910.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/953452"},"title":"A COMPARISON BETWEEN GEOMETRIC QUASI-FUNCTORS AND FOURIER-MUKAI FUNCTORS","internalauthor":"DASTI, LORENZO","type":"Tesi di dottorato","year":"2023","abstract":"In this PhD thesis I have delt with the relationship between the most important class of functors between derived categories, i.e. Fourier-Mukai functors, and quasi-functors which are the morphisms in the localization Hqe of the category of dg categories with respect to quasi-equivalences.  To be more precise: let X and Y be two smooth and proper schemes over a field. I have defined an explicit bijection between the isomorphism class of the triangulated category of perfect complexes over X×Y and the set of morphism in Hqe between two (fixed) dg enhancemenst of the categories  of perfect complexes over X and over Y , respectively. Moreover, I have showed that this bijection associates to the dg lift of a Fourier-Mukai functor the isomorphism class of its kernel, giving a positive answer to a conjecture of Toën.","language":"eng","citation":"A COMPARISON BETWEEN GEOMETRIC QUASI-FUNCTORS AND FOURIER-MUKAI FUNCTORS / L. Dasti ; tutor: P. Stellari ; correlatore: A. Canonaco ; coordinatore: V. Mastropietro. Università degli Studi di Milano, 2023 Jan 26. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12400.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/953452/2135790/phd_unimi_R12400.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1213145"},"title":"APPLICATION OF COMPLEMENTARY METHODS BEYOND STANDARD PATHOLOGY TO INVESTIGATE KETAMINE NEUROTOXICITY IN MODELS OF PEDIATRIC ANESTHESIA","internalauthor":"CANESI, SIMONE","type":"Tesi di dottorato","year":"2026","abstract":"Ketamine is widely used as a pediatric anesthetic; however, growing evidence suggests that exposure during critical windows of brain development may induce neurotoxicity. This thesis aimed to preclinically characterize ketamine-induced neurotoxicity in the rat neonatal brain, elucidate the affected cell populations and mechanisms, and refine both in vivo methodology and human-relevant new approach methods (NAMs).  A standardized in vivo model was established using Sprague-Dawley rats at postnatal day 7, a period of intense synaptogenesis and high vulnerability to anesthetic injury. Repeated intraperitoneal ketamine administrations (5 x 20 mg/kg at 90-minute intervals) produced a prolonged anesthetic state and neurotoxic effects were evaluated in cortex, hippocampus, and corpus callosum using a panel of histological and immunohistochemical markers (H&E, Cleaved Caspase-3, γH2AX, GFAP, Iba-1, Olig2, NeuN). A preliminary study compared whole-area analysis with standardized microscopic field sampling, demonstrating that 12 fields per region provided quantitative results comparable to whole-area assessment. A subsequent methodological study systematically tested progressive field reduction using correlation, agreement, and group-comparison statistics, confirming that this level of sampling remains necessary for robust quantification of apoptosis and DNA damage, whereas some glial and neuronal markers can be reliably assessed with fewer fields.   Across in vivo studies, ketamine consistently induced transient but marked apoptosis and DNA damage, peaking 2 hours after the last injection and returning to baseline by 16 hours, with no sex-dependent differences. γH2AX emerged as a sensitive marker of ketamine-induced DNA damage, paralleling apoptosis, detected section and Cleaved Caspase-3. The inclusion of both vehicle-treated and unmanipulated control groups demonstrated that neither handling nor vehicle administration significantly influenced apoptotic or cellular endpoints, excluding a procedure-related effect. Double immunofluorescence and confocal microscopy confirmed that neurons and oligodendrocytes are the primary apoptotic population, while microglia and, to a lesser extent, astrocytes predominantly contribute to phagocytosis of neuronal apoptotic debris. Detection of Cleaved Caspase-9 in affected cells supported the activation of the intrinsic, mitochondria-dependent apoptotic pathway, consistent with a mechanism involving oxidative stress, mitochondrial dysfunction, and downstream caspase activation.  A pharmacokinetic study following a single ketamine injection confirmed rapid brain penetration and clearance of the parent drug, supporting the rapid onset of observed effects and guiding to selection of relevant concentrations for in vitro testing. Finally, ketamine effects were investigated in a human iPSC-derived BrainSphere model cultured on microelectrode arrays. Ketamine produced a rapid, concentration-dependent reduction in spikes, bursts, and network synchronization, followed by partial recovery and rebound hyperexcitability after washout, differentially affecting glutamatergic, GABAergic, and dopaminergic components. These findings confirmed NMDA receptor-mediated modulation of human neuronal networks and established a pharmacologically relevant NAM that captures key functional aspects of ketamine action.   Overall, this work provides a rigorously characterized neonatal rat model, an optimized quantitative method of digital image analysis, and a complementary human in vitro system, advancing understanding of the temporal and cellular mechanisms underlying ketamine-induced neurotoxicity in the developing brain.","language":"eng","citation":"APPLICATION OF COMPLEMENTARY METHODS BEYOND STANDARD PATHOLOGY TO INVESTIGATE KETAMINE NEUROTOXICITY IN MODELS OF PEDIATRIC ANESTHESIA / S. Canesi ; tutor: C. Recordati ; coordinatore: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2026 Feb 12. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13798.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 09-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1057692"},"title":"THE IMMUNE MOLECULAR LANDSCAPE OF BREAST CANCER DURING PREGNANCY","internalauthor":"SAJJADI, ELHAM","type":"Tesi di dottorato","year":"2024","abstract":"Introduction: Breast cancer during pregnancy (PrBC) is a rare and aggressive type of early onset breast cancer (EOBC) with only partially known biologic determinants. The interplay between the anti-tumor immune response and the mechanisms of maternal-fetal immune is not clear at all, underscoring the complexity of PrBC biology. We hypothesize that a deeper understanding of the molecular processes of immune pathways interplay is required for refining the clinical management of PrBC. This project aimed to profile the immune molecular landscape of PrBC, with the goal of identifying potential actionable biomarkers.  Methods: We selected n=83 PrBC and n=89 pregnancy-unrelated EOBC cases from our institutional registry and assessed tumor-infiltrating lymphocytes (TILs) as well as CD4, CD8, forkhead box P3 (FOXP3), and programmed death-ligand 1 (PD-L1) (clone 22C3) expression by immunohistochemistry. Additionally, RNAs extracted from n=75 PrBC and n=67 EOBC cases were subjected to gene expression analysis using a next-generation sequencing assay (Oncomine™ Immune Response Research Assay, ThermoFisher) targeting 395 immune-related genes. The expression of the identified differentially expressed genes (DEGs), was further validated by immunohistochemistry (IHC) in all cases with available material (n=70 PrBC and n=65 EOBC). The statistical approach encompassed Fisher’s and Chi-squared tests, with appropriate adjustments for multiple comparisons, logistic regression models, and survival analyses based on the Kaplan–Meier method. The sequencing output yielded read counts, which served as input for the DEGs analysis by the R Statistical Software package DeSeq2 version 1.42.0. Gene Ontology Enrichment analysis of DEGs was conducted utilizing Enrichr and TopGene software packages.  Results: In PrBC, a lower frequency of hormone receptor (HR)-positive tumors were noted, alongside a higher prevalence of low/null PD-L1 and CD8+TILs, particularly in HR+/HER2- cancers. PrBC exhibited significantly elevated risks of relapse and disease-related mortality compared to EOBC, with CD8+TILs significantly associated with disease relapse and higher mortality rates in PrBC. Poorly differentiated (G3) neoplasms increased with advancing gestational age. Histologic subtypes, HR, and HER2 status remained stable across pregnancy trimesters. Notably, higher proportions of tumors with high/moderate TILs were observed in early pregnancy, along with increased FOXP3 expression in HR+/HER2- subtype. PD-L1 negativity was more common in relapsed cases during the first trimester, without significant differences in survival outcomes across trimesters. Comparison between PrBC and EOBC unveiled a total of n=7 DEGs. Notably, the Melanoma Antigen Gene Family A (MAGEA) gene family exhibited consistent upregulation across all cohorts, irrespective of molecular subtypes. Classification of DEGs into superfamilies unveiled distinct genetic characteristics for the HR-/HER2- subgroup, including interleukins (ILs), lipoxygenases (Lox), and Toll-like receptors (TLRs) expression. While TILs density did not impact the expression of the DEGs in PrBC, notable associations were observed between the differential expression of MAGEA and CD4 and CD8 positivity. A significant positive correlation was observed between MAGEA genes read counts (specifically the immune response activator MAGEA1) and protein expression by IHC.  Conclusion: The TME in PrBC exhibits distinct TILs subpopulation patterns, bearing significant biological and prognostic implications. Routine evaluation of TILs and their subtypes in these patients could enhance pathology reports, aiding in the identification of clinically relevant subsets of women with PrBC. The TME dynamics of HR+/HER2- PrBC vary according to gestational age, implying that immune tolerance expression during later stages of pregnancy may account for the heightened aggressiveness of tumors. The dysregulation of MAGEA family genes in PrBC, particularly MAGEA1, indicates its possible role in PrBC tumorigenesis and tumor progression.","language":"eng","citation":"THE IMMUNE MOLECULAR LANDSCAPE OF BREAST CANCER DURING PREGNANCY / E. Sajjadi ; tutor: N. Fusco ; coordinatore: C. Sforza. Università degli Studi di Milano, 2024 Jun 17. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12976.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1057692/2426094/phd_unimi_R12976.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1212515"},"title":"PALLADIUM-BASED SYSTEMS IN HOMOGENEOUS CATALYSIS: EXPLORING NITROGEN LIGANDS FOR CO-MEDIATED REACTIONS","internalauthor":"GALIE, SIMONE","type":"Tesi di dottorato","year":"2026","abstract":"This work explores palladium‑based systems in homogeneous catalysis, focusing on CO‑mediated transformations and the role of nitrogen ligands. Building on the efficiency of palladium-phenanthroline catalytic system in reductive cyclization of nitroarenes, the study investigates CO and its surrogates as reductant for the synthesis of different nitrogen-containing heterocycles. Furthemore, the use of  guanidines as ligands in carbonylation and alkoxycarbonylation of olefins has been attempted.","language":"eng","citation":"PALLADIUM-BASED SYSTEMS IN HOMOGENEOUS CATALYSIS: EXPLORING NITROGEN LIGANDS FOR CO-MEDIATED REACTIONS / S. Galie ; supervisor: F. M. Ferretti ; co-supervisor: F. A. C. Ragaini ;  coordinatore :D. Passarella ; revisori: C. Tubaro (unipd), A. Penoni (uninsubria). Dipartimento di Chimica, 2026 Feb 11. 38. ciclo, Anno Accademico 2025.","filename":"phd_unimi_R13714.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1212515/3241428/phd_unimi_R13714.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1232459"},"title":"PRACTICAL DIGITAL LITERACY: YOUTHS¿ PRACTICAL MASTERY OF PLATFORM EXPERIENCES","internalauthor":"GIUFFRE', LUCA","type":"Tesi di dottorato","year":"2026","abstract":"Contemporary digital environments are increasingly shaped by algorithmic recommender systems that curate the content experienced by young people on social media platforms. Despite a wealth of research on digital literacy, existing frameworks tend to adopt either top-down, skill-based approaches tied to economic and civic imperatives or bottom-up perspectives grounded in lived cultural practices. This dissertation argues that current understanding of digital competencies inadequately accounts for the tacit, collectively developed, and sociotechnically embedded knowledge that teenagers cultivate through contemporary platform engagement. To address this gap, the study introduces the concept of practical digital literacy, that is, a multidimensional practical mastery conceptualised through Pierre Bourduey’s theory of practice. Such knowledge comprises three interrelated dimensions: shared, dispositional, and structured.  The research investigates these dimensions through two complementary fieldworks. The first involved 719 upper-secondary students across nine schools in northern Italy, combining class-level group interviews with a survey analysed through Multiple Correspondence Analysis. The second comprised a computational ethnography of TikTok, examining 60 algorithmically recommended videos and over 26,000 user comments through word embeddings, dimensionality reduction visualisations, and semantic analysis based on dependency parse trees.  Findings reveal that teenagers develop practical digital literacy collectively, through peer-mediated processes of platform socialisation rather than through isolated skill acquisition. Young people engage with algorithmic flows via what I refer to as algorithmic standouts, namely content that breaks through the recommendation stream, and algorithmic copiloting, which are tactical, reflexive practices through which users co-shape recommendation outputs. The dispositional analysis shows that social media consumption is structured primarily along axes of gendered identity performance, cultural engagement, and modes of participation, with parental capital exerting surprisingly limited influence. The TikTok fieldworker further demonstrates that algorithmic feeds and comment sections co-produce gendered cultural environments, reproducing and at times bridging gender binaries through iterative human-algorithm interaction.  These findings contribute to digital literacy studies by foregrounding the sociotechnical, peer-driven, and dispositonal nature of young people’s platform competencies, with implications for pedagogical practice and media education policy.","language":"eng","citation":"PRACTICAL DIGITAL LITERACY: YOUTHS' PRACTICAL MASTERY OF PLATFORM EXPERIENCES / L. Giuffre' ; supervisor: M. Airoldi ; co-tutor: C. Genova ; director of the doctoral programme: P. Rebughini. - Milan. Dipartimento di Scienze Sociali e Politiche, 2026 Apr 09. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13701.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1232459/3296104/phd_unimi_R13701.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/935711"},"title":"A TRIPLE FLORIGEN SYSTEM IS ESSENTIAL FOR FLOWERING AND PANICLE ARCHITECTURE IN RICE","internalauthor":"GIAUME, FRANCESCA","type":"Tesi di dottorato","year":"2022","abstract":"The transition from a vegetative phase to a reproductive one has always been deeply studied in plants and in particular in the cereals due to the relevance of this trait for seed yield. The transition occurs upon the arrival of a mobile flowering signal, the florigen, at the shoot apical meristem (SAM).  In rice (Oryza sativa), there are two different florigens: Heading Date 3a (Hd3a), that promotes flowering in short day (SD) conditions and Rice Flowering Locus T 1 (RFT1) that promotes flowering in both short and long- days (LD). They are transcribed and translated in leaves once environmental conditions are optimal, and then transported through the phloem to the SAM. After reaching the shoot they form a heterohexameric complex named Florigen Activation Complex (FAC) binding to two 14-3-3 proteins and to two bZIP transcription factors and activate conversion of the shoot apex into an inflorescence by promoting expression of inflorescence- identity genes.  Here, we show that Hd3a and RFT1 arrival at the SAM activates FLOWERING LOCUS T-LIKE 1 (FT-L1), encoding a third florigen-like protein showing atypical characteristics.  Expression data from qRT-PCR, in situ hybridization and transcriptional marker lines indicated that its mRNA is mainly expressed in the SAM and persists during all developmental stages of inflorescence development. Misexpression of FT-L1 from meristem- and tissue-specific promoters indicates that only when expressed in the SAM, FT-L1 has florigenic activity.  Isolation and analysis of EMS and CRISPR mutants showed that FT-L1 strengthens the effects of Hd3a and RFT1 during conversion of the vegetative meristem into inflorescence, in an addictive manner. Furthermore, it controls panicle branching by inhibiting secondary branching and promoting spikelet meristem differentiation.  Thus, we propose a triple florigenic module that promotes a balanced progression of inflorescence identity and determinacy.","language":"eng","citation":"A TRIPLE FLORIGEN SYSTEM IS ESSENTIAL FOR FLOWERING AND PANICLE ARCHITECTURE IN RICE / F. Giaume ; scientific supervisor: F. Fornara ; phd school coordinator: M. Kater ; revisore: G. Valè, S. Boden. Dipartimento di Bioscienze, 2022 Jul 21. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12317_4.pdf","fileformat":"Adobe PDF","fileversion":"preprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/935711/2059077/phd_unimi_R12317_4.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1202282"},"title":"THE CHALLENGE OF DOMAIN SHIFT IN REAL-WORLD ROBOTIC VISION: TOWARD SCALABLE, UNSUPERVISED, AND CLOUD-BASED ADAPTATION","internalauthor":"ANTONAZZI, MICHELE","type":"Tesi di dottorato","year":"2025","abstract":"Mobile robots are an emergent technology more and more present in contexts such as homes, offices, and hospitals to assist humans in daily life activities. Given the complexity of human-centric environments, robotic vision, namely computer vision embedded in mobile robots, has become an essential capability to acquire a semantically-rich understanding of the environment for improving core robotics tasks (such as navigation and localization), but also to enable high-level activities such as manipulation or human-robot interaction. Given the recent advances of deep learning, the naive solution to implement robotic vision is to leverage publicly available deep neural networks that can be mounted in robotic platforms with limited effort. Despite being widely adopted, this approach suffers from important limitations caused by the so-called domain shift problem: being trained on simulated or generic datasets (source domain), deep neural networks dramatically fail to tackle the complexity of the real-world environments (target domain) in which the robots operate. This dissertation investigates the challenges of domain shift in robotic vision and proposes novel adaptation strategies to enable robust and scalable real-world deployments of mobile robots. The contributions are structured into three complementary parts. First, we analyze the limitations of the mainstream pipeline to implement robotic vision that combines pre-trained neural networks with manual fine-tuning. We propose photorealistic simulation-based pre-training using data compliant with the robot's perception modality, and we demonstrate that fine-tuning with limited high-quality manual annotations substantially increases the model's robustness in the specific operational environment of the robot. Second, we remove the need for human supervision, proposing two alternative approaches for unsupervised model's adaptation. Our methods exploit the spatial constraints between neural network's predictions and the 3D world to enhance the quality of the pseudo-labels, thus enabling self-supervised adaptation. Third, we address adaptation in cloud-based robotic perception, where intensive inference required by neural networks is offloaded to remote servers to deal with the limited hardware configuration of mobile robots. In this context, we design solutions to ensure the scalability of domain adaptation and enable privacy preservation, designing lightweight neural networks that can be run locally by the robot. We validate our approaches using both real-world datasets and extensive experiments with real robotic platforms, considering multiple perception tasks such as object detection, 3D pose estimation, and semantic segmentation.","language":"eng","citation":"THE CHALLENGE OF DOMAIN SHIFT IN REAL-WORLD ROBOTIC VISION: TOWARD SCALABLE, UNSUPERVISED, AND CLOUD-BASED ADAPTATION / M. Antonazzi ; supervisor: N. Basilico ; co-supervisor: M. Luperto ; coordinator: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2025 Dec 09. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13700.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1202282/3203688/phd_unimi_R13700.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/951075"},"title":"COFFEE AND TEA CONSUMPTION AND GASTRIC CANCER: A POOLED ANALYSIS IN AN INTERNATIONAL CONSORTIUM OF EPIDEMIOLOGICAL STUDIES.","internalauthor":"MARTIMIANAKI, GEORGIA","type":"Tesi di dottorato","year":"2023","abstract":"The main focus of my doctoral research was to examine the effect of coffee and tea drinking on gastric (stomach) cancer risk. Coffee and tea are among the most popular drinks worldwide after water, and their consumption is expected to rise by an average of 17% over the next several years. The World Cancer Research Fund and the American Institute for Cancer Research (WCRF/AICR) concluded in their most recent report (2018) that there is insufficient data to draw any conclusions about the relationship between coffee and tea consumption and gastric cancer. To estimate their relationship with gastric cancer risk, individual-participant pooled analyses in a unique global consortium of epidemiological studies on gastric cancer - the Stomach cancer Pooling (StoP) project- were carried out. The StoP project included thirty case-control (CC) studies and five nested case-control within the cohort (NCC) studies, from seventeen different countries worldwide. For each study, coffee and tea consumption were assessed using self- or interviewer-administered food frequency questionnaires (FFQ) prior to the diagnosis of gastric cancer cases or prior to the onset of disease, hospital admission for hospital-based controls, or recruitment for population-based controls. Data on coffee intake were available from eighteen studies, which included 8,198 gastric cancer cases and 21,419 controls, while on tea twenty-two studies totaled 9,438 gastric cancer cases and 20,451 controls. Coffee and tea consumption was measured by the number of cups, times, or frequency of consumption reported in each study and further expressed in the standard unit of cups per day. Coffee was considered either caffeinated coffee or decaffeinated coffee separately, as well as their combined intake. Various types of tea reported were calculated as total tea intake. In addition, the temperature and strength at which tea was consumed were assessed. Logistic generalized linear mixed-effects models including terms             Dissertation Advisor: Professor Carlo La Vecchia                                                            Georgia Martimianaki    for sex, age, study design, Helicobacter pylori (H. pylori) infection, and several other main recognized risk factors for gastric cancer were used to estimate the associations between gastric cancer and coffee and tea consumption, through both two- and one-stage modeling analyses. Subgroup analyses across strata of several factors and dose-response relationships were also carried out. Multinomial mixed-effects models were also applied to estimate the ORs and corresponding 95% CIs of gastric cancer by the anatomical site (cardia and non-cardia) and histological type (intestinal, diffuse, and mixed/unspecified by Lauren categorization) for regular tea drinkers and high coffee drinkers. Heterogeneity between strata was evaluated by Cohran’s Q test and by the I2 test between studies. The results showed a slightly inverse association (OR: 0.92, 95% CI: 0.82–1.05) between tea drinking and gastric cancer but no relevant association (OR: 1.03, 95% CI: 0.94-1.13) between coffee consumption and gastric cancer. Regular tea drinkers had a lower gastric cardia cancer risk (OR: 0.64, 95% CI: 0.49-0.84), than heavy coffee drinkers, who were positively associated (OR:1.61, 95% CI: 1.27–2.05) with gastric cardia cancer. Contrary to tea intake, which was more strongly linked to lower risk in Asian countries (OR: 0.67, 95% CI: 0.49-0.91, in studies from China and Japan), there was no evidence of regional differences in the effect of coffee consumption on the risk of gastric cancer. Consuming hot or very hot tea did not increase the risk of gastric cancer, drinking warm or cold tea was related to a lower risk.    Last but not least, I also discuss additional research projects I have undertaken through my doctoral studies. These include other dietary analyses within the Stomach Cancer Pooling project consortium, my work with the Hellenic Health Foundation to evaluate the usual diet of the Greek adult population, and a project I carried out during my six-month visiting research period at Harvard T.H. Chan School of Public Health on the association between olive oil consumption and prostate cancer in the US Health Professionals Follow-up Study (HPFS) and the Greek part of the European Prospective Investigation into Cancer and Nutrition (EPIC-Greece) cohort study.","language":"eng","citation":"COFFEE AND TEA CONSUMPTION AND GASTRIC CANCER: A POOLED ANALYSIS IN AN INTERNATIONAL CONSORTIUM OF EPIDEMIOLOGICAL STUDIES / G. Martimianaki ; tutor: LA VECCHIA, CARLO VITANTONIO BATTISTA. Dipartimento di Scienze Cliniche e di Comunità, 2023 Jan 17. 35. ciclo","filename":"phd_unimi_R12573.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/951075/2121130/phd_unimi_R12573.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/960456"},"title":"A NOVEL RIT2-LRRK2 AXIS MODULATES LYSOSOME FUNCTION: INSIGHT FOR PARKINSON'S DISEASE PATHOPHYSIOLOGY","internalauthor":"PIZZI, SARA","type":"Tesi di dottorato","year":"2023","abstract":"Lysosome dysfunction is recognized as a critical factor in Parkinson’s disease (PD) pathogenesis. Leucine-rich repeat kinase 2 (LRRK2) has a kinase-dependent role in autophagy and lysosomal function, and its pharmacological inhibition is protective against neurodegeneration and α-synuclein (αSyn) pathology. However, the precise signaling pathways involving LRRK2 and how alterations lead to pathology have not been clarified yet. In this work, we unravel a novel functional interaction between LRRK2 and the small GTPase Rit2, previously reported to participate in MAPK-signaling, neurite outgrowth and dopamine transporter trafficking. Polymorphisms in the RIT2 locus are associated to increased risk of PD and are predicted to alter gene expression. We found that RIT2 mRNA levels are reduced in substantia nigra pars compacta (SNpc) dopaminergic neurons of idiopathic PD patients and in different in vitro and in vivo PD models. Rit2 overexpression in G2019S-LRRK2 neuroblastoma cells restores lysosomal defects and diminishes αSyn accumulation, phenocopying pharmacological LRRK2 kinase inhibition. Moreover, Rit2 selective overexpression in SNpc dopaminergic neurons in A53T-αSyn virally injected mice reduces neurodegeneration and αSyn pathology. Notably, we uncovered that Rit2 interacts with LRRK2, and its overexpression inhibits LRRK2 kinase activity both in vitro and in vivo. In addition, Rit2 is required for lysosomal function, since its gene silencing in cell lines and DA neurons leads to lysosomal defects. We showed promising preliminary data indicating that the mechanism of Rit2 action in autophagy might involve lysosomal calcium release, that represents a convergent point in LRRK2-mediated regulation of autophagy. We propose Rit2 and its interplay with LRRK2 as novel targets for future, disease-modifying therapeutic approaches in PD.","language":"eng","citation":"A NOVEL RIT2-LRRK2 AXIS MODULATES LYSOSOME FUNCTION: INSIGHT FOR PARKINSON'S DISEASE PATHOPHYSIOLOGY / S. Pizzi ; co-tutor: M. Volta ; scientific supervisor: G. Cappelletti. Dipartimento di Bioscienze, 2023 Mar 30. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12603.pdf","fileformat":"Adobe PDF","fileversion":"preprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/960456/2155924/phd_unimi_R12603.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1132397"},"title":"EXPLORING PHYSIOLOGICAL, PATHOLOGICAL AND PARAPHYSIOLOGICAL BRAIN ACTIVITY ACROSS SCALES WITH SIMULTANEOUS INVASIVE AND NON-INVASIVE EEG","internalauthor":"ZAULI, FLAVIA MARIA","type":"Tesi di dottorato","year":"2025","abstract":"\"This thesis explores the integration of non-invasive high-density electroencephalography (hd-EEG) with invasive stereoelectroencephalography (SEEG) to enhance understanding of brain electrophysiology in pathological, physiological and paraphysiological contexts. The combination of these two methods, known as \"\"co-registration,\"\" leverages the high temporal resolution and full-brain coverage of hd-EEG with the spatial precision of SEEG, allowing for a more comprehensive view of brain activity. The thesis is divided into three primary areas of investigation.  First, it examines pathological brain activity, specifically focusing on interictal epileptiform discharges (IEDs). These discharges, often difficult to detect with scalp EEG alone, were successfully localized using co-registration. By guiding hd-EEG analysis with SEEG data, hidden epileptic activity was revealed, contributing to more accurate non-invasive identification of epileptic foci, which is critical for surgical planning in drug-resistant epilepsy cases.  Second, the study investigates physiological brain responses to sensory stimuli using median nerve stimulation. Co-registration enabled the analysis of how brain signals propagate from primary sensory regions to higher-order areas involved in perception. While hd-EEG captured fast, large-scale activity, SEEG provided detailed recordings from deep cortical structures. This integration revealed both phasic and tonic gamma band brain responses, offering new insights into sensory processing and conscious perception.  Third, the thesis evaluates brain responses to artificial stimulation via single-pulse electrical stimulation (SPES), which evoked cortico-cortical evoked potentials (CCEPs). Co-registration allowed for a detailed analysis of how artificial stimulation propagates through brain circuits. While SEEG detected localized responses, hd-EEG captured broader patterns of brain activation, enhancing the understanding of brain connectivity and reactivity to external stimuli.  Overall, the combination of hd-EEG and SEEG offers unique advantages, providing a more accurate and detailed picture of brain dynamics. This method not only refines neuroimaging techniques but also holds promise for improving clinical diagnostics and treatments, particularly in epilepsy. In essence, this thesis demonstrates that co-registration can bridge the gap between non-invasive and invasive brain recordings, offering significant benefits for both neuroscience research and clinical applications.\"","language":"eng","citation":"\"EXPLORING PHYSIOLOGICAL, PATHOLOGICAL AND PARAPHYSIOLOGICAL BRAIN ACTIVITY ACROSS SCALES WITH SIMULTANEOUS INVASIVE AND NON-INVASIVE EEG / F.m. Zauli ; tutor: M. Massimini ; supervisori: A. Pigorini, E. Mikulan ; PhD coordinator: F. Guala. - DIPARTIMENTO DI SCIENZE BIOMEDICHE E CLINICHE \"\"LUIGI SACCO\"\" (MILANO). Dipartimento di Scienze Biomediche e Cliniche, 2025 Jan 16. 37. ciclo, Anno Accademico 2024.\"","filename":"phd_unimi_R13198_3.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1132397/2628038/phd_unimi_R13198_3.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1026030"},"title":"SYNTHESIS OF N-HETEROCYCLES VIA PALLADIUM-CATALYZED REDUCTIVE CYCLIZATION REACTIONS OF NITROARENES AND NITROALKENES USING FORMIC ACID DERIVATIVES AS CO SURROGATES","internalauthor":"ABDELLATIF, MANAR AHMED FOUAD","type":"Tesi di dottorato","year":"2024","abstract":"The reductive cyclization reaction of nitroarenes to produce N-heterocycles has been ‎investigated for more than four decades using CO as a cheap reductant, but it is still a ‎fascinating area for research and advancements. On the other hand, using toxic CO gas is ‎accompanied by many disadvantages. Thus, the thesis focuses on the use of phenyl formate and ‎formic acid as cheap, affordable, efficient and safe in-situ CO surrogates for the reductive ‎cyclization of various nitroarenes. Notably, in most cases, the isolated yield of the desired ‎heterocycle was higher than those previously obtained for the same reaction when gaseous CO ‎had been employed, which indicates that the use of these surrogates should not necessarily be ‎considered a second choice when the use of CO gas is not possible. A cheap thick-walled glass ‎‎“pressure tube” can be used instead of less-available autoclaves.‎","language":"eng","citation":"SYNTHESIS OF N-HETEROCYCLES VIA PALLADIUM-CATALYZED REDUCTIVE CYCLIZATION REACTIONS OF NITROARENES AND NITROALKENES USING FORMIC ACID DERIVATIVES AS CO SURROGATES / M.a.f. Abdellatif ; tutor: F. A. C. Ragaini ; coordinator: D. Passarella. Dipartimento di Chimica, 2024 Jan 31. 35. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R12792.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1026030/2352445/phd_unimi_R12792.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/816678"},"title":"A STOCHASTIC FORAGING MODEL OF ATTENTIVE EYE GUIDANCE ON DYNAMIC STIMULI","internalauthor":"D'AMELIO, ALESSANDRO","type":"Tesi di dottorato","year":"2021","abstract":"Understanding human behavioural signals is one of the key ingredients of an effective human-human and human-computer interaction (HCI). In such respect, non verbal communication plays a key role and is composed by a variety of modalities acting jointly to convey a common message. In particular, cues like gesture, facial expression, prosody etc. have the same importance as spoken words. Gaze behaviour makes no exception, being one of the most common, yet unobtrusive ways of communicating.     To this aim, many computational models of visual attention allocation have been proposed; although such models were primarily conceived in the psychological field, in the last couple of decades, the problem of predicting attention allocation on a visual stimuli has started to catch the interest of the computer vision and pattern recognition community, pushed by the fast growing number of possible applications (e.g. autonomous driving,  image/video compression, robotics).     In this renaissance of attention modelling, some of the key features characterizing eye movements were at best overlooked; in particular the explicit unrolling in time of eye movements (i.e. their dynamics) has been seldom taken into account. Moreover, the vast majority of the proposed models are only able to deal with static stimuli (images), with few notable exceptions.     The main contribution of this work is a novel computational model of attentive eye guidance which derives gaze dynamics in a principled way, by reformulating attention deployment as a stochastic foraging problem. We show how treating a virtual observer attending to a video as a stochastic composite forager searching for valuable patches in a multi-modal landscape, leads to simulated gaze trajectories that are not statistically distinguishable from the ones performed by humans while free-viewing the same scene.    Model simulation and experiments are carried out on a publicly available dataset of eye-tracked subjects displaying conversations and social interactions between humans.","language":"eng","citation":"A STOCHASTIC FORAGING MODEL OF ATTENTIVE EYE GUIDANCE ON DYNAMIC STIMULI / A. D'amelio ; supervisor: G.Grossi; co-supervisor: G. Boccignone ; coordinatore: P. Boldi. Dipartimento di Informatica Giovanni Degli Antoni, 2021 Mar 22. 33. ciclo, Anno Accademico 2020. [10.13130/d-amelio-alessandro_phd2021-03-22].","filename":"phd_unimi_R11866.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/816678/1710072/phd_unimi_R11866.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1239062"},"title":"PHENOTYPIC AND GENOTYPIC DIVERSITY AMONG POTENTIAL NEXT-GENERATION PROBIOTICS","internalauthor":"SQUARZANTI, DILETTA FRANCESCA","type":"Tesi di dottorato","year":"2026","abstract":"The gut microbiota constitutes a complex and dynamic community of microorganisms that plays a central role in host physiology, including digestion, metabolic regulation, immune function, and maintenance of intestinal barrier integrity. In the gut of healthy individuals, major bacterial phyla such as Firmicutes, Bacteroidetes, Actinobacteria, and Verrucomicrobia co-exist in a balanced state that supports homeostasis and protects against pathogenic colonization. Among these, Akkermansia muciniphila, a Gram-negative anaerobe localized in the colonic mucus layer, has gained increasing attention due to its functional relevance. This bacterium degrades mucin glycoproteins, thereby contributing to mucus turnover, strengthening barrier function, and limiting systemic exposure to pro-inflammatory molecules. In addition, A. muciniphila participates in metabolic cross-talk within the microbiota through short-chain fatty acid production and modulation of host immune responses, making it a key indicator of gut health.  In this study, multiple A. muciniphila isolates were comparatively evaluated against the reference strain MucT to investigate their peculiar functional properties. The results highlighted strain-specific activities, with pasteurized forms consistently outperforming their live counterparts in several in vitro assays. In particular, pasteurized cells promoted enhanced epithelial repair, increased ATP and NAD⁺ production, and stronger activation of hTLR2 and SIRT1 signaling pathways. These findings were supported by in vivo experiments in Caenorhabditis elegans, where nematodes fed with A. muciniphila revealed an extended lifespan, together with improved healthspan indicators, including locomotion and neuromuscular function. Notably, these effects were highly strain-dependent and associated with distinct metabolic profiles, especially in terms of short-chain fatty acid production. Safety assessment confirmed the absence of antimicrobial resistance genes and virulence-related traits, supporting the suitability of A. muciniphila for biotechnological applications.  Overall, this work reinforces the concept of A. muciniphila as a next-generation probiotic (NGP) with potential applications beyond metabolic health. The use of pasteurized formulations represents a stable and safe alternative to live microorganisms, with promising systemic effects. However, further validation will be essential to translate these findings into effective nutritional strategies.","language":"eng","citation":"PHENOTYPIC AND GENOTYPIC DIVERSITY AMONG POTENTIAL NEXT-GENERATION PROBIOTICS / D.f. Squarzanti ; tutor: S. Arioli ; co-tutor: D. Mora e P. Malfa. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2026 May 22. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13695.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 28-OTT-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/930765"},"title":"IL CONTROLLO DELLE CONCENTRAZIONI NELL¿UNIONE EUROPEA A OLTRE TRENT¿ANNI DALLA SUA INTRODUZIONE: LA RICERCA DI UN NUOVO MODELLO TRA SPINTE TECNOLOGICHE E NUOVE STRATEGIE POLITICHE","internalauthor":"DALLA VALENTINA, GIACOMO","type":"Tesi di dottorato","year":"2022","abstract":"This thesis presents the results of a study on the shortcomings and reform perspectives of EU merger control rules, currently laid down by Regulation (EC) 139/2004. In the institutional and regulatory framework of the EU, merger control plays an atypical role, perhaps minor vis-à-vis the other tools of EU competition law, as proved by the absence of a wide-ranging literature (at least national). Merger control has, however, become the subject of an increasingly heated debate, involving scholars, institutional actors, and private parties, which concerns its effectiveness in the global, digitalized, and dynamic economy of this era. This debate, enthused by some socio-political events of great resonance, has been partially internalized by the EU institutions in the context of a wide inquiry, which is still at an early stage. Many of the needs for reform that have been voiced reflect, as a matter of fact, some tensions which have characterized the foundational and development stages of EU merger control. These tensions will be described in Chapter I, which will illustrate the sensitivity of EU merger control to the different approaches and objectives that emerged in the different phases of the European integration. Chapter II is, then, devoted to a critical examination of the role played by public interests (both national and supranational) within the system of EU merger control. Finally, Chapter III aims to provide an answer to the many questions posed by the digitization and the emergence of a new model of regulation of power relations among undertakings in the platform economy, which prevent a timely and appropriate intervention by the European Commission vis-à-vis concentrations that are potentially harmful to competition.","language":"ita","citation":"IL CONTROLLO DELLE CONCENTRAZIONI NELL¿UNIONE EUROPEA A OLTRE TRENT¿ANNI DALLA SUA INTRODUZIONE: LA RICERCA DI UN NUOVO MODELLO TRA SPINTE TECNOLOGICHE E NUOVE STRATEGIE POLITICHE / G. Dalla Valentina ; tutor:  M. Condinanzi ; coordinatrice: F. Biondi. Università degli Studi di Milano, 2022 Jun 06. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12281.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/930765/2038428/phd_unimi_R12281.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1189485"},"title":"\"QUALE EMERGENZA? IL \"\"DELITTO POLITICO MAFIOSO\"\" NELLA TEORIA GENERALE DEL REATO.\"","internalauthor":"INTOCCIA, PAOLO","type":"Tesi di dottorato","year":"2025","abstract":"The dissertation examines the relationship between mafia crime and political crime, the applicability of the criminal offenses implemented to counteract the mafia phenomenon to the statute of political crimes, and the impact these offenses have on the general theory of crime and the fundamental principles of criminal law.  The research aims to lay the theoretical foundations for anti-mafia legislation to be perceived not as a special branch of criminal law, but as a component of the legal system that participates in and engages in dialogue with the general theory of crime, helping to clarify the broad applicability of its principles.","language":"ita","citation":"\"QUALE EMERGENZA? IL \"\"DELITTO POLITICO MAFIOSO\"\" NELLA TEORIA GENERALE DEL REATO / P. Intoccia ; tutor:  F. Basile ; coordinatore: F. Basile. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2025 Oct 30. 37. ciclo [10.13130/intoccia-paolo_phd2025].\"","filename":"phd_unimi_R13302.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 27-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1206071"},"title":"CHARACTERIZATION OF THE INTERACTION BETWEEN HEPARAN SULFATE AND THE SPIKE (S) PROTEIN OF THE LATEST SARS-COV-2 VARIANTS","internalauthor":"MANDALARI, MARCO","type":"Tesi di dottorato","year":"2026","abstract":"Heparan sulfate is a linear, highly sulfated polysaccharide that belongs to the glycosaminoglycan (GAG) family. The disaccharide repeating unit includes a uronic acid residue (either D-glucuronic or L-iduronic) 1→4 linked to a glucosamine (GlcN). The glucosamine residues can be mono- or polysulfated at the N-, 6-O, and rarely at the 3-O positions, while the uronic acids can be sulfated at the 2-O position. Furthermore, HS displays heterogeneity in chain length and block composition, in which acetyl- and sulfate-rich sequences alternate. HS is covalently attached to the membrane protein (via the O- or the N-glycosylation of a Ser or Asn residue, respectively), forming heparan sulfate proteoglycans (HSPGs). Due to the pronounced density of negative charge of HS, HSPGs play a key role in several biological processes, including cell hydration, intercellular communication, storage, protection, and exchange of biomolecules (e.g., cytokines, chemokines), and the regulation of receptors and proteolytic enzymes (e.g., tyrosine kinase-type growth factor). Moreover, HS is also involved in diverse physiological and pathological events, such as embryonic development, inflammatory response, blood coagulation, and bacterial and viral infection. In the latter context, several studies show that a wide range of pathogens can interact with HS during the early stage of the infection. This aspect has recently drawn significant attention following the outbreak of the SARS-CoV-2 pandemic. Indeed, the virus exploits HS in the extracellular matrix to tether viral particles to the host cell surface, thereby promoting the specific interaction between the cell surface human angiotensin-converting enzyme 2 receptor (hACE2) and the receptor binding domain (RBD) that decorates the capsid of SARS-CoV-2. In fact, this event triggers the fusion between the cell and virus membranes. The RBD region (and, more broadly, the S1 subunit) contains several positively charged amino acids that are solvent-exposed and form a positive channel in which HS chains can be hosted without overlapping the hACE2 binding site.   The primary goal of this study is to understand how the role of HS in these early molecular recognition events differs in the latest and most widespread variants of SARS-CoV-2, through the application of complementary computational and experimental approaches that combine NMR spectroscopy and different computational tools.   We have selected two hexasaccharides as HS mimetics to probe their interactions with different RBDs using docking calculations. We then focused our study on the Omicron variant and one of the hexasaccharide mimetics, performing molecular dynamic simulations and 1H-NMR Saturation Transfer Difference experiments. Structural insights into its binding modes were obtained using RedMat, an NMR-based analysis tool for the analysis of molecular dynamic simulation trajectories, and they were compared with the ligand interactions observed for the wild-type RBD. This knowledge will contribute to the structural biology knowledge of SARS-CoV-2 and to the development of new antiviral strategies and antiviral drugs.","language":"eng","citation":"CHARACTERIZATION OF THE INTERACTION BETWEEN HEPARAN SULFATE AND THE SPIKE (S) PROTEIN OF THE LATEST SARS-COV-2 VARIANTS / M. Mandalari ; tutor: M. Civera ;  co-tutor: S. Elli ; PhD coordinator: D. Passarella. Dipartimento di Chimica, 2025 Jan 22. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13728.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1206071/3217519/phd_unimi_R13728.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/946992"},"title":"EFFECTS OF STRESS HYPERGLYCEMIA ACCORDING TO DIABETICSTATUS IN PATIENTS WITH ST-ELEVATION MYOCARDIALINFARCTION AND ITS RELATIONSHIP WITH CARDIAC CELL INJURYAND MITOCHONDRIAL DAMAGE: A TRANSLATIONAL APPROACH","internalauthor":"COSENTINO, NICOLA","type":"Tesi di dottorato","year":"2023","abstract":"Background: Acute hyperglycemia (AH) is common in ST-elevation myocardial   infarction (STEMI) and predicts outcomes. AH is a more powerful prognostic   predictor in patients without diabetes mellitus (DM) than with DM, emphasizing the   role of an acute glucose rise compared to chronic elevations. Moreover, AH may   exacerbate, thorough mitochondrial dysfunction, infarct size (IS). We investigated   the association between AH and chronic glycemia, considered separately or in   combination, with mitochondrial injury and myocardial IS in STEMI patients with or   without DM.  Methods: We measured admission serum glucose (AH), cytochrome c and   mitochondrial DNA levels (mitochondrial biomarkers), and estimated chronic   glucose in all patients. We calculated the acute on chronic (A/C) glycemic ratio. The   primary endpoint was IS at cardiac magnetic resonance. The composite of in hospital mortality, acute-pulmonary-edema, and shock was the secondary endpoint.  Results: 100 STEMI patients with DM and 100 without were included. IS was 25gr   and 19gr and the secondary endpoint occurred in 21% and 8% of patients with and  without DM, respectively (p=0.02 and p=0.01, respectively). The A/C ratio only   significantly correlated with cytochrome c and mitochondrial DNA levels in DM   patients. However, at reclassification analyses, A/C glycemic ratio showed the best   prognostic power in predicting the primary and secondary endpoints as compared   to AH in DM (net-reclassification-index 28% and 31%, respectively) but not in non DM patients (net-reclassification-index 1% and 2%, respectively). In DM patients,   A/C glycemic ratio, but not AH, significantly predicted 1-year mortality, after   adjustment for major confounders.  4  Conclusions: In STEMI patients with DM, A/C glycemic ratio seems to be a better   predictor of IS and in-hospital and 1-year outcome than AH. This study highlights   the prognostic role of A/C ratio, its impact on mitochondrial impairment and   outcomes, and may pave the way to interventional trials targeting AH according to   A/C ratio in DM patients with STEMI.","language":"eng","citation":"EFFECTS OF STRESS HYPERGLYCEMIA ACCORDING TO DIABETICSTATUS IN PATIENTS WITH ST-ELEVATION MYOCARDIALINFARCTION AND ITS RELATIONSHIP WITH CARDIAC CELL INJURYAND MITOCHONDRIAL DAMAGE: A TRANSLATIONAL APPROACH / N. Cosentino ; tutor: G. Marenzi, P. Agostoni ; coordinator: C. Sforza. Dipartimento di Scienze Cliniche e di Comunità, 2023 Jan 23. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12565.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/946992/2103772/phd_unimi_R12565.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1151338"},"title":"IMPACT OF KETOGENIC DIET TREATMENT IN GLUT1 DEFICIENCY SYNDROME: DISCOVERY OF MOLECULAR MECHANISMS RESPONSIBLE FOR PHENOTYPE CHANGES IN BOTH PEDIATRIC AND ADULT PATIENTS","internalauthor":"MAURI, ALESSIA","type":"Tesi di dottorato","year":"2025","abstract":"GLUT1 deficiency syndrome (GLUT1-DS) is a rare, effectively treatable, neurometabolic disease. It is caused by loss-of function mutations in the SLC2A1 gene, encoding GLUT1 protein, which supplies glucose to the brain. A genetic defect in this transporter leads to cerebral energy deficiency, resulting in a complex spectrum of neurological symptoms, including seizures and movement disorders.   Although many clinical and molecular features have been deeply studied, there are still some not completely understood aspects, including (i) clinical variability and wide spectrum of SLC2A1 variations, (ii) phenotype age-related changes, and (iii) response to ketogenic diet (KD) treatment, which are investigated in this research study through a multi-omics approach.  Firstly, we explored the clinical, biochemical and molecular data of 27 pediatric patients with GLUT1-DS, identifying (1) different clinical phenotypes (from early- to late-onset), (2) 25 disease-related SLC2A1 variants of which 10 never reported before, (3) a mutational hotspots in exon 4, suggesting a vulnerable region for glucose uptake associated to clinical manifestations, and (4) strong correlations between variant types, clinical and biochemical severity patterns.  Next, we analyzed the transcriptional profiles and isoform switches in GLUT1-DS patients, before and after KD, focusing on three comparisons: (a) adults versus children, both untreated; (b) children in pre- versus post-KD; and (c) responders versus non-responders to KD in GLUT1-DS children. Overall, enrichment analysis revealed a reduction in inflammatory pathways in GLUT1-DS patients who experienced clinical improvements in seizure frequency and severity, whether in response to KD or during adulthood. These processes involve type I IFN signatures, which have an impact on mitochondrial function and signaling, suggesting a specific role in GLUT1-DS pathogenesis. Supporting these suggestions, the detected lncRNAs are also related to inflammatory response, as RMRP and LINC02555, or to ketone biosynthesis and oxidative phosphorylation processes, like PAX8-AS1, for which emerges its potential regulatory role in KD response. Another significant molecular pathway contributing to mitigate clinical signs is the alternative splicing of ion channel genes, such as P2X7 receptor which is, in turn, liked to inflammasome pathway. As well as this, the methylome profiles, performed by ONT, revealed altered methylation patterns in similar genes, like GRIN3A, suggesting also in this analysis an ion channel signaling deregulation.  Lastly, these novel and suggestive findings underline the complex interplay that transcriptional variations, isoform switching and methylation patterns may have in the phenotype age-dependent changes and response to KD in patients with GLUT1-DS.","language":"eng","citation":"IMPACT OF KETOGENIC DIET TREATMENT IN GLUT1 DEFICIENCY SYNDROME: DISCOVERY OF MOLECULAR MECHANISMS RESPONSIBLE FOR PHENOTYPE CHANGES IN BOTH PEDIATRIC AND ADULT PATIENTS / A. Mauri ; tutor: G.V. Zuccotti, C. Cereda ;  coordinatore: F. Cheli. Dipartimento di Scienze Biomediche e Cliniche, 2025 Mar 26. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13562_1.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1151338/2705994/phd_unimi_R13562_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/962048"},"title":"RAPPRESENTAZIONE DELLO SPAZIO E ARCHITETTURE NARRATIVE NELLA NOVELLISTICA DI SOLDATI (1959-1979)","internalauthor":"FARINA, ALESSANDRA","type":"Tesi di dottorato","year":"2023","abstract":"\"“Representation of Space and Narrative Architectures in Soldati's short stories 1959-1979\"\" investigates the literary production of this versatile writer in his varied professional life, having space as its main perspective and interpretative guideline.  As space actually represented an essential category for Soldati in the very perception of his own existence, a fortiori it pervades his literary work, which became copious in the two decades that are examined in this dissertation. This production, which was very heterogeneous and is still nowadays pretty neglected by critics, was also fueled by his collaboration with newspapers, on which many of his novellas were first published. On the other hand, the frequent and extensive authoring of short stories is somehow contrasted by the long-time generation of his novel of a lifetime, Le due città, which the author had been working on since 1959.  Two crucial places in Soldati's creative geography, Rome and Turin are offered as paradigmatic models of a complex treatment of space, in which autobiographical notes, symbolic suggestions, realistic accuracy, imaginative intervals and intertextual or intermedial echoes are to be found. Accordingly, the investigation aims at identifying the solid network of narrative, rhetorical and stylistic devices that support the shaping of space and of its meanings. In Soldati’s collections space is offered in its articulate and multifaceted aspects, all of them being relevant in La Messa dei villeggianti, 55 novelle per l’inverno and its \"\"complementary\"\" 44 novelle per l’estate: space in descriptions, space as passed through in the journeys of a pilgrim literate holidaymaker (villeggiante), space as evoked, as well as the concepts of liminality and heterotopia.   In the reconstruction of Soldati’s narrative architectures, the importance of space as space of a text or macrotext has also been considered, a strategic system and distribution of places through the collections support their consistency and organic feature.\"","language":"ita","citation":"RAPPRESENTAZIONE DELLO SPAZIO E ARCHITETTURE NARRATIVE NELLA NOVELLISTICA DI SOLDATI (1959-1979) / A. Farina ; tutor: B. Falcetto; coordinatore: F. Slavazzi. Università degli Studi di Milano, 2023 Mar 17. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12260.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/962048/2170854/phd_unimi_R12260.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/956999"},"title":"EFFECT OF FERMENTATION AND POST-FERMENTATION PARAMETERS ON THE VIABILITY, ROBUSTNESS, AND PROBIOTIC TRAITS OF LACTIC ACID BACTERIA AND BIFIDOBACTERIA","internalauthor":"MARTINOVIC, ANDELA","type":"Tesi di dottorato","year":"2023","abstract":"Background: The probiotic market is increasing world-wide as well as the number of products marketed as probiotics. According to the definition, claimed probiotic health benefits depend on viability and dose administered. Probiotic viability may be affected by various factors during the production process, and storage including growth medium composition, mechanical stress, pH, temperature conditions, oxygen stress, and cell dehydration. Additionally, probiotic effectiveness depends on its ability to survive the host gastrointestinal tract conditions (e.g.,acidic gastric environment, the disturbing activity of digestive enzymes and bile). Therefore, delivering viable probiotics at the host site of action in sufficient amounts represents an industrial challenge. The viability of probiotics can be improved by various strategies such as stress adaptations through pre-treatment, mutagenesis, the addition of various protective compounds (e.g., cryoprotectants, lyoprotectants), encapsulation, or microencapsulation techniques. Many probiotic food supplements and probiotic foods contain Streptococcus thermophilus strain(s). S. thermophilus is considered one of the most important lactic acid bacteria (LAB) of industrial relevance, and it is the only LAB that shows a significant level of urease activity. However, the scientific evidences demonstrating survival of S. thermophilus strains are not convincing due to the absence of reliable molecular tools able to discriminate S. thermophilus from other phylogenetically related species. Furthermore, there is a need to further investigate the role of urease activity on the growth and energy metabolism of S. thermophilus.    Aims: The aims of this PhD thesis are: (i) to address and give possible solutions related to challenges of in vivo gastrointestinal (GIT) tract survival of S. thermophilus probiotic strains; (ii) evaluate how production condition parameters affect the viability, and traits of a S. thermophilus probiotic strain; (iii) investigate the role of urease activity on the growth and energy metabolism of S. thermophilus.    Results: The PhD thesis highlights the importance of accurate taxonomic identification of S. thermophilus strains to evaluate theirs in vivo GIT survival. In reviewed literature identification of S. thermophilus strains from stools is not carried out with the necessary taxonomic accuracy to avoid their misidentification from common human commensal, and species phylogenetically close to S. thermophilus. Therefore, a strain-specific molecular tool combined with a culturebased method for accurate identification of S. thermophilus BT01 probiotic strain was developed. Further, a newly developed strain-specific tool was used to evaluate the role of two cryoprotectants (downstream production phase) on S. thermophilus probiotic strain GIT tract survival, and level of urease activity in a fecal sample. Even though, difference between the two cryoprotectants did not show to be significant for in vivo GIT survival of S. thermophilus BT01 strain, S. thermophilus cryoprotected with one of the cryoprotectants was able to significantly decrease the initial level of urease activity in the fecal sample. Finally, urease activity and its role in the energy metabolism of S. thermophilus were investigated. By using special procedure of S. thermophilus cells preparation, and in the presence of fermentable carbon sources, ammonia produced from urease activity showed to have a “booster” effect on  homolactic fermentation. Furthermore, ammonia, specifically ammonium ions were a potent effector of the key glycolytic enzyme – phosphofructokinase.","language":"eng","citation":"EFFECT OF FERMENTATION AND POST-FERMENTATION PARAMETERS ON THE VIABILITY, ROBUSTNESS, AND PROBIOTIC TRAITS OF LACTIC ACID BACTERIA AND BIFIDOBACTERIA / A. Martinovic ; tutor and phd dean: D. Mora. -  : . Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2023. ((35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12651.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/956999/2152854/phd_unimi_R12651.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/816806"},"title":"LA MOBILITÀ TRANSNAZIONALE DEI LAVORATORI. CONTRIBUTO ALLO STUDIO DEI PROFILI GIUSLAVORISTICI E DI SICUREZZA SOCIALE","internalauthor":"MORRA, GAIA","type":"Tesi di dottorato","year":"2021","abstract":"The object of this final dissertation is to provide an analysis of the evolving and debated phenomenon of transnational posting of workers. At first, posting of workers is analysed in a private international law dimension, since the rules established by directive 96/71/CE are mandatory rules as described in art. 9 of Rome I regulation (chapter I). Posting of workers is then investigated in its relevant EU regulatory framework, starting from the case by case approach of the European Court of Justice in the 80s. The jurisprudence of the early stage and its implication are dealt with in chapter II. According to directive 96/71/EC, a “posted worker” is an employee who is sent by his employer to carry out a service in another EU Member State on a temporary basis, in the context of a contract of services, an intra-group posting or a hiring out through a temporary agency. The scope of the directive is to provide, in addition to the application of the sending State law, i.e. the habitual place of work, a set of mandatory rules of the host State so that to grant the posted worker an “hard core of minimum protection”. On the other hand, the directive aims at providing a level-playing field in the market of the provision of services. The above described rules have proved not to be effective to prevent social dumping and therefore the European legislator promoted the recent adoption of the Directive 2018/957/EU amending the Posting of Workers Directive 96/71/EC. The new approach undertaken by the EU legislator with the establishment of the principle of ‘same pay for the same work at the same workplace’ for posted and local workers is evaluated deeply in chapter III. The exam of the legal framework of the social security provisions in the EU is followed by a critical definition of the consequences of those provisions on the effectiveness of the social protection of posted workers (chapter IV). As to the conclusive remarks, a selection of possible legal instruments which would help to build a better protection of the posted workers are analysed, taking in consideration the suggestions of the European trade Unions and the academic community.","language":"ita","citation":"LA MOBILITÀ TRANSNAZIONALE DEI LAVORATORI. CONTRIBUTO ALLO STUDIO DEI PROFILI GIUSLAVORISTICI E DI SICUREZZA SOCIALE / G. Morra ; tutor: A. Tursi ; coordinatore del dottorato: G. Ludovico. Dipartimento di Diritto Privato e Storia del Diritto, 2021 Feb 22. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11859.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/816806/1710486/phd_unimi_R11859.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1016248"},"title":"THE PROBLEM OF WORK IN AXEL HONNETH'S CRITICAL THEORY","internalauthor":"DEACONU, ALEX FLAVIUS","type":"Tesi di dottorato","year":"2024","abstract":"This thesis shows that although Axel Honneth's recognition based analysis of market-mediated social labour is resilient, it still requires further refinement and improvement. The objective of this thesis is to contribute to this end. Firstly, the thesis provides a qualified internal critique of Honneth's account, incorporating three elements: a) a systematic discussion of his arguments covering his early interventions on the topic up to and including his more recent writings; b) defence of Honneth's normative approach showing that the recognition theory provides robust rejoinders to functionalist objections, and to objections challenging the adequacy of his normative reconstruction method; c) a critique showing that Honneth's account has limited critical import in the context of contemporary 'ethicized' capitalism. The critique is based on the assessment that: i) recognition and autonomy, i.e. the norms underpinning Honneth's model representing preconditions of social freedom, have been integrated into the recent forms of work organisation while being re-signified in the process; ii) divorced from the moral grammar of social freedom norms acquire an ambivalent character and lose their critical potential. Secondly, the thesis shows that a recognition-based critique of 'ethicized' capitalism can be recovered should changes be made to Honneth's standard recognition model. The thesis argues that, in addition to Honneth's claim that social actors need primary forms of recognition to realise their social freedom, moral self-realisation should be acknowledged as an additional condition of social freedom and a possibility of social labour. Further, it shows that the relationship between work, moral responsibility, and recognition is relevant for a critique of work because novel forms of work organisation face workers today with increased demands for autonomy and responsibility while denying them organisational preconditions for assuming moral responsibility for their work, i.e. co-determination rights. Because 'ethicized' capitalism is underpinned by the promise of moral self-realisation, which it systematically fails to fulfil, moral responsibility acquires critical potential.","language":"eng","citation":"THE PROBLEM OF WORK IN AXEL HONNETH'S CRITICAL THEORY / A.f. Deaconu ; tutor: M. Geuna ; coordinator: A. Pinotti. Dipartimento di Filosofia Piero Martinetti, 2024 Jan 09. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12536.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1016248/2322269/phd_unimi_R12536.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1235836"},"title":"L'EFFETTIVITÀ DEL DIRITTO DEL LAVORO E IL SUO GIUDICE. PREMESSA A UNO STUDIO","internalauthor":"DI MOLFETTA, SIMONE","type":"Tesi di dottorato","year":"2026","abstract":"The work investigates the relationship between the effectiveness of labour law and the role of the judge entrusted with its enforcement, starting from the premise that labour rights acquire concrete meaning only through judicial application. By tracing the historical evolution of labour procedure and examining the procedural instruments that characterise the labour judge’s powers, the study highlights how this specific procedure is designed to address the structural imbalance between employer and employee. An analysis of selected judicial testimonies and case law illustrates, however, that the degree of effectiveness ultimately depends on how judges interpret and exercise their role in practice, thereby pointing to the relevance of interdisciplinary perspectives for understanding judicial decision-making in labour law.","language":"ita","citation":"L'EFFETTIVITÀ DEL DIRITTO DEL LAVORO E IL SUO GIUDICE. PREMESSA A UNO STUDIO / S. Di Molfetta ; tutor: M. T. Carinci ;  co-tutor: G. Ludovico ; coordinatore: G. Ludovico. Dipartimento di Diritto Privato e Storia del Diritto, 2026 Apr 23. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13805.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1235836/3305052/phd_unimi_R13805.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/958269"},"title":"NEW-ONSET HYPERGLYCEMIA AFTER SARS-COV-2 INFECTION","internalauthor":"IPPOLITO, ELIO","type":"Tesi di dottorato","year":"2023","abstract":"Abstract  Patients who were hospitalized for coronavirus disease 2019 (COVID-19) have a higher prevalence of hyperglycemia. By altering glucose homeostasis, cytokine release brought on by The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection may hasten the onset of metabolic changes. Here, they are described different abnormalities, such as glycometabolic regulation, insulin resistance, and loss of beta cell function in COVID-19 patients. Most of those individuals had no prior history of diabetes or diabetes diagnosis. Additionally, it is reported the presence of glycaemic abnormalities in patients who were followed up several months after the onset of the illness. We discovered that 46% of patients in a sample of 551 patients hospitalized for COVID-19 in Milan were hyperglycemic, 27% were normoglycemic, while the remaining 27% were diabetic. Even in individuals with normoglycemia, we were able to identify altered glycometabolic regulation, insulin resistance, and an aberrant cytokine profile using clinical tests and continuous glucose monitoring in a sample of patients. Patients who healed from COVID-19 have been monitored for glycemic irregularities for at least two months.  Moreover, in individuals who developed hyperglycemia following COVID-19, direct and indirect effect of SARS-CoV-2 on human pancreatic islets could possibly occur. The serum of these patients showed toxicity on human pancreatic islets despite the lack of peripheral anti-islet autoimmunity, which could be reversed by the administration of anti-interleukin-1 beta (anti IL-1B), anti-interleukin-6 (anti IL-6), and tumor necrosis factor-alpha (TNF-alpha), cytokines that are known to be significantly upregulated during COVID-19 infection.  It's interesting to note that human pancreatic islets had high levels of expression of the cytokine receptors indicated above. Several COVID-19 patients showed an increase in peripheral unmethylated INS DNA, a sign of cell death. The pancreas of deceased COVID-19-positive hyperglycemic patients showed modest lymphocytic infiltration of the islets and pancreatic lymphonodes. Additionally, postmortem pancreatic tissues contained SARS-CoV-2-specific viral RNA and numerous immature insulin granules or proinsulin, suggesting altered proinsulin processing as well as beta-cell degeneration and hyperstimulation.  Our findings show that COVID-19 is linked to poor glycometabolic regulation, and that these abnormalities can last even after recovery.  In conclusion, SARS-CoV-2 may impair human pancreatic islet survival and function by inducing inflammatory conditions, possibly with a direct tropism, which may then result in metabolic abnormalities observed in COVID-19 patients.","language":"eng","citation":"NEW-ONSET HYPERGLYCEMIA AFTER SARS-COV-2 INFECTION / E. Ippolito ; tutor: P. Fiorina ; supervisori: F. D'Addio, I. Pastore ; chair of the doctoral program: L. Pinotti. Dipartimento di Scienze Biomediche e Cliniche, 2023 Mar 30. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12522.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/958269/2159508/phd_unimi_R12522.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1211356"},"title":"ULTRA-PROCESSED FOODS:FROM NUTRITIONAL CHARACTERISTICS TO THE IMPACT ON HUMAN HEALTH","internalauthor":"PELLEGRINI, BEATRICE","type":"Tesi di dottorato","year":"2026","abstract":"Historically, nutritional science has focused on individual nutrients or bioactive compounds as determinants of health. While this reductionist approach led to major discoveries, such as the prevention of nutrient deficiencies, it proved inadequate for addressing complex chronic diseases, where the effects of foods depend on the interactions between multiple components and the broader dietary context. Consequently, the field has shifted toward studying whole foods, and more recently the overall dietary pattern, intended as adequate portion and frequencies of consumption of foods. It has been argued that the issue from the point of human health is not nutrients nor foods, as the type, degree and purpose of processing. In this context, the NOVA classification introduced the concept of “ultra-processed foods”. Although this framework has been widely adopted, its scientific robustness and reproducibility remain under debate. This PhD thesis aimed to explore the role of food processing, serving sizes, and UPFs in shaping food-based dietary guidelines (FBDGs) and influencing human health. The research comprised four main components.  The first section of the work included a global scoping review of 100 national FBDGs. This first review revealed large variability in how countries define serving sizes and consumption frequencies, ranging from quantitative to purely qualitative formats, with limited harmonization. These inconsistencies hinder effective public health communication and cross-country comparability. The second review of this first section consisted in the analysis of terminology and wording related to food processing in worldwide FBDGs. In total, 75 national guidelines were investigated. Among the 89% of documents referring to processing, 25% mention UPFs and fewer cite the NOVA system, reflecting conceptual ambiguity and uneven integration of processing-related terminology in policy documents. In view to the fact that industrial foods are often perceived with a lower nutritional quality and safety with respect to home-made preparations, the second section of this work is a comparative experimental analysis of home-made versus industrially produced foods (plum cake, fish sticks, tomato sauce, cereal bars). This study demonstrated that when the same ingredients and methods are used, nutritional composition and contaminants levels (e.g., acrylamide) are largely comparable. These findings challenge the assumption that industrial foods are intrinsically less healthy or less safe than home-made equivalents. Moreover, based on the consideration that most current evidence on UPF derives from observational studies, in the third section of this thesis a systematic review of randomized controlled trials on UPF consumption was performed. The analysis revealed heterogeneous methodologies and inconclusive results, though some studies suggested higher energy intake and adverse changes in body composition with UPF-rich diets supporting that nutritional quality of diet play a pivotal role in determining the effect on human health. Finally, in the last section, the PROMENADE randomized controlled crossover trial evaluated the inclusion of five daily UPF servings within an isocaloric Mediterranean diet (MD) in overweight adults. Preliminary data showed no adverse effects on anthropometric, or lipid parameters after 12 weeks, suggesting that moderate UPF inclusion in a balanced MD does not impair short-term cardiometabolic health. In conclusion, this thesis highlights that the health impact of a diet cannot be fully explained by the degree of processing alone. Instead, the overall dietary context, quality, and balance play a pivotal role. Therefore, further well-designed and rigorously conducted research is essential to inform future food policies, as relying solely on broad or unobjective classifications of food processing risks fostering confusion and misinterpretation rather than promoting clear, evidence-based public health guidance.","language":"eng","citation":"ULTRA-PROCESSED FOODS: FROM NUTRITIONAL CHARACTERISTICS TO THE IMPACT ON HUMAN HEALTH / B. Pellegrini ; supervisor: D. Martini ; cosupervisor: C. Del Bo', C. Menchise ; coordinator: D. Mora. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2025 Jan 19. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14060.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 27-LUG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1140383"},"title":"SYNTHESIS OF EFFICIENT PHOTOCATALYSTS IN EXTREME TEMPERATURE CONDITIONS FOR THE DEGRADATION OF AIR POLLUTANTS.","internalauthor":"FRIAS ORDONEZ, MARCELA","type":"Tesi di dottorato","year":"2025","abstract":"This research arises from the significant thermal limitations of existing nitrogen oxides (NOx) reduction materials, particularly TiO2, which undergoes an irreversible phase transition (from anatase to rutile) at 600°C, severely compromising its photocatalytic efficiency. In addition, TiO2’s wide energy bandgap (~ 3.2 eV), and a rapid recombination rate of electron-hole pairs hinder its light absorption and overall photocatalytic performance. To overcome these challenges, this study proposes an innovative design strategy for strontium titanate (STO), a material with a similar energy band gap to TiO2 but offering enhanced durability due to its unalterable cubic crystal structure at high temperatures. Therefore, STO enables the development of more efficient systems for NOx photocatalytic reduction under LED irradiation and supports high-temperature industrial applications.  This work explored various synthesis methods for the fabrication of STO-based materials. A comprehensive life cycle assessment (LCA) was conducted to assess the sustainability of six different synthesis routes. Preliminary findings indicate that methods with the calcination step as the final stage, such as sol-gel, solid-state, and sonochemical (in ascending order of sustainability), emerged as the most eco-friendly approaches for STO fabrication. These insights provided valuable guidance for the continued development of sustainable, novel, and efficient STO-based photocatalysts in this investigation.  Furthermore, modification strategies to enhance the photocatalytic performance of STO, such as the incorporation of noble metal nanoparticles onto the STO surface, were also investigated. The localized surface plasmon resonance (LSPR) effect, along with the formation of the Schottky barrier between the metal and semiconductor, improves electron/hole pair separation, significantly benefiting the overall photocatalytic efficiency of STO-based materials. Among the noble metals, silver (Ag) offers the best balance between cost-effectiveness, visible light photo-response enhancement, and antibacterial properties. Due to these advantages, silver has been widely employed as a TiO2 modifier in literature and is similarly employed in this work to enhance STO performance.  Therefore, an Ag-STO system was synthesized through a wet impregnation method, where the STO surface was modified with Ag particles pre-synthesized via the electrochemical method, using Ag+ enriched-solution wastewater as a starting material. This multistep approach led to a significant increase in NOx photodegradation rates, achieving approximately 77% ± 3%. Meanwhile, a novel one-pot, water-based synthesis using AgNO3 as a pure Ag precursor enabled dual modification of STO, incorporating both Ag+ doping into STO crystal lattice and Ag nanoparticles onto STO surface. This dual modification system demonstrated thoroughly NOx degradation under LED illumination within 180 minutes. Moreover, the role of Ag in enhancing electron-hole separation was confirmed, with Ag nanoparticles on the STO surface proving crucial to the photocatalytic efficiency of the system.  Lastly, the optimization of solvents, amount of silver, and calcination conditions (temperature and residence time) was evaluated for producing Ag-modified STO photocatalysts. Notably, an 8 wt.% Ag-modified STO sample synthesized via sol-gel, using a 1:3 water/ethanol solvent mixture, exhibited the highest photocatalytic efficiency. And, it was observed that, even with short residence times at 1100°C, the photocatalytic performance did not significantly decrease, demonstrating strong thermal resistance.  Overall, this work underscores the development and assessment of novel strontium titanate (STO) - based photocatalysts as effective materials for air purification, offering high thermal stability and sustainability. These findings pave the way for the industrial integration of photocatalysts in air quality management, contributing to environmental sustainability.","language":"eng","citation":"SYNTHESIS OF EFFICIENT PHOTOCATALYSTS IN EXTREME TEMPERATURE CONDITIONS FOR THE DEGRADATION OF AIR POLLUTANTS / M. Frias Ordonez ; tutor: C. L. Bianchi ;  co-tutor: S. Ardizzone ;  coordinatore del corso: D. Roberto. Dipartimento di Chimica, 2025 Jan 13. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R13127.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1140383/2652057/phd_unimi_R13127.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1015888"},"title":"TARGETED DNA DAMAGE BOOST WITH LONCASTUXIMAB TESIRINE IN COMBINATION WITH PARP INHIBITORS IN DIFFUSE LARGE B-CELL LYMPHOMA","internalauthor":"FUSANI, STEFANIA","type":"Tesi di dottorato","year":"2023","abstract":"Overexpression of the MYC oncogene is a key event in lymphomagenesis and a frequent characteristic of refractory Diffuse Large B Cell Lymphoma (DLBCL); MYC overexpression leads to genomic instability and inherent DNA damage, which is attenuated by several mechanisms including constitutive activation of DNA damage response (DDR) pathway. In addition, MYC-driven cancers frequently overexpress PARP-1, relying on its activity to attenuate endogenous replicative stress. This evidence prompted us to target DDR with PARP inhibitors as synthetic lethal therapeutic strategy for MYC-driven DLBCL. Antibody-drug conjugates bind antigens expressed on the surface of cancer cells and specifically transfer cytotoxic payloads. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate directed against CD19 which causes DNA damage by delivering a DNA crosslink-inducing pyrrolobenzodiazepine dimer into target B-cells. With the purpose of enhancing Lonca-mediated DNA damage induction, in this project we tested the specific PARP-1 inhibitor Talazoparib in combination with Lonca in a panel of DLBCL cell lines.  Loncastuximab/Talazoparib combination showed significant anti-lymphoma activity in most of DLBCL cell lines irrespective of MYC/BCL2 rearrangements or TP53 mutational status. The BRCA2-mutated cell line Dohh2 showed the highest sensitivity to PARP inhibition in line with the well-known synthetic lethality between BRCA mutations and PARP inhibition. Lonca/Talazoparib combination resulted in specific changes in cell cycle dynamics such as an increased fraction of cells arrested in S phase, suggesting a mechanistic interaction between the two compounds. RNA-Seq analysis resulted in specific gene expression profile changes such as downregulation of Aurora Kinase A, which is involved in S and G2/M transition of cell cycle. Similar results were obtained replacing Loncastuximab with a different crosslinking agent, cisplatin, indicating a class effect. Notably, Lonca and Talazoparib as single agents or in combination did not determine significant DNA damage on healthy T cells. In line with its mechanism of action, Lonca determined detectable DNA damage in healthy B cells, which was not enhanced by the addition of Talazoparib.   The synergistic interaction between Lonca and Talazoparib was further confirmed in vivo in a MYC/BCL2 double hit PDX model with a significant reduction in tumor growth associated with increased overall survival.   These data provide the rationale for future therapeutic strategies based on selective induction of DNA damage in neoplastic B cells in combination with DDR inhibition in aggressive B cell lymphoma.","language":"eng","citation":"TARGETED DNA DAMAGE BOOST WITH LONCASTUXIMAB TESIRINE IN COMBINATION WITH PARP INHIBITORS IN DIFFUSE LARGE B-CELL LYMPHOMA / S. Fusani ; internal advisor: B. Amati ; supervisor: E. Derenzini ; phd coordinator: S. Minucci. Università degli Studi di Milano, 2023 Dec 12. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12688.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1015888/2321249/phd_unimi_R12688.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1023151"},"title":"STUDIO DELL¿ASSOCIAZIONE TRA INQUINAMENTO ATMOSFERICO E DISTURBO DEPRESSIVO MAGGIORE: RUOLO DI MARCATORI BIOLOGICI ED EPIGENETICI","internalauthor":"BORRONI, ELISA","type":"Tesi di dottorato","year":"2024","abstract":"INTRODUCTION: Major Depressive Disorder (MDD) is the most common mental disorder worldwide, affecting about 13% of adults and representing the second leading cause of disability. Despite its important social impact, etiopathology of the disease is still unknown. It has been suggested that MDD is a multifactorial disease, where genetic, environmental and biological factors may play a role. Among biological changes, epigenetic, immunological, and hormonal abnormalities have been found in MDD patients. Furthermore, recent studies have investigated whether air pollution may be a potential contributor of the onset of the disease, finding positive associations.   AIMS: In a sample of MDD patients: evaluate the association between exposure to air pollution and MDD severity; evaluate the relationship between MDD severity and different biological (inflammatory, epigenetic, hormonal) markers; evaluate the association between air pollution and the biological variables of interest; quantify the specific contribution of the investigated biological variables in the chain of events linking air pollution exposure to MDD severity (in the present study, we will focus on epigenetic alterations only).   METHODS: Overall, 416 MDD patients accessing the psychiatry unit of the Policlinico Hospital in Milan (Italy) from September 2020 to December 2022 have been recruited. Enrolled patients answered two questionnaires to collect demographic and lifestyle information, and history and characteristics of depression; they also donated a blood sample to examine biomarkers of interest. Severity of MDD was evaluated through five severity-of-illness rating scales: Montgomery-Asberg Depression Rating Scale (MADRS); Hamilton Depression Rating Scale (HAMD); Clinical Global Impression (CGI); Global Assessment of Functioning (GAF) and Sheehan Disability Scale (SDS). Daily exposures to particulate matter with diameter less than or equal to 10 (PM10) and 2.5 μm (PM2.5), and nitrogen dioxide (NO2) were estimated as daily means through the Flexible Air quality Regional (FARM) chemical transport model of the Lombardy regional Environmental Protection Agency (ARPA Lombardia), and assigned to each subject on the basis of his/her residential address. Daily average exposure to apparent temperature was also estimated, combining daily measurements of ambient temperature, humidity, and wind speed, retrieved from ARPA weather monitoring stations closest to patients’ residential addresses. Daily estimates of both apparent temperature and air pollutants were averaged to obtain moving averages of exposure. Multivariate regression models were used to assess the associations between air pollutant concentrations and MDD severity scales, air pollutants and methylation of CLOCK (circadian locomotor output cycles protein kaput) and CLOCK-related genes, and methylation of CLOCK and CLOCK-related genes and MDD severity scales.   RESULTS: Two-thirds of included patients were females and about one-third had a family history of depression. Most women had depression with symptoms of anxiety, while men had predominantly melancholic depression; they were also more likely to experience suicidal and addictive behaviors. Average exposure to NO2 in the two weeks preceding recruitment (lag0-14) was associated with a worsening of MDD severity [HAMD: β=2.09, 95% CI (0.63; 3.56); CGI: β=0.27, 95% CI (0.02; 0.51); and GAF: β=-1.96, 95% CI (-3.60; -0.33)], while particulate matter exposure (PM10, PM2.5) was associated with MDD severity only when temperatures were low or among hypersusceptible subjects. Short-term exposure to PM10 was associated with hypomethylation of CRY2 and hypermethylation of OX1R, CRY1, and ARNTL at different lags of exposure within the two weeks preceding recruitment. Long-term exposure to PM10 (average of the three- and six-months preceding recruitment) was positively associated with CRY1 and negatively associated with CRY2. Results were similar for PM2.5 exposure. When short-term exposure to NO2 was considered, we observed an increase methylation of CRY1 and a reduced methylation of CRY2. Long-term exposure to NO2 was positively associated to the methylation of CRY1 and HERVW. In the whole population, hypermethylation of CLOCK was associated with less severe scores of depression. This association was found to be stronger in the subtype of depression “with strong symptoms of anxiety”. Hypermethylation of OXTR was associated with more severe “melancholic / psychotic / no prevalent” type depression.    CONCLUSIONS: Exposure to PM10 and PM2.5 did not exert a direct effect on the severity of depressive symptoms, while their influence emerged more clearly among hypersusceptible subjects. In addition, PMs had a greater significant impact on MDD severity when temperatures were very low. NO2 exposure was strongly associated with MDD severity in the whole population and showed higher effects among hypersusceptible subjects as well as with concomitant exposures to low temperatures.    Short- and long-term exposure to particulate matter resulted associated with altered methylation of CLOCK and CLOCK-related genes, which can be involved in circadian rhythms, often affected by depression.    The hypermethylation of CLOCK was associated with lower scores of MDD severity suggesting (conversely) that the hypomethylation of CLOCK could be associated with a worsening of depressive symptoms. A finding consistent with preliminary data from the literature (1) which have highlighted an increased expression of CLOCK in subjects affected by MDD.  Taken as a whole, these findings suggest a possible role of CLOCK and CLOCK-related genes in the pathway linking air pollution exposure to the worsening of MDD severity.","language":"eng","citation":"STUDIO DELL'ASSOCIAZIONE TRA INQUINAMENTO ATMOSFERICO E DISTURBO DEPRESSIVO MAGGIORE: RUOLO DI MARCATORI BIOLOGICI ED EPIGENETICI / E. Borroni ; tutor: A. C. Pesatori ; coordinatore: C. La Vecchia ; supervisori: A. Ranzi, D. M. Cavallo. Dipartimento di Scienze Cliniche e di Comunità, 2023. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12927.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1023151/2342504/phd_unimi_R12927.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1213197"},"title":"SUSTAINABILITY STRATEGIES AND GREENWASHING ALONG FOOD VALUE CHAINS: AN EMPIRICAL ANALYSIS OF THE DETERMINANTS","internalauthor":"MARSCHNER, STELLA","type":"Tesi di dottorato","year":"2026","abstract":"The food system is vital in sustaining livelihoods on the planet, but it also entails major impacts in terms of environmental and social sustainability. In order to address the sustainability-related challenges, companies have been increasingly taking an active role in promoting sustainability, by adopting voluntary sustainability standards (VSS). Companies may not be necessarily truthful when communicating their sustainability activities, and this trend has given rise to greenwashing. To enhance sustainability, it is crucial to identify which variables promote or hinder sustainability strategies adoption and greenwashing behaviour. In our analysis, an integrated theoretical framework is developed by combining Stakeholder theory, GVC theory and Risk dependence theory to explain sustainability strategies adoption, and the focus is on the role of firm characteristics. Three samples of companies operating along different agri-food value chains were selected, and three original datasets were created by combining data from the Orbis database and from a content analysis carried out on company websites. In Chapter 1, I explore the firm characteristics which shape the pattern of sustainability strategies adoption in the cocoa-chocolate global value chain (GVC), by collecting data over a sample of 304 cocoa-chocolate companies. In Chapter 2, I assess the relationship between firm characteristics and the communication of environmental VSS in the European beef value chain. In Chapter 3, I analyse the extent to which firm characteristics relate to greenwash behaviour in the value chains of five different agri-food products, namely coconut, coffee, processed tomatoes, shrimps, soft drinks and tea. A tailored empirical strategy was developed for each chapter, and a different regression model was employed based on the characteristics and distribution of the dependent variables. The thesis demonstrates that a vast proportion of companies do not communicate any sustainability activity. Moreover, our findings suggest that highly visible, close to consumer agri-food firms are likely to make efforts to achieve sustainability. However, they are simultaneously more inclined to disclose misleading sustainability claims and engage in a greenwashing behaviour. Therefore, results imply that stronger efforts are needed to meet the SDGs set by the UN Agenda 2030.","language":"eng","citation":"SUSTAINABILITY STRATEGIES AND GREENWASHING ALONG FOOD VALUE CHAINS: AN EMPIRICAL ANALYSIS OF THE DETERMINANTS / S. Marschner ; tutor: S. Stranieri co-tutor: L. Orsi coordinatrice: M. P. M. Guarino. Dipartimento di Scienze e Politiche Ambientali, 2026 Jan 29. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13710.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 10-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1230878"},"title":"FORME PRECARIE  IL CALCIO PROFESSIONISTICO COME OSSERVATORIO ORGANIZZATIVO EMBLEMATICO DELLE EVOLUZIONI DEL LAVORO E DEI PROCESSI DI SVILUPPO DELLE COMPETENZE","internalauthor":"PALUMBO, MARTINA","type":"Tesi di dottorato","year":"2026","abstract":"This doctoral project, funded by the PNRR, explores the precariousness in Italian professional football. The research is structured into three studies, guided by a psychosociological perspective and integrated within a sequential mixed-methods design.    Professional football and precariousness may appear paradoxical; however, the contrast between an idealized institutional representation and the fragility of professional experiences makes this sector emblematic for investigating the ‘insidious and plural’ (Seubert et al., 2023) forms of contemporary precariousness, as well as the assumptions underpinning processes of competence development. Within this perspective, the linear association between precariousness and the enhancement of individual competencies is critically questioned, as it is often conceived as an individual remedy to what is, instead, a systemic fragility.    The first study, qualitative and exploratory, adopts a grounded theory methodology and involves 16 opinion leaders in the field, through in-depth interviews. On the one hand, inductive analysis identifies (I) the particular form of precariousness experienced within professional football, providing a specific description. On the other hand, this same empirical contingency offers conceptual elements for (II) a theoretical modelling of the construct of precariousness, highlighting its multidimensional structure—symbolic, organizational, social, and individual. The emerging substantive theory (III core category: institutional subjectivation) captures a broader process that appears to cut across contemporary occupational systems. The fragility of Work shifts onto individuals functions that were previously institutionally guaranteed (Jahoda, 1982). Within this framework, the development and use of individual competencies become the primary means through which individuals construct and sustain their professional trajectories, effectively ‘privatizing’ responsibility, meaning, and quality (Dubar, 2010).    The second study, based on an online survey involving 215 professionals from technical football staff, tests the multidimensional construct of precariousness developed in the first study through a structural equation model (SEM). The results (I) validate its theoretical structure and (II) show that individually focused support interventions have limited impact on the relationship between precariousness and distress, unless embedded within an integrated intervention logic. This finding highlights the limits of ‘psychologizing’ approaches to precariousness, focused on individual support (Reddy & Amer, 2023), and underscores the need for coordinated actions at institutional, organizational, and social levels.    The third study presents the results of a clinical-organizational Action Research.  On the one hand, it investigates coach education in professional football, aiming to understand: (I) the dominant representation of learning currently in use (learning as adaptation), (II) how competence is configured within the current training model (organized into rigid, non-integrated categories—technical, or relational, or individual), and (III) which training needs coaches consider most crucial for dealing with precariousness (predominantly individual, reflecting a potentially collusive perspective and a rhetoric of resilience, alongside a strong latent relational need). Data were collected through a revised version of the Performance Profile (Butler & Hardy, 1982), completed by 134 coaches.  On the other hand, the study takes the form of a training intervention. A temporary organization was set up, involving researchers and professionals (coaches, technical coordinators, managers) jointly engaged from design to discussion of results. The empirical findings were used within a broader participatory process of organizational reflection aimed at transforming tacit needs into shared working hypotheses and fostering the renewal of current training practices.","language":"ita","citation":"FORME PRECARIE  IL CALCIO PROFESSIONISTICO COME OSSERVATORIO ORGANIZZATIVO EMBLEMATICO DELLE EVOLUZIONI DEL LAVORO E DEI PROCESSI DI SVILUPPO DELLE COMPETENZE / M. Palumbo ; supervisore: C. Gozzoli ;  co-supervisore: E. Zanoli ; coordinator: C. Gozzoli. - Milano, Università Cattolica del Sacro Cuore. Università degli Studi di Milano, 2026 Apr 21. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13717.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1230878/3291970/phd_unimi_R13717.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/959076"},"title":"UNDERSTANDING THE MOLECULAR MECHANISM LINKING ATM TO METABOLIC REGULATION.","internalauthor":"EL KHAREF, CATIANA","type":"Tesi di dottorato","year":"2023","abstract":"Ataxia Telangiectasia (A-T) is a pleiotropic autosomal recessive disease characterized by progressive neurodegeneration, immunodeficiency, sensitivity to ionizing radiation and premature aging. The molecular basis of A-T is loss of function of the gene encoding A-T-mutated (ATM), a serine/threonine kinase that acts as a master regulator of the DNA damage response, leaving A-T patients highly predisposed to cancers. In addition to its classical role in orchestrating the DNA damage response, recent evidence reports a role for ATM in cellular metabolism, oxidative stress response and insulin signaling. However, it is unclear how defective ATM-dependent response to oxidative stress contributes to A-T clinical manifestations. Here we show that ATM activates glycolysis upon oxidative stress and that its loss leads to impairment of glycolysis and impairment of metabolism in A-T cells. In addition, we identified a metabolic regulator as a major driver of glycolysis impairment and poor cell growth in A-T tissues. Respectively, the downregulation and inactivation of this metabolic regulator in A-T cells restored normal glycolysis, reduced metabolites accumulation and improved A-T cells survival and proliferation. Taken together, our results shed light on a new role of ATM in activating glycolysis and cellular metabolism upon oxidative stress and help to identify a metabolic checkpoint activated in ATM-deficient cells to suppress cellular anabolic pathways and cellular growth. Our study also identified a potential therapeutical target that exerts a synthetic survival effect upon downregulation, to slow down the progression and symptoms of A-T disease.","language":"eng","citation":"UNDERSTANDING THE MOLECULAR MECHANISM LINKING ATM TO METABOLIC REGULATION / C. El Kharef ; tutor: M. Vinciguerra; internal Advidor: K. Havas ; tutor: V. Costanzo ; phd coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2023 Apr 13. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12439.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/959076/2161248/phd_unimi_R12439.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1025570"},"title":"BIOINSPIRED POLYAMIDOAMINES AS INNOVATIVE FLAME RETARDANTS FOR CELLULOSIC FABRICS","internalauthor":"BEDUINI, ALESSANDRO","type":"Tesi di dottorato","year":"2024","abstract":"In the three years of my PhD course, I focused my attention and efforts onto 5 research lines:  1. Polyamidoamines derived from natural a-amino acids as effective flame retardants for cotton fabrics;  2. Study of the polyamidoamine decomposition products upon heating;  3. Phosphorous-sulphur-based polyamidoamines as flame retardants for cotton fabrics;  4. Study of the synergism between a-aminoacid derived-polyamidoamines and sodium montmorillonite for enhancing the flame retardancy of cotton fabrics;  5. Study of a novel approach for investigating the flame retardancy of upholstery materials.    1. This project was carried out in collaboration with Prof. Federico Carosio of Politecnico di Torino    In this work, bioinspired polyamidoamines (PAAs) were synthesized by Michael-type polyaddition from N,N’-methylenebisacrylamide, M, and nine natural α-amino acids, namely L-alanine (M-ALA), L-valine (M-VAL), L-leucine (M-LEU), L-histidine (M-HIS), L-serine (M-SER), L-asparagine (M-ASN), L-glutamine (M-GLN), L-aspartic acid (M-ASP) and L-glutamic acid (M-GLU) and their performance as flame retardants (FRs) for cotton determined.  The aim of this work was to establish if the ability to protect cotton from fire by intumescing mechanism, previously observed for the glycine-derived, M-GLY, was a general feature of α-amino acid-derived PAAs. The intumescence is the ability of a material to swell when it is subjected to heating; a thermally stable carbonaceous structure (char) is formed on the surface, and it behaves as a physical barrier reducing the heat, mass and oxygen transfer to the substrate below.    2. This project was carried out in collaboration with Dr. Claudia Forte of CNR of Pisa, Istituto di Chimica dei Compositi Organometallici    The aim of this research is to study the decomposition products of polyamidoamines upon heating, when PAAs are used as flame retardants. This work is divided in two different parts, the first one is focused on studying the release of volatile species using a TGA microbalance coupled with infrared spectroscopy (TG-IR), while the second one regards the study of PAA condensed phase using different analytical techniques, X-ray Photoelectron (XPS), Raman spectroscopies and Solid-State Nuclear Magnetic Resonance (SS-NMR).     3. This project was carried out in collaboration with Prof. Domenico Albanese of Università degli Studi di Milano.    In a previous work, cystine-derived PAAs synthesized by N,N’-methylenebisacrylamide, M, and L-cystine, CYSS, coded as M-CYSS, was found to impart flame retardant properties to cotton fabrics in HFSTs thanks to its ability to act as radical scavenger in the gas phase, interrupting cotton self-sustained combustion.   Phosphorous compounds were widely used to substitute some bromine derivatives; in fact, they can work in the condensed phase, increasing the amount of the char residue formed at elevated temperatures.  In this context, a new monomer containing both sulphur and phosphorus, coded as PCASS, was used as monomer in a synthesis with the N,N’-methylenebisacrylamide and the resulting polymers, coded as M-PCASS,  were tested in HFSTs.     4. This project was carried out in collaboration with Prof. Federico Carosio of Politecnico di Torino    Previous research found PAAs derived from α-amino acids effective in extinguishing cotton combustion, but they struggled with vertical flame spread tests. To address this limitation, researchers explored combining PAAs with inorganic nanoparticles like sodium montmorillonite (NaMMT) to enhance flame retardancy. The study aimed to investigate the interaction between PAAs derived from glycine, arginine, and glutamic acid and NaMMT on cotton fabric's thermal-oxidative stability and flame retardancy. In fact, NaMMT can easily interact with PAAs due to their amphoteric nature, as already demonstrated for tissue-engineering applications.    5. This work was carried out during my 6-month abroad stage in the National Institute of Standards and Technology (USA) under the supervision of Dr. Mauro Zammarano.    In this work, some bioinspired PAAs, which have already shown their flame retardant (FR) abilities, were selected for being evaluated in a new cutting-edge test, named Cube test. In detail, six different PAAs were chosen, formed by N,N’-methylenebisacrylamide, M, and 6 different α-amino acids, namely L-glycine (M-GLY), L-arginine (M-ARG), L-glutamine (M-GLN) and L-glutamic acid (M-GLU). Furthermore, also the polymer synthesized from M and L-cystine (M-CYSS) and the copolymer M-GLY50-CYSS50 were identified for the work.  The Cube test is a bench-scale test based on the oxygen-consumption cone calorimeter that has been developed at the NIST to capture the mass and heat transfer phenomena in a representative cross-section of a multi-component product including a flammable core, formed by a flexible polyurethane foam (FPUF) cube and superficial layers (i.e. cotton fabrics) that may act as fire barriers. This type of test wants to mimic a full-scale chair mock-up test, obtaining some important parameters without the building of a real armchair.","language":"eng","citation":"BIOINSPIRED POLYAMIDOAMINES AS INNOVATIVE FLAME RETARDANTS FOR CELLULOSIC FABRICS / A. Beduini ; tutor: J. Alongi ; co-tutor: E. Ranucci ; coordinatore del corso: D. Roberto. Dipartimento di Chimica, 2024 Feb 12. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12907.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1025570/2351260/phd_unimi_R12907.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/894685"},"title":"FROM SEWAGE SLUDGE TO RENEWABLE FERTILIZER: EFFICACY AND ENVIRONMENTAL RISKS IN OPEN FIELD EXPERIMENT.","internalauthor":"PIGOLI, AMBROGIO","type":"Tesi di dottorato","year":"2022","abstract":"The increasing of human population worldwide set, among others, two challenges: food provision, which lead to fertilizers production and waste disposal. Sewage sludge, that can be harmful if not-correctly managed, if properly treated with anaerobic digestion can be used as worthy fertilizer/soil conditioner, while producing energy through biogas combustion. This thesis focusses on a full-scale anaerobic digestion plant treating mainly sewage sludge at thermophilic condition (55°C) for relatively long time (HRT about 50 days) leading to the production of a highly stabilized digestate. Furthermore, the plant has a stripping system which recover ammonia from the substrate, producing ammonium sulphate that can be used as N fertilizer.   The recovered fertilizers produced (digestate and ammonium sulphate) were characterized and monitored along three years. Moreover, an experimental maize field was set up for three crop seasons to study the use in agriculture of the recovered fertilizers produced (digestate in pre-sown and ammonium sulphate in topdressing), in comparison with parallel use of synthetic fertilizers (urea in pre-sown and ammonium sulphate in topdressing). The digestate was injected in soil at a depth of 15 cm, urea was spread on soil surface, and ammonium sulphate given as fertigation.  During the pre-sown fertilizations were measured ammonia, and odour emissions. The emission of greenhouse gases from the experimental fields was also determined for the ten months following the spreading in pre-sowing. Furthermore. Along the three years yield were quantified and grain quality was tested. At the beginning and at the end of the period were run complete soil analyses. Finally, an LCA study was conducted comparing the environmental impacts of the recovered fertilizers studied and the traditional synthetic urea fertilization.   Digestate characterization showed a high N (47% in ammonia form) and P concentration, while a lower K content. All organic and inorganic pollutants (emerging pollutants among the others) were far below the legal limit for its use in agriculture and microbiologic analyses showed an almost complete sanitation of the substrate. Ammonium sulphate (7% N) was free from pollutant, showing a high purity level. Ammonia emissions in open field were similar for digestate and urea, and odour were slightly lower for digestate than urea, being ammonia coming from urea hydrolysis responsible for odour productions. The emission of greenhouse gases throughout the crop season was equivalent between fields fertilized with recovered fertilizers and synthetic fertilizers. Furthermore, soil analyses showed no significant differences in organic or inorganic pollutants. Digestate ensured an ammonia availability for plant equal to urea fertilization and agronomic yield were similar for digestate and urea treatment, while significantly higher than untreated plot, as expected. Finally, in the LCA study, digestate showed a better environmental performance than urea, due the impact of synthetic urea production and considering the renewable energy production of biogas. In conclusion the high stabilized digestate and ammonium sulphate can effectively and safely substitute the traditional chemical fertilization on crop, bringing the advantage of being renewable and helping waste management.","language":"eng","citation":"FROM SEWAGE SLUDGE TO RENEWABLE FERTILIZER: EFFICACY AND ENVIRONMENTAL RISKS IN OPEN FIELD EXPERIMENT / A. Pigoli ; coordinatore: G.F. Ficetola ; supervisor: F. Tambone. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2022 Jan 17. 34. ciclo, Anno Accademico 2021. [10.13130/pigoli-ambrogio_phd2022-01-17].","filename":"phd_unimi_R12146.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/894685/1945188/phd_unimi_R12146.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1144456"},"title":"CORTICAL INHIBITION OF HYPERACTIVE ADAM10 PREVENTS CORTICO-STRIATAL CIRCUITRY DEFECTS IN HUNTINGTON¿S DISEASE","internalauthor":"SCOLZ, ANDREA","type":"Tesi di dottorato","year":"2025","abstract":"Huntington's disease (HD), a devastating neurodegenerative disorder caused by a CAG triplet expansion in exon 1 of the huntingtin gene (HTT), is characterized by progressive neuronal loss, predominantly in the striatum and cortex. Neuroimaging and electrophysiological studies consistently reveal that cortical projection neurons, the main presynaptic input to the striatum, are compromised early in the disease. While both cortical and striatal neurons are affected by mutant Htt, in vivo and in vitro studies have shown that selective mutant Htt expression specifically in cortical neurons is both necessary and sufficient to disrupt cortico-striatal circuitry integrity and drive striatal pathology. This highlights presynaptic cortical dysfunction as a critical contributor to striatal degeneration in HD, presenting an intriguing target for the development of novel drugs for HD. At the molecular level, the disruption of Brain- Derived Neurotrophic Factor (BDNF) synthesis and transport in cortical neurons is solidly associated with cortico-striatal circuitry dysfunction and striatal pathology in HD. As part of the continuing efforts to unravel the molecular mechanisms driving HD-related synaptic dysfunction, our group discovered A Disintegrin And Metalloproteinase Domain-containing protein 10 (ADAM10) as novel synaptic partner of Htt. ADAM10 exerts fundamental roles in the homeostasis of neuronal networks through its proteolytic activity on a plethora of synaptic adhesion proteins. In HD, the ADAM10/Htt complex is hampered, leading to ADAM10 accumulation at the synapse, which in turn disrupts synaptic function and contributes to cognitive decline in HD mice. More recent findings revealing ADAM10’s pivotal role in presynaptic homeostasis—specifically in the regulation of synaptic vesicle transport and release—have led us to propose the intriguing hypothesis that increased accumulation of active ADAM10 in HD cortical neurons may trigger cortico-striatal dysfunction and striatal pathology in HD. The aim of this PhD thesis is to investigate the contribution of presynaptic (cortical) ADAM10 in HD cortico-striatal circuitry dysfunction. To reconstruct the HD cortico-striatal circuitry I employed a microfluidic-based cellular platform with separated cortical and striatal compartments. The selective ADAM10 inhibitor GI254023X was administered independently to cortical and striatal neurons within the reconstructed network, and cortico-striatal connectivity was evaluated. Finally, to assess translational potential, we tested the therapeutic efficacy of intranasally delivered GI254023X in an HD mouse model.","language":"eng","citation":"CORTICAL INHIBITION OF HYPERACTIVE ADAM10 PREVENTS CORTICO-STRIATAL CIRCUITRY DEFECTS IN HUNTINGTON¿S DISEASE / A. Scolz ; scientific tutor: E. Cattaneo ;  scientific tutor: C. Zuccato ;  coordinator of the PhD school: S. Ricagno. Dipartimento di Bioscienze, 2025 Feb 17. 37. ciclo","filename":"phd_unimi_R13364.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1144456/2670296/phd_unimi_R13364.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1198336"},"title":"TOWARDS ACCELERATION OF QUANTUM-CLASSICAL ORCHESTRATION","internalauthor":"ROBBIATI, MATTEO","type":"Tesi di dottorato","year":"2025","abstract":"Quantum computing is expected to act as a hardware accelerator within future computing infrastructures, complementing classical processors in the same way GPUs accelerate specific workloads today. While algorithms such as Shor’s and Grover’s suggest potential advantages, the practical use of quantum devices will occur within hybrid architectures where classical and quantum resources coexist. Artificial intelligence illustrates this balance: classical methods, such as Transformers and their scalable variants, remain dominant, while quantum computing may only contribute to selected subroutines. At the same time, AI methods are increasingly applied to quantum computing, supporting calibration, control, and error mitigation of near-term devices. This two-way relationship underlines the need for hybrid solutions and for efficient orchestration of heterogeneous resources.   This thesis investigates the design and implementation of hybrid classical-quantum solutions, with emphasis on their real-time orchestration within heterogeneous infrastructures. The work has been carried out within the Qibo environment, a fully open-source framework that spans the entire quantum computing stack: from high-level interfaces for algorithm design, to efficient simulation backends on classical hardware, to integration with quantum devices down to the hardware and pulse level on self-hosted systems. This modularity makes Qibo a suitable platform to explore orchestration strategies across classical and quantum resources.  Within this framework, we introduce algorithmic and software contributions that accelerate hybrid workloads. We present general-purpose open-source libraries, such as Qiboml for hybrid quantum-classical machine learning, and mpstab for a hybrid stabilizer-tensor network representation of quantum states. By preserving the familiar interfaces of classical machine learning frameworks, Qiboml enables the design of hybrid architectures and their execution on both simulators and quantum hardware. We also develop algorithmic solutions for real-time quantum error mitigation, implemented in Qiboml and relying on Qibo. We further discuss applications, including multi-variable integration, probability density estimation, and ground-state search, as well as an application in which quantum systems operate as precision sensors for fundamental physics. These serve as test cases to validate the proposed approaches and to provide practical examples of how the heterogeneous components of a future quantum-classical infrastructure can be effectively orchestrated.","language":"eng","citation":"TOWARDS ACCELERATION OF QUANTUM-CLASSICAL ORCHESTRATION / M. Robbiati ; supervisore: S. Carrazza, S. Vallecorsa ;  coordinatore: A. Mennella. Dipartimento di Fisica Aldo Pontremoli, 2025 Nov 28. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13832.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1198336/3191023/phd_unimi_R13832.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/884458"},"title":"GENE THERAPY FOR GYRATE ATROPHY OF CHOROID AND RETINA AND FOR USH1B RETINITIS PIGMENTOSA","internalauthor":"DELL'AQUILA, FABIO","type":"Tesi di dottorato","year":"2021","abstract":"Inherited Retinal Diseases (IRDs) represent a major cause of blindness worldwide. Adeno-associated viral (AAV) vector-based gene therapies represent the most promising treatments. We aimed to develop gene therapies for gyrate atrophy of the choroid and retina (GA) and Usher syndrome type 1B (USH1B) retinitis pigmentosa.  GA is characterized by ornithine aminotransferase [OAT, coding sequence (CDS) ∽1.3 Kb] deficiency. We demonstrated in vitro expression and activity of 3XFlag-tagged human OAT (hOAT-3XFlag). AAV vector carrying the hOAT-3XFlag expression cassette improved the structural retinal defects in the Oat-/- mouse model of GA.  Bi-allelic mutations in the Myosin7A gene (MYO7A) (CDS ∽6.7 Kb) cause USH1B, the most common combination of inherited congenital deafness and blindness. We demonstrated effective delivery and expression of MYO7A in mice and pigs using dual AAV vectors. During AAV manufacturing, we found a contaminant vector resulting from recombination between two homologous sequences in the AAV vector containing the 5’ half of hMYO7A. This was removed by changing one of the two sequences while maintaining the same MYO7A expression levels in vivo. We selected three therapeutic doses of dual AAV-hMYO7A that rescue retinal defects in shaker-1 mice, a mouse model of USH1B. These doses will be translated in patients with USH1B. In the same mouse model, we confirmed biological potency of dual AAV-hMYO7A that will be used in the clinical trial.  Overall, these studies offer promising results, paving the way for a gene therapy of GA and for the clinical translation of dual AAV vectors in USH1B subjects.","language":"eng","citation":"GENE THERAPY FOR GYRATE ATROPHY OF CHOROID AND RETINA AND FOR USH1B RETINITIS PIGMENTOSA / F. Dell'aquila ; tutor: A. Auricchio ; internal supervisor: I. Conte ; external supervisor: V. Marigo. Università degli Studi di Milano, 2021 Dec 13. 33. ciclo, Anno Accademico 2021. [10.13130/dell-aquila-fabio_phd2021-12-13].","filename":"phd_unimi_R12094.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/884458/1916432/phd_unimi_R12094.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1172052"},"title":"DEVELOPMENTS IN E&EM GEOPHYSICS:JOINT INVERSION, TIME-SERIES ANALYSIS AND SYSTEM CALIBRATION","internalauthor":"SIGNORA, ALESSANDRO","type":"Tesi di dottorato","year":"2025","abstract":"The research presented in this Ph.D. thesis stemmed from the largest Airborne Electromagnetic (AEM) campaign ever conducted in Italy between 2021 and 2023, and from the specific challenges arising from this project. The campaign aimed to investigate the geological and hydrogeological architecture of a region in northern Italy at multiple observational scales—large, medium, and high-detail—to support long-term hydro-management strategies.  The first expected outcome of the Ph.D. was the establishment of the HydroGeosITe within the AEM survey area. This site was conceived as a reference and bridge between the large-scale geophysical models derived from the airborne campaign and their lithostratigraphic interpretation. At the same time, the HydroGeosITe was designed to serve as a calibration site for AEM systems, supporting future campaigns. Accordingly, a key research objective was to advance the state of the art in AEM calibration procedures, setting a new standard for Italy.  At the HydroGeosITe, an extremely dense E&EM dataset was acquired using multiple systems to ensure broad sensitivity and spectral coverage. The first technical development has been a novel joint inversion approach for E&EM data, applied for the first time to model the HydroGeosITe, retrieving subsoil models with unprecedented resolution validated with borehole comparison. This joint approach enabled a new level of translation from geophysical to geological information, supported at the HydroGeosITe also by extending the high-resolution 2D joint models into a full 3D volume.  In the second part of the thesis, the research shifted toward temporal analysis of E&EM data, addressing both specific challenges in time-lapse analysis and leveraging those advancements to improve EM calibration procedures.  In this context, seasonal temperature effects were first examined through a long-term monitoring survey using galvanic data. Here, temperature oscillations masked the target anomalies, rendering the data unusable. To overcome this, a novel inversion scheme was developed to filter out temperature effects by inverting for ground thermal diffusivity—without requiring in-situ temperature measurements at the time of acquisition.  Since similar seasonal effects were found to influence subsurface models during EM instrument calibrations—particularly when calibrations are performed in different seasons—a dedicated study was conducted to investigate the impact of temperature on EM data, highlighting the risk of misinterpreting thermal variations as instrument-related differences.  Still within temporal analysis, the study continued with an AEM time-lapse dataset from southern Australia. The dataset was modelled to investigate the hydrogeological evolution of a hypersaline floodplain and its freshwater recharge at basin scale. A dedicated time-lapse inversion framework was developed specifically for airborne EM data. Beyond its standalone results, this multitemporal modelling scheme provides a tool for future AEM campaigns opening the way to time-lapse acquisitions.  Finally, the last chapter converges into a discussion on how the research results presented should be used for reference and calibration purposes. First, the analysis of temperature effects is further deepened—showing they can have a greater impact than some commonly prioritized transfer function parameters. Then, the application of the full joint workflow, from acquisition to modelling, to the CSIRO calibration line in Australia demonstrates the value of high-resolution sites as references for large-scale geophysical studies.","language":"eng","citation":"DEVELOPMENTS IN E&EM GEOPHYSICS:JOINT INVERSION, TIME-SERIES ANALYSIS AND SYSTEM CALIBRATION / A. Signora ; tutor: G. Fiandaca, A. Comunian; coordinatore: G. Muttoni. Dipartimento di Scienze della Terra Ardito Desio, 2025 Jun 25. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13547.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1172052/3094917/phd_unimi_R13547.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1119477"},"title":"LA GIUSTIZIA RIPARATIVA. DAL CONCETTO ALLA RIDEFINIZIONE","internalauthor":"LAGALLA, MARIA LUDOVICA","type":"Tesi di dottorato","year":"2024","abstract":"The body of scientific literature on Restorative Justice is vast and continues to expand at a relentless pace. At first glance, choosing this topic might seem far from original. Yet, it is precisely the overwhelming scale of this literature that provides the starting point for this work.  Paradoxically, the more one explores the extensive writings on Restorative Justice, the less clear its meaning appears to become. This research does not claim to offer a definitive solution to this semantic confusion. Instead, it stems from a pressing need for conceptual clarity. Addressing this need involves, first, identifying a common ground and, second, putting forward a redefinition.  The structure of this work reflects this approach, dividing the analysis into three chapters.  The first chapter, ‘‘Problemi e metodo di un’analisi della giustizia riparativa’’, serves two purposes. It introduces the subject of the research, focusing on the significant conceptual vagueness surrounding the term ‘‘Restorative Justice’’, and outlines the objectives and methods adopted to achieve them.  Two key objectives guide the research.  The first is to determine whether it is possible to identify shared assumptions about Restorative Justice that are broadly accepted within the relevant scholarly and professional community. In simpler terms, the aim is to establish whether a stable conceptual core of Restorative Justice exists.  The second objective is to propose a re-definition of Restorative Justice.  The second chapter, “Alla ricerca di un’area solida”, is devoted to achieving the first objective.  The analytical method used here is meta-dogmatic and meta-normative. It involves examining key doctrinal definitions (from both international and Italian contexts) and significant normative definitions (both national and supranational) to identify shared assumptions regarding the term ‘‘Restorative Justice’’.  The doctrinal definitions selected for analysis are those that occupy a central or highly influential position in the academic debate on the conceptual and definitional aspects of Restorative Justice. Normative definitions were chosen using two criteria: their contemporary relevance and their institutional representativeness.  This meta-jurisprudential approach not only identifies common ground but also brings to light the central and most contentious issues surrounding the concept. This insight proves particularly valuable for the subsequent redefinition effort.  In the third chapter, titled “A Redefinitional Proposal”, the redefinition is presented. This redefinition builds on the findings of the second chapter and is further developed in light of the solutions proposed to the contentious issues previously outlined.","language":"ita","citation":"La giustizia riparativa. Dal concetto alla ridefinizione / M.l. Lagalla ; Tutors: V. Velluzzi, S. Zorzetto ; coordinatrice: F. Poggi. - Dipartimento Scienze Giuridiche ''Cesare Beccaria''. Università degli Studi di Milano, 2024 Nov 21. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13391.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1119477/2593905/phd_unimi_R13391.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/916544"},"title":"MYXOMATOUS MITRAL VALVE DISEASE IN CAVALIER KING CHARLES SPANIEL: CLINICAL, GENETIC, AND CARDIAC BIOMARKERS STUDY","internalauthor":"BAGARDI, MARA","type":"Tesi di dottorato","year":"2022","abstract":"One hundred and sixty-five CKCS subjects, both healthy and affected by different stages of MMVD, were examined from November 2018 to June 2021 at the Veterinary Teaching Hospital in Lodi – University of Milan – Cardiology Section. Each dog was submitted to a clinical examination and echocardiographic, radiographic, and morphometric data were collected. Whole blood and plasma were collected for genetic analysis and biomarker (miRNA) evaluation.   The objectives of this study were: 1) To describe breed-specific reference values for vertebral heart score (VHS), vertebral heart atrial size (VLAS), M-VLAS, and radiographic left atrial enlargement (RLAD) in healthy adults CKCS; 2) To conduct a genomic study on a population of Italian CKCS; 3) To characterize echocardiographic features of the mitral valve in this breed, focusing on dogs classified as American College of Veterinary Internal Medicine (ACVIM) B1, without clinical signs and without left atrial and ventricular enlargement; 4) To analyze the relationships and the prognostic value of morphometric variables in CKCS affected by MMVD; 5) To analyze the expression of miRNAs described in the literature as being involved in the pathophysiology of MMVD, and identified in dogs’ plasma.   Results: 1) Healthy CKCS had a median VHS of 10.08 ± 0.56v, a VLAS, M-VLAS and RLAD respectively of 1.79 ± 0.3v, 2.23 ± 0.44v and 1.2 ± 0.34v; 2). The top 1% single-nucleotide polymorphisms (SNPs) of both Wright’s fixation index (FST) and cross-population extended haplotype homozygosity (XP-EHH) analyses localized 10 consensus genes on chromosomes 3-11-14-19; 3) Within class B1, older subjects showed significantly higher values of anterior mitral valve area (AMVA), width (AMVW), mitral valve annulus in diastole (MVAd) and systole (MVAs) and lower sphericity index (SI); 4) A more severe mitral regurgitant jet size and a thicker anterior mitral valve leaflet were observed in CKCS smaller than standard proposed by the Ente Nazionale della Cinofilia Italiana (ENCI) and with morphometric characteristics tending to brachycephalism; 5) miR-30b-5 was significantly higher in ACVIM B1 compared to healthy subjects (ACVIM class A) and the AUC was 0.79. According to the age of dogs, the expression of miR-30b-5p remained significantly higher in group B1<3y (2.3 folds p=0.03), B1 3-7y (2.2 folds p=0.03), and B1>7y (2.7 folds p=0.02) than in stage A. The AUCs were fair in discriminating group B1<3y and A (AUC 0.78), and B1 3-7y and A (AUC 0.78), and good in discriminating group B1>7y and A (AUC 0.82).   Conclusions: 1) Findings supported previous studies recommending the use of breed-specific reference values for VHS, VLAS, M-VLAS and RLAD and provided background data for future radiographic evaluations of CKCS dogs with clinical signs of cardiac disease; 2) This genetic analysis expands the knowledge of the genetic basis of MMVD by identifying genes involved in the early onset of MMVD in CKCS; 3) This is the first study that describes measurements of the anterior mitral valve leaflet and the mitral valve annulus in the CKCS affected by MMVD at different stages. Differently aged B1 dogs have different clinical and echocardiographic patterns. Further investigations with a larger study population and an appropriate follow-up would highlight prognostic factors related to disease worsening within this heterogeneous ACVIM class; 4) The morphological study of CKCS showed that a more severe regurgitant jet size was observed in subjects with a shorter head and nose. Subjects with a smaller head stop angle had thicker anterior mitral valve leaflets. Dogs with cephalic morphology more similar to the King Charles spaniel breed, that is with a brachycephalic morphotype, showed a more severe regurgitant jet size and valvular characteristics related to worse forms of MMVD (thicker anterior mitral valve leaflet, greater mitral valve annulus and lower sphericity index); 5) miR-30b-5p increases in the plasma of asymptomatic CKCS and this can be considered a potentially promising biomarker even at an asymptomatic stage of disease, particularly at a young age.","language":"eng","citation":"MYXOMATOUS MITRAL VALVE DISEASE IN CAVALIER KING CHARLES SPANIEL: CLINICAL, GENETIC, AND CARDIAC BIOMARKERS STUDY / M. Bagardi ; tutor: P.G. Brambilla ; revisori interni: D.D. Zani, S. Romussi ; coordinatori: V. Grieco fino a settembre 2021, F. Ceciliani fino a marzo 2022.. Dipartimento di Medicina Veterinaria e Scienze Animali, 2022 Mar 31. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12221.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/916544/2002924/phd_unimi_R12221.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1035708"},"title":"NF-YA ISOFORMS ROLES IN CLAUDIN LOW CANCERS","internalauthor":"LONDERO, MICHELA","type":"Tesi di dottorato","year":"2024","abstract":"NF-Y is a pioneer transcription factor that regulates the expression of genes involved in cell cycle progression and metabolism. It is composed of: NF-YA, NF-YB and NF- YC subunits. NF-YA recognizes and binds to the CCAAT box, a DNA element found enriched in the promoters of cancer-specific genes in several tumor gene expression profiles analyzed, including those of breast, colon, thyroid, prostate, and leukemia cancers. NF-YA is present in two major isoforms called NF-YAl (long), and NF-YAs (short), which alternative splice exon 3. NF-YAl/NF-YAs ratio changes in different tissues, cell lines and differentiational stages. A robust increase in mRNA levels of NF- YA has been observed in different tumors of epithelial origin, among which BRCA and STAD. In human breast and gastric cancers and cell lines, NF-YAs isoform is highly expressed in all subtypes except in Claudinlow in which NF-YAl isoform is predominant. Recently it has been identified a 158 genes signature defining Claudinlow tumor subclass common to BRCA and STAD, correlating with high NF-YAl/NF-YAs ratio.  For the first part of my PhD project, I worked with two different BRCA Claudinlow cell lines that mainly express NF-YAl. Through CRISPR/Cas9n genome-editing I obtained homozygous exon 3 deleted clones (NF-YAl-KO). NF-YAl-KO clones had an impaired ability to form compact aggregates, their migration, extravasation, invasion, and metastasis formation abilities were significantly impaired both in vitro and in vivo compared to negative controls. RNA-seq data underlined pathways downregulated in all NF-YAl-KO clones, among which EMT and angiogenesis, corroborating in vitro and in vivo data.  In parallel, I have investigated the role of different RNA-binding proteins in driving NF-YA alternative splicing, among which RBFOX2, QKI and CELF2 both in BRCA and in STAD cell lines. Through transient overexpression, I validated RBFOX2 as splicing factor promoting the maturation of NF-YAl.  Finally, through a frameshift mutation in NF-YA gene, I have investigated the effect of NF-YA alternative translation initiation sites (TISs) usage in HeLa cells and its impact at cellular and molecular levels.","language":"eng","citation":"NF-YA ISOFORMS ROLES IN CLAUDIN LOW CANCERS / M. Londero ; tutor: R. Mantovani. Dipartimento di Bioscienze, 2024 Mar 08. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13018_3.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1035708/2376231/phd_unimi_R13018_3.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1211096"},"title":"STREPTOMYCES SPP. AS SEED TREATMENT: HOW THEY HELP THE PLANT COPE WITH BIOTIC AND ABIOTIC STRESSES","internalauthor":"MATTEI, VALERIO","type":"Tesi di dottorato","year":"2026","abstract":"Fusarium spp. are ubiquitous soil-borne pathogens that can affect different food and horticultural crops, causing vascular wilts, rots and damping-off diseases. Fusarium head blight, caused by Fusarium graminearum (Fg), is a major threat to global wheat production and food safety due to mycotoxin production such as deoxynivalenol (DON), that contaminates the harvested product. Similarly, in horticultural crops like tomato, Fusarium oxysporum f. sp. lycopersici (Fol) causes vascular wilts leading to significant yield losses.  Abiotic stresses such as iron (Fe) deficiency and water scarcity are two of the most important agronomical concerns that pose a risk to food security. Both biotic and abiotic stresses are intensified by climate change, which in turn leads to an extent use of agrochemicals (pesticides, fertilizers) in open fields. In this regard, plant beneficial microbes (PBM) are a valuable option to lower plant diseases while maintaining crop productivity.  Streptomyces spp. are Gram-positive soil-dwelling bacteria that are known as both plant growth-promoting rhizobacteria (PGPR) and biocontrol agents (BCAs) because of the bioactive molecules they produce that can both stimulate plant growth and limit pathogen diseases. Seed treatment and soil drench are two scalable routes effective for delivering promising strains from lab to field application.  This PhD project aimed to evaluate Streptomyces-based strategies in wheat and tomato under both biotic and abiotic stress, and to decipher the Streptomyces spp. mode of action (MoA) through multi-omics approaches to link lab research to field trials. To achieve this, proteomics analyses of wheat roots exposed to a factorial combination of Fg infection, mild water deficit, and Streptomyces sp. DEF39 was carried out (Chapter I) revealing DEF39 capability to restore and enhance a PR-3 chitinase during the DEF39-Wheat-Fg tripartite interaction, otherwise suppressed by the fungus when alone in the pathosystem.  Genomics analyses of Streptomyces sp. DEF17, coupled with greenhouse assays in tomato plants grown under Fe-limiting regimes, highlighted both the capability of the strain to produce siderophores and mobilise Fe and to increase plant height and Fe content in tomato leaves under Fe(III) supply, supporting a genome-to-phenotype in tomato (Chapter II).  Untargeted LC-MS/MS was done to characterise tomato roots and exudates after seed biopriming using either DEF17 or Streptomyces sp. DEF19, together with functional assays  ii  against Fol. Both streptomycetes remodelled the tomato metabolome. DEF17-treated plants produced metabolites such as gamma-glutamyl dipeptides and phenylacetic acid derivatives that might explain Fol germ tubes repulsion in chemotropism assay, and the reduction of Fol disease severity in planta (Chapter III). Overall, omics analyses suggested an indirect, plant-mediated defence route that cannot be predicted from in vitro assays alone.  Finally, the lab-to-field delivery was evaluated in Chapter IV. After seed biopriming, DEF39 induced an earlier seedling emergence in vitro than the control. A field trial was carried out in a rain-limited season in Carpiano (MI). Here, FHB severity was lower in DEF39 seed-treated plants compared to controls in Fg-infected plots. Non-infected plots exposed to drought showed comparable results regarding the total grain productivity (seed number), whereas seed weight was higher in DEF39 treatment. Regarding the tomato field done in Cornaredo (MI) an autonomous 3D canopy phenotyping robotic platform was coupled with agronomic and physiological analysis (data analysis ongoing).  Across chapters, the thesis supports seed treatment and soil drench as a practical route to move from strain selection to field trials. Moreover, it demonstrates how omics approaches can be exploited to guide the lab-to-field delivery while potentially supporting strategies leading to the reduction in chemical inputs.","language":"eng","citation":"STREPTOMYCES SPP. AS SEED TREATMENT: HOW THEY HELP THE PLANT COPE WITH BIOTIC AND ABIOTIC STRESSES / V. Mattei ; supervisore: M. Pasquali ; cosupervisore: A. Ferrante ; coordinatore PhD: D. Mora. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2026 Jan 27. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13929.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 27-LUG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1047189"},"title":"INTERACTOMICS FOR RICE FLOWERING: A PROXIMITY LABELLING APPROACH","internalauthor":"CHIRIVI, DANIELE","type":"Tesi di dottorato","year":"2024","abstract":"Flowering regulation in rice (Oryza sativa) involves a complex induction pathway that senses environmental inputs in the leaves and transmits signals to the shoot apical meristem (SAM) for reproductive differentiation. The transcription factor Hd1, homologous to Arabidopsis CONSTANS, is pivotal photoperiodic sensor, promoting flowering under short-day (SD) and repressing it under long-day (LD) conditions. Hd1 function is modulated through the interaction with other flowering regulators, such as Ghd7 and NF-Y proteins, to activate or repress the transcription of the florigen genes Hd3a and RFT1. A recently characterized florigen-like protein, called FTL1, contributes to meristem differentiation during inflorescence and panicle development, relying on interactions with OsFD transcription factors. During my PhD, I studied Hd1 and FTL1 function with traditional transcriptional and biochemical techniques, as well as through innovative proteomic approaches. Proximity Labelling (PL) was employed for the first time in our laboratory to explore novel protein-protein interaction of Hd1 and FTL1. PL relies on fusing TurboID (TbID), an optimized biotin ligase, to the protein of interest to obtain specific tagging of its interactors in vivo. Identification of the proximal proteome is enabled by selective precipitation of biotinylated proteins and mass spectrometry analysis. Our research has established an efficient PL protocol in agroinfiltrated N. benthamiana leaves and transgenic rice plants expressing TbID-fused proteins. TbID-fused FTL1 and Hd1 were successfully created, and protein analyses confirmed their stability and enzymatic efficiency, helping refining the optimal PL pipeline. A preliminary PL analysis was carried out on Hd1-TbID using agroinfiltrated N. benthamiana leaves. Furthermore, application of PL on rice FTL1-TbID floral meristems yielded >3000 proteins, with 102 identified as potential FTL1 interactors, revealing associations with chromatin, RNA metabolism, and cell structural elements (cell wall, plasmodesmata and microtubules). Ongoing research promises additional proteomic information, while validation experiments are underway to verify the novel information retrieved on FTL1 localization and function. With these experiments, we demonstrate that PL can expand our understanding of rice flowering regulating network, and that the obtained data can be a valuable resource to maximize the breeding of cultivated rice varieties.","language":"eng","citation":"INTERACTOMICS FOR RICE FLOWERING: A PROXIMITY LABELLING APPROACH / D. Chirivi ; tutor: F. Fornara ; coordinatore: R. Mantovani. - Milano. Dipartimento di Bioscienze, 2024 Jun 21. 36. ciclo","filename":"phd_unimi_R13015.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1047189/2403610/phd_unimi_R13015.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1254958"},"title":"FATTY ACIDS IN PHYSIOLOGY AND PATHOLOGY: FOCUS ON ALPHA-LINOLENIC ACID (ALA) AND PUFAS","internalauthor":"BERTONI, CAMILLA","type":"Tesi di dottorato","year":"2026","abstract":"This thesis investigates the clinical and pathophysiological roles of polyunsaturated fatty acids (PUFAs), focusing on alpha-linolenic acid (ALA), and linoleic acid (LA), within a broad range of human biological processes. PUFAs are essential nutrients involved in modulating cell membrane fluidity, intracellular signaling, and gene regulation, as well as serving as precursors to bioactive lipid mediators such as eicosanoids and prostaglandins. Following a general overview of fatty acid classification, structure, metabolism, and biochemistry, the thesis explores the relevance of ALA and LA in emerging clinical domains including assisted reproduction, pregnancy, sarcopenia, and neuropsychiatric disorders like ADHD and depression, while identifying key factors influecing long-chain PUFA conversion efficiency and the impact of individual variables (sex, age, diet, genetics).     The methodoloy comprises a narrative analysis of clinical, epidemiological, and experimental evidence published from 2005 to 2023, prioritizing studies on diverse human populations across various life stages, including children, older adults, and pregnant or lactating women. Results indicate that appropriate PUFA intake, especially from plant-based sources rich in ALA, is associated with positive effects on fertility, cognitive development, inflammation regulation, and the prevention of chronic diseases (cardiovascular, neurodegenerative, affective). Nevertheless, the literature reveals considerable heterogeneity in results, attributable to interindivdual differences in lipid metabolism and varying nutritional strategies across studies. Special attention is given to sensitive populations, such as children, the elderly, pregnant women, and those with neuropsychiatric conditions, where the omega-6/omeha-3 balance proves particularly crucial.     The conclusion highlight the need for additional randomized clinical and interventional studies to clarify the efficacy of PUFA-based nutritional support in chronic disease prevention and management, and to define personalized protocols based on individual characteristics. The thesis provides new perspectives for the implementation of innovative, targeted dietary strategies, emphasizing the potential of PUFAs as adjuvants in conventional therapies and as key factors in public health promotion.","language":"eng","citation":"FATTY ACIDS IN PHYSIOLOGY AND PATHOLOGY: FOCUS ON ALPHA-LINOLENIC ACID (ALA) AND PUFAS / C. Bertoni ; tutor: C. Agostoni ; cotutor: G. P. Milani ; coordinatore: E. Damiani. - CLINICA DE MARCHI. Dipartimento di Scienze Cliniche e di Comunità, 2026 Apr 07. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R14045.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1254958/3354631/phd_unimi_R14045.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1132035"},"title":"CLASSIFICATION RESULTS FOR SEMILINEAR ELLIPTIC EQUATIONS","internalauthor":"POLVARA, CAMILLA CHIARA","type":"Tesi di dottorato","year":"2025","abstract":"This thesis addresses classification problems of solutions to semilinear elliptic equations, with a particular focus on the study of symmetry and rigidity results. The thesis is divided into four chapters.    In Chapter 1 we consider solutions to some semilinear elliptic equations on complete noncompact Riemannian manifolds and study their classification as well as the effect of their presence on the underlying manifold.  When the Ricci curvature is non-negative, we prove both the classification of positive solutions to the critical equation and the rigidity for the ambient manifold. The same results are obtained when we consider solutions to the Liouville equation on Riemannian surfaces. The results are obtained via a suitable P-function whose constancy implies the classification of both the solutions and the underlying manifold.  The analysis carried out on the P-function also makes it possible to classify non-negative solutions for subcritical equations on manifolds enjoying a Sobolev inequality and satisfying an integrability condition on the negative part of the Ricci curvature.  Some of our results are new even in the Euclidean case.     In Chapter 2 we consider a family of critical elliptic equations which arise as the Euler-Lagrange equation of Caffarelli-Kohn-Nirenberg inequalities, possibly in convex cones in R^N, with N bigger or equal than 2. We classify positive solutions without assuming energy assumptions on the solution and when the intrinsic dimension n in (3/2,5]. These results will follow as an application of the approach introduced in Chapter 1.     Chapter 3 concerns two main topics. The first one is about semilinear elliptic equations with mixed boundary conditions in spherical sectors inside a cone. We show that a radial symmetry result of Gidas-Ni-Nirenberg type for positive solutions does not hold in general nonconvex cones. This symmetry breaking result is achieved by studying the Morse index of radial positive solutions and analyzing how it depends on the domain D on the unit sphere which spans the cone. In particular, it is proved that the Neumann eigenvalues of the Laplace Beltrami operator on D play a role in computing the Morse index. The second one is about a similar breaking of symmetry result, obtained for positive solutions of the critical Neumann problem in the whole unbounded cone. In this case, it is proved that the standard bubbles, which are the only radial solutions, become unstable for a class of nonconvex cones.    Chapter 4 is about a quantitative Sobolev inequality in cones satisfying the property that Aubin-Talenti bubbles are the only minimizers (for instance convex cones). We follow a Bianchi-Egnell approach to obtain a quantitative estimate in terms of the first Neumann eigenvalue of the Laplace Beltrami operator on the set D on the unit sphere, which spans the cone.","language":"eng","citation":"CLASSIFICATION RESULTS FOR SEMILINEAR ELLIPTIC EQUATIONS / C.c. Polvara ; tutor: G. Ciraolo ; phd coordinator: D. Bambusi. Dipartimento di Matematica Federigo Enriques, 2025 Jan 21. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13422.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1132035/2627269/phd_unimi_R13422.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1219228"},"title":"INVESTIGATION OF RESILIENCE AND ITS GENETICSTHROUGH THE USE OF LONGITUDINAL DATA","internalauthor":"DELLEDONNE, ANDREA","type":"Tesi di dottorato","year":"2026","abstract":"This thesis investigates resilience in dairy cattle using an integrated approach that combines phenotypic characterization, simulation of perturbations, and genomic analysis. The research was motivated by the need to breed animals capable of maintaining productivity amid the environmental and economic challenges facing modern agriculture. Thanks to close collaboration with a medium-large dairy farm in Northern Italy, we had access to a comprehensive dataset of daily milk records and genotype information, which formed the  basis for the analysis.  Over the past twenty years, resilience assessment in livestock has become feasible thanks to new technologies that enable the collection of high-frequency longitudinal data. Resilience indicators are recently defined proxies that combine routinely collected data, such as milk yield records, to capture an animal’s response to environmental challenges. Although it has been demonstrated that resilience indicators possess some genetic merit to some extent, their true significance and methodological foundations require further investigation to enhance the understanding of these phenotypes and their application in breeding programs.  Lactation curve models aiming to represent the unperturbed state of each individual cow are essential for deriving meaningful resilience indicators; however, their impact on these indicators has not been systematically evaluated.  This thesis addresses these gaps through three main studies: (1) characterization of resilience indicators derived from various lactation curve models; (2) a simulation study evaluating the ability of resilience indicators to capture true genetic resilience; (3) a genome-wide association study (GWAS) identifying genomic regions associated with resilience indicators. Additionally, one further contribution is included: (4) construction of a copy  number variation map for the population studied. The characterization study demonstrated that methodological choices in lactation curve modelling significantly influence phenotypic resilience indicator values and cow rankings.  The simulation study revealed that current resilience indicators capture only a fraction of true genetic resilience, with the best model-indicator combinations achieving correlations of 0.15 to 0.25 with simulated resilience breeding values. The genome-wide association study identified genomic regions associated with resilience indicators, confirming the polygenic nature of the trait and highlighting genes involved in immune response, energy metabolism, and tissue integrity. Additionally, the copy number variation map provided a valuable genomic resource for future integrated analyses.  These findings advance our understanding of resilience as a complex, multifaceted trait while providing practical tools for its genetic improvement. The practical implications are clear: breeding programs should incorporate resilience indicators derived from meaningfully selected lactation curve models, set realistic expectations for genetic progress given the modest correlations with true resilience, and balance selection for resilience alongside production and other traits through appropriately weighted selection indices. Looking ahead, continued refinement of resilience phenotypes, functional characterization of candidate genes and economic analyses will advance breeding for resilience.","language":"eng","citation":"INVESTIGATION OF RESILIENCE AND ITS GENETICS THROUGH THE USE OF LONGITUDINAL DATA / A. Delledonne ; tutor: A. Bagnato, M. G. Strillacci ;  coordinatore: E. Damiani. - Dipartimento di Informatica. Dipartimento di Medicina Veterinaria e Scienze Animali, 2026 Feb 26. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14033.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1219228/3266051/phd_unimi_R14033.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1247955"},"title":"ASSESSING THE EFFECTIVENESS OF THE EUROPEAN UNION AS A MILITANT DEMOCRACY AGENT: PROMOTING DEMOCRACY IN THE NEIGHBOURHOOD","internalauthor":"TADDIA, IACOPO","type":"Tesi di dottorato","year":"2026","abstract":"The thesis examines the conditions under which the European Union (EU) can act as an effective militant democracy in its external relations amid renewed, heterogeneous autocratization across Europe and its neighbourhood. It challenges linear narratives of democratic advance or uniform recession, arguing instead that democratic erosion varies in trajectory, scope, and timing, and that EU responses differ across member states, enlargement countries, and European Neighbourhood Policy (ENP) partners. Building on research on democratization and autocratization, external democracy promotion, and militant democracy, the study conceptualizes and evaluates the EU’s external democratic militancy ambition.  Empirically, the project asks under what conditions the EU improves democratic quality in partner countries. It tests two EU-related conditions – membership incentives and partnership investments – using fuzzy-set Qualitative Comparative Analysis (fsQCA) for 22 country partners that meet explicit EU scope conditions on democracy, the rule of law, and human rights. The outcome, Quality of Democracy, is calibrated as directional trajectories from V-Dem indices (polyarchy, rule of law, women’s empowerment). Explanatory conditions include structural factors (development, inequality, ethnolinguistic fractionalization, freedom from autocratic influence) and proximate factors (power-sharing, government effectiveness), alongside the two hypothesis conditions: EU membership and EU partnership.  Three sufficient pathways to democratic improvement emerge. First, in low- and middle-income contexts, either high levels of equality or robust EU partnership investments can offset low levels of development promoting democracy. Second, where accession prospects are credible, membership incentives, combined with limited power-sharing, are associated with gains in democratic quality. Third, positive outcomes are also visible in settings without membership prospects but with extensive power-sharing.  Within-case studies of Georgia (low development plus high EU investment) and Albania (accession-driven reforms under concentrated executive authority) were conducted to complement configurational evidence with context-sensitive analysis, probing mechanisms and scope conditions.","language":"eng","citation":"ASSESSING THE EFFECTIVENESS OF THE EUROPEAN UNION AS A MILITANT DEMOCRACY AGENT: PROMOTING DEMOCRACY IN THE NEIGHBOURHOOD / I. Taddia ; tutor: A. Cassani ;  cotutor: A. Kyriazi ;  coordinatore: F. Franchino. Dipartimento di Scienze Sociali e Politiche, 2026 May 29. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13809.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1247955/3338776/phd_unimi_R13809.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/802263"},"title":"THE ROLE OF PLASTICS AS CARRIER OF ENVIRONMENTAL POLLUTANTS: AN INTEGRATED APPROACH TO ASSESS TOXICITY ON AQUATIC AND TERRESTRIAL SPECIES.","internalauthor":"PARENTI, CAMILLA CARLA","type":"Tesi di dottorato","year":"2021","abstract":"The uniqueness of plastic is given by its several advantages, including low cost, lightweight, flexibility and resistance. These properties exponentially increased the global demand for plastic in the last 70 years, turning this revolutionary material into a global environmental threat. Indeed, the mismanagement of plastic waste, most of which is still sent to landfills or directly littered in the environment by human improper behaviour, is becoming a serious threat for ecosystems. The effects of plastic dispersal in the environment potentially increase when considering the fragments of smaller dimension, which derive from the degradation of macroplastics or are intentionally produced for industrial applications. A lower dimension may therefore enhance the plastic fragment capacity to accumulate at tissue level, but also to act as vector for chemical contaminants. The project was aimed at evaluating the environmental impact due to the presence of micro- and nanoplastics, exposing aquatic and terrestrial species and observing the potential adverse effects using multi-tiered approaches. Several laboratory experiments were conducted using both freshwater model species, the vertebrate Danio rerio and the invertebrate Dreissena polymorpha, and, for the first time, the terrestrial model Bombyx mori. Moreover, the role of plastics as carrier of environmental contaminants was investigated on zebrafish larvae. All organisms showed the accumulation of plastics and their infiltration in different tissues. The biochemical analyses highlighted only slight effects of micro- and nanoplastic exposures, while more relevant results emerged from behavioural tests, which deserve further studies. Furthermore, the effects at individual level, combined with proteomic analyses, pointed out a shift in the toxicity of plastics and chemical contaminants when co- administered, suggesting a more complicated relationship then an additive or synergistic effect. Finally, the study paves the way for the use of B. mori larva as model organism for the evaluation of the effects of plastic particles on terrestrial ecosystems, which are still largely unknown.","language":"eng","citation":"THE ROLE OF PLASTICS AS CARRIER OF ENVIRONMENTAL POLLUTANTS: AN INTEGRATED APPROACH TO ASSESS TOXICITY ON AQUATIC AND TERRESTRIAL SPECIES / C.c. Parenti ; tutor: A. Binelli ; co-tutor: C. Della Torre ; coordinatore: F. Ficetola. Dipartimento di Bioscienze, 2021 Jan 29. 33. ciclo, Anno Accademico 2020. [10.13130/parenti-camilla-carla_phd2021-01-29].","filename":"phd_unimi_R12044.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/802263/1665790/phd_unimi_R12044.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1221309"},"title":"SUGAR EDITING FOR THE SYNTHESIS OF GLYCOMIMETICS","internalauthor":"CAVAZZOLI, GIANLUCA","type":"Tesi di dottorato","year":"2026","abstract":"This doctoral thesis explores strategies for the synthesis of structurally advanced glycomimetics. The first project focuses on the design of selective antagonists of C-type lectins, specifically targeting L-SIGN over DC-SIGN, two closely related receptors involved in viral recognition and SARS-CoV-2 infection. Inspired by the selective ligand Man84, a library of C2-triazole-modified mannosides bearing guanidine isosteres was synthesized. Structure–activity relationship studies combined with SPR assays identified several potent and selective L-SIGN ligands, including Man96, Man97, and Man102, displaying low micromolar affinity. X-ray crystallography of the L-SIGN/Man96 complex revealed the key interactions determining affinity and selectivity, highlighting the important role of residues E370, F325, and N385 in L-SIGN CRD. The second project develops a nickel-photoredox methodology for the synthesis of α-C-arylglycosides via deoxygenative arylation of unprotected anomeric hydroxyl groups. By replacing expensive iridium photocatalysts with sustainable organic dyes such as 5CzBN, an efficient and economical catalytic system was established. The protocol proved compatible with various monosaccharides and (hetero)aryl bromides, affording α-selective C-arylglycosides under mild conditions. Mechanistic investigations, including fluorescence quenching experiments, supported a radical pathway initiated by reductive quenching of a sugar–NHC adduct. The third project investigates racemic crystallization as a novel strategy for structural studies of glycans. Through automated glycan assembly, both D- and L-enantiomers of a galactosylated xyloglucan hexasaccharide were synthesized. Preliminary results suggest that racemic crystallization may overcome longstanding challenges in glycan structural analysis.   Overall, this work expands the chemical space of glycomimetics, introduces sustainable synthetic methodologies for C-arylglycosides, and pioneers structural approaches for complex oligosaccharides, contributing to the advancement of medicinal and structural glycoscience.","language":"eng","citation":"SUGAR EDITING FOR THE SYNTHESIS OF GLYCOMIMETICS / G. Cavazzoli ; tutor: A. Bernardi ;  coordinator: D. Passarella. - Aula V1, Settore Didattico, via Venezian 15, 20133 Milano (MI). Dipartimento di Chimica, 2026 Mar 03. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13900_2.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 04-SET-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1204994"},"title":"A NOVEL CLASS OF DECAHYDROQUINOXALINE-BASED CHIRAL PHOSPHORIC ACIDS","internalauthor":"GAZZOTTI, MARGHERITA","type":"Tesi di dottorato","year":"2025","abstract":"Chiral phosphoric acids (CPAs) have found extensive application in  many chemical transformations, becoming invaluable tools for syn  thesizing pharmaceuticals and natural products. This study introdu  ces a novel class of CPAs based on a chiral decahydroquinoxaline  scaffold. The synthetic strategy for the construction of the chiral  backbone involves as a key step a completely stereoselective pina  col coupling of Salen-like bisimines, obtained by condensation of  different aromatic aldehydes with enantiopure trans-1,2-diaminocy  clohexane. By using two different approaches, a small library of  novel CPAs is synthesized, which are successfully employed to cat  alyze the Friedel–Crafts addition of indoles to N-tosylimines, yield  ing the desired enantioenriched products in high yield and up to  97% ee. The new enantiopure Brønsted acids are highly tunable,  can be efficiently prepared in four steps from inexpensive materials,  and exhibit high chemical and stereochemical efficiency, in some  instances exceeding results obtained from traditional CPAs based  on binaphthol scaffolds.  The stereoselective electroreductive intramolecular imino-pinacol coupling has been investigated by an electrochemical approach. The  methodology was successfully developed under both batch and continuous flow conditions, and afforded enantiomerically pure  products with complete stereoselectivity. Substrates bearing electron-donating or electron-withdrawing groups on the aromatic rings provided good to excellent yields, indicating that both types of substituents are well tolerated under the reaction conditions. Al  though modest yields were obtained under flow conditions, the continuous process afforded higher productivities and space-time  yields than the batch reactions due to a short residence time. This work provides a mild, efficient, and scalable alternative to traditional methods for the synthesis of tetrasubstituted enantiopure piperazines.","language":"eng","citation":"A NOVEL CLASS OF DECAHYDROQUINOXALINE-BASED CHIRAL PHOSPHORIC ACIDS / M. Gazzotti ; tutor: M. Benaglia ;  co-tutor: S. Rossi. Dipartimento di Chimica, 2025 Dec 15. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13948.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 22-GIU-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/949930"},"title":"SCALABLE GRAPH REPRESENTATIONAL LEARNING ALGORITHMS FOR NETWORK MEDICINE","internalauthor":"CAPPELLETTI, LUCA","type":"Tesi di dottorato","year":"2023","abstract":"\"In the era of big data, advanced computational techniques are needed to process,  analyze and visualize increasing amounts of data generated by high-throughput technologies. In this context, analyzing biomedical Knowledge Graphs that embrace bio-  logical and medical concepts structured in ontologies and data generated from high-  throughput bio-technologies represents a central Machine Learning and Computational  Biology challenge.  Indeed several compelling problems in Network Medicine, ranging from gene-disease  prioritization to drug-target prediction or drug repurposing can be modelled as node  label or edge prediction problems in graphs, where nodes represent bio-medical entities such as genes, drugs or diseases and edges interactions or relationships between them.  Recently Graph Representation Learning (GRL) methods opened new possibilities for  addressing complex, real-world problems represented by graphs. However, many graphs  used in these applications comprise millions of nodes and billions of edges and are be-  yond the capabilities of current methods and software implementations.  To deal with this open problem, the first contribution of this thesis is the design and  development of the GRAPE (Graph Processing and Embedding) resource for GRL,  able to scale with big graphs thanks to specialized and innovative data structures  and algorithms efficiently implemented through parallel computation. Compared with  state-of-the-art software resources, GRAPE shows an improvement of orders of magnitude in empirical space and time complexity, as well as a substantial and statistically  significant improvement in edge prediction and node label prediction performance.  GRAPE provides over 80, 000 graphs from the literature and other sources, standardized interfaces allowing a straightforward integration of third-party libraries, 61 node  embedding methods, 25 inference models, and three modular pipelines to allow a findable,  accessible, interoperable, and reusable (FAIR) and reproducible comparison of methods  and libraries for graph processing and embedding. GRAPE can quickly generate billions  of sampled random walks for random-walk-based GRL algorithms, such as DeepWalk  of Node2vec, thus leading to very accurate embedded graphs and boosting machine  learning methods' performance that learns from the embedded vector representation  of nodes and edges. The scaling properties of GRAPE concerning state-of-the-  art resources have been analyzed through extensive experiments with real-world big  graphs, including, e.g. Wikipedia, the Comparative Toxicogenomic Database (CTD)  and a big biomedical Knowledge Graph generated by PheKnowLator. GRAPE significantly outperforms state-of-the-art libraries in terms of empirical time and space  complexity, edge prediction performance and can process big graphs even when the  other competing state-of-the-art resources fail.  As a second contribution for efficiently processing and analyzing big graphs, this the-  sis proposes a novel algorithmic framework, efficiently implemented in GRAPE, that we named ALPINE: Abstract Landmark Properties-Inferred Node Embedding. The  breakthrough characteristics of this algorithmic framework allow us to deal with several  issues affecting SOTA GRL methods:  1. The embedding features are independently computed, each from the others, thus  overcoming the space and time complexity limitations due to their dependent  computation.  2. Feature computation is based on the \"\"landmarks\"\", i.e. sets of nodes representing  meaningful concepts about the structure or the semantics of the underlying graph,  thus assuring the interpretability of the embeddings.  3. Small integers are used for embedded features values: this assures a small memory  footprint, hardware acceleration, and a good compression ratio because of the  scale-free distribution of node degrees that often characterize biomedical networks  4. \"\"Democratic\"\" feature representation, thus avoiding the bias towards a high degree  nodes characteristic of embedding methods based on topological sampling.  We present two algorithms based on the ALPINE framework: a) SPINE (Shortest  Paths Inferred Node Embedding), based on the efficient computation of the shortest  path distance from the landmarks; b) WINE (Windows Inferred Node Embedding)  based on the efficient computation of the co-occurrences of each node with the land-  marks within windows of a given size during a breadth-first search. The breakthrough  scaling properties of the proposed algorithms are shown in experiments with real-world  big graphs.  GRAPE and ALPINE implementations are available from https://github.com/AnacletoLAB/  grape.  The thesis is organized as follows. In chapter 2, the architecture of GRAPE, the graph-  processing and graph-representation learning algorithms it provides are described. In  chapter 3, we sketch both the open libraries for graph processing and the datasets that  have been used to perform the experiments for comparing GRAPE to state-of-the-art  works. Chapter 4 describes all the experimental settings and the achieved comparative  evaluation results in detail. In chapter 5, we focus on the novel ALPINE  algorithmic framework and compare its performance with those of state-of-the-art  models. The conclusions summarize the main contributions of the thesis, as well as  the drawbacks and limitations of the proposed methods and depict ongoing and future  work on scalable GRL methods and their application to Network Medicine.\"","language":"eng","citation":"SCALABLE GRAPH REPRESENTATIONAL LEARNING ALGORITHMS FOR NETWORK MEDICINE / L. Cappelletti ; tutor: G. VALENTINI ; co-supervisore: E. CASIRAGHI ; coordinator: R. SASSI. Dipartimento di Informatica Giovanni Degli Antoni, 2023 Jan 30. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12725.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/949930/2116265/phd_unimi_R12725.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/846415"},"title":"ASSESSMENT OF WOOD BIOMASS AND CARBON STOCK AND EVALUATION OF MACHINERY CHAINS PERFORMANCES IN ALPINE FORESTRY CONDITIONS: AN INNOVATIVE MODELLING APPROACH","internalauthor":"NONINI, LUCA","type":"Tesi di dottorato","year":"2021","abstract":"The PhD Thesis focuses on two topics: (i) assessment of forest wood and carbon (C) stock and (ii) forestry mechanization applicable at the forest stand level for any given conditions among those found in the Italian Alpine and pre-Alpine mountainous areas. Both these topics aim to improve the use of forestry resources for climate change mitigation, starting from a bottom-up approach scaled on the information made available by Forest Management Plans (FMP).  After an introduction on the topics given in chapter 1, the first topic (assessment of forest wood and C stock) is investigated in chapters 2, 3, 4 and 5, by taking the Valle Camonica District (Lombardy Region, Italy) as Case Study Area. The aim is to develop a stand-level model to estimate the mass of wood (t·yr-1 dry matter, DM) and C (t·yr-1 C) in aboveground wood biomass, belowground wood biomass and dead organic matter (i.e., deadwood and litter), quantifying, at the same time, the mass of potentially available logging residues (i.e., branches and tops; t·yr-1 DM) for energy generation and the corresponding potentially generated energy (GJ·yr-1), under the assumption that wood replaces non-renewable energy sources.  Chapter 2 presents the first version of the model, called “WOody biomass and Carbon ASsessment” (WOCAS v1), aimed at the quantification of the mass of wood and C in the forest pools in a predefined reference year, by using a methodology already applied at the regional and national level. The model was tested on a dataset of 2019 public forest stands extracted from 45 FMPs (area: 37000 ha) covering the period from 1984 (year in which the oldest FMP came into force) to 2016 (most recent available data from the local FMPs). Preliminary results showed that, in 2016, the total C stock (given by the sum of C stock in aboveground wood biomass, belowground wood biomass, and dead organic matter) achieved 76.02 t·ha-1 C. The model also gives the possibility to analyze future scenarios based on the continuation of the current management practices rather than improved practices, to define a possible mitigation strategy for the activation of a local Voluntary Carbon Market.  WOCAS v1 was implemented into a second version (WOCAS v2), by introducing, first of all, an improved methodology to calculate the mass of wood (t·yr-1 DM) and C (t·yr-1 C) within the forest pools from the year in which the FMPs entry into force until a predefined reference year (chapter 3). The main innovative aspect of the improved methodology is that the gross annual increment of each stand is calculated through an age-independent theoretical non-linear growth function based on the merchantable stem mass, solving the limitation of WOCAS v1 in which the gross annual increment of the stand is assumed as constant, as reported by the FMPs. This improved methodology was applied to the same dataset used for WOCAS 1 (i.e., 2019 forest stands, 45 FMPs; forest area: 37000 ha; period: 1984-2016). The total weighted average wood yield, calculated as the sum of wood yield in all the above-mentioned forest pools, ranged from 53.36±53.13 t∙ha-1∙yr-1 DM (1984) to 156.38±79.76 t∙ha-1∙yr-1 DM (2016). The total weighted average C yield ranged from 26.63±26.80 t∙ha-1∙yr-1 C (1984) to 77.45±40.19 t∙ha-1∙yr-1 C (2016). The average C yield related to the whole analyzed period (1984-2016) was 66.04 t∙ha-1 C. Of this, C yield in the aboveground wood biomass, belowground wood biomass and dead organic matter was equal to 72.0%, 15.8% and 12.2%, respectively.  Validation of the results at the stand level was performed by comparing the value of the gross annual increment provided by the FMPs with the one predicted by WOCAS v2. The model caused, in some cases, an overestimation and, in other cases, an underestimation. For example, for Larix decidua Mill. and for Picea abies L., the Pearson coefficient of correlation (r2) between predicted and provided increments was r2 = 0.69 and r2 = 0.46, respectively. This was due to the fact that the methodology currently implemented into WOCAS v2 is based on average values of growth parameters valid for the whole Lombardy Region, and does not consider the productivity class of the stands since specific information was not always made available by the FMPs.  WOCAS v2 also includes an innovative methodology (chapter 4 and chapter 5) to quantify – as an additional climate change mitigation strategy – the mass of potentially available residues (t·yr-1 DM) for energy generation, the potentially generated heat and electricity (GJ·yr-1) and the potentially avoided CO2 emissions into the atmosphere related to the final combustion process (t·yr-1 CO2), under the assumption that wood substituted non-renewable energy sources. In chapter 4, since not all the required data were initially made available for the Case Study Area, the mass of residues was computed by considering only the stand’s function and the stand’s management system, covering the period from 1994 (year in which the first wood cut was performed) to 2016.  The calculation was then improved (chapter 5) by taking into account also the stand’s accessibility, the forest roads’ transitability and the energy market demand. Information on topographic features, landscape morphology and characteristics of the forest roads were collected by combining the FMPs data coming from WOCAS v2 and a Digital Elevation Model (DEM) in a Geographic Information System (GIS) software. The georeferenced stands were characterized by both single contiguous areas (single stands), as well as different non-contiguous areas (sub-stands). Overall, 2157 polygons – consisting of both single and sub-stands – were analyzed, covering the period from 2009 (most recent available data on forest roads’ transitability) and 2016.  The mass of potentially available residues calculated for the analyzed period was used to estimate the current sustainable supply (i.e., 1.82∙103±6.61∙102 t·yr-1 DM). Under the hypothesis that these residues were prepared into woodchips to feed the Organic Rankine Cycle (ORC) unit of the local centralized heating plant of Ponte di Legno, the potentially generated heat and electricity (GJ·yr-1) and the potentially avoided CO2 emissions into the atmosphere (t∙yr-1 CO2) for the final combustion process were estimated by assuming that: (i) heat generated by the ORC unit replaced the one produced by natural gas-based heating plants; (ii) electricity generated by the ORC unit replaced the one generated by the Italian natural gas-based plants-mix for combined heat and electricity production and distributed through the National grid. Results showed that if only the current sustainable mass of residues was used to feed the ORC unit of the plant, the potentially generated heat and electricity would represent at most 28.7% of that generated by the unit in the year 2019. The thermal and electric power would be equal to 0.70 MW and 0.17 MW, with an average power load of the ORC unit of 23.6%.  Experimental tests are needed to collect information on the harvesting method, used machines and technologies – which considerably affect the mass of available resides – as well as the currently harvested mass of residues for the validation of the results, that up to now is not possible since no measured data are available yet at the stand level.  The second topic (forestry mechanization) is investigated in chapter 6. The aim is to develop an innovative approach in order to: (i) select the most suitable Forestry Machinery Chain (FMC) to adopt at the stand level for wood collection (harvesting and transport) and (ii) compute the economic costs (€·h-1; €·t-1 DM; €) of the selected FMC.  To make the selection feasible, a user-friendly stand-level model called “FOREstry MAchinery chain selection” (FOREMA v1) was developed. FOREMA v1 supports the user in selecting the FMC according to seven technical parameters that characterize the stand. For each FMC, the model defines the sequence of the operations and the types of machines that can be used. The economic costs of the selected FMC are then quantified by taking into account the fixed and the variable costs. The approach was applied for a Case Study concerning the collection of woodchips from a coppice stand in the Italian Alps for energy generation. The analyzed FMC was made up of the following operations: (i) felling, (ii) bunching and extraction, (iii) chipping and (iv) loading and transport. For the whole FMC, the cost per unit of time was 669.3 €·h-1; the cost per unit of product was 113.0 €·t DM, whereas the cost of production amounted to 6893.2 €. Results provided by FOREMA v1 still need to be validated; experimental tests are required to collect information on the operating conditions in which the machines are actually used and, consequently, on the corresponding economic costs. Obtained results on the costs of the operations were compared with that reported in literature and related to studies performed under similar forestry and operating conditions.","language":"eng","citation":"ASSESSMENT OF WOOD BIOMASS AND CARBON STOCK AND EVALUATION OF MACHINERY CHAINS PERFORMANCES IN ALPINE FORESTRY CONDITIONS: AN INNOVATIVE MODELLING APPROACH / L. Nonini ; Tutor: M. Fiala ; Coordinatore: D. Bassi. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2021 Jun 11. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11897.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/846415/1809752/phd_unimi_R11897.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1159159"},"title":"ETERNAL SUNSHINE TO THE FAPLESS MASCULINITY:A DIGITAL ETHNOGRAPHY OF THE R/NOFAP COMMUNITY ON REDDIT PROMOTING ABSTENTION FROM PORNOGRAPHY CONSUMPTION AND MASTURBATION.","internalauthor":"PERIN, CHIARA","type":"Tesi di dottorato","year":"2025","abstract":"This study examines the NoFap phenomenon, a homosocial digital movement promoting abstinence from pornography and masturbation to overcome self-diagnosed porn addiction and “compulsive sexual behaviors”. Critical literature on the topic has identified heterosexist, patriarchal, and misogynistic discourses associated with this practice, dominated by evolutionary narratives on gender and sexuality, men’s sexual entitlement to women, and the imperative of heteronormative coital sex. Building on this literature, this research offers three key contributions to deepen our understanding of the widespread NoFap phenomenon and provide analytical tools for examining the reproduction of contemporary masculinities and the heteropatriarchy in digital spaces. First, NoFap is conceptualized as a Foucauldian technique of internalized biopower that seeks to discipline a body constructed as hetero-masculine, reinforcing regulatory ideals of hetero-masculinity and contributing to the (re)production of a heteropatriarchal society. Second, I introduce the concept of “affordances of the (gendered) self”, which conceptualizes the embodied use of affordances in r/NoFap as Foucauldian technologies of the self, integral to men’s self-improvement and self-optimization in pursuit of a post-masturbatory heteromasculinity. Third, I argue that r/NoFap can be understood as a form of a “diluted manosphere”, where manosphere content is “watered down”. In this context, NoFap presents itself as a space that appears to promote equality while still allowing participants to engage “safely” with ideologies, practices, and discourses that protect male privileges and uphold gendered power relations. This study is based on a year-long ethnographic investigation of r/NoFap, Reddit’s central hub for the movement, which had 1.1 million members in 2022. To navigate Reddit’s vast, real-time, networked, and algorithmically structured environment, a novel approach to digital ethnography was developed. This approach integrates computational tools within the ethnographic continuum, not to impose rigor on qualitative findings but to support, guide, and inform them throughout their production. By doing so, it subverts the platform’s algorithmic logics, ensuring that less visible content, suppressed by Reddit’s algorithms, is also considered.","language":"eng","citation":"ETERNAL SUNSHINE TO THE FAPLESS MASCULINITY:A DIGITAL ETHNOGRAPHY OF THE R/NOFAP COMMUNITY ON REDDIT PROMOTING ABSTENTION FROM PORNOGRAPHY CONSUMPTION AND MASTURBATION / C. Perin ; supervisor: R. Ferrero Camoletto ; co-supervisor: A. Caliandro ; director of doctoral program: A. Rebughini. Università degli Studi di Milano, 2025 May 05. 37. ciclo","filename":"phd_unimi_R13212.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1159159/2820787/phd_unimi_R13212.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1024208"},"title":"UNVEILING THE ROLE OF THE MANNOSE RECEPTOR IN CARDIOMETABOLIC DISEASES","internalauthor":"NOUR, JASMINE","type":"Tesi di dottorato","year":"2024","abstract":"AIM: Cardiometabolic diseases are characterized by an underlying inflammatory state, active supporter of the pathogenesis, suggesting that identifying players of the immune activation could offer novel therapeutic targets. The mannose receptor (Mrc1) is a C-type lectin receptor expressed on immune cells, sinusoidal endothelial cells of liver, bone marrow (BM), and secondary lymphatic organs, and is also released as soluble form. It recognizes mainly mannose, fucose and N-acetylglucosamine as terminal glycan moieties and was shown to be involved in the resolution of inflammation. Thus, aim of our study was to investigate the impact of Mrc1 deficiency on diet-induced obesity and experimental atherosclerosis, with a focus on the plasma N-glycome and the immunometabolic phenotype.  METHODS: To study Mrc1 in obesity, WT and Mrc1 -/- male C57BL/6J mice were fed with a high fat diet (HFD, 45% Kcal/diet) for 20 weeks. Weight gain and glucose and insulin tolerance were evaluated and extensive flow cytometry profiling, histological, and proteomic analyses of tissues of interest were performed. In addition, total plasma N-glycome (TPNG) was studied. To investigate Mrc1 deficiency in experimental atherosclerosis, Mrc1 -/- mice were crossed with Ldlr -/- and ApoE -/- mice to generate atheroprone animals, which were fed with a cholesterol-enriched diet (western-type diet, WTD) for 12 weeks to promote atherosclerosis. Next, the impact of Mrc1 deficiency was evaluated through TPNG analysis, plasma lipid profiling, histological analysis of the atheroma at the aortic sinus and liver steatosis, and immunophenotyping by flow cytometry.  RESULTS: After 20 weeks of HFD feeding, no differences were found in mannose as terminal moiety of circulating glycans of Mrc1 -/- mice, which however presented a significant reduction in core and antennary fucosylation compared to controls. In parallel, Mrc1 -/- mice exhibited improved glucose and insulin response and reduced weight gain following HFD feeding compared to WT mice, matched by a decrease in hepatic steatosis and inflammation, as seen by histological and proteomics analysis. Flow cytometry revealed a reduced leukocyte infiltration in liver and VAT, in line with a modulation of blood inflammatory myeloid cells, which decreased in Mrc1 -/- mice compared to controls. Accordingly, a bone marrow (BM) reprogramming was observed, with reduced myeloid progenitors and mature cells, paralleled with an increase in the number – but not in the area – of BM adipocytes in Mrc1-deficient mice compared to controls.   After 12 weeks of WTD feeding, Mrc1 deficiency in mice on both atheroprone backgrounds did not affect the levels of circulating mannosylated structure, but only the distribution of complex glycans. In addition, Mrc1 -/- mice were not protected from atherosclerosis, as confirmed in terms of comparable circulating lipids, atherosclerotic plaque area and composition, liver phenotype, blood immune cells distribution and their BM production in the experimental groups.  CONCLUSION: These data suggest a redundancy in terms of receptors responsible of plasma glycoprotein clearance, as the lack of Mrc1 resulted in modest shifts of the circulating glycome, which may reflect the systemic inflammatory status more than a direct effect of the receptor. Moreover, in diet-induced obesity Mrc1 deficiency improved BM and circulating immune cell subsets distribution, in association with reduced systemic inflammation and protection from obesity-driven dysmetabolic phenotype. Nevertheless, this protection was not observed in experimental atherosclerosis, as Mrc1 deficiency led to a comparable development of this pathological condition.","language":"eng","citation":"UNVEILING THE ROLE OF THE MANNOSE RECEPTOR IN CARDIOMETABOLIC DISEASES / J. Nour ; coordinatore: G. D. Norata ; tutor: G. D. Norata. Dipartimento di Scienze Farmacologiche e Biomolecolari, 2024 Jan 18. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12940.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1024208/2345632/phd_unimi_R12940.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/938266"},"title":"EXPLORING DIFFERENT ORGANOCATALYTIC STRATEGIES FOR THE STEREOSELECTIVE SYNTHESIS OF CHIRAL NITROESTERS","internalauthor":"CAMARERO GONZALEZ, PATRICIA","type":"Tesi di dottorato","year":"2022","abstract":"Among unnatural α-amino acids, α,α-disubstituted amino acids are key biological scaffolds with many specific roles and properties that have made them increasingly attractive in the fields of organic chemistry, biochemical research and drug discovery. Structurally, they have unique properties, and this represents an important feature for their use in the design of new pharmaceutically active compounds as well as intermediates for the study of pathological pathways and the role of peptides and their applications in the treatment of the same pathologies they are involved in. Furthermore, their utility as chiral frameworks are critical and so, enantioselectivity plays a key role in their pharmaceutical activity. However, there are limited examples in the literature of highly enantioselective synthetic approaches for these compounds or their precursors, that result in sufficient enantioselectivity suitable for their peptidomimetic applications. The global objective of this PhD thesis is to discover unprecedented synthetic strategies for the synthesis of α,α-disubstituted-α-amino acids and/or their precursors, focusing on the stereoselective reactions and employing known and also newly designed organocatalysts, including chiral phase transfer catalysts. To achieve our goals, two main strategies will be studied: o The enantioselective conjugate addition of nitroesters to α,β-unsaturated ketones mediated by Cinchona derived thiourea or squaramide catalysts, for the construction of nitroesters bearing a quaternary stereocenter. o An alternative strategy that started from easily available ketones, converted to tetrasubstituted nitroolefins, which would be organocatalytically reduced to afford enantioeneriched nitroalkanes, featuring two stereocenters, as highly functionalized starting materials for a further alkylation step to generate a quaternary stereocenter In summary, new synthetic approaches for the generation of α,α disubstituted α amino acids, using organocatalysis were studied. A reproducible strategy for the synthesis of tetrasubstituted nitroalkenes was successfully developed, and enantioselective organocatalyzed reductions performed, to afford the functionalized nitroalkanes. However, several challenges were found in the further alkylation step, and despite trying different variations to the process, the synthesis of a α,α disubstituted α amino acid derivative was not accomplished, following this route. The reactivity of the new synthetized tetrasubstituted nitroalkenes was also studied. Unfortunately, it was only possible to obtain the Michael adduct 136, after long reaction times in comparison with their trisubstituted analogues. The organocatalyzed conjugate addition of nitroesters 118, 130 to unsaturated ketones 120, 125 to get enantiopure nitroesters 123,126,131,132 bearing a quaternary stereocenter, which were obtained with good to moderate yields. These compounds are not extensively reported in literature, in some cases they are only reported as a racemic mixture, so to the best of our knowledge, for the first time it was demonstrated that it is possible to do this transformation in an enantioselective manner.","language":"eng","citation":"EXPLORING DIFFERENT ORGANOCATALYTIC STRATEGIES FOR THE STEREOSELECTIVE SYNTHESIS OF CHIRAL NITROESTERS / P. Camarero Gonzalez ; tutor: M. Benaglia ; co-tutor: M. Sanz ; members of scientific committee:  A. Puglisi, D.Becvk, S.Rossi, S. Umbreen. Università degli Studi di Milano, 2022 Sep 20. 34. ciclo, Anno Accademico 2021. [10.13130/camarero-gonzalez-patricia_phd2022-09-20].","filename":"phd_unimi_R12467.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/938266/2068414/phd_unimi_R12467.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1201457"},"title":"THE IMPACT OF VASCULAR SMOOTH MUSCLE CELL SENESCENCE ON MITOCHONDRIA DYSFUNCTION AND ANGIOGENESIS","internalauthor":"ROSSI, CLARA","type":"Tesi di dottorato","year":"2025","abstract":"INTRODUCTION: Atherosclerosis, the principal underlying cause of most cardiovascular diseases, progresses from early fatty streaks to advanced unstable plaques that, if ruptured, cause life-threatening events. A hallmark of plaque instability is intraplaque angiogenesis, the formation of neovessels. These neovessels are often immature and leaky, facilitating intraplaque haemorrhage, which exacerbates inflammation, promotes plaque growth, and culminates in rupture and thrombotic complications. While hypoxia is a critical driver of this process, additional pro-angiogenic mechanisms within the plaque microenvironment remain incompletely defined. Atherosclerosis is also an age-associated disease characterized by the accumulation of senescent cells, particularly vascular smooth muscle cells (VSMCs), which remain metabolically active but exhibit significant morphological changes, mitochondrial dysfunction and adopt a senescence-associated secretory phenotype (SASP). Despite growing recognition of senescent VSMCs’ detrimental roles in atherosclerosis, like sustained local inflammation, matrix degradation, and tissue remodelling, their potential contribution to intraplaque angiogenesis through pro-angiogenic SASP has not yet been elucidated.   Moreover, while statin therapy, the most widely used drugs for the prevention and treatment of atherosclerosis, plays a crucial role in managing atherosclerosis by reducing cholesterol levels and promoting plaque stability, its impact on mitochondrial dysfunction and SASP in senescent VSMCs remains largely unexplored.     AIM: This study aimed to investigate the interplay between VSMC senescence, mitochondrial dysfunction, SASP, and angiogenesis, and to evaluate the effect of simvastatin on these processes, and to test whether targeting specific SASP-related pathways (VEGF/VEGFR2 and NF-κB) may represent more effective therapeutic strategies.     RESULTS: We demonstrated, using both single-cell RNA sequencing datasets and immunohistochemistry, that senescent VSMCs are significantly more abundant in human unstable carotid atherosclerotic plaques than in stable ones. Consequently, based on these premises and in order to study senescent VSMCs more thoroughly, we developed and characterized two in vitro models of VSMC senescence: replicative (or old cells) and doxorubicin-induced mimicking stress-induced premature senescence, by assessing key senescence features such as cell morphology, cell cycle arrest, SASP, and mitochondrial dysfunction. Interestingly, both senescent models displayed an accumulation of dysfunctional mitochondria characterized by reduced mitochondrial membrane potential (MMP) and respiration, accumulation of reactive oxygen species (ROS), and an altered mitochondria morphology when compared to their young cells control. Moreover, TFAM and TOM70 expression was found to be downregulated only in old cells suggesting a reduction of mitochondrial biogenesis. In addition, both models of senescent VSMCs showed a significant increase in the gene expression and protein production of pro-inflammatory cytokines, including IL-1β, IL-6, and IL-8, thereby validating the SASP profile.  Next, we investigated whether simvastatin could ameliorate age-associated phenotypes in senescent VSMCs. Simvastatin (0.1 μM) improved mitochondrial respiration and reduced ROS production and the inflammatory SASP in both doxorubicin-induced and old VSMCs.  Notably, when mevalonic acid, a downstream product of the HMG-CoA reductase pathway, was added, these beneficial effects of simvastatin on mitochondrial function and the SASP were no longer observed. This indicates that simvastatin's impact on mitochondrial respiration and SASP is specifically mediated through the inhibition of HMG-CoA reductase, the enzyme targeted by statins in the cholesterol biosynthesis pathway.  Multiplex analysis of the inflammatory SASP in the cell culture medium of the senescent VSMCs confirmed the appropriateness of our in vitro models as doxorubicin-treated and old cells produced significantly more pro-inflammatory proteins such as IL-1β, IFN-γ and TNF-α compared to young cells, as already reported in the literature. Surprisingly, we also found that doxorubicin and old VSMCs produced significantly more pro-angiogenic molecules like Angiopoietin 1 and 2, IL-6, IL-8 and VEGFa, compared to young control cells. Interestingly, VEGFa showed a 4-fold increased concentration in doxorubicin and old cells when compared to young control cells.  We next investigated the paracrine effect of the SASP derived from both our senescent VSMC models on angiogenesis, by exposing Human Umbilical Vein Endothelial Cells (HUVECs) to senescent VSMC-conditioned media. HUVECs treated with conditioned media from senescent cells showed enhanced endothelial cell proliferation, migration, and tube formation when compared the their control treated with conditioned medium from young cells.   Notably, simvastatin-treated senescent VSMCs secreted significantly lower levels of pro-angiogenic factors, especially VEGFa, compared to their untreated control. Consistently, conditioned media from simvastatin-treated senescent VSMCs led to a significant reduction in HUVECs proliferation, migration, and tube formation compared to untreated media from senescent VSMCs.   As VEGF stood out as the main pro-angiogenic factor in our multiplex analysis, we supplemented the conditioned media from senescent VSMCs with rivoceranib, a selective VEGFR2 inhibitor, and assessed its impact on angiogenesis. Interestingly, VEGFR2 inhibition completely abolished SASP induced HUVEC proliferation, migration, and tube formation, confirming the central role of VEGF and its receptor VEGFR2 in mediating the paracrine pro-angiogenic effects of the SASP produced by senescent VSMCs.   Since NF-κB is a well-known regulator of the SASP, we pharmacologically inhibited NF-κB activity and we found a significant reduction in VEGF production in senescent VSMCs, suggesting that targeting this pathway could reduce the angiogenic potential of senescent VSMCs.     CONCLUSIONS: Overall, our findings underscore the multifaceted role of VSMC senescence in promoting atherosclerotic plaque progression and vulnerability. By integrating transcriptomic, histological, and functional analyses, we identify cellular senescence not only as a passive hallmark of vascular aging but as an active driver of plaque destabilization, particularly through mitochondrial dysfunction and the pro-angiogenic secretory phenotype.","language":"eng","citation":"THE IMPACT OF VASCULAR SMOOTH MUSCLE CELL SENESCENCE ON MITOCHONDRIA DYSFUNCTION AND ANGIOGENESIS / C. Rossi ; tutor: A. Corsini ; co-tutor: S. Bellosta ; coordinatore: G.D. Norata. - Milano. Dipartimento di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti, 2025 Dec 16. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13829_3.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1201457/3200994/phd_unimi_R13829_3.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1131995"},"title":"ROLE OF ATM IN THE PATHOPHYSIOLOGY OF MAJOR DEPRESSIVE DISORDER (MDD)","internalauthor":"BRIGUGLIO, SABRINA","type":"Tesi di dottorato","year":"2025","abstract":"Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase involved in the DNA damage repair (DDR) and many other cell processes. In neurons, ATM contributes to vesicles trafficking, neurotransmitter release, excitatory/inhibitory balance maintenance, the development of GABAergic system and neuroinflammation. Mutations in ATM cause Ataxia-telangiectasia (A-T), a syndrome characterized by devastating neurological symptoms ascribable primarily to cerebellar neurodegeneration. A-T patients have been reported to experience neuropsychiatric symptoms, including mood disturbances.  Major depressive disorder (MDD) is a debilitating neuropsychiatric disease, characterized by affective, neurovegetative and cognitive symptoms and affecting about 300 million people worldwide with severe social and economic consequences. MDD is a complex disorder, and its aetiology is generally modelled on the “diathesis-stress hypothesis” that considers it to be the result of the interaction between the individual’s inherent vulnerability and the environmental stressors to which they are exposed. MDD’s pathophysiology features dysfunctions in the monoaminergic and glutamatergic systems, dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, altered neuroplasticity and neurogenesis and increased oxidative stress and inflammation. Notably, many of these mechanisms have been found to be controlled also by ATM.  Given these premises and considering that in our previous study the antidepressant drug fluoxetine was sufficient to counteract cognitive defects of ΔAtm mice, the aim of this thesis was to investigate the involvement of ATM in major depressive disorder. To achieve this, we approached the research from multiple perspectives, using MDD models and ATM-deficient models both in vivo and in vitro.  First, we demonstrated that rats vulnerable to chronic mild stress (CMS) are characterized by a significant reduction of ATM protein in the hippocampus, compared to control and resilient animals. Such reduction was independent of transcriptional mechanisms and was partially rescued by an acute administration of ketamine.  Concurrently, we found that ATM-deficient mice feature depressive-like behaviours already in basal conditions and that Atmy/y females appear to be more vulnerable to chronic restrain stress than WT mice.  While setting up our in vitro model of MDD, we unveiled that chronic exposure to corticosterone causes a significant decrease of ATM in hippocampal astrocytes but not in neurons. Thus, to assess how neuronal transmission could be affected by corticosterone-treated astrocytes, we used their conditioned medium (ACM) to treat mature hippocampal neurons. ACM treatment resulted in the impairment of excitatory pre-synaptic function and structure – as evidenced by the reduction of mEPSCs frequency and of VGLUT1 expression – after 1 hr, but not after 24 hr indicating an acute effect of factors release by astrocytes.  Remarkably, neurons treated with the ACM of astrocytes where Atm mRNA was silenced via siRNA, exhibited the same functional defects, reinforcing ATM’s role in corticosterone-induced dysfunctions in the hippocampus.  Finally, to identify proteins released by astrocytes that could be responsible for the synaptic defects encountered, we performed liquid chromatography tandem with mass spectrometry on all ACMs produced. We isolated 31 proteins significantly varied in a coherent way to our results. Further studies will be necessary to pinpoint the specific factors released by astrocytes that are causative of the synaptic defects unveiled in this work.  This is the first time, to our knowledge, that ATM has been directly investigated in the context of neuropsychiatric disorders, specifically in major depressive disorder. Our findings provide new insights into ATM’s role in MDD pathophysiology, potentially opening new avenues for future research and treatment approaches.","language":"eng","citation":"ROLE OF ATM IN THE PATHOPHYSIOLOGY OF MAJOR DEPRESSIVE DISORDER (MDD) / S. Briguglio ; tutor: F. Antonucci; coordinatore: N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2025 Jan 28. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13441.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1131995/2627089/phd_unimi_R13441.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1214455"},"title":"PRE-NUCLEATION IN MOLECULAR LIQUIDS: A MOLECULAR DYNAMICS PERSPECTIVE","internalauthor":"SIRONI, LUCA","type":"Tesi di dottorato","year":"2026","abstract":"Crystals are ubiquitous in everyday life and play a central role in pharmaceuticals, the food industry, and materials science, enabling a wide range of advanced technological applications. Despite their importance, the initial stage of crystal formation, i.e. nucleation, remains poorly understood. Experimental techniques are largely insensitive to nucleation due to the extremely high spatial and temporal resolution and sensitivity required, while computational approaches are challenged by the rare-event nature of nucleation, which demands long simulations of large systems. In this work, pre-nucleation phenomena such as partial ordering and aggregation in molecular liquids are investigated through a combination of computer simulations and crystallization experiments.  This research pursues three main objectives: first, to study the effect of confinement on the partial ordering of molecular liquids; second, to investigate the formation and properties of subcritical clusters during the pre-nucleation stage; and third, to explore the role of aromatic stacking interactions in pre-nucleation phenomena.  Benzoic acid was selected as the model compound owing to its limited molecular flexibility, small number of atoms, and ability to engage in a variety of intermolecular interactions, including hydrogen bonding and aromatic stacking. Some derivatives were also examined for comparison. The primary methodologies employed include molecular dynamics (MD) simulations using the MiCMoS software, static energy calculations with the PIXEL method, DFT-D calculations, and crystallization experiments performed with the Crystal16 multi-reactor crystallizer.  To address the first objective, a confining algorithm was developed and implemented in MiCMoS. Exploratory MD simulations of up to eight benzoic acid molecules confined within small cubic nanocavities were carried out to analyze aggregation behavior and interaction motifs, while DFT-D calculations were used to assess the stability of cyclic aggregates. Subsequently, simulations of confined liquids were performed in different geometries, ranging from nanolayers to nanotubes and nanocavities. Compared to the unconfined bulk liquid, confinement leads to an increase in viscosity and enhanced stacking interactions, driven by partial ordering near the confining barriers, where adsorbed molecular layers form. Increasing the stiffness of confinement induces a liquid-liquid transition between low-density and high-density states in nanocavities. Confinement was further pushed to the limit by adopting a nanolayer geometry allowing only a single molecular layer, in which a catemeric aggregate composed of 26 molecules was observed. This aggregate closely resembles a motif previously identified in crystal structure prediction studies and suggests that, under these conditions, access to a previously unobserved polymorphic form of benzoic acid, reported as monomorphic to date, may be possible.  The second objective focuses on nanoscale inhomogeneities in bulk liquids. Density fluctuations are significantly enhanced in the undercooled liquid, likely due to the formation of larger and more persistent aggregates, identified as subcritical clusters. To investigate these features, a dedicated analysis tool was developed to characterize aggregate formation, and a new definition of subcritical clusters was introduced based on interaction energy, time persistence, and excess energy, which measures whether the cohesive energy of an aggregate exceeds its interactions with the surrounding liquid. Aggregate size distributions reveal trimers as the most abundant species, while dimers, corresponding to the dominant motif in the crystal structure, are the second most common. However, these aggregates are too small to qualify as subcritical clusters. The largest and most persistent subcritical cluster is observed in the undercooled liquid and consists of 17 molecules with a lifetime exceeding 130 ps. This cluster adopts a globular shape formed by a folded chain of hydrogen-bonded molecules, with intermittent aromatic stacking interactions contributing to its stabilization.  The third objective addresses the role of aromatic stacking interactions in nucleation. Approximately 200 dimeric structures of benzoic acid derivatives were retrieved from the Cambridge Structural Database (CSD), and their stacking energies were estimated using the PIXEL method. After applying a series of selection criteria, four candidate compounds were identified for experimental investigation. Kinetic solubility was screened in several solvents, and isopropanol was selected as the most suitable. Following an accurate determination of thermodynamic solubility, one compound was excluded due to insolubility and another due to time reasons. The remaining two compounds were subjected to crystallization experiments using Crystal16 to determine nucleation rates. Owing to the stochastic nature of nucleation, 80 repetitions were performed at five different supersaturation levels, yielding a total of 400 experiments per compound. Nucleation rates were obtained by fitting the cumulative probability of nucleation as a function of induction time. Complementary MD simulations were conducted to correlate nucleation propensity with aromatic stacking interactions, supported by the development of a new analysis tool specifically designed to characterize stacking behavior. Compounds exhibiting higher nucleation propensities also display stronger stacking energies, a greater number of stacking interactions with longer lifetimes, and the formation of larger stacked aggregates. These aggregates adopt pillar-like arrangements reminiscent of crystal packing motifs, while still retaining a significant degree of structural disorder.","language":"eng","citation":"PRE-NUCLEATION IN MOLECULAR LIQUIDS: A MOLECULAR DYNAMICS PERSPECTIVE / L. Sironi ; tutor: L. Lo Presti ;  co-tutor: S. Rizzato ;  coordinatore: D. Passarella. Dipartimento di Chimica, 2026 Feb 09. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13759.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1214455/3247376/phd_unimi_R13759.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/814963"},"title":"CRITICAL PHENOMENA IN RANDOM DIMER MODELS","internalauthor":"FABBRICATORE, RICCARDO","type":"Tesi di dottorato","year":"2021","abstract":"This thesis introduces the concept of criticality and universal behaviour for vastly different systems. The assumption of conformal invariance for systems at critical temperature is shown to yield incredible predictions with the use of Conformal Field Theory. By focusing on the properties of geometrical shapes at criticality, we introduce Schramm-Loewner Evolution (SLE), a powerful tool to extract information about conformality.   Rigorously proving that a discrete system exhibits critical behaviour and conformal invariance in the thermodynamic limit is no easy task. When the system is imbued with quenched disorder, this task becomes even harder. As of today, there is no rigorous proof that a single disordered system exhibits SLE-compatible excitations. This thesis, albeit not providing any such proof, analyses numerically and extensively shows under which conditions such behaviour can be observed in a system with quenched disorder, namely the Random Dimer Model.  The Random Dimer Model consists of a dimer cover of a weighted graph. Its ground state corresponds to the minimum-weight perfect matching. Dimers are often used in Statistical Mechanic, providing a fruitful mapping from a model to a combinatorial problem. By topological perturbations, we obtain excitations in the form of fractal curves. Observables based on these geometrical objects, such as their length, are shown to behave as power laws compatible with other well-known systems at critical point.  Moreover, the extensive analysis of winding angle and Left Passage Probability at the thermodynamic limit, strongly suggests that excitation curves in the Random Dimer Model are conformal and compatible with Schramm-Loewner Evolution. The latter casts light on the yet vastly unexplored question of conformal behaviour for disordered models at critical temperature in the thermodynamic limit.","language":"eng","citation":"CRITICAL PHENOMENA IN RANDOM DIMER MODELS / R. Fabbricatore ; supervisore: S. Caracciolo; coordinator: M. Paris. Dipartimento di Fisica Aldo Pontremoli, 2021 Feb 10. 33. ciclo, Anno Accademico 2020. [10.13130/fabbricatore-riccardo_phd2021-02-10].","filename":"phd_unimi_R11894.pdf","fileformat":"Unknown","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/814963/1705132/phd_unimi_R11894.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1026728"},"title":"LA PRESSE CLANDESTINE DE LA RÉSISTANCE FRANÇAISE (1941-1944) : STYLES, LANGAGES, RHÉTORIQUE ET ARGUMENTATIONS","internalauthor":"DELLA ROCCA, ALESSIA","type":"Tesi di dottorato","year":"2024","abstract":"Studies conducted to date on the French Resistance and the closely related clandestine press have been based on an analysis of the themes conveyed by Resistance periodicals and the way in which clandestine newspapers were produced and distributed during the Occupation. However, little attention has been paid, either historically or linguistically, to the primary nature of the Resistance's clandestine press and what it really represents: a medium. This thesis project is part of the field of linguistic studies and aims to focus on the linguistic, stylistic, rhetorical and argumentative strategies used in clandestine periodicals to disseminate content that contrasts with the dominant official discourse. The aim of this thesis is therefore to place itself in the intermediate space between the major historical studies of the French Resistance and the existing analyses of the clandestine press, by proposing a contribution to what has not yet been sufficiently considered. The analysis of the linguistic, argumentative and rhetorical strategies opens the possibility of completing from a linguistic point of view, insufficient to date, the studies on memory and the Resistance. The study of the as yet little-explored field of language also provides a better understanding of the aims of the Resistance and the contradictions that characterised one of the most troubled periods in contemporary history, and thus makes a necessary contribution to a subject that continues to occupy a prominent place in France's collective memory.","language":"fre","citation":"LA PRESSE CLANDESTINE DE LA RÉSISTANCE FRANÇAISE (1941-1944) : STYLES, LANGAGES, RHÉTORIQUE ET ARGUMENTATIONS / A. Della Rocca ; tutor: M. Barsi, A.-R. Hermetet. - Università degli Studi di Milano. Dipartimento di Lingue, Letterature, Culture e Mediazioni, 2024 Mar 26. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12874_1.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1026728/2354273/phd_unimi_R12874_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1162559"},"title":"BOARD DIVERSITY E PRINCIPIO DI LIBERA SCELTA DEGLI AMMINISTRATORI TRA PROFITTO E SOSTENIBILITÀ","internalauthor":"MICHIELIN, SARA","type":"Tesi di dottorato","year":"2025","abstract":"The thesis examines the issue of diversity in the composition of the management body (so-called board diversity) of listed joint-stock companies, analysing how this aspect fits into the constraints on the shareholders’ meeting’s power to appoint directors. In particular, in an era where the ultimate purpose of companies is being reconsidered, assigning the board of directors the task of guiding the company in pursuit of its “sustainable success”, the question arises whether this change in perspective can also influence the configuration of the board itself. From this perspective, the paper starts by reconstructing the historical and economic reasons that led to the limitation of the shareholders’ meeting’s freedom in choosing the members of the management body. Starting from the introduction of figures such as the independent and minority director, it reaches the current focus on gender equality and the overall “diversity” of the board.  The second chapter is therefore focused on a careful examination of the regulatory constraints that circumscribe the discretion of the shareholders’ meeting, analysing the exceptions to the principle of appointment by the shareholders’ meeting, the rules on the origin of candidate lists, structural and temporal constraints, as well as the subjective, individual and collective requirements demanded of directors. Subsequently, the study delves into the concept of “diversity” in the composition of the management body. The treatment of this topic in international corporate governance principles and national codes is examined, with particular attention to European banking regulations. The link between diversity and ESG issues is also explored, analysing the most recent directives and standards in this area. The chapter concludes with reflections on the distinction between intrinsic and extrinsic diversity, emphasizing the importance of the principles of proportionality and flexibility in applying these concepts.  Finally, the third chapter focuses on the practical aspects related to identifying the “optimal” composition of the board of directors. The tools provided for this purpose are examined, such as the diversity policy, the board’s self-assessment, and guidelines on its composition. The analysis extends to the various phases of the appointment process, the role of the subjects involved, and the possible consequences of failing to appoint an “optimal” board of directors. Lastly, the chapter reflects on the potential role of board diversity in the context of adequate organizational structures that directors are required to set up pursuant to Article 2086 of the Italian Civil Code.","language":"ita","citation":"BOARD DIVERSITY E PRINCIPIO DI LIBERA SCELTA DEGLI AMMINISTRATORI TRA PROFITTO E SOSTENIBILITÀ / S. Michielin ; tutor: M. Rescigno ; coordinatore: G. Ludovico. Dipartimento di Diritto Privato e Storia del Diritto, 2025 May 15. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13536.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1162559/3026061/phd_unimi_R13536.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1163655"},"title":"LA RIFORMA OSPEDALIERA A FABRIANO. ASSISTENZA, POLITICA ED ECONOMIA IN UNA ¿QUASI-CITTÀ¿ DEL CENTRO ITALIA (SECOLI XII-XV).","internalauthor":"CAMELI, RENATO","type":"Tesi di dottorato","year":"2025","abstract":"\"The thesis, \"\"LA RIFORMA OSPEDALIERA A FABRIANO. ASSISTENZA, POLITICA ED ECONOMIA IN UNA \"\"QUASI-CITTÀ\"\" DEL CENTRO ITALIA (SECOLI XII-XV)\"\", is the culmination of my doctoral research conducted between 2021 and 2024. The study offers an in-depth examination of the hospital phenomenon in late medieval Fabriano, focusing on the communal era from the early 13th to the late 15th century.    From the 13th to the 15th century, Fabriano, situated at the foot of the Apennines, provides a privileged vantage point to closely analyze the evolution of the local welfare system. It starts with the first hospital structures, of monastic origin, documented in the Fabriano district, and extends to the 14th and 15th centuries, when these institutions emerged as municipal enterprises established within the city limits.    The richness of Fabriano’s case is primarily due to the abundance of documentation, particularly from the 14th and 15th centuries, allowing for the examination of a significant number of hospital sources, which can be roughly divided into two categories: administrative and accounting records. The consultation and analysis of volumes and registers housed in the Fabriano municipal archives provided the ideal conditions for reconstructing the hospital system in the late medieval period.    A defining characteristic of this hospital network is the increasing involvement of laypeople and city authorities in charitable work. While initially, charitable institutions were the exclusive domain of monastic communities, from the 13th century onward—coinciding with Fabriano’s expansion in the surrounding countryside—the commune, along with guilds and devotional organizations, began to assume responsibility for them and promote new ones. In the second chapter of the thesis, particular attention is given to how the municipalization of monastic hospitals in the surrounding areas became a crucial step in the territorial growth of this Apennine stronghold.    For the 14th century, the greater availability of documents allowed for a detailed investigation into the creation and management of charitable institutions. At that time, the Marche region was experiencing a period of significant industrial and commercial growth, with the city government controlled by guilds, which actively promoted the establishment of hospitals. It was the leaders of the manufacturing sector, organized into numerous confraternities in Fabriano, who took on the responsibility of founding facilities to assist those in need. It is no coincidence that by the mid-14th century, 18 hospitals were recorded in Fabriano. In Chapter Three, the first part outlines the context in which these charitable institutions arose, while the second part explores their organizational and operational strategies.    A separate discussion is reserved for the major hospital of Santa Maria del Gesù, a foundling hospital founded in the heart of Fabriano in 1456. This charitable endeavor, established with contributions from the commune, a preacher from the Observant Franciscan order, confraternities, and guilds, is the subject of the last two chapters of the thesis. The wealth of documentation produced by the institution warranted a dedicated section, providing a clearer understanding of its impact on the city’s social fabric.    Santa Maria del Gesù distinguished itself for the coherence of its welfare project, which involved meticulous planning of both the hospital and commercial aspects. This gave rise to a structure that represented one of the most sophisticated mechanisms for addressing social distress in the communal era.    The study of the foundling hospital concludes the thesis, closing the circle of a research project centered on reconstructing the welfare landscape of a city that, with its impressive number of hospitals, found its most mature expression of charity in Santa Maria del Gesù.\"","language":"ita","citation":"\"LA RIFORMA OSPEDALIERA A FABRIANO. ASSISTENZA, POLITICA ED ECONOMIA IN UNA \"\"QUASI-CITTÀ\"\" DEL CENTRO ITALIA (SECOLI XII-XV) / R. Cameli ; tutor: M. Gazzini, S. Marino ; coordinatore: P. Grillo. - Milano. Dipartimento di Studi Storici \"\"Federico Chabod\"\", 2025 May 13. 37. ciclo, Anno Accademico 2024/2025.\"","filename":"phd_unimi_R13258.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1163655/3065830/phd_unimi_R13258.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1202836"},"title":"EXPANSION OF CLINICAL PHENOTYPE AND USE OF KETOGENIC DIET IN RARE GENETIC CONDITIONS: GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY SYNDROME AND SCN8A-RELATED DISORDERS","internalauthor":"PREVITALI, ROBERTO","type":"Tesi di dottorato","year":"2026","abstract":"Rare diseases affect between 264 and 446 million people worldwide and include a broad group of genetic conditions that manifest with epilepsy and neuropsychiatric disorders with paediatric onset.  This thesis focused on the study of two rare genetic disorders: Glucose Transporter Type 1 Deficiency Syndrome (GLUT1-DS) and conditions associated with pathogenic variants in the SCN8A gene. The aim was to expand the understanding of the clinical phenotype and disease progression, as well as to evaluate the efficacy of the ketogenic diet (KD) as a treatment.  Regarding GLUT1-DS, data were collected at the Italian reference centre “Vittore Buzzi” Children’s Hospital, the main site of the doctoral research, in collaboration with IRCCS “Carlo Besta”, both located in Milan. The studies investigated disease progression in adulthood and familial cases, considering clinical, psychological, and quality of life aspects. A tendency toward worsening of the clinical picture across generations within family units was observed, which is relevant for genetic counselling. In adulthood, paroxysmal movement disorders and fatigue were identified as the most common symptoms, while other symptoms tended to attenuate with age. The adult phenotype appeared highly variable: some patients presented sporadic symptoms and achieved academic and professional goals, while others showed more significant clinical manifestations. Approximately 50% of subjects exhibited psychological difficulties, particularly anxiety and depression, highlighting the need for a multidisciplinary approach to care. About two-thirds of adult patients received a late diagnosis, often following diagnosis in their children, indicating that the condition, although relatively recently identified, remains poorly recognized and underdiagnosed.  Stroke-like episodes were observed in approximately 20% of patients, especially in post-pubertal females, including one documented case of ischemic stroke. Therefore, attention should be paid to the occurrence of acute neurological symptoms in patients with GLUT1-DS, and conversely, this syndrome should be considered as a differential diagnosis in patients with ischemic episodes of unknown origin, particularly in the presence of a family history of epilepsy, intellectual disability, or movement disorders.  The use of the ketogenic diet in this population, even over the long term, confirmed good efficacy and tolerability, with good adaptive behaviours and executive functions in patients treated for extended periods, despite the reported challenges affecting the quality of life of patients and their families.  For individuals with SCN8A-related conditions, the reference centre was the Filadelfia Epilepsy Hospital in Dianalund (Denmark), with the participation of an international network of clinicians and the contribution of the Hertie Institute for Clinical Brain Research at the University of Tübingen (Germany) for functional studies, and the Center for Neurogenetics at the University of Texas, Health Science Center in Houston (USA) for computational analyses. The study focused on the clinical analysis of individuals carrying loss-of-function (LoF) variants. Variant selection followed a rigorous process integrating clinical data, in silico predictions, and functional studies. Patients with LoF variants exhibited a broad phenotypic spectrum, consisting of five main clinical presentations: (1) without epilepsy, (2) generalized epilepsy (both previously described in the literature), (3) developmental and epileptic encephalopathy (DEE), previously reported only anecdotally and here analysed in detail, presenting a severe clinical picture but overall milder than in patients with DEE harbouring gain-of-function variants; (4) focal and myoclonic epilepsy, a phenotype not previously described requiring further confirmation; and (5) unclassified epilepsy. Accurate interpretation of the variant’s function is crucial for phenotype definition, prognostic counselling, and therapeutic decision-making.  KD proved effective and well tolerated in patients with SCN8A-related DEE, with a reduction in seizure frequency greater than 50% in two-thirds of patients and complete seizure freedom in 22.2% of cases. Additionally, KD contributed to a reduction in life-threatening events, such as status epilepticus and generalized tonic-clonic seizures, resulting in decreased hospitalizations. Beyond seizure control, improvements were observed in cognitive functions, neuropsychiatric symptoms, and sleep quality.  In conclusion, this work investigated two rare genetic diseases with the aim of improving the understanding of their clinical features, genotype-phenotype correlations, and progression, in order to provide tools for more accurate prognostic counselling, guide therapeutic choices, and contribute to the development of diagnostic and care models for comprehensive patient management.","language":"eng","citation":"EXPANSION OF CLINICAL PHENOTYPE AND USE OF KETOGENIC DIET IN RARE GENETIC CONDITIONS: GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY SYNDROME AND SCN8A-RELATED DISORDERS / R. Previtali ; tutor: P. Veggiotti, S. Bertoli ; co-tutor:  E. Gardella ; coordinator: F. Cheli. Dipartimento di Scienze Biomediche e Cliniche, 2025 Jan 26. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13908.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 12-GIU-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/931766"},"title":"ADVANCED METHODOLOGIES FOR VISUAL OBJECT TRACKING","internalauthor":"DI NARDO, EMANUEL","type":"Tesi di dottorato","year":"2022","abstract":"Visual Object Tracking is a continuously developing and competitive field in computer vision and machine learning. It is based on the idea of being able to follow any object, unknown up to that moment, in its movements without losing it or letting it run away.   It is of fundamental importance to keep under observation a specific object otherwise difficult to track, in particular in very sensitive contexts such as security, more specifically in video surveillance, or autonomously guided or unmanned aerial vehicles (UAV), and in contexts in which it is of great help to perform automated tasks, such as in video production.   As in any other field, deep learning methodologies became part of visual tracking, bringing with them the state-of-the-art of many methodologies including object detection, super-resolution, adversarial generative networks, and image classification. Most of these methodologies cooperate in a single architecture dedicated to tracking, to the point that the computational resources required for this purpose are very intensive, having to coexist and collaborate with multiple deep models.   Visual object tracking has evolved more and more over the years from using correlation models based on transformations in the frequency domain, to allowing a global and highly efficient correlation, compatible, with learning based on gradient descent. It evolved again using models based on correlation of elements with similar characteristics extracted from a module that is able to recognize the characteristics of objects previously trained on the classification of images with large datasets. Moreover, we have recently witnessed the advent of transformers models with their explosion in the field of NLP and computer vision. These models were also rapidly included in methodologies for the field of visual tracking.   The following thesis aims to inspect methodologies that can enrich the current state-of-the-art by building and exploring architectures not yet defined in the literature as well as trying to improve those already developed.   We started our research with the idea of using Generative Adversarial Networks for their reconstruction power, putting the tracking problem in the point of view of subject segmentation.   Going further into the topic, the work continued with the application of models based on Siamese networks that effectively allow to correlate the element to be tracked with the research space itself. However, these models have already been widely studied which has led us to develop even more complex networks. Although we remained in the context of Siamese networks, we started from the use of conventional convolutional networks to novel techniques in computer vision as the Transformers. These have proven to be the center of interest of a large part of the scientific community in every field and, therefore, we tried to apply them in a field that is new compared to the state-of-the art. As a result we obtained a method that is able to be compared with all current techniques, obtaining scores that allow the implemented methodology, not only to enter in high positions in the benchmark leaderboards of the various datasets, but also to participate in VOT2022, which is the challenge of reference for the world of visual tracking and which is the goal of every tracking algorithm.   In addition, we investigated what the tracking algorithms are actually observing through methodologies of eXplainable Artificial Intelligence (XAI) and how the transformers and the attention mechanism play a very important role.   During the research activity learning models that are different from those based on traditional crisp logic have also been developed. The aim was to try to find a common point that could combine fuzzy logic with the flexibility of deep learning and how this can be used to explain the relationships between the data as the complexity of the neural network increases. Fuzzy logic was applied to transformers to build a Fuzzy Transformer, where the attention component is more easily explained given the success of fuzzy models in the field of explainability.   All the work of XAI has allowed us to verify how our idea of using the internal components of the mechanism of attention has produced a direct link between this and the elements on which we are actually going to act in order to produce the desired output. In addition, the experiments conducted on the fuzzy components, in this first phase, seems to validate our idea that not only can using a specific highly interpretable component produce results similar to the state of the art, but this also makes it easier to understand them.","language":"eng","citation":"ADVANCED METHODOLOGIES FOR VISUAL OBJECT TRACKING / E. Di Nardo ; tutor: P. Boldi ; co-tutor: A. Ciaramella ; coordinatore: P. Boldi. Dipartimento di Informatica Giovanni Degli Antoni, 2022 Jul 18. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12445.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/931766/2046690/phd_unimi_R12445.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/974168"},"title":"NEW INSIGHTS INTO PATHOGENESIS AND PROGNOSIS OF CANINE SARCOMAS","internalauthor":"GODIZZI, FRANCESCO","type":"Tesi di dottorato","year":"2023","abstract":"The majority of canine soft tissue and visceral sarcoma prognostic studies have been influenced by a “one size fits all” approach which lead researchers to merge different subtypes of sarcomas in the same study population. The consequent heterogeneity of cases hampered the interpretation of the results per each tumor category and impeded the comparison of the results among different studies and their application in veterinary clinical oncology. The majority of these studies have also been characterized by non-standardized and non-rigorous methods. Given these premises, the aims of this thesis were to identify valuable prognostic factors specific for different canine sarcoma subtypes, following rigorous and repeatable methods, leading to a better definition of patient outcome, as well as provide novel insights into canine sarcoma pathogenesis, providing a basis for improved clinical management and possibly targeted therapy.  The introduction provides an overview of classification and prognostic factors in cutaneous and subcutaneous soft tissue sarcomas (STSs), as well as visceral sarcomas, with a special focus on canine perivascular wall tumors (cPWTs) and splenic stromal sarcomas (SSSs).  The introduction is followed by the description of four distinct investigations. The first study analysed the impact of clinical and histopathological variables on local recurrence (LR) and overall survival time (OST) in a large series of retrospectively collected surgically excised cPWTs finding that histological grade, tumor necrosis, mitotic count, status of surgical margins, tumor ulceration, and location on distal extremities had an impact on LR and that ulceration, grade III, necrosis >50% and higher mitotic count were correlated with shorter OST. The study results suggested that all these prognostic factors need to be considered to predict cPWTs prognosis more accurately.   The second study aimed at evaluating the immunohistochemical expression of survivin and β-catenin in a series of retrospectively collected surgically excised cPWT samples to investigate their possible involvement in the tumorigenesis and progression of these tumors. Additionally, the study attempted to recognize the prognostic impact of survivin, β-catenin, and Ki-67, together with histopathological and clinical variables, on LR and OST. cPWTs variably expressed survivin and β-catenin at both nuclear and cytoplasmic level, and increased nuclear survivin was associated to a reduced OST. Inclusion of survivin immunohistochemical expression analysis when diagnosing cPWTs may allow to better define patient prognosis and to eventually plan adjuvant treatments in selected dogs. Additionally, survivin and β-catenin may be potential therapeutic targets for more aggressive phenotypes of these tumors. Finally, the study confirmed the prognostic role of mitotic count and tumor size in cPWTs.  The third study focused on canine STSs surgical margin assessment investigating the impact of clean but close margins (CbCMs) on LR. The study reported that the cumulative incidence of LR at three years differed significantly between infiltrated margins, CbCMs, and tumor-free margins. Canine STSs excised with infiltrated margins had the greatest risk of LR, and the rate of LR with CbCMs was greater than LR rate of tumor-free margins. Both when CbCMs were grouped with infiltrated margins and when CbCMs were grouped with tumor-free margins, a significant difference between groups persisted. Thus, the conclusion was that CbCMs should be considered as a separate prognostic category for canine STSs.  The fourth study assessed the impact of pathological and clinical variables on the occurrence of metastasis in 32 cases of canine SSSs, which were classified into different subtypes on the basis of histomorphological and immunohistochemical features. The research has demonstrated a potential prognostic role of the grading system usually applied to canine cutaneous and subcutaneous STSs, and a statistically significant prognostic role of mitotic count in predicting SSS metastatic spread. Furthermore, the study results suggested that differentiating between different SSS subtypes  may not have prognostic value. Finally, age and sex of dogs, and administration of adjuvant chemotherapy seemed not to impact the risk of development of metastases, although further studies are needed.  This thesis shed light on some aspects of the pathology and prognostication of canine sarcomas. The author hopes that the reported results will be relevant to veterinary pathologists and surgical oncologists who are involved in canine sarcomas diagnosis and treatment. Furthermore, the author expects that the studies included in this thesis may provide novel insights for future research in this field.","language":"eng","citation":"NEW INSIGHTS INTO PATHOGENESIS AND PROGNOSIS OF CANINE SARCOMAS / F. Godizzi ; tutor: P. Roccabianca; coordinatore: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2023 Jun 09. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12485.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/974168/2214789/phd_unimi_R12485.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1045788"},"title":"DEVELOPMENT OF NEW OLIGODENDROCYTE-BASED MODELS TO IDENTIFY PHARMACOLOGICAL AGENTS WITH REMYELINATING ACTIVITY","internalauthor":"CASTRO E SILVA, JULIANA HELENA","type":"Tesi di dottorato","year":"2024","abstract":"Multiple Sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system, characterized by neuroinflammation and demyelination. While immunomodulatory disease-modifying drugs offer relief from MS symptoms in its relapsing-remitting forms, they do not support remyelination in the progressive and most severe forms of the disease. This is because, up to date, drugs do not target the myelin-producing cells of the central nervous system: oligodendrocytes (OLs). To produce myelin and remyelinate, OLs must differentiate from oligodendrocyte precursor cells (OPCs) to their most mature form (mOLs). At intermediate stages, immature OLs (iOLs) transiently express in their cell membrane the G protein-coupled receptor 17 (GPR17). This expression is essential for their correct maturation; however, it needs to be downregulated to allow proper OL maturation. Accumulation of GPR17-positive cells has been observed in various neurodegenerative disease models, including demyelination and in the inflamed normal-appearing white matter of human MS post-mortem brains, suggesting a potential role of GPR17-positive cells in inflammation. In the first part of the present thesis, we aimed at establishing an inflammatory model of OL differentiation impairment that is representative of MS and targeting GPR17 in this model. We developed an in vitro model of inflammation to rat primary OPCs exposing them to a cocktail of pro-inflammatory cytokines commonly found in MS brain lesions: IFN-γ, TNF-α, and IL-1β (CTK). We observed that subtoxic concentrations of CTK (2 ng/mL) significantly hindered OPC differentiation, reducing the number of myelin basic protein (MBP)-positive cells and increasing the gene expression of GPR17 and chemokines associated with infiltration of leukocytes into the MS brain (CCL-2, CCL-5 and CXCL-10). In this model, we evaluated whether different GPR17 ligands could facilitate OL maturation. We demonstrated that, after a single 6-hour pretreatment with CTK, the selective GPR17 agonist galinex promoted OL maturation increasing the number of MBP-positive cells, without affecting OL inflammation genes. Conversely, montelukast, a GPR17 antagonist and known anti-inflammatory drug, together with a novel a putative partial agonist PCD-2 could not significantly counteract the effects induced by CTK. Given that myelination is a tightly regulated phenomenon that relies on both OL-intrinsic and extrinsic features, in our second strategy, we aimed at establishing oligodendrocyte-enriched human brain organoids to study the effects of repurposed remyelinating drugs on different OLs subclusters using single-cell RNA sequencing. For this, fibroblasts of a healthy donor were dedifferentiated to human induced pluripotent stem cells (hiPS) and then to neural precursor cells (NPCs). NPCs were transfected to express the Sox10 transcription factor and kept under constant agitation to obtain organoids. We treated organoids with MTK and lovastatin (LOVA) for four weeks and performed single-cell RNA sequencing (scRNA-seq). Control-, MTK- and LOVA-treated organoids presented a similar number of neurons, astrocytes, NPCs and OLs, these last in turn distributed into OPCs, iOLs and mOLs. The comparison between differentially expressed genes (DEGS) induced by both MTK and LOVA treatment allowed the identification of 377 common genes when considering the entire organoid, and of 64 common exclusive genes belonging to iOL cluster. Functional enrichment analysis showed that MTK and LOVA iOLs datasets presented common enriched terms that included the Wnt and protein tyrosine kinase pathways and glial differentiation, indicating that the drugs share possible protective mechanisms of action in this cluster. Overall, the present study sheds light on the potential of the GPR17 agonist galinex to support OL maturation under inflammation and identifies pathways of interest to give rise to novel compounds that could offer new promising therapeutic means for MS.","language":"eng","citation":"DEVELOPMENT OF NEW OLIGODENDROCYTE-BASED MODELS TO IDENTIFY PHARMACOLOGICAL AGENTS WITH REMYELINATING ACTIVITY / J.h. Castro E Silva ; tutor: M. P. Abbracchio ; co-tutor: D. Lecca ; coordinator: G. D. Norata. Dipartimento di Scienze Farmaceutiche, 2024 Apr 18. 36. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13054.pdf","fileformat":"Adobe PDF","fileaccess":"Closed"}
,{"handle":{"url":"https://hdl.handle.net/2434/1057308"},"title":"JUDICIAL COLLECTIVE ENFORCEMENT OF FUNDAMENTAL RIGHTS  IN A MULTILEVEL EUROPEAN CONSTITUTIONAL PERSPECTIVE. A FOCUS ON THE ITALIAN CLASS ACTION REGIME","internalauthor":"MAGLICA, ANDER","type":"Tesi di dottorato","year":"2024","abstract":"The current societal transformations, brought by globalisation and technological innovation, have disrupted the multilevel constitutional landscape, now fragmented in standardised and massified relationships where inequalities are increasingly amplified. Against such backdrop, the democratic mechanisms of representation, on the one hand, and the traditional civil law dualistic paths of litigation, on the other hand, appear ineffective in enforcing rights, especially fundamental ones.  The present research, theoretical and empirical, aims to evaluate the role of class actions as a means of overcoming such challenges and ensuring concrete access to justice. Adopting an innovative constitutional-law standpoint, it focuses on the Italian jurisdiction, as part of the broader European multilevel system, and in particular the Italian 2019 reform which introduced a dual (injunctive and compensatory) collective procedure of general application. For this purpose, the investigation analyses, also with a comparative lens, the constitutional foundations of collective enforcement (as opposed to individual one), the specific use of collective proceedings to enforce fundamental rights and the potential drawbacks in light of possible abuse and fair trial guarantees. The topicality of the study is also given by the recent EU Directive 2020/1828 on representative actions for the protection of the collective interests of consumers.","language":"eng","citation":"JUDICIAL COLLECTIVE ENFORCEMENT OF FUNDAMENTAL RIGHTS  IN A MULTILEVEL EUROPEAN CONSTITUTIONAL PERSPECTIVE. A FOCUS ON THE ITALIAN CLASS ACTION REGIME / A. Maglica ; tutor: B. Randazzo, S. Voet ; coordinatori: F. Biondi; O. de Graef. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2024 Jun 17. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12985.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1057308/2428036/phd_unimi_R12985.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1023858"},"title":"STUDY ON HISTONE DEACETYLASE 3 AND ITS PHARMACOLOGICAL REGULATION IN THE PATHOPHYSIOLOGY OF ADIPOSE TISSUE","internalauthor":"COPPI, LARA","type":"Tesi di dottorato","year":"2024","abstract":"Introduction: Obesity is a chronic complex disease that poses the risk of developing a plethora of serious health complications (e.g., type 2 diabetes, cardiovascular and cerebrovascular disease, and cancers). Browning of white adipose tissue (WAT) can drain excess nutrients via thermogenesis and thus can be used as a strategy to tackle obesity. Epigenetics and metabolism are closely intertwined in both physiological and pathological conditions. Histone deacetylases (HDACs) are epigenome modifiers regulating adipocyte metabolism. Our previous studies with chemical inhibitors or genetic alterations of HDAC3 have shown metabolic rewiring of white adipocytes towards browning via the activation of a futile cycle of lipolysis and lipogenesis. Obesity is characterized by chronic low-grade inflammation due to secretion of pro-inflammatory cytokines by immune cells, but recent studies demonstrated that adipocyte-derived inflammation is necessary for healthy adipose tissue expansion. Ferroptosis is an iron-dependent programmed cell death characterized by the accumulation of lipid peroxides and may have a role in pathophysiology of adipose tissue.  Aim: This thesis is focused on the role of histone deacetylase 3 (HDAC3) in WAT browning and obesity with the following aims: 1) assess the effectiveness of HDAC3 knockdown in precursors and mature adipocytes to i) confirm that HDAC3 is the key HDAC that directs adipocyte fate and to ii) evaluate the window of opportunity for this treatment; 2) evaluate the effects of the peculiar metabolic profile observed in HDAC3 KO mice on adipocyte health, viability, and immunophenotype of adipose tissue; 3) study the effects of LA9498, a novel selective inhibitor of HDAC3, in comparison to MS275, a class I HDAC inhibitor which has already been characterized by our group, to evaluate the efficacy and the optimal effective concentration required to achieve browning of white adipocytes.  Results: 1) Hdac3 silencing at early stages of differentiation of C3H/10T1/2 adipocytes promoted a metabolic rewiring of the phenotype towards browning. In particular, adipocyte differentiation and functionality, oxidative metabolism, browning, and mitochondrial functionality increased. In addition, adipocyte pro-inflammatory genes were induced by early silencing of Hdac3. On the other hand, silencing Hdac3 in mature adipocytes did not affect cell phenotype. 2) Ablation of HDAC3 in adipocytes determined the increase in total number of macrophages resident in the epiWAT, but this increase was mostly contributed by the M2 subpopulation. Moreover, Hdac3fatKO mice displayed increased proliferation and differentiation of adipocyte progenitors. FACS analysis confirmed increased adipocytes proliferation and macrophage activation following HDAC3 depletion with RNAi in cultured adipocytes. Alongside new adipocytes, we observed dead adipocytes surrounded by macrophages, suggesting WAT renewal. Integrated analysis of omics data and qPCR analysis revealed ferroptosis as one of the upregulated pathways in WAT of Hdac3fatKO mice and in adipocytes upon silencing of HDAC3 with shRNA adenovector; thus, ferroptosis may be a relevant mechanism triggered in Hdac3fatKO mice to remove metabolically exhausted adipocytes. 3) The HDAC3-selective inhibitor LA9498 is more potent than MS275 and causes upregulation of genes important in i) adipocyte differentiation and functionality, ii) lipid mobilization and β-oxidation, and iii) browning and mitochondrial functionality. LDH test did not reveal toxicity of the compounds at the tested concentrations. Furthermore, LA9498 increased lipid accumulation and parameters of mitochondrial functionality (i.e., basal respiration, ATP production, proton leak, maximal respiration, spare respiratory capacity and non-mitochondrial oxygen consumption).  Conclusions: The early epigenetic events mediated by HDAC3 silencing are crucial to commit adipocyte precursors towards a metabolic phenotype characterized by increased oxidative metabolism and mitochondrial function. These results highlight how epigenome modifications of precursor cells could determine the phenotype and functionality of terminally differentiated adipocytes. Immunophenotype of visceral WAT is affected by increased oxidative metabolism of adipocytes in which HDAC3 is deleted. We propose that HDAC3 functions as a metabolic rheostat to modulate WAT rejuvenation by the removal of old adipocytes and differentiation of new progenitors. In addition, specific pharmacological inhibition of HDAC3 with LA9498 induces a transcriptional program similar to Hdac3 silencing, but effects on mitochondrial respiration are boosted; this suggests that the role played by HDAC3 in some cellular processes could be independent from deacetylase activity. Based on the results obtained in these investigations, we propose that regulation of HDAC3 activity could play a crucial role in improving pathophysiology of metabolic disorders in WAT.","language":"eng","citation":"STUDY ON HISTONE DEACETYLASE 3 AND ITS PHARMACOLOGICAL REGULATION IN THE PATHOPHYSIOLOGY OF ADIPOSE TISSUE / L. Coppi ; tutor: M. Crestani ; co-tutor: A. Ferrari ; coordinatore: G. D. Norata. - Dipartimento di Scienze Farmacologiche e Biomolecolari. Dipartimento di Scienze Farmacologiche e Biomolecolari, 2024 Jan 18. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12984.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1023858/2345299/phd_unimi_R12984.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1119675"},"title":"THE ROLE OF HYPOGLYCEMIC AGENTS IN AMELIORATING COGNITIVE FUNCTIONS AND PSYCHIATRIC SYMPTOMS: FROM THE PSYCHIATRIC PATIENT TO EVIDENCE-BASED AND PHARMACOEPIDEMIOLOGIC APPROACHES FOR SUPPORTING THE CLINICAL PRACTICE","internalauthor":"BATTINI, VERA","type":"Tesi di dottorato","year":"2024","abstract":"Background: Research highlights a complex link between diabetes-related factors such as insulin resistance, hyperglycemia, and chronic inflammation, all contributing to cognitive decline. Schizophrenia and depression, which often co-occur with type 2 diabetes mellitus, show a bidirectional relationship with diabetes, involving both brain and systemic responses. Antidiabetic drugs such as metformin and drug targeting Glucagon-Like Peptide-1 (GLP-1) are being proposed for psychiatric and cognitive treatments, although their use for non-diabetic purposes remains debated.   Methods: The role of antidiabetic drugs in ameliorating psychiatric and cognitive functions was explored across various real-world settings where these drugs are already used for glycemic control. A meta-analysis and meta-regression were conducted to study metformin in schizophrenic patients. Innovative approaches regarding disproportionality analysis of concomitant therapies in pharmacovigilance databases were used to explore all antidiabetic drugs (ATC code: A10) in combination with antidepressants. Survival analysis was performed using Danish healthcare registers to evaluate the potential benefits of GLP-1 analogues (GLP-1a) in older patients.   Results: Metformin showed a positive trend without reaching strong statistical significance in ameliorating psychiatric symptoms in a meta-analysis of randomized controlled trials involving schizophrenic patients [SMD (95%CI) = -0.40 (-0.82;0.01), OR (95%CI) = 0.5 (-2.4;3.4)] and reducing the reporting risk of therapy failure in depressive patients [ROR95=1.14, PPR(p)= 1.07 (0.00), EBGM95=0.96 ERAM95=0.89 in FAERS and ROR95=1.48 PPR(p)= 1.34 (0.00) EBGM95=1.22 and ERAM95=0.86 in VigiBase]. GLP-1a and DPP-4 inhibitors (DPP-4i) resulted in better outcomes with a preference for GLP-1a for reducing the risk of major cognitive impairment (dementia) in old diabetic patients [aHR (95% CI) = 1.5 (1.16-2.04), p = 0.003 for DPP-4i compared to GLP1-a (reference group)]. GLP-1a resulted also in a lower reporting rate of therapy failure in depressive patients compared to DPP-4i [ROR95=0.66 vs 0.86 in FAERS and ROR95=0.92 vs 1.06 in VigiBase, respectively].   Conclusions: GLP-1 analogues may offer more substantial clinical benefits. Regarding metformin, there is insufficient evidence of its cognitive benefits. Further research is necessary to confirm these findings and explore their clinical significance.","language":"eng","citation":"THE ROLE OF HYPOGLYCEMIC AGENTS IN AMELIORATING COGNITIVE FUNCTIONS AND PSYCHIATRIC SYMPTOMS: FROM THE PSYCHIATRIC PATIENT TO EVIDENCE-BASED AND PHARMACOEPIDEMIOLOGIC APPROACHES FOR SUPPORTING THE CLINICAL PRACTICE / V. Battini ; tutor: E. Clementi ; co-tutor: C. Carnovale ; coordinatore: G. Norata. - 97. Dipartimento di Scienze Biomediche e Cliniche, 2024 Dec 19. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13248.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1119675/2594849/phd_unimi_R13248.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1119878"},"title":"BEES AND WASPS IN A CHANGING ENVIRONMENT: MULTIPLE RESPONSES TO ANTHROPISED LANDSCAPES","internalauthor":"FERRARI, ANDREA","type":"Tesi di dottorato","year":"2024","abstract":"Bees and predatory wasps provide highly relevant ecosystem services, the former being the main pollinator group and the latter regulating arthropod populations. Anthropisation, the way in which human activities shape natural ecosystems, threatens these insects from the community to the individual level. However, little is known about intraspecific shifts in morphological, physiological, behavioural, and ecological functional traits (i.e. those important for the health and fitness) of bees and wasps in response to anthropisation. The aim of this project was to understand how two different anthropogenic disturbances affect functional traits in bees and wasps: urbanisation and agricultural practices. Urbanisation, which leads to increased temperature and impoverishment and fragmentation of vegetated areas, was investigated in the Metropolitan City of Milan (Northern Italy). The use of sewage sludge, which may contain toxic trace elements, as agricultural soil amendment was studied in the Parco Adda Sud (Northern Italy). Five target species were considered: the bees Anthophora plumipes Pallas, 1772 (Hymenoptera: Apidae), Apis mellifera Linnaeus, 1758 (Hymenoptera: Apidae), Halictus scabiosae (Rossi, 1790) (Hymenoptera: Halictidae) and Osmia cornuta (Latreille, 1805) (Hymenoptera: Megachilidae), and the wasp Polistes dominula (Christ, 1791) (Hymenoptera: Vespidae). The field studies were preceded by a re-analysis of published data on wild bee communities in different cities around the world, which showed how highly urbanised areas filter for bee species with specific functional traits (social, polylectic, above-ground nesting). The predicted effects on morphology, physiology and behaviour at the intra-specific level were instead formalised in a dedicated opinion paper. With field observations, microscopy techniques, histological observations, and chemical and genetic analyses investigations, I have found that urbanisation affected many of the considered functional traits, albeit often with species-specific patterns. Morphologically, smaller individuals (H. scabiosae, O. cornuta, and P. dominula) as well as individuals with a longer galea (A. plumipes), better flight-related wing characteristics (H. scabiosae, O. cornuta, and P. dominula) and higher values of wing fluctuation asymmetry (a proxy for larval developmental stress) (A. plumipes, H. scabiosae, and P. dominula) were found in hotter and more fragmented urban areas. Furthermore, O. cornuta (in more fragmented urban areas) and A. plumipes (in hotter urban areas) appeared to have a visual sensory system that probably improves image resolution, while O. cornuta (in hotter urban areas) additionally reduced resource investment in cold-adapted thermoreceptors. Finally, one species (H. scabiosae) showed greater histological damage to the midgut epithelium in urban areas with higher road cover, while P. dominula showed a reduced yellow pigmentation in hotter urban areas. Physiologically, hotter urban areas increased the mean chain length of the cuticular hydrocarbon profile of O. cornuta and the relative abundance of some long chain n-alkanes in H. scabiosae and P. dominula. In addition, A. mellifera from hotter and less green urban areas showed reduced activity of Aminopeptidase N, a proteolytic enzyme. Finally, hotter urban areas reduced the abundance of some bee viruses in A. plumipes and O. cornuta, while fragmentation increased the presence of the protozoan Apicystis bombi in A. plumipes, O. cornuta, and P. dominula. Behaviourally, hotter areas increased the aggressiveness of O. cornuta females towards conspecifics. Finally, urbanisation seemed to provide key habitats for the shift in the geographical distribution of H. scabiosae over the recent decades. Sewage sludge has been found to contain the known toxic elements Cd, Pb and Hg, among other trace elements. Apis mellifera with higher levels of Pb were smaller, those sampled from sites with high levels of Hg had higher fluctuating asymmetry and more histological damage to the midgut epithelium, and those sampled from sites with higher levels of Cd had higher carbohydrate content. Overall, these studies have important conservation implications. Temperature is a crucial factor in determining morpho-physiological changes in bees and wasps in urbanised areas. Improving green areas would likely mitigate these higher temperatures. This would also counteract other detrimental elements of the urban matrix: the reduction and fragmentation of green spaces. The spatial configuration of green areas plays a key role in affecting bees and wasps. In particular, the creation of ecological corridors and the reduction of mowing regimes could certainly bring benefits in terms of trophic and nesting resources for these insects. Overall, these practices could also have positive effects at a community level, possibly sustaining functionally diverse bee and wasp communities. Regarding the practice of sewage sludge use, this study highlighted the possible negative effects of this practice and the need to include ecotoxicological tests on model animal organisms to authorise the spreading of the sludge. Future studies should consider the genetic basis of the observed variation to clarify whether the observed phenotypic shifts are the result of phenotypic plasticity or genetic adaptation. In addition, other biological aspects of bees and wasps should be investigated, such as the effects of anthropisation on the gut microbiome, the food resources or the nesting choices of these insects.","language":"eng","citation":"BEES AND WASPS IN A CHANGING ENVIRONMENT: MULTIPLE RESPONSES TO ANTHROPISED LANDSCAPES / A. Ferrari ; tutor: C. Polidori ; head of the phd course: M. P. M. Guarino. - Università degli Studi di Milano, Milano. Dipartimento di Scienze e Politiche Ambientali, 2024 Dec 19. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13421.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1119878/2595727/phd_unimi_R13421.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1157360"},"title":"\"FRA RAGIONI ED ESPERIENZE. LA MATEMATICA \"\"PRATICA\"\" E I SUOI INTERPRETI: LIBRI D'ABACO E ABACISTI NEL XV SECOLO.\"","internalauthor":"PAPI, ANDREA","type":"Tesi di dottorato","year":"2025","abstract":"\"The PhD thesis stands at the crossroads of various areas of historical methodology: the history of culture and education, examined in relation to the dissemination of mathematical knowledge through abacus treatises (abaci) and specialized educational institutions such as abacus schools; social history, with a particular focus on the professional and familial trajectories of abacists (both teachers and practitioners) who learned and applied this knowledge through the creation of abacus manuscripts; and monetary and mathematical history, explored through the analysis of computational techniques and monetary data derived from the mathematical texts under examination. The aim of the research was the study and reconstruction of the characteristics, production mechanisms and circulation of abacus treatises, with particular regard to the manuscripts written during the 15th century; a period in which the production of abaci reached its peak in Italy, spreading also to France, Germany and Spain. By defining a sample of manuscripts (19), predominantly Tuscan, a comparative analysis of their mathematical content revealed affinities and divergences. The research therefore focused on the actors of the transmission of mathematical and computational knowledge at the end of the Middle Ages: the abacists, understood in a broadest sense. Through this dual perspective, we have explored the calculation techniques and practical applications (commercial, algebraic and geometric) found in the manuscripts, relating them to the broader context of abacus schools and educational practices of the period and shedding new light on the processes of literacy and professionalisation that accompanied the expansion of mathematical knowledge in Europe. Particular attention has been paid to the reconstruction of three figures: the Florentine merchant Matteo di Niccolò Cerretani (1444-1519), author of the \"\"Libro di ragioni\"\" preserved in codex Palatino Baldovinetti 229 at the Biblioteca Nazionale Centrale in Florence; the franciscan friar and abacus master, Mariotto di ser Giovanni Guiducci (1427-post 1496), author of the \"\"Libro d’arismetricha\"\" contained in codex Conventi Soppressi J X 36 at the same library; and the Faentine apothecary Giovanni Battista di Michele da Sant’Eufemia (†1487), author of the \"\"Libro sopra arismetricha\"\" and the \"\"Rasone de perticha\"\", preserved in codex Plimpton 195 at Columbia University in New York.\"","language":"ita","citation":"\"FRA RAGIONI ED ESPERIENZE. LA MATEMATICA \"\"PRATICA\"\" E I SUOI INTERPRETI: LIBRI D'ABACO E ABACISTI NEL XV SECOLO / A. Papi ; tutor: M. Gazzini, M. Bompaire, L. Travaini ; coordinatore: P. Grillo. - Milano. Dipartimento di Studi Storici \"\"Federico Chabod\"\", 2025 Apr 11. 36. ciclo\"","filename":"phd_unimi_R12967.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open from 02-APR-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1026728"},"title":"LA PRESSE CLANDESTINE DE LA RÉSISTANCE FRANÇAISE (1941-1944) : STYLES, LANGAGES, RHÉTORIQUE ET ARGUMENTATIONS","internalauthor":"DELLA ROCCA, ALESSIA","type":"Tesi di dottorato","year":"2024","abstract":"Studies conducted to date on the French Resistance and the closely related clandestine press have been based on an analysis of the themes conveyed by Resistance periodicals and the way in which clandestine newspapers were produced and distributed during the Occupation. However, little attention has been paid, either historically or linguistically, to the primary nature of the Resistance's clandestine press and what it really represents: a medium. This thesis project is part of the field of linguistic studies and aims to focus on the linguistic, stylistic, rhetorical and argumentative strategies used in clandestine periodicals to disseminate content that contrasts with the dominant official discourse. The aim of this thesis is therefore to place itself in the intermediate space between the major historical studies of the French Resistance and the existing analyses of the clandestine press, by proposing a contribution to what has not yet been sufficiently considered. The analysis of the linguistic, argumentative and rhetorical strategies opens the possibility of completing from a linguistic point of view, insufficient to date, the studies on memory and the Resistance. The study of the as yet little-explored field of language also provides a better understanding of the aims of the Resistance and the contradictions that characterised one of the most troubled periods in contemporary history, and thus makes a necessary contribution to a subject that continues to occupy a prominent place in France's collective memory.","language":"fre","citation":"LA PRESSE CLANDESTINE DE LA RÉSISTANCE FRANÇAISE (1941-1944) : STYLES, LANGAGES, RHÉTORIQUE ET ARGUMENTATIONS / A. Della Rocca ; tutor: M. Barsi, A.-R. Hermetet. - Università degli Studi di Milano. Dipartimento di Lingue, Letterature, Culture e Mediazioni, 2024 Mar 26. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12874_2.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1026728/2354274/phd_unimi_R12874_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1198115"},"title":"DECODING CELLULAR AND TEMPORAL VARIABILITY IN HUMAN CORTICAL DEVELOPMENT. INTEGRATING SINGLE-CELL TRANSCRIPTOMICS ACROSS DEVELOPMENTAL STAGES AND EXPERIMENTAL MODELS.","internalauthor":"ZONCA, ASIA","type":"Tesi di dottorato","year":"2025","abstract":"The human cortex is composed of heterogeneous neurons and glia that interact to facilitate complex brain functions. However, studying their development over decades has been technically challenging due to limitations in data access and representation. Recent advances in single-cell profiling have provided a wealth of data on fetal and adult human cortex cells, but extracting insights from this information remains a significant hurdle.  To address this challenge, we present NeuRoDev, an innovative analytical and data resource that leverages existing data to resolve temporal and cellular variability across the entire process of human cortex development. From 5 weeks post-conceptional to 65 years of age, NeuRoDev provides a highly curated data platform with simple analytical tools to facilitate the study of brain cell physiology.  NeuRoDev achieves this by introducing an integrative network-based approach that connects reproducible transcriptional patterns across single-cell transcriptomes. This framework enables the contextualization of gene function and iPSC-derived experimental models within human neurodevelopment, providing new insights into the dynamics of cellular processes and the basis of brain disorders.  We use NeuRoDev to investigate cell physiological processes, neuronal and glial cell maturation, and collective behavior in brain disorders. All analytical tools and data resources are freely available through the R packages NeuRoDev and NeuRoDevDB.","language":"eng","citation":"DECODING CELLULAR AND TEMPORAL VARIABILITY IN HUMAN CORTICAL DEVELOPMENT. INTEGRATING SINGLE-CELL TRANSCRIPTOMICS ACROSS DEVELOPMENTAL STAGES AND EXPERIMENTAL MODELS / A. Zonca ; tutor: J. Davila Velderrain ; co-tutor: G. Testa ; phd programme coordinator: D. Pasini. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Dec 16. 37. ciclo","filename":"phd_unimi_R13534.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 24-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1208815"},"title":"IGF2R: A NEW PLAYER IN THE INSULIN LIKE GROWTHFACTOR 2 (IGF2) PATHWAY SUSTAINING ADRENOCORTICAL TUMOURS CELL GROWTH","internalauthor":"NOZZA, EMMA","type":"Tesi di dottorato","year":"2026","abstract":"Adrenocortical tumours (ACT) are a highly heterogeneous class of endocrine cancers, ranging from the common adrenocortical adenoma (ACA) to the rare and aggressive adrenocortical carcinoma (ACC). ACT management is currently relying on the surgical approach; however, the identification of novel therapeutic strategies constitutes an urgent need especially in the management of advanced and metastatic ACC.   During the years, several approaches directed at different overexpressed target have constituted the core of clinical and preclinical studies. Of particular interest, the insulin-like growth factor 2 (IGF2), overexpressed in the majority of ACC, is a growth factor responsible for the autocrine proliferative loop that sustains ACC growth. In the IGF2 system, two well addressed tyrosine-kinase receptors, IGF1R and IR, were found responsible for the IGF2 pro-mitotic signal transduction. Unfortunately, even if promising in in vitro settings, the inhibition of these receptors was not successful in prolonging the overall survival of ACC patients in clinical trial.   Furthermore, in the IGF2 system is involved another specific IGF2 receptor, IGF2R, which was historically addressed as anti-oncogenic, due to its role in promoting IGF2 lysosomal degradation. However, recent studies in other cancers determined a possible tumorigenic action of IGF2R. Thus, the main aim of this PhD project was to uncover the presence, role, and mechanism of action of the IGF2R in the ACT context.  The project was conducted in vitro, using 4 different ACC cell lines, derived from either primary or metastatic tumours, to better reflect ACC heterogeneity. Moreover, data were corroborated using several ACA, uncertain malignant potential tumours (UMP), and ACC primary cultures.   Firstly, IGF2R was found overexpressed in ACT compared to normal adrenal tissue (NA), and we confirmed IGF2 overexpression in ACC versus ACA. Then we proceeded to assess whether the role of IGF2R was pro or anti-oncogenic, both on stabilized models and primary cultured cells. Knockdown and inhibition of IGF2R at its IGF2-binding site confirmed a reduction of proliferative activity and coherently, IGF2R transient transfection promoted both proliferation and viability increase.   This evidence of a pro-tumorigenic role for IGF2R was a complete novelty in ACT context, thus it needed a supporting mechanism of action. Indeed, we investigated the IGF2-IGF2R binding as well as the possible downstream effectors of IGF2R.   The evaluation of the IGF2 impact on IGF2R mitogenic action was conducted in the only cell line, H295R, where IGF2 extracellular levels were affected by IGF2R presence. Indeed, we administer retinoic acid (RA), another IGF2R ligand, known to facilitate IGF2 internalization and stimulate apoptosis. Surprisingly, RA treatment increased IGF2 extracellular levels, and even though this accumulation was potentially able to promote cellular proliferation via IGF1R and IR, we observed a decrease in cellular proliferation. This anti-mitotic effect was confirmed to be mediated by IGF2R and due to the increase of IGF binding proteins (IGFBP2 and 6) induced by RA, that determined the extracellular sequestering of IGF2. We also confirmed the pro-apoptotic effect of RA, even though it was not attributable only to IGF2R.  The downstream mechanism of IGF2R was object of study in other cellular models, mainly by the group of El Shewy, who identified two enzymes, the sphingosine kinases (SphKs), and their product S1P, as responsible for the activation of PI-3K/Akt and MAPK pathways. Indeed, we confirmed the overexpression of SphK, mainly the isoform SphK1, in ACT compared to NA. Moreover, this was the first project to correlate IGF2R with SphK in ACT, proving that in case of IGF2R knockdown or inhibition the activity of SphK is hampered.   The identification of these novel actors in the ACT pathogenesis opened the possibility to investigate SphKs as therapeutic targets. Indeed, we tested two different inhibitors, safingol and fingolimod. The two drugs were able to impair cell proliferation, viability, and cortisol secretion, both on ACC cell lines and primary cultures. Moreover, we compared their antitumoral activity with the current therapeutic strategy for advanced ACC, the EDP-M scheme, and the combination of safingol or fingolimod with EDP-M resulted additive in controlling cell viability.  Overall, in this PhD project a novel pro-oncogenic role of IGF2R in the ACT context was demonstrated. In particular, we proved its connection with IGF2 and most importantly with SphK, able to activate a downstream proliferative cascade sustaining tumorigenesis. Remarkably, we successfully tested two SphK inhibitors in vitro, laying the foundations of new preclinical pharmacological studies.","language":"eng","citation":"IGF2R: A NEW PLAYER IN THE INSULIN LIKE GROWTH FACTOR 2 (IGF2) PATHWAY SUSTAINING ADRENOCORTICAL TUMOURS CELL GROWTH / E. Nozza ; tutor: E. Peverelli ;  supervisor: R. Catalano ;  director: N. Landsberger. - LITA. Dipartimento di Scienze Cliniche e di Comunità, 2026 Jan 21. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13844.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1208815/3227114/phd_unimi_R13844.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1202476"},"title":"LINKING CHROMATIN REMODELING TO MITOCHONDRIAL DYSFUNCTION: A ROLE FOR THE SMARCA5-MYC-TFAM AXIS IN HEPATOCELLULAR CARCINOMA","internalauthor":"PALERMO, FRANCESCA","type":"Tesi di dottorato","year":"2025","abstract":"Hepatocellular carcinoma (HCC) is an aggressive primary liver malignancy characterized by poor prognosis, limited therapeutic options, and frequent resistance to conventional treatments. Metabolic reprogramming, particularly involving mitochondria, is a hallmark of cancer and represents a potential therapeutic vulnerability.  In this study, a CRISPR/Cas9-based reverse genetic screen targeting novel mitochondrial regulators identified Smarca5 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily A, Member 5), an ATP-dependent chromatin remodeler of the ISWI family, as essential gene for maintaining mitochondrial function, proliferation, and viability in HCC cells.  Depletion of SMARCA5 led to severe impairments in mitochondrial respiration, reduced ATP production, and widespread disruption of bioenergetic and biosynthetic pathways. These effects included impaired β-oxidation of fatty acids, diminished nucleotide synthesis, and defective amino acid catabolism, indicating a collapse in mitochondrial biosynthetic processes, leading to cancer cell death.  Mechanistically, loss of SMARCA5 emerged as a major driver of MYC signaling impairment, resulting in reduced expression of MYC target genes. Notably, SMARCA5 depletion decreased the level of MYC binding to chromatin and promoted its cytoplasmatic localization. In this context, MYC aberrantly interacts with TFAM, a key regulator of mitochondrial DNA transcription, thereby blocking its import into mitochondria. Supporting this model, our findings showed a reduction of mitochondrial TFAM protein levels together with an increased MYC–TFAM interactions in the cytoplasm, which likely contribute to the mitochondrial dysfunction observed upon SMARCA5 downregulation.  Together, these results establish SMARCA5 as a critical regulator of mitochondrial function by modulating a MYC–TFAM signaling axis. This work provides new insight into nuclear-mitochondrial crosstalk in HCC and opens potential therapeutic strategies for targeting metabolic vulnerabilities in cancers.","language":"eng","citation":"LINKING CHROMATIN REMODELING TO MITOCHONDRIAL DYSFUNCTION: A ROLE FOR THE SMARCA5-MYC-TFAM AXIS IN HEPATOCELLULAR CARCINOMA / F. Palermo ; tutor: N. Mitro ; co-tutor: S. M. L. Ghisletti ; coordinatore: G. D. Norata. Dipartimento di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti, 2025 Dec 16. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13741.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 09-GIU-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/964696"},"title":"ANALYSIS OF WHOLE-BLOOD TRANSCRIPTOME DIFFERENCES AND FUNCTIONAL INFERENCES IN SUBJECTS WITH NON-OBSTRUCTIVE OR OBSTRUCTIVE CAD, DETECTED BY CCTA, COMPARED TO SUBJECTS WITHOUT CORONARY ATHEROSCLEROSIS","internalauthor":"VAVASSORI, CHIARA","type":"Tesi di dottorato","year":"2023","abstract":"Background - Despite the presence of the same CAD symptoms and pre-tests suggestive for the presence of CAD, a not irrelevant number of coronary computed tomography angiography do not detect the presence of coronary atherosclerosis. In fact, individuals could share the same symptoms even having different disease profiles from a biological point of view. Thus, there is an urgent unmet need of new tools/gene-expression patterns that allowed to detect the presence and the severity of coronary artery disease. In this context, the aim of this thesis project is to identify, through RNA-sequencing: i) gene-expression patterns in the whole blood that could differentiate patients with obstructive and non-obstructive coronary atherosclerosis, detected by coronary CT angiography (CCTA), from subjects without the presence of coronary stenosis; ii) biological processes and/or pathways associated to obstructive or non-obstructive CAD.  Methods - A total of 730 consecutive patients, undergoing coronary computed tomography angiography (CCTA) for suspected CAD, have been enrolled and coronary stenosis was quantified. Total RNA was isolated from whole blood collected at baseline. The whole-blood transcriptome of 315 patients, matched for age, sex and with (obCAD, n=105) or without (non-obCAD, n=105) obstructive coronary stenosis and of subjects with complete absence of coronary atherosclerosis (noCAD=105), was profiled and compared by RNA-sequencing. Statistical and data analysis was performed with R packages, GSEA and GraphPad Prism.  Results - Differential gene expression analysis reveals that whole blood gene expression patterns could differentiate obstructive and non-obstructive CAD patients from subjects with the complete absence of coronary atherosclerosis. Gene-Set Enrichment Analysis revealed that both obstructive and non-obstructive CAD were negatively associated to the regulation of innate and adaptive immunity. Non-obstructive coronary artery disease were positively associated to B cell receptor signalling pathway while obstructive CAD to circadian rhythms.  Conclusions - Whole-blood transcriptome profiling revealed differences between patients with obstructive or non-obstructive coronary artery disease as detected by CCTA and subjects with complete absence of coronary atherosclerosis. The main findings confirm the hypothesis that the integration of non-invasive imaging and whole-blood transcriptional profiles could be useful for new tools/blood-based test, able to detect the presence and the severity of coronary atherosclerosis as detected by CCTA and find biological processes associated with obstructive and non-obstructive CAD.","language":"eng","citation":"ANALYSIS OF WHOLE-BLOOD TRANSCRIPTOME DIFFERENCES AND FUNCTIONAL INFERENCES IN SUBJECTS WITH NON-OBSTRUCTIVE OR OBSTRUCTIVE CAD, DETECTED BY CCTA, COMPARED TO SUBJECTS WITHOUT CORONARY ATHEROSCLEROSIS / C. Vavassori ; supervisore: G. I. Colombo ; tutor: P. Agostoni ; coordinatore: C. Sforza. Dipartimento di Scienze Cliniche e di Comunità, 2023 Apr 20. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12611.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/964696/2179658/phd_unimi_R12611.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1064068"},"title":"FUNCTIONAL CHARACTERIZATION OF VPS13 DURING SEXUAL AND APOMICTIC PLANT REPRODUCTION: THE MISSING GENE FOR PLANT BREEDING?","internalauthor":"CORNARO, LETIZIA","type":"Tesi di dottorato","year":"2024","abstract":"In the near future, food production must increase to ensure food security for the growing world population. One of the methods to improve production is the generation of F1 hybrids, which have increased characteristics compared to their parental lines, including higher yield. Apomixis is an asexual way of reproduction that allows the fixation of any increased characteristics for all subsequent generations by the production of a clonal progeny. Despite that, apomixis is absent from economically important crops; therefore, its introduction into sexually reproducing crops could potentially change the plant breeding field. A candidate gene for apomixis regulation in plants is VPS13, identified in apomictic dandelion.  During my Ph.D. project, I studied the possible role of VPS13 in plant reproduction in two species, dandelion and Arabidopsis, model plants for asexual and sexual reproduction, respectively. Here, I show that apomictic dandelion maintains the machinery to perform sexual meiosis, repressed by a yet unknown mechanism. Furthermore, the analysis of a knockout mutant suggested that VPS13 might act in concert with other factors to accomplish diplospory in apomictic dandelion.  I also report that VPS13S has a crucial role in female germline development in sexual Arabidopsis, demonstrated by the severe defects observed in vps13 mutant ovules. Several analyses suggested the potential function of VPS13S in modulating the expression of key factors at the protein level by regulating their turnover. The results presented in this thesis indicate that the VPS13S association with the membranes is fundamental to its function in ovule development, and they provide insight into the regulatory networks that control ovule development in plants.","language":"eng","citation":"FUNCTIONAL CHARACTERIZATION OF VPS13 DURING SEXUAL AND APOMICTIC PLANT REPRODUCTION: THE MISSING GENE FOR PLANT BREEDING? / L. Cornaro ; scientific tutor: L. Colombo ; course coordinator: R. Mantovani. Dipartimento di Bioscienze, 2024 Jun 21. 36. ciclo","filename":"phd_unimi_R12965_3.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 18-DIC-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/828416"},"title":"EFFECT OF DIET THERAPY ON GUT MICROBIOME IN RARE GENETIC DISEASES","internalauthor":"BASSANINI, GIULIA","type":"Tesi di dottorato","year":"2021","abstract":"In the last decades, several studies have explored the human microbiota in different body niches, notably in the gastrointestinal tract. The gut microbiota has been recognized as an additional organ that co-evolves with humans and interacts with host physiology. The gut microbiota plays a key role in the host metabolism and the extraction of energy from food.   Diet is the strongest factor shaping the gut microbiota: differences in macronutrient intake may select the growth of specific microbial taxa. Indeed,   the diet provides different substrates such as undigested carbohydrates for fermentation, affecting the composition of the gut microbiota and,   consequently, the production of microbial metabolites. Short chain fatty acids (SCFAs), mainly acetate, propionate, and butyrate, are the major end products of anaerobic fermentation by gut microbes.    Modifications in the proportions of the gut microbes and, consequently, the production of SCFAs have been suggested to play a role in several pathological conditions. If the diet is modifiable to stimulate the growth of beneficial microbes, it could represent a target for prevention and treatment of   a possible dysbiosis.    In congenital metabolic disorders such as phenylketonuria (PKU) and glycogen storage disease (GSD), diet is considered the mainstay for the treatment of the pathology. PKU diet is based on the restriction of phenylalanine intake and the supplementation of essential amino acids and micronutrients. PKU diet is similar to a vegan alimentation since all the animal products are excluded. GSD dietary management provides the intake of slow-release carbohydrates to prevent hypoglycaemia and limits the assumption of simple sugars.  In this research, we aimed to analyze the impact of dietary therapy on the composition of the gut microbiota and the production of SCFAs in two congenital metabolic disorders (PKU and GSD). PKU and GSD diseases showed an alteration of the gut microbiome. If diet represents the only treatment of the disease and is not modifiable, a personalized intervention to restore a healthy gut microbiome is to consider. Nowadays, the attention is focused on the supplementation of probiotics and prebiotics.","language":"eng","citation":"EFFECT OF DIET THERAPY ON GUT MICROBIOME IN RARE GENETIC DISEASES / G. Bassanini ; tutor: G. Morace; cotutor: C. Alteri; coordinator: L. Pinotti. Università degli Studi di Milano, 2021 Apr 12. 33. ciclo, Anno Accademico 2020. [10.13130/bassanini-giulia_phd2021-04-12].","filename":"phd_unimi_R11870.pdf","fileformat":"Unknown","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/828416/1744166/phd_unimi_R11870.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/961176"},"title":"OMICS APPROACHES FOR OMEGA-6/OMEGA-3 POLYUNSATURATED FATTY ACID RATIO IN PIGS","internalauthor":"MANAIG, YRON JOSEPH","type":"Tesi di dottorato","year":"2022","abstract":"In general, meat quality is heavily influenced by fatty acid (FA) composition and intramuscular fat, which is mostly dependent on the dietary fat intake of pigs, but it is also affected by genetic variants. In this PhD thesis, we elucidated the effects of dietary lipids, in terms of omega-6 (n-6)/omega-3 (n-3) polyunsaturated fatty acid (PUFA) ratio, on porcine meat quality and the integration of OMICS technologies such as genomics, transcriptomics, and proteomics. With the aim of understanding the association between n-6/n-3 PUFA ratios, porcine transcriptome expression, and biological processes related to PUFA metabolism, we performed RNA-Seq and microRNA-Seq on longissimus dorsi muscle samples from 20 Iberian x Duroc pigs with extreme values for n-6/n-3 FA ratio and identified differentially expressed messenger RNAs (mRNAs) and microRNAs (miRNAs). Our findings highlighted mRNA genes, miRNAs and enriched pathways that were related to lipid metabolism, cell growth and inflammation, according to differences in muscle n-6/n-3 PUFA ratio. Relevant miRNA-to-mRNA regulatory networks were also uncovered (i.e., mir-15b to ARRDC3; mir-7142-3p to METTL21C), and linked to lipolysis, obesity, myogenesis, and protein catabolism. We also determined on how sow diets with high or low n-6/n-3 PUFA ratios of 13:1 (SOY) and 4:1 (LIN), influenced the reproductive performance of sows, growth performance of pre-weaned piglets, and fat deposition, including proteins and protein-coding genes using proteomics analysis. In sows, LIN decreased dead-born piglets and pre-weaning mortality. Although piglet weight and weight gain varied in between n-6/n-3 PUFA ratios, weaning weight and overall weight gain were not affected by dietary interventions. Proteomic analysis revealed 4 and 11 overabundant proteins in muscle and adipose tissues, respectively, in SOY compared to LIN. Additionally, the pro-inflammatory role of n-6 PUFAs may be associated to the observed overabundance of haptoglobin, an acute-phase protein, and the stimulation of protein-coding genes and proteins relevant to the innate immune response and acute inflammatory response. Using the same population, we applied the use of exon-intron split analysis (EISA) approach to account for post-transcriptional changes, driven by putative functional miRNA repression, in response to extreme values of n-6/n-3 PUFA ratio in longissimus dorsi muscle in male and female piglets. EISA revealed 11 and 97 mRNA genes within the top 5% negative PTc scores with at least 1.5-fold exonic region reduction in SOY-male (SOY-M) and LIN-male (LIN-M) piglets, respectively. Furthermore, the detected upregulated miRNAs harbored binding sites on 72.73% (SOY-M) and 61.86% (LIN-M) of these post-transcriptionally downregulated genes. Moreover, the overall PTc signals in females were not as strong and clear as those from the males. In addition, we discovered genes that are predominantly associated in the modulation of immune responses and lipid-related metabolism, which may be related to the pro- and anti-inflammatory properties of n-6 and n-3 PUFAs, respectively. Our use of EISA enabled us to identify regulatory networks that complemented traditional analyses of differential expression, providing us a more comprehensive understanding of muscle metabolic changes in response to PUFA concentration.","language":"eng","citation":"OMICS APPROACHES FOR OMEGA-6/OMEGA-3 POLYUNSATURATED FATTY ACID RATIO IN PIGS / Y.j. Manaig ; tutor: A. Sanchez, Folch, JM, G. Savoini; coordinatore: F. Ceciliani. Università degli Studi di Milano, 2022 Dec 21. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12694.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/961176/2167764/phd_unimi_R12694.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/957902"},"title":"EPIGENETIC MODIFICATIONS REGULATING LIVER HOMEOSTASIS AND TUMORIGENESIS","internalauthor":"D'AMBROSIO, ALESSANDRO","type":"Tesi di dottorato","year":"2023","abstract":"Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide and the fourth cause of death. The major risk factors predisposing to HCC are well known although the lack of reliable markers and efficient pharmacological treatments for HCC patients remains a major problem. In the recent years, several driver mutations have been identified, including signaling molecules and epigenetic modifiers. Specifically, mutations that affect the activity of SWI/SNF chromatin remodeling complex have been commonly reported. Mutational studies clearly indicated a role for epigenetic modifications in HCC development. However, it is still unclear whether SWI/SNF mutations have a role in tumor formation. Our data suggest a new role of Arid1A as one of the key players in HCC tumor development.  In our study, we show that ARID1A predispose to HCC formation with the establishment of chronic inflammation. HCC derived from Arid1A deprivation are characterized by the selection of mutations able to induce immune escape. Conversely, the abrogation of all the cBAF complexes, targeting both Arid1A and Arid1B subunits, led to synthetic lethality in a couple of weeks. Moreover, loss of all the Arid1 proteins caused a strong effect on transcriptional profile with loss of all liver specific metabolic pathway. Furthermore, we observed how the absence of both the ARID1 proteins characterized a complete loss of H3K4me1 and H3K27Ac histone modifications on all the FoxA2 targets both on promoter and enhancers. Ultimately, cBAF complex is necessary to maintain the liver metabolism and its homeostasis. Mechanistically, ARID1A loss induced chronic inflammation and, probably indirectly, genomic instability with the upregulation of the interferon pathway due to an increase of micronuclei. This statement imposed a selective pressure which deeply predispose to HCC formation by promoting viral mimicry. All these findings led to actively select mutations to bypass this block induced by the innate immune response activation, among these mutations were found MYC, YAP1, PTEN and S33A β-Catenin mutation.","language":"eng","citation":"EPIGENETIC MODIFICATIONS REGULATING LIVER HOMEOSTASIS AND TUMORIGENESIS / A. D'ambrosio ; tutor: F. Chiacchiera ; co-tutor: D. Pasini ; phd coordinator: S. Minucci. Dipartimento di Scienze della Salute, 2023 Apr 13. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12413.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/957902/2158278/phd_unimi_R12413.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/970507"},"title":"SUBSTANTIAM REI MUTARE. FISICA ARISTOTELICA ED AZIONE MIRACOLOSA NELLA FONDAMENTAZIONE DUECENTESCA DELLA PLENITUDO POTESTATIS","internalauthor":"CASTELLI, MARCO","type":"Tesi di dottorato","year":"2023","abstract":"\"The goal of the thesis is to investigate the thirteenth-century origins of the concept of \"\"plenitudo potestatis\"\" (plenitude of power) by utilising the tools provided by political theology and adopting a legal-ontological perspective. Following this path, after an introduction that outlines some concepts employed in the research, the first topic examined is the medieval reception of Aristotle's physical texts, analysing the parallels between the teaching prohibitions imposed on these texts and those affecting Roman law. Building on this ground, the analysis explores the potential influence of these new conceptual frameworks on the development of the notion of \"\"miracle\"\" within scholastic thought. Additionally, it examines how this understanding of divine action aligns with the dichotomy between ordained (\"\"ordinata\"\") and absolute power of God (\"\"absoluta potentia Dei\"\"), particularly as seen in the thoughts of Thomas Aquinas. With the philosophical and theological framework established, the thesis then delves into the evolution of the concept of \"\"plenitudo potestatis\"\", aiming to determine how it became associated with the idea of absolute divine power in the mid-thirteenth century. In the final section, the thesis focuses on the most significant claim tied to \"\"plenitudo potestatis\"\", namely, the Pontiff's power to \"\"change the substance of a thing\"\" (\"\"substantiam rei mutare\"\"). By studying thirteenth-century doctrine, the thesis ultimately reconstructs how these assertions of power were resolved through the interpretive faculties of power and the application of the \"\"canonical\"\" fiction of law (\"\"fictio iuris\"\").\"","language":"ita","citation":"SUBSTANTIAM REI MUTARE. FISICA ARISTOTELICA ED AZIONE MIRACOLOSA NELLA FONDAMENTAZIONE DUECENTESCA DELLA PLENITUDO POTESTATIS / M. Castelli ; tutor: R. Bianchi Riva, E. Fusar Poli ; coordinatore: F. Poggi. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2023 May 31. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12607.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/970507/2202136/phd_unimi_R12607.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1205020"},"title":"SALICYLALDEHYDE-TAGGED PEPTIDES FOR THE REVERSIBLE-COVALENT ENGAGEMENT OF PROTEIN LYSINE RESIDUES","internalauthor":"MASON, MATTIA","type":"Tesi di dottorato","year":"2026","abstract":"Covalent drug discovery has recently re-emerged as a powerful approach for targeting  clinically-relevant proteins, offering enhanced potency and selectivity through controlled  covalent interactions. In particular, reversible covalent (RC) chemistry combines the strength  of covalent binding with the tunability of non-covalent interactions, mitigating the risks of  permanent off-target reactivity. Within this context, this PhD thesis explores the use of  salicylaldehyde (SA) as a reversible electrophilic warhead for peptide-based ligand design.  The first part of this thesis focuses on the synthesis of SA-modified amino acids and their  incorporation into model peptides. Later on, a more straightforward and versatile approach  was devised, consisting in the late-stage peptide functionalization with copper-catalyzed azide-  alkyne cycloaddition (CuAAC). This second strategy enabled efficient installation of SA  moieties onto pre-assembled peptides specific for two protein targets, namely SHP2 and  NEMO. Moreover, using human serum albumin as model target, the CuAAC protocol was  instrumental for the design of a new combinatorial approach to SA-tagged small molecules.  The final part of the work, carried out at the University of Tokyo, integrates SA-based reversible  covalent chemistry into the RaPID (Random nonstandard Peptides Integrated Discovery)  platform, paving the way to a novel strategy towards macrocyclic peptide libraries displaying a  Lys-engaging electrophile.  Overall, this work expands the chemical space of peptide-based RC ligands, providing new  synthetic and methodological tools to access selective, tunable covalent binders to target  specific proteins or to inhibit clinically-relevant protein-protein interactions.","language":"eng","citation":"SALICYLALDEHYDE-TAGGED PEPTIDES FOR THE REVERSIBLE-COVALENT ENGAGEMENT OF PROTEIN LYSINE RESIDUES / M. Mason ; tutor: A. Dal Corso ;  PhD coordinator: D. Passarella. - Milan. Dipartimento di Chimica, 2025 Jan 16. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13913.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 23-DIC-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1085089"},"title":"L'ENERGIA DEL COMMERCIO. IL RUOLO DEGLI SCAMBI DELLE FONTI D'ENERGIA NELLO SVILUPPO DELLA DDR","internalauthor":"SCOGNAMIGLIO, ANNA MARIA","type":"Tesi di dottorato","year":"2024","abstract":"In its short life, the German Democratic Republic was one of the most powerful symbols and one of the hottest Cold War flashpoints of the European continent. Its existence was marked by its ability to manage and maintain a balance in its relations with the two blocs, while at the same time ensuring a degree of internal stability that would guarantee the permanence of the SED regime.  Like all other states embedded in the increasingly globalized marketplace of the second half of the twentieth century, the East German state apparatus soon realized that one of the indispensable elements for consolidating its position was to strengthen its economic system, and that the foundation for its success was a sound energy security policy.  The interest of contemporary historical research in the energy sector and the impact of the oil shocks of the last century at the national and international level is growing, driven also by the need to understand the profound historical evolution of the networks of dependencies in the current energy market. However, the development of the energy sector of the GDR in particular, the use of sources by the state, the rules and the markets of energy exchange, remain understudied to this day.  Therefore, this paper, offers a new reconstruction of East Germany's development through the use of a perspective that adopts energy trade as a prism of observation, with a chronological focus on the development in the 1970s and 1980s, and specifically analyzes the policies, dynamics, negotiations and routes of buying and selling primary sources (lignite and oil) and secondary sources (petroleum products and electricity).  First, the genesis of the GDR's economic, then industrial and energy systems is outlined. In fact, in order to fully understand its subsequent transformation it is not possible to ignore the years during which the entire economic policy of the new State was conceived and imposed: thus, the general situation from which it evolved and the main features on which the new energy structure was based are outlined and framed in the general historical context of the birth of the “border state”, the dynamics of the Cold War and the creation of the various international economic organizations within the blocs.  It then analyzes the evolution of the energy system, considering the social and international context that the GDR had to deal with, up to the inevitable cooperation with West Germany before reunification. The main features of the economic and energy policies of the five-year plans, their adaptation to domestic needs, the economic and political goals to be achieved, and the upheavals in relations within Comecon and with other non-socialist countries are then highlighted. Some specific and original features of the use of some sources at the expense of others, the development of traditional and new trade routes aimed at ensuring a certain energy security - and, consequently, the economic stability and the proper functioning of the industrial sector - of the East German state are explored; the desired objectives and the concrete temporary and long-term results of the policies implemented are highlighted, as well as the perception that the government apparatus had of their importance in the general framework of state security.  The study reveals a close correlation between energy and economic dynamics, which at times conflicted with each other, but at other times underscored the political and international needs of the GDR. What also emerges is an abiding interest on the part of the state's governmental and decision-making apparatus in the energy trade, the securing of which remained until the very end one of the primary objectives of the SED's economic maneuvers and the foundation on which the country's stability was believed to rest, and which was therefore attempted to be managed to the very end, regardless of political propaganda.","language":"ita","citation":"L'ENERGIA DEL COMMERCIO. IL RUOLO DEGLI SCAMBI DELLE FONTI D'ENERGIA NELLO SVILUPPO DELLA DDR / A.m. Scognamiglio ; tutor: G. M. I. Lami ; cotutor: M. Elli. Università degli Studi di Milano, 2024 Sep 10. 36. ciclo","filename":"phd_unimi_R12826.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1085089/2499154/phd_unimi_R12826.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1116676"},"title":"SUSTAINABILITY OF AGRICULTURAL TRACTORS USAGE IN OPEN FIELD AND IN SPECIALIZED CROPS, FROM THE PERFORMANCE AND ENVIRONMENTAL STANDPOINTS","internalauthor":"GALLI, LAVINIA ELEONORA","type":"Tesi di dottorato","year":"2024","abstract":"\"In the current global context, environmental challenges are increasingly drawing attention to the impacts caused by fossil fuel-powered vehicles. Among these, self-propelled agricultural machines, which are predominantly equipped with diesel internal combustion engines, play a significant role. Diesel combustion produces various gaseous pollutants that are released into the atmosphere, including carbon monoxide (CO), unburnt hydrocarbons (HC) and, most notably, particulate matter (PM) and nitrogen oxides (NOx).  To mitigate the impact of these emissions, regulatory frameworks similar to the Euro standards for on-road vehicles were introduced also for non-road vehicles, including agricultural machinery, starting in 1996 in both Europe and the United States. These regulations have progressively imposed stricter limits on emissions for newly introduced vehicles.  As a result, manufacturers of internal combustion engines fitted on self-propelled agricultural machines have been compelled to implement technical improvements and/or additional devices to minimize pollutant emissions and comply with regulatory thresholds.   The primary aim of this study is to assess the performance of a number of selected tractor models, representative of the Italian machinery fleet, in terms of energy efficiency and gaseous pollutant emissions.   Experimental data were compared against current emission regulations, including also comparative assessments with older tractors that are not subject to these standards due to their technical obsolescence.  The methodological approach involved analysing specific fuel consumption (i.e. energy efficiency) and the concentration of key pollutants in exhaust emissions, taking into account the actual operating conditions of the tractors within the agricultural sectors in which they are typically employed. This approach enabled the calculation of the true efficiency of the machines under investigation, providing a comprehensive overview of their sustainability in use.  The experimental framework of this study is built upon three key pillars.  First pillar  The first pillar of this study focused on the comparative assessment of the energy efficiency of four tractors employed in performing ten agricultural tasks within the viticulture sector. For each task, the nominal and under-load engine speeds, torque, and power output at the PTO were identified, along with hourly fuel consumption. These values were then normalized by specific power to calculate specific fuel consumption.   To highlight the efficiency level of the tasks, the data obtained were classified using a \"\"traffic light\"\" system.  The specific fuel consumption of the tractors varies depending on both the model analysed for a given task and the operating conditions of the same tractor.   To facilitate a more immediate comparison of the energy efficiency and environmental impact of the tested machines, colour labels, assigned based on defined ranges of specific fuel consumption (SFC) values, were further classified into categories (ranging from A to G), providing a standardized evaluation.    Second pillar  The second pillar involved the preliminary definition of operational scenarios for various agricultural sectors. Each sector was associated with a specific tractor model, with detailed specifications of its working conditions. This approach enabled a comprehensive and realistic assessment of the environmental impact of each tractor under investigation.  Thanks to targeted simulations of real working conditions operated at fixed-point, pollutant gas emissions were measured and subsequently compared with the limits established by relevant regulations, adopting a color code to evaluate the emissions impact at a glance.   For each task, the duration and frequency of execution on an annual basis and for an average-sized farm were estimated to determine the overall impact of a specific tractor.   The obtained values enabled the calculation of emissions for each agricultural sector throughout the entire growing season, allowing for a comparative assessment that considers the overall environmental impact.    Third pillar  Gaseous pollutant emissions have long been recognized as harmful not only to the environment but also to human health. The third pillar of this study focused on analysing the acute and chronic effects of exposure to these emissions, drawing on evidence from medical literature, particularly regarding workers who are continuously exposed to exhaust fumes from internal combustion engines in a professional setting.   The most commonly reported health issues include respiratory, pulmonary and cardiovascular diseases. Recent research, however, has suggested a possible link between exposure to certain pollutants and the onset of neurodegenerative disorders.  The technical legislation in this area is at present significantly lacking, with no robust current regulations available to identify potentially harmful operating conditions.\"","language":"eng","citation":"SUSTAINABILITY OF AGRICULTURAL TRACTORS USAGE IN OPEN FIELD AND IN SPECIALIZED CROPS, FROM THE PERFORMANCE AND ENVIRONMENTAL STANDPOINTS / L.e. Galli ; tutor: D. Pessina ; coordinatore: R. S. Pilu. - Università degli studi di Milano. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2024 Dec 16. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13268.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1116676/2583099/phd_unimi_R13268.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1128936"},"title":"DA CAMPESINOS A PARAMILITARI: ORIGINE, CONSOLIDAMENTO ED ESPORTAZIONE DEL MODELLO URABÁ NELLE AUTODEFENSAS COLOMBIANE","internalauthor":"FOSSATI, MATTIA","type":"Tesi di dottorato","year":"2025","abstract":"This doctoral thesis analysis the history of Colombian paramilitarism in order to determine which elements influenced the transition of the juntas de autodefensas, originally created to carry out counterinsurgent activities, into structured criminal organizations dedicated to drug trafficking and to armed colonization of new territories. The research was structured along three lines of investigation, concerning the origin, consolidation and future prospects of paramilitary groups in Colombia. The study of the main periodizations allows for dividing paramilitarism into three historical phases, each of which expresses a particular paramilitary model. Using the methodology of historical research and various types of sources, this thesis documents the qualitative leap of paramilitary groups in Urabá region (Urabá model) compared to the previous experience in Puerto Boyacá (Magdalena Medio model). This particular organizational method was the key to spread the paramilitary phenomenon to other regions of Colombia and later to the consolidate the autodefensas groups in Urabá after the demobilization of the AUC.","language":"ita","citation":"DA CAMPESINOS A PARAMILITARI: ORIGINE, CONSOLIDAMENTO ED ESPORTAZIONE DEL MODELLO URABÁ NELLE AUTODEFENSAS COLOMBIANE / M. Fossati ; tutor: M.A.L.M. Rosti ;  co-tutor: G. A. Ruiz Romero ;  coordinatore: F. Basile. Dipartimento di Studi Internazionali, Giuridici e Storico - Politici, 2025 Apr 15. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13305.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1128936/2619979/phd_unimi_R13305.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1068913"},"title":"CHARACTERIZATION OF IMMUNE RESPONSE IN EXPERIMENTAL MOUSE MODELS","internalauthor":"BERTOLA, LUCA","type":"Tesi di dottorato","year":"2024","abstract":"This PhD research project aimed to investigate immune system functions in healthy and pathologic experimental murine models, through immunohistochemical characterization of immune cell populations in healthy steady state, inflammatory and neoplastic settings.  The following fields were investigated:    Study I – Mononuclear phagocyte system cells in murine healthy organs and selected pathological conditions.     Study II – Sex-dependent modulation of inflammation in a murine caerulein-induced acute pancreatitis model.    Study III – Comparison between two methods of digital image analysis (hot-spot fields vs whole-slide) for the assessment of immune cell infiltrations in a murine caerulein-induced acute pancreatitis model.    Study IV – Tumor immune system interaction in a murine model of orthotopic pleural mesothelioma.","language":"eng","citation":"CHARACTERIZATION OF IMMUNE RESPONSE IN EXPERIMENTAL MOUSE MODELS / L. Bertola ; supervisor: C. Recordati ; cosupervisor: C. Lecchi ; coordinatore: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2024 Jul 08. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13053.pdf","fileformat":"Adobe PDF","fileversion":"preprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1068913/2457715/phd_unimi_R13053.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1209821"},"title":"THE PERSISTENCE OF INDETERMINACY: CONTEMPORARY THEORIES AND KRIPKENSTEIN'S CHALLENGE TO  REPRESENTATIONAL CONTENT","internalauthor":"PAPIC, SARA","type":"Tesi di dottorato","year":"2026","abstract":"This thesis is concerned with the foundations of representational content. There is a familiar feature of words, sentences, beliefs, and perceptions: they are about, or mean, or represent something. The sentence “cats are cute” is about cats being cute, and my belief that cats are cute is also about cats being cute. Most things in the world are not about something else – they just are. In virtue of what, then, do words, sentences, beliefs, and perceptions represent the things they represent? In other words, in virtue of what do they have the contents that they do?  In Wittgenstein on Rules and Private Language (1982/1995), Saul Kripke argued that there is no fact of the matter about what we mean by our words. Though Kripke intended to target theories of meaning in the linguistic sense, his arguments ultimately challenge theories of mental content as well. The effects of Kripke’s argument have been devastating: Theories of content have struggled to avoid his sceptical paradox ever since. The aim of this work is to investigate and determine whether several contemporary approaches to meaning broadly understood meet the sceptical challenge Kripke set up nearly fifty years ago. These contemporary approaches include causal theories of reference, teleosemantic theories of mental content, and phenomenal intentionality theories. The result of my investigation is, unfortunately, negative. None of the contemporary approaches examined in this work successfully isolate what makes representations have the contents that they do.","language":"eng","citation":"THE PERSISTENCE OF INDETERMINACY: CONTEMPORARY THEORIES AND KRIPKENSTEIN'S CHALLENGE TO  REPRESENTATIONAL CONTENT / S. Papic ; tutor: E. Paganini ; coordinator: N. Guicciardini Corsi Salviati. Dipartimento di Filosofia Piero Martinetti, 2026 Jan 22. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13201.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1209821/3230338/phd_unimi_R13201.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1118274"},"title":"ON THE PROBABILISTIC MODELLING OF PAIN","internalauthor":"PATANIA, SABRINA","type":"Tesi di dottorato","year":"2024","abstract":"Pain is a complex subjective experience encompassing sensory, affective, and cognitive dimensions. Evidence challenges the linear relationship between nociceptive activation and pain perception, revealing scenarios where pain is felt without nociceptive input or vice versa. This research is based on the understanding that pain arises not merely from bottom-up stimuli but also from a blend of subjective components and contextual evaluations. The aim of this study is to develop a probabilistic and computational model of pain that aligns with both behavioural data and neurobiological constraints, aspiring to represent pain at various levels. This includes incorporating perceptual, affective, motivational, and social aspects into a comprehensive framework, and proposing implementation models tailored to specific contexts and varying levels of abstraction. The model uses Bayesian approaches to capture the probabilistic and dynamic nature of the phenomenon. The upcoming discussions will adopt a multidisciplinary lens, converging philosophical, psychological, and neurobiological insights to shape the envisaged model.","language":"eng","citation":"ON THE PROBABILISTIC MODELLING OF PAIN / S. Patania ; tutor: G. Boccignone; coordinatore: R. Sassi. - Milano. Università degli Studi di Milano, 2024 Oct 01. 36. ciclo [10.13130/patania-sabrina_phd2024-10-01].","filename":"phd_unimi_R12986.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1118274/2588544/phd_unimi_R12986.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1205593"},"title":"NEUROBIOLOGIA DEL SUICIDIO NEL DISTURBO DEPRESSIVO MAGGIORE: STUDIO MORFOLOGICO POST-MORTEM PER L¿INDAGINE DEL NETWORK GLIALE E VASCOLARE, CON ANALISI TOSSICOLOGICHE PER LA VALUTAZIONE DELL¿ADERENZA ALLA TERAPIA PSICHIATRICA","internalauthor":"TAMBUZZI, STEFANO","type":"Tesi di dottorato","year":"2026","abstract":"Suicide is one of the leading causes of death worldwide, with over 700,000 deaths each year. In recent years, numerous studies have focused on analyzing its epidemiology and predisposing factors. Among the biological factors involved, cerebral glial cells have attracted growing attention due to postmortem evidence linking their pathological alterations to major depressive disorder (MDD) and suicidal behavior. The research project underlying this thesis focused on the postmortem analysis of human brain tissue from individuals diagnosed with MDD who died by suicide, with the aim of investigating alterations in the glial network—astrocytes and microglia—as well as in cerebral vascularization, in brain regions involved in mood regulation and suicide vulnerability. The experimental approach combined morphological, immunohistochemical, and immunofluorescence techniques with tissue clearing and 3D reconstruction using the X CLARITY™ system. Additionally, a toxicological analysis was carried out to assess adherence to psychiatric pharmacological therapy in individuals with mood disorders undergoing treatment at the time of death. The analysis of astrocytic markers (GFAP – Glial Fibrillary Acidic Protein – , S100β – calcium binding protein S100β –, AQP4 – Aquaporin-4 –, ALDH1L1 – Aldehyde Dehydrogenase 1 Family Member L1) showed a trend toward increased cell number and marker expression in suicide cases, particularly in the dorsolateral prefrontal cortex (dlPFC) and white matter. GFAP/S100β colocalization patterns varied by sex and brain region, with higher expression and overlap in male suicide cases. Conversely, densitometric analysis revealed higher expression levels in females, with significant regional differences. No significant changes were observed in AQP4 expression, while pilot testing with ALDH1L1 validated the experimental staining protocol. Regarding microglia, the analysis of IBA1 (Ionized calcium-binding adapter molecule 1) and LEA (Lycopersicon esculentum Agglutinin) markers revealed reduced LEA/IBA1 colocalization in male suicide cases compared 11 to controls in the cortical areas examined. In contrast, increased colocalization was observed in the dlPFC of female suicide cases. Although these differences were not statistically significant, densitometric analysis indicated a trend toward reduced microglial activity in males and increased activity in females. The use of the X-CLARITY™ technique enabled high-resolution 3D reconstruction of glial and vascular architecture. Three-dimensional analysis revealed a statistically significant reduction in cerebral vascularization in suicide cases compared to controls, with a 52.8% decrease, suggesting a potential role of vascular network dysfunction in the pathophysiology of suicide. Finally, the toxicological investigation highlighted poor adherence to psychiatric therapy in individuals with mood disorders who died by suicide: in 70% of the cases analyzed, pharmacological levels were either absent or only partially consistent with prescribed therapy. Overall, the neuromorphological findings suggest the presence of complex and interconnected alterations in the glial and vascular networks in individuals with mood disorders who died by suicide, with notable differences based on sex and brain region. These findings contribute to a deeper understanding of the neurobiological mechanisms underlying suicidal behavior and open new avenues for research in neuropathological, clinical, and forensic contexts. Given that treatment adherence is a key factor in suicide prevention, prospective monitoring of postmortem drug levels, along with synergistic collaboration between clinicians and forensic pathologists, could improve the effectiveness of therapeutic interventions and support the development of more targeted suicide prevention strategies.","language":"ita","citation":"NEUROBIOLOGIA DEL SUICIDIO NEL DISTURBO DEPRESSIVO MAGGIORE: STUDIO MORFOLOGICO POST-MORTEM PER L' INDAGINE DEL NETWORK GLIALE E VASCOLARE, CON ANALISI TOSSICOLOGICHE PER LA VALUTAZIONE DELL' ADERENZA ALLA TERAPIA PSICHIATRICA / S. Tambuzzi ; tutor: C. Cattaneo ;  co-tutor: A. Amadeo ;  coordinatore: M. Guarino. Dipartimento di Scienze Biomediche per la Salute, 2026 Jan 19. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13973.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 05-LUG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/978209"},"title":"L'ABUSO DI DIRITTO NEL SISTEMA EUROPEO COMUNE DI ASILO","internalauthor":"COLOMBO, ERIKA","type":"Tesi di dottorato","year":"2023","abstract":"This doctoral thesis aims to analyze the legal category of the prohibition of abuse of rights within the complex framework of European Asylum law and the relevant case law on the matter. The main objective of the research is to ascertain the scope of this concept within the Common European Asylum System (CEAS), to assess whether it can be established and legitimately justified. To do so, the research activity has been focused, first, on the notion of “abuse of rights” as elaborated by the European Court of Justice and as qualified by the relevant literature, with reference to other EU Law areas other than the CEAS.  Through the analysis of this notion in different EU Law areas, I established a classification method that allowed me to categorize various abusive conducts in the wider framework of European Asylum law.  Specifically, the classificatory method has been based upon i) the characteristics of the practices qualified as “abusive”; and ii) the legal qualification variously attributed to the prohibition of the abuse of rights. At the same time, I considered relevant for the research an accurate definition of the right to asylum, evaluated both from the perspective of international law, and in the light of the secondary law instruments adopted within the framework of the Common European Asylum System. This in-depth analysis has been necessary considering the complexities that characterize this right, both from a subjective point of view, with reference to the identification of the holder of such a legal position, and from an objective point of view, with respect to the definition of its content. Finally, I addressed the issue of the prohibition of abuse within the context of the Common European Asylum System by applying the classification method elaborated above. First, I identified the references to the notion of “abuse” within the EU Asylum legal framework and the jurisprudence of the Court of Justice of the EU. Then, I tried to draw potential conclusions on the qualification and the legal significance of this concept. An issue accompanied the entire analysis: since different notions of the right to asylum can be considered – which alternatively identify the State or the individual as the right holder –, it is necessary to identify who is actually responsible for the abuse: the asylum seeker or, rather, the State.","language":"ita","citation":"L'ABUSO DI DIRITTO NEL SISTEMA EUROPEO COMUNE DI ASILO / E. Colombo ; tutor: A. Lang ; coordinatore: F. Biondi. Dipartimento di Studi Internazionali, Giuridici e Storico - Politici, 2023 Jul 04. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12577.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/978209/2226216/phd_unimi_R12577.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/901810"},"title":"A PROPAGATION OF SINGULARITIES THEOREM AND A WELL-POSEDNESS RESULT FOR THE KLEIN-GORDON EQUATION ON ASYMPTOTICALLY ANTI-DE SITTER SPACETIMES WITH GENERAL BOUNDARY CONDITIONS","internalauthor":"MARTA, ALESSIO","type":"Tesi di dottorato","year":"2022","abstract":"In this thesis we study the Klein-Gordon equation on asymptotically anti-de Sitter (aAdS) spacetimes with boundary conditions implemented by pseudodifferential operators (PDOs) of order up to 2. Using techniques of microlocal analysis and b-calculus, we prove two propagation of singularities theorems, one for pseudodifferential operators of non-positive order and one for PDOs of order 0 < k <= 2, and we establish a well-posedness result in certain twisted Sobolev spaces. In particular, we discuss the existence and uniqueness of the advanced and retarded fundamental solutions for the Klein-Gordon equation with prescribed boundary conditions and we characterize their wavefront set. At last, as a concrete application, we build the fundamental solutions for a massless Klein-Gordon equation on a static aAdS spacetime with admissible boundary conditions using the formalism of boundary triples.","language":"eng","citation":"A PROPAGATION OF SINGULARITIES THEOREM AND A WELL-POSEDNESS RESULT FOR THE KLEIN-GORDON EQUATION ON ASYMPTOTICALLY ANTI-DE SITTER SPACETIMES WITH GENERAL BOUNDARY CONDITIONS / A. Marta ; supervisori: L. Pizzocchero, C. Dappiaggi ; coordinatore: V. Mastropietro. Dipartimento di Fisica Aldo Pontremoli, 2022 Jan 27. 34. ciclo, Anno Accademico 2021. [10.13130/marta-alessio_phd2022-01-27].","filename":"phd_unimi_R12297.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/901810/1965637/phd_unimi_R12297.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1041712"},"title":"OPERANDO X-RAY ABSORPTION SPECTROSCOPY STUDIES OF (PHOTO)ELECTRODE MATERIALS FOR H2 PRODUCTION/CONVERSION","internalauthor":"HE, XIUFANG","type":"Tesi di dottorato","year":"2024","abstract":"The field of hydrogen economy has emerged due to energy scarcity and environmental pollution. As a result, there is a growing emphasis on the development of efficient generation and storage solutions for hydrogen, along with its utilization as a clean, renewable fuel source to generate electricity to meet human activities. In this sense, it involves various electrochemical reactions, and one of the main tasks is understanding the reaction mechanisms in the reaction process to rationally design high-efficiency electrodes. Therefore, this thesis is focused on this topic.  In this thesis, the works mainly contain 3 parts:  (1) Transition metals (Fe, Cu, Mn) are used to dilute or alternate expensive electrode materials for oxygen reduction reaction (ORR), oxygen evolution reaction (OER), and photoelectrochemical water splitting. The prepared electrodes were characterized by a series of advanced techniques, including scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray absorption spectroscopy (XAS), X-ray diffraction (XRD), and Brunauer–Emmett–Teller (BET) analysis.   (2) The electrochemical performance, reaction mechanism, charge transfer kinetics, and overpotential of the synthesized electrodes were rigorously evaluated by cyclic voltammetry (CV), Linear sweep voltammetry (LSV), and Tafel slope.   (3) Operando X-ray absorption spectroscopy (XAS), as an elemental selective and powerful technique, was utilized to obtain specific elemental electronic structure information (such as the oxidation state, and coordination number) and illustrate the reaction mechanisms over electrodes during above mentioned reaction. At the same time, the pump and probe XAS technique was applied to illustrate the photoinduced electron transfer path during the photoelectrochemical water splitting process.   Finally, operando XAS stands as a cornerstone in this investigation, offering a deeper understanding of the electronic structures of the electrodes in real time. It provides insights into the rational design or regeneration strategies for electrodes in the development of efficient and sustainable energy production and conversion technologies","language":"eng","citation":"OPERANDO X-RAY ABSORPTION SPECTROSCOPY STUDIES OF (PHOTO)ELECTRODE MATERIALS FOR H2 PRODUCTION/CONVERSION / X. He ; supervisor: A. Minguzzi ; co-supervisor: A Vertova, M. Fracchia ; coordinator: D. Passarella. - Milano. Dipartimento di Chimica, 2024 Mar 27. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12954.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1041712/2389617/phd_unimi_R12954.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1123757"},"title":"SARCOPENIA, LIVER AND CARDIOVASCULAR ALTERATIONS IN A MULTICENTRIC COHORT OF PATIENTS WITH MASLD: EVALUATION OF CLINICAL PRESENTATION AND GENETIC PREDISPOSITION","internalauthor":"CESPIATI, ANNALISA","type":"Tesi di dottorato","year":"2024","abstract":"Background and Aims: Sarcopenia, characterized by the progressive loss of skeletal muscle mass (SMM), strength, and function, is not solely an age-related condition but is also associated with several diseases, including chronic liver disease (CLD) and cardiovascular (CV) disease. Metabolic-dysfunction associated steatotic liver disease (MASLD) is defined by the presence of liver steatosis combined with, at least, one cardiometabolic risk factor, with liver fibrosis serving as a critical determinant of liver-related and CV-related events and mortality. Sarcopenia is highly prevalent in advanced MASLD, although recent studies have highlighted myosteatosis, the accumulation of fat within muscle, as a key driver of liver disease progression. Studies conducted mainly in Asia have reported a high prevalence of sarcopenia even in early MASLD, though it is not routinely assessed. Both sarcopenia and MASLD contribute to atherosclerotic CV damage, especially in the presence of advanced liver fibrosis, and share common pathogenetic mechanisms such as insulin-resistance (IR), low-grade chronic systemic inflammation, mitochondrial dysfunction, and oxidative stress. Additionally, genetic predisposition plays a role in MASLD, with specific polymorphisms in PNPLA3, TM6SF2, MBOAT7, and GCKR promoting severe liver disease, while the HSD17B13 variant appears protective against MASLD. Despite this background, most studies evaluating the relationship between sarcopenia, MASLD, and CV disease are cross-sectional, primarily involving Asian populations, limiting the generalizability of findings and the ability to determine whether the relationship is bidirectional. Furthermore, the absence of standardized criteria for diagnosing sarcopenia in MASLD complicates comparisons across studies, leading to conflicting results. To date, no studies have yet explored the role of genetic variants predisposing to MASLD in the risk of developing sarcopenia and CV damage. This project aims to address these gaps by 1) evaluating the impact of sarcopenia on liver and CV damage in non-cirrhotic MASLD patients, 2) investigating the influence of MASLD-related genetic variants on muscle mass and CV damage, and 3) assessing changes in muscle, liver, and CV parameters over a 5-year follow-up in a subset of patients.  Methods: 856 non-cirrhotic MASLD patients were recruited from liver outpatient clinics in Milan, Palermo, and London. At enrollment, anthropometric, demographic, and laboratory data were collected. Liver steatosis was assessed using abdominal ultrasound (US) and controlled attenuation parameter (CAP) measurements via Fibroscan, while liver fibrosis was evaluated using liver stiffness measurement (LSM) at Fibroscan. Severe steatosis was defined as CAP > 280 dB/m, and advanced fibrosis was identified as LSM ≥ 8 kPa. Liver biopsies were performed on 370 patients. Sarcopenia was assessed using bioelectrical impedance analysis (BIA), a non-invasive and radiation-free technique, with the skeletal muscle index (SMI) calculated as SMM/height^2. Patients were divided into gender-specific tertiles based on SMI (lowest, middle, and highest). CV damage was evaluated using carotid doppler US, with carotid intima-media thickness (cIMT) ≥ 0.9 mm or carotid plaques indicating CV damage. In 502 patients, epicardial fat thickness (EFT) was measured via echocardiography, and carotid-femoral pulse wave velocity (cfPWV) via tonometry. EFT ≥ 9.5/7.5 mm in men/women was considered a marker of visceral adiposity, while EFT ≥ 5.2 mm was associated with coronary artery disease. cfPWV > 10 m/sec was used as a marker of arterial stiffness. CV risk was calculated for all patients using SCORE2 and SCORE2-OP algorithms according to European Society of Cardiology (ESC) guidelines, with SCORE2-Diabetes applied to diabetic patients. Genetic polymorphisms in PNPLA3, TM6SF2, MBOAT7, GCKR, and HSD17B13 were analyzed in 437 patients. Finally, 104 patients underwent a 5-year follow-up to reassess muscle mass at BIA, CAP and LSM, cIMT and carotid plaques, and EFT.  Results: Patients had a mean age of 51 years, with 63% males. Patients in the lowest SMI tertile were older (54 vs 48 years, p<0.001), had lower body mass index (BMI) (27 vs 33.4 kg/m2, p<0.001), lower waist circumference (WC) (99 vs 110 cm, p<0.001), higher prevalence of dyslipidemia (56% vs 46%, p=0.03) compared to those in the highest tertile. Regarding liver damage, patients in the lowest SMI tertile had lower CAP (293 vs 317 dB/m, p<0.001), LSM (4.9 vs 6.4 kPa, p<0.001), grade 3 fibrosis prevalence (20% vs 25%, p=0.009), and MASH rates (30% vs 53%, p=0.04) compared to those in the highest tertile. For CV damage, patients in the lowest SMI tertile had a higher percentage of patients with increased cIMT (p=0.01). No significant associations were observed between SMI and the genetic polymorphisms studied. In the lowest SMI tertile, PNPLA3 CG/GG variant was linked to increased LSM (OR 1.82, p=0.03), lower cIMT (OR 0.39, p=0.04), and increased cfPWV (OR 2.1, p=0.01). The TM6SF2 wild-type allele was associated with increased cIMT (OR 3.4, p=0.004), while the CT/TT variant correlated with reduced hypertension (OR 0.09, p=0.02) and lower WC (OR 0.25, p=0.02) in the lowest SMI tertile. In multivariate analysis, low SMI was significantly associated with lower BMI (OR 0.61, p<0.001), lower WC (OR 0.92, p=0.001), female sex (OR 2.21, p=0.008), increased cIMT (OR 2.10, p=0.02), and slightly older age (OR 1.04, p=0.002). Among hypertensive MASLD patients, low SMI was independently associated with increased cIMT (OR 2.06, p=0.03) and cfPWV (OR 2.73, p=0.03). In non-diabetic MASLD patients, low muscle mass was associated with increased cIMT (OR 1.66, p=0.03), carotid plaques (OR 1.56, p=0.02), less fibrosis on histology (OR 0.29, p=0.04), lower ALT levels (OR 0.54, p=0.001), higher LDL (OR 4.38, p=0.02), and lower HDL (OR 1.03, p=0.002). At 5-year follow-up, a significant reduction in mean BMI (29.1 vs 28.4, p=0.001), a decrease in patients in the lowest SMI tertile (42% vs 22%, p<0.001), and a regression of steatosis in 9% of patients, with significant reductions in CAP (300 vs 289 dB/m, p=0.02) and LSM≥8 kPa prevalence (17% vs 7%, p<0.001) were observed. Regarding CV damage, a significant increase in carotid plaques (34% vs 54%, p<0.001), mean EFT (7.5 vs 9.0 mm, p<0.001), and high CV risk categorization (56% vs 63%, p=0.004) were observed. Baseline low muscle mass was significantly associated with changes in delta LSM (HR 2.30, p=0.013), BMI (HR 0.61, p=<0.001), and dyslipidemia (HR 5.74, p=0.007) at follow-up.   Discussion: This multicentric study revealed a significant independent relationship between sarcopenia and increased markers of atherosclerotic damage in non-cirrhotic MASLD patients, particularly among those with hypertension and without diabetes. Notably, patients with low muscle mass exhibited a lower prevalence of liver damage, possibly due to reduced visceral adiposity. However, longitudinal analysis demonstrated that low muscle mass was independently associated with an increase in mean LSM, suggesting that sarcopenia contributes to liver damage progression over time. Additionally, while persistent low muscle mass appeared to exacerbate CV damage, a definitive independent association was not observed, possibly due to the relatively short duration of follow-up. The study also identified a protective effect of the TM6SF2 polymorphism against CV damage, underscoring its potential role in mitigating CV risk.   In conclusion, this research highlights the importance of integrating imaging techniques to evaluate both liver and CV damage alongside genetic profiling for a more holistic understanding of the interplay between sarcopenia and CV damage in non-cirrhotic MASLD patients. Preserving muscle mass emerges as a key strategy for preventing both liver and CV diseases, and future public health initiatives should prioritize interventions aimed at supporting and enhancing muscle mass health.","language":"eng","citation":"SARCOPENIA, LIVER AND CARDIOVASCULAR ALTERATIONS IN A MULTICENTRIC COHORT OF PATIENTS WITH MASLD: EVALUATION OF CLINICAL PRESENTATION AND GENETIC PREDISPOSITION / A. Cespiati ; tutor: A L. Fracanzani ; supervisore: R. Lombardi ; coordinatore: M. Del Fabbro. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2024 Dec. 37. ciclo","filename":"phd_unimi_R13405_2.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1123757/2606092/phd_unimi_R13405_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1119197"},"title":"SOMATIC SIGNALS REGULATING MRNA TRANSLATION IN MAMMALIAN OOCYTE.","internalauthor":"LADRON DE GUEVARA, MAGDALENA","type":"Tesi di dottorato","year":"2024","abstract":"In oocytes, resumption and completion of meiosis I are driven by post-transcriptional mechanisms on a background of repressed mRNA transcription. However, a comprehensive understanding of this regulation in higher-order mammals has been limited by challenges in isolating polysome-associated mRNAs. This study aims to shed light on these processes and how they can be affected by in vitro maturation (IVM). This objective has been pursued through three sequential steps that addressed the specific aims.   First, we employed a bioinformatics approach to gain information on mRNA polysome association (GSE56603 and GSE196484) and polyadenylation (GSE61717) in immature and in vitro matured bovine oocytes. The GEO-retrieved datasets were re-analyzed to determine differentially polyadenylated/polysome-associated genes using edgeR. While the overlap of differentially polyadenylated/polysome-associated genes between datasets was limited when comparing mature oocytes (27 genes), all comparisons conducted in immature oocytes were substantial (372 genes p<0.05). These findings indicate that the experimental approaches potentially yield comparable results, but that this homogeneity is lost with IVM, possibly suggesting that culture conditions contribute to changes in mRNA translation patterns. Next, we tested whether hormones/growth factors supplementation may participate in the regulation of the translation of some maternal transcripts by activating the oocyte PI3K/AKT/mTOR axis in bovine oocytes, as demonstrated for mice. For this, the previously mentioned datasets were compared with polysome-associated transcripts of mouse oocytes exposed to the EGF-like growth factor, amphiregulin (GSE46640). Notably, one bovine dataset showed a significant correlation with EGF network activation, supporting, at least in part, the observation that IVM conditions might affect mRNA translation.  Secondly, to experimentally confirm the role of the EGF network, we monitored AKT phosphorylation during IVM using western blots in bovine oocytes and immunofluorescence in bovine and human oocytes. We observed significant phosphorylation in response to amphiregulin, indicating activation of the pathway. Furthermore, the activation of the PI3K/AKT/mTOR pathway required the physical presence of cumulus cells (CCs). AKT phosphorylation during rescue IVM of denuded human immature oocytes, as predicted by our model, failed to activate, providing a putative explanation for the suboptimal outcomes of rescue IVM in humans.  Third, to understand if AKT activation affected translation, we investigated polyadenylation in target transcripts using two approaches. The first method attempted to indirectly catch differences in the reverse transcription efficiency in association with short or long poly(A) tail. The mRNA was split in half and reverse transcribed using random hexamers or oligo(dT). This assay did not highlight differences between immature and mature oocytes or IVM conditions. The second method consisted in directly assaying the poly(A) tail length in target transcripts and revealed significant polyadenylation in genes related to cell cycle progression and spindle stabilization such as AURKA and NEDD1, in amphiregulin-supplemented IVM. Furthermore, this assay allowed to assess that the poly(A) tail in immature oocytes was 100 bp-long, providing an explanation for the inability of observing differences when using random hexamers and oligo(dT).  Since the extension of the poly(A) tail is necessary for polysome association and translation, these results confirm that, despite differences in timing and initial tail length, also in higher-order mammals, translation of genes crucial for proper oocyte maturation are regulated by the EGF network, likely through PI3K/AKT/mTOR.  This research provides a mechanistical explanation of the empirical observations that hormones/growth factors supplementation and structural integrity of the cumulus-oocyte complex affect the quality of the in vitro matured bovine oocytes.","language":"eng","citation":"SOMATIC SIGNALS REGULATING MRNA TRANSLATION IN MAMMALIAN OOCYTE / M. Ladron De Guevara ; tutor: F. Franciosi ; co-tutor: V. Lodde ; coordinatore:  F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2024 Dec 05. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13185.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1119197/2592753/phd_unimi_R13185.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/954904"},"title":"EFFECT OF CIGARETTE SMOKING ON CARDIORESPIRATORY AND METABOLIC RESPONSE TO DIFFERENT PROTOCOLS IN YOUNG ACTIVE MALES","internalauthor":"BORRELLI, MARTA","type":"Tesi di dottorato","year":"2023","abstract":"Cigarette smoking is one of the most impacting risk factors for cardiopulmonary morbidity and a major cause of mortality. It leads to systemic modifications that alter the cardiorespiratory and metabolic response at rest and during exercise. Indeed, stimulates the sympathetic nervous system, elevating the heart rate (HR) and cardiac work. Likewise, tar impairs O2 diffusion across the alveolar-capillary barrier, and carbon monoxide reduces O2 transport and extraction. The analysis of the cardiorespiratory and metabolic transitions at different work rates can provide insights in the O2 transport and delivery mechanisms. Hence, this dissertation aimed to provide a comprehensive examination of the effect of cigarette smoking on the cardiorespiratory and metabolic responses to exercise in young, physically active males. The smokers, compared to a no-smoker group, were evaluated in different exercise protocols: i) moderate intensity square-wave work rates to assess the cardiorespiratory and metabolic kinetics; ii) incremental stepwise protocols to determine the maximum oxygen uptake (V ̇_(O_2 max)), a benchmark for cardiorespiratory fitness, recovery kinetics, and exercise capacity; iii) moderate and iv) heavy intensity sinusoidal work rates. Cigarette smoking has detrimental effects on cardiorespiratory and metabolic response to different exercise protocols in young, physically active males. Despite young age, high fitness level and similar pulmonary function, the smokers were characterized by slower cardiorespiratory and metabolic kinetics during moderate exercise and during the recovery of an incremental test. Interestingly, there were no differences between the smokers and controls during both sinusoidal exercises, except for a shorter time to exhaustion that may suggest peripheral dysfunction.","language":"eng","citation":"EFFECT OF CIGARETTE SMOKING ON CARDIORESPIRATORY AND METABOLIC RESPONSE TO DIFFERENT PROTOCOLS IN YOUNG ACTIVE MALES / M. Borrelli ; advisor: F. Esposito ; phd coordinator: C. Sforza. Dipartimento di Scienze Biomediche per la Salute, 2023 Apr 18. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12499.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/954904/2142076/phd_unimi_R12499.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1135295"},"title":"APPLY LADDER OF CHEMICAL CIRCULARITY: RECYCLING OF RARE EARTH ELEMENTS RECOVERED FROM ELETRONIC WASTE AS A CATALYST IN ORGANIC REACTION.","internalauthor":"DONATO, EMANUELA","type":"Tesi di dottorato","year":"2025","abstract":"This thesis investigates the application of lanthanide-based Lewis acids and copper  catalysts in asymmetric and homogeneous catalysis, with a specific focus on  continuous flow chemistry.  The research extensively examines the Michael addition reaction between indoles and  benzylidene malonates, employing these catalysts to achieve high reaction efficiency  and selectivity. Additionally, a Diels-Alder cycloaddition was performed using chiral  auxiliaries, promising results in terms of both reaction yield and enantioselectivity.  The thesis also explores sustainable catalytic approaches by testing reactions using  fluorescent lamps recovered from electronic waste (e-waste), achieving significant  results in various catalytic environments, including homogeneous, heterogeneous,  and continuous flow systems.  During my period abroad in the group of Prof. C. Stevens at Ghent University, I  further investigated the synthesis of aminotriazoles via a sequential Cu(I)-catalyzed  dipolar cycloaddition (between azido pyridine and propiolate) followed by Cu(II)-  catalysed C-H amination (through reaction with an amine), which resulted in  satisfactory yields and selectivity. These results are reported in Chapter 5.  The final part of the thesis is focused to the synthesis of Tezacaftor, focusing on an  alternative and simplified synthetic protocol. Specifically, this study investigates the  5-endo cyclization of 2-(alkynyl)-anilines to indoles, a reaction traditionally known  to proceed under Pd-catalysis but successfully carried out under Zn(II) catalyst. This  approach offers a more accessible and potentially more sustainable route for the  synthesis of this important pharmaceutical compound. The results are reported in  Chapter 6.","language":"eng","citation":"APPLY LADDER OF CHEMICAL CIRCULARITY: RECYCLING OF RARE EARTH ELEMENTS RECOVERED FROM ELECTRONIC WASTE AS A CATALYST IN ORGANIC REACTIONS / E. Donato ; tutor:  M. Benaglia ; co-tutor:  S. Rossi ; PhD coordinator:  L. Prati. - Università degli Studi di Milano. Dipartimento di Chimica, 2025 Jan 20. 37. ciclo","filename":"phd_unimi_R13648.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1135295/2635208/phd_unimi_R13648.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1227935"},"title":"GEOGRAPHY AND CYBERSPACE.  THE FORGOTTEN RELEVANCE OF TERRITORY FOR DIGITAL POWER","internalauthor":"LANDONI, EDOARDO MARIA","type":"Tesi di dottorato","year":"2026","abstract":"By stepping away from disembodied accounts of cyberspace, this study recasts the digital order as irreducibly spatial and materially grounded. While it is true that cyberspace is a great “destroyer” of distances and in some ways “leveler” of places, it is nevertheless impossible to think of it without considering its underlying base of physical networks still exposed to the constraint of location, the action of the atmospheric elements, the “centripetal force” of territoriality, and the control of actors exercising political power over the territory. It is precisely this materiality − and the nexus linking cyberspace, geography, and the territoriality of political power, including its digital expressions − that constitutes the core focus of this dissertation.  Two research questions guide the inquiry. First, how do geographical factors condition the global distribution and topology of core infrastructures? Second, to what extent does the pursuit of cyber power translate into territorial strategies of governance by great powers? The design is mixed-methods. Chapter I offers a critical genealogy of cyberspace that dismantles the liberal, immaterial vision and identifies three phases from strategic genesis to securitized contestation. Focusing on the United States, it documents the move from market-driven to state-centered governance and argues for reintegrating spatial and geopolitical analysis to explain cyber power and digital sovereignty. Chapter II maps submarine fiber-optic cables, landing stations, and data centers. Through historical reconstruction, GIS-based spatial analysis, and graph metrics, it advances and tests four hypotheses: (1) cables disproportionately concentrate around maritime chokepoints; (2) the cable system is hierarchical, with a limited set of states anchoring connectivity and regional brokers linking clusters; (3) data centres are highly concentrated in advanced, digitally interconnected regions; and (4) siting reflects a balance between climatic advantages and energy stability, avoidance of multihazard areas, and proximity to large demand basins to compress latency. The empirical work integrates purpose-built datasets on cables, landing sites, and data-center locations with climate surfaces, multihazard exposure, and gridded population density. Chapter III shifts to agency through a comparative analysis of the United States and China. Reading doctrines, regulatory instruments, industrial policy, and outward infrastructure initiatives, it traces how states territorialize the cloud by localizing and protecting data, constraining extraterritorial leverage, subsidizing domestic ecosystems, projecting standards abroad, and financing external cables and facilities. The chapter advances the claim that cyber power hinges on positional centrality: the ability to occupy, build, and govern pivotal nodes and corridors that convert connectivity into political, economic, and security leverage.  Findings are threefold. First, the submarine cable network is highly concentrated at classic maritime chokepoints and regional gateways; networks centrality metrics indicate that a small number of states function as system anchors, while others act as brokers linking clusters. Second, the global distribution of data centers is patterned rather than random: facilities agglomerate where cooler climates and reliable, affordable power coincide with proximity to dense demand and low-latency routes, while exposure to extreme hazards is frequently underweighted in siting decisions. Third, centrality operates less as an equalizer than as a power multiplier: actors located at or near the core are better positioned to regulate flows, surveil or interdict adversaries, and set technical and legal standards, whereas peripheral actors face structural dependence. The United States’ incumbency in infrastructures and platforms, and China’s efforts to construct parallel ecosystems, illustrate how spatial and territorial logics and network position reproduce hierarchy and intensify rivalry.  The dissertation contributes directly to neo-classical geopolitical scholarship, showing that geography continues to shape even the ostensibly virtual domain of cyberspace. Using historical reconstruction, GIS mapping, and network metrics, it demonstrates how chokepoints, jurisdictional embedding, and path dependence generate durable, unequal topologies. Building on this foundation, it contributes to strategic studies by explaining how positional centrality at nodes and corridors yields bargaining power and coercive options; and to IR debates on great-power behavior by showing U.S.–China convergence on territorially anchored infrastructural strategies.   From the findings of this work stems two clear policy recommendations. First state should prioritize infrastructural redundancy where topology concentrates risk by funding disjoint cable routes and inland backhauls, requiring dual landings, hardening critical crossings, and pre-arranging mutual-aid and repair access; especially since markets under-provide redundancy on marginal routes. Second, ensure that critical infrastructures can shift rapidly to an “islanded” territorial air-gapped posture when compromise is suspected − preserving core functions and containing propagation − through architectures that support fast, scoped disconnection and tested restoration procedures.   Taken together, the dissertation reframes cyberspace as an infrastructural and territorial domain in which geographic position and material networks condition power, and reconstructs an image of it not as a borderless global common but rather as a polycentric, semi-sovereign patchwork. Cables and data centers cluster at chokepoints; central actors convert positional centrality into regulatory, economic, and coercive leverage; and great powers territorialize the “cloud” through localization, standards projection, and outward infrastructure finance. Prospectively, interconnection will persist through selective gateways shaped by territorial strategies and political blocs. Two non-exclusive pathways are likely to co-evolve: firstly, bloc consolidation around U.S.- and China-anchored ecosystems with managed, treaty-like interoperability. Secondly, layered substitution that adds incremental flexibility (e.g., low-Earth-orbit satellites constellations) without, however, eliminating completely geographical chokepoint vulnerabilities exposure. The policy recommendation is thus to optimize exposure: remain central enough to shape rules and reap scale, while embedding redundancy, and emergency authorities to absorb shocks and resist coercion. In the coming decade, performance will hinge on the capacity to keep systems interoperable in ordinary times while shielding critical functions in crises − without allowing emergency measures to ossify into permanent fragmentation.","language":"eng","citation":"GEOGRAPHY AND CYBERSPACE.  THE FORGOTTEN RELEVANCE OF TERRITORY FOR DIGITAL POWER / E.m. Landoni ; supervisore: A. Carati ;  co-supervisore: A. Locatelli. - Università degli Studi di Milano. Dipartimento di Studi Internazionali, Giuridici e Storico - Politici, 2026 Apr 07. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13800.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1227935/3282871/phd_unimi_R13800.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1000488"},"title":"PATHOPHYSIOLOGY OF VON WILLEBRAND FACTOR IN BLEEDING AND THROMBOSIS","internalauthor":"PAGLIARI, MARIA TERESA","type":"Tesi di dottorato","year":"2023","abstract":"von Willebrand factor (VWF) is a multimeric glycoprotein mainly known to be involved in primary hemostasis recruiting platelets at the site of damaged vessels and acting as factor VIII (FVIII) carrier.  Quantitative or qualitative alteration of VWF protein is responsible for von Willebrand disease (VWD). Conversely, increased VWF levels have been found to be associated to different thrombotic disorders such as arterial thrombosis, ischemic stroke and venous thromboembolisms. The dual role of VWF in both bleeding and thrombosis, with a focus on VWD and deep vein thrombosis (DVT), are discussed in this thesis.   In the first part, we described the approach used to perform VWD diagnosis, including the use of in silico tools and heterologous cell systems to confirm the disease-causing role of VWF variants.  In Chapter 2, we described the approach used to perform a differential diagnosis between type 2A and 2B VWD in a pediatric patient carrying a de novo and novel variant. The biochemical characterization allowed us to exclude type 2M due to a loss of high molecular weight multimers and reduced VWF:CB. The finding of a novel deletion, despite its localization in the A2 domain, did not allow for discrimination between type 2A and 2B VWD. The conventional approach would require to perform the ristocetin-induced platelet aggregation (RIPA) to discriminate type 2B VWD from the other type 2. This assay needs a relatively large amount of fresh blood, which is especially undesirable in the case of a pediatric patient. Therefore, we opted for an alternative approach using a platelet-dependent VWF activity (VWF:GPIbM) ELISA. This assay is able to discriminate type 2B VWD patients from the other type 2 VWD patients and it can be done using a small amount of frozen plasma sample. This led us to confirm that our patient was affected by type 2A VWD.   In Chapters 3 and 4, we combined the use of predictive in silico tools and heterologous cell systems to prove the pathogenic role of the VWF variants identified in our VWD patients. In both chapters, in vitro expression studies have been performed by transient transfection of wild type and mutant expression vector into HEK293 cells. In Chapter 3, we evaluated the effect of the previously reported type 1 variant p.Arg1379Cys, identified in five unrelated patients. Of them, one was diagnosed as affected with type 1 VWD, whereas the other four had a type 2M diagnosis. These latter patients also carried a polymorphism p.Ala1377Val, which role has been initially underestimated. The in silico evaluation showed that both variants destabilize the A1 domain, leading us to hypothesize a synergistic effect resulting in a decreased capacity of VWF to bind GPIb. Then, we tested the capacity of the wild-type, mutant, and hybrid recombinant (r) VWF to bind recombinant glycoprotein Ibα (rGpIbα) in presence of an increasing concentration of ristocetin. In this way, we were able to confirm that the synergistic effect exerted by these two variants was responsible for patients’ type 2M phenotype.   Chapter 4 described the characterization of two unrelated Italian patients diagnosed as affected by type 1 VWD. Both were found to be heterozygous carriers for the same novel variant p.Thr274Pro localized in the VWF propeptide (VWFpp). This variant showed a dominant negative effect in contrast with other previously reported variants found nearby it, which have been described to be responsible for type 3 or type 2A/IIC VWD.  Therefore, we decided to perform an in vitro study including immunofluorescence with the aim to elucidate the disease-causing mechanism. Our results showed that the p.Thr274Pro was responsible for patients’ phenotypes through a combined mechanism including defective synthesis, secretion and an impaired multimerization process.  The second part of this thesis focused on the characterization of type 3 VWD,  the rarest and most severe manifestation of this bleeding disorder. In Chapter 5 we evaluated if the VWFpp over VWF antigen (VWF:Ag) ratio and FVIII coagulant activity (FVIII:C) over VWF:Ag ratio can be used to determinate the pathophysiological mechanism of this disease. We showed that the VWFpp/VWF:Ag ratio was able to identify homozygous/compound heterozygous carriers for a missense variant as already described for type 1 VWD patients. Moreover, it also indicated that the extremely reduced VWF levels measured in these patients were at least partly due to a faster VWF clearance from the circulation. On the contrary, FVIII/VWF:Ag ratio failed to discriminate carriers for null defects from those carrying missense variants.  Treatment for type 3 VWD patients includes the administration of concentrates containing VWF or rVWF. The development of VWF alloantibodies and/or anaphylactic reactions are rare but important side effects of replacement therapy administrated to type 3 VWD patients.  In Chapter 6, the prevalence of alloantibodies against VWF in the 3WINTERS-IPS cohort has been assessed. Because of the lack of a gold-standard, we chose to carry out an indirect ELISA assay able to detect all anti-VWF antibodies and a Bethesda-based method using VWF:CB. Anti-VWF alloantibodies were found in 8.4% of the study population. We confirmed that the development of neutralizing antibodies represents a rare event with a prevalence of 6% and it is mainly found in type 3 patients homozygous for null defects. Two other Bethesda-based methods using either VWF:GPIbM or VWF:Ag ELISA were performed in subgroups of patients. Both methods were able to identify VWF inhibitors in a lower number of patients. However, the Bethesda-based method using VWF:GPIbM identified a further patient who tested negative for VWF:CB inhibitors. Taken together, these data confirmed that prevalence estimation is strongly affected by the epitope recognized by the alloantibodies and therefore by type of assay used.   Last part of the thesis aimed to evaluate whether the reduction of ADAMTS13 activity or the alteration of ADAMTS13-VWF equilibrium may play a role in DVT pathogenesis.   In Chapter 7, we performed a case-control study to evaluate the association between ADAMTS13, VWF, and FVIII plasma levels and DVT. We showed that a slight decrease in ADAMTS13 activity levels was associated with a moderately increased risk for DVT, whereas we confirmed the strong association between increased VWF:Ag and FVIII:C levels and DVT.  More interestingly, we showed that the combination of slightly reduced plasma ADAMTS13 activity levels and increased VWF levels was responsible for a markedly increased DVT risk. These latter findings were further confirmed performing a sensitivity analysis after the exclusion of patients whose samples were collected less than three months from DVT event and/or during anticoagulant therapy.   Subsequently, we decided to investigate if variants localized in ADAMTS13, VWF, and F8 genes may contribute to explain the altered levels of the respective, encoded proteins, as described in Chapter 8. For this purpose, a larger population of DVT cases and healthy volunteers has been sequenced using NGS. We confirmed that rare ADAMTS13 variants alone are associated with DVT risk. Moreover, DVT patients carrying a rare ADAMTS13 variant had a lower ADAMTS13 activity than non-carriers. In contrast, neither rare VWF nor F8 variants were associated with DVT, thus indicating that other mechanisms are responsible for increased VWF and FVIII plasma levels.  Finally, Chapter 9 includes a general discussion and future perspectives about the topics described in this thesis.","language":"eng","citation":"PATHOPHYSIOLOGY OF VON WILLEBRAND FACTOR IN BLEEDING AND THROMBOSIS / M.t. Pagliari ; supervisore Università degli Studi di Milano: F. Payvandi ; supervisori Leiden University Medical Center: H. Eikenboom, F.R. Rosendaal ; coordinatore dottorato in Medicina Traslazionale: C. Sforza. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2023 Sep 20. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R13167.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1000488/2283331/phd_unimi_R13167.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/982788"},"title":"LA NARRATIVA DI LUIGI MALERBA TRA TESTUALITÀ, GENERI E RICEZIONE","internalauthor":"FARINA, MICHELE","type":"Tesi di dottorato","year":"2023","abstract":"My doctoral dissertation focuses on the production of Luigi Malerba (Berceto 1927  – Roma 2008) as a writer of short forms from the early stages to the end of his literary  career. The introduction situates him within the Italian literary canon of the 20th  century by describing the evolution of his poetics through the years and giving an  overview of the critical reception of his oeuvre in recent decades.  In the second chapter I analyse Le lettere di Ottavia (1956), the author’s first effort  as a literary writer, together with La scoperta dell’alfabeto (1963) and Le rose  imperiali (1974), respectively his debut and second collection of short stories. The  third chapter continues the stylistic and thematic examination of Malerba’s work as  a short-story writer by taking into consideration the other collections published by  the author before his death: Dopo il pescecane (1979), Testa d’argento (1988), Ti  saluto filosofia (2004), along with Sull’orlo del cratere (2018), posthumously  published. On the content level, these four collections of short stories could be read  as different moments in a consistent representation of the Italian middle class of  the second half of the century.  The final chapter aims to integrate the critical portrait of Malerba outlined in the  previous chapters by considering his enduring interest in writing literature for  younger readers. This is a significant feature of his literary activity– often overlooked  by the critics – which draws attention once again to the pivotal role played by short  forms in his oeuvre. Situating Malerba within the illustrious tradition of Italian  short narrative from the medieval novella to 20th century storytellers such as  Zavattini, Calvino, Moravia and Celati indicates a way of reading his works beyond  avant-garde and postmodern interpretations, bringing them into the critical debate  around the position of short forms in the Italian literary canon of the last century.","language":"ita","citation":"LA NARRATIVA DI LUIGI MALERBA TRA TESTUALITÀ, GENERI E RICEZIONE / M. Farina ; coordinatore: F. Slavazzi ; tutor: G. Turchetta. Dipartimento di Lingue, Letterature, Culture e Mediazioni, 2023 Jul 10. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12486.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/982788/2240602/phd_unimi_R12486.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/807615"},"title":"DEVELOPMENT OF AN IN-VITRO HUMANIZED MICROFLUIDIC PLATFORM TO STUDY NEURONAL TAU AGGREGATION AND PROPAGATION","internalauthor":"FICULLE, ELENA","type":"Tesi di dottorato","year":"2021","abstract":"Background: Alzheimer’s disease (AD) is the most common cause of dementia, characterized by the presence of extracellular \uf062-amyloid plaques and intracellular neurofibrillary tangles (NFTs) composed of aggregated and hyperphosphorylated tau. Since it has been shown that tau aggregates correlate with cognitive decline much better than \uf062-amyloid formations, it is important to understand how tau can spread in the brain. Moreover, the spatiotemporal spread of tau observed during clinical manifestation suggests that it propagates along the axonal network between synaptically connected neurons. On these bases, some early-phase Clinical Trials are aiming to target tau during transcellular spreading in order to prevent its internalization by recipient neurons, using both compounds and antibodies. For the experimental evaluation of candidates before in vivo studies, there have been many attempts to replicate this network in vitro, most of which used microfluidic approaches; however, these experiments have often utilized parameters that may reduce the physiological relevance of the assay, such as by overexpressing tau, using fluorescent tags, or by introducing MAPT mutations. New methods that can improve these assays are required to help the screening of efficient and effective treatments.    Aim of the work: The main purpose of this research project has been to establish a humanized, in vitro neuronal microfluidic platform to recapitulate and study tau aggregation and propagation in a qualitative and quantitative way. Microfluidic devices represent a miniaturized alternative tool to recapitulate tau spreading conditions, by enabling the culture of synaptically connected, but environmentally isolated, neuronal populations that can be seeded, thereby inducing endogenous tau aggregation and subsequent propagation. This model system could be ideal for testing the effect of potential tau therapeutics that modulate transneuronal tau propagation.    Material & Methods: Before developing the microfluidic propagation assay, a rat cortical neuron (RCN) aggregation assay that uses seeding-competent material from human AD brains (hAD seed) to induce endogenous aggregation was validated. Subsequently, the same conditions were used to develop a RCN microfluidic assay that can show endogenous tau aggregation, and consequent propagation, using High Content Imaging (HCI) and a proprietary interactive computer program for image quantification. Finally, using a transgenic mouse line that expresses human MAPT, a humanized and miniaturized version of the assay has been developed in order to have a physiologically relevant, medium-throughput platform to test tau therapies.    Results: After a phase of optimization, it has been shown that hAD seed induces endogenous rodent tau aggregation and transneuronal propagation in a quantifiable manner in a microfluidic culture model. Moreover, this assay was statistically validated and further converted to a medium-throughput format allowing the user to handle 16 two-chamber devices simultaneously in the footprint of a standard 96 well plate. Furthermore, this assay was humanized in order to study hTau aggregation and propagation using primary neurons from a mouse model that expresses human tau only. It has been proved that Anle 138b, a literature small molecule that has been previously shown to impair protein aggregation, can block the transneuronal transfer of tau aggregates, suggesting that this novel system can be used to evaluate mechanisms of tau spreading and to find therapeutic interventions. Moreover, preliminary experiments have shown that the aggregation of endogenous tau induces not only an increase of neuronal excitability but also an activation of astrocytes which might also have a role in tau pathology.    Conclusions: This work has been successfully developed a robust and quantitative microfluidic assay that can model an isolated mechanism of tau propagation. Using both RCNs and hTau mouse cortical neurons seeded with hAD seed, it was possible to quantify the formation and propagation of endogenous tau inclusions and demonstrate that a putative inhibitor of tau propagation is active in this assay. It was also shown that these models can be further employed for exploratory studies, such as monitoring the functional activity and connectivity of the neuronal cultures, as well as investigating the role of different cell types in tau aggregation and propagation. Most importantly, this manuscript exhibits the latent potential of microfluidic assays as screening platforms for the preclinical evaluation of tau propagation inhibitors.","language":"eng","citation":"DEVELOPMENT OF AN IN-VITRO HUMANIZED MICROFLUIDIC PLATFORM TO STUDY NEURONAL TAU AGGREGATION AND PROPAGATION / E. Ficulle ; tutore: Professor M. S. Clerici ; co-tutore:  Dottoressa S. Bose ; coordinatore: Professor M. Samaja. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2021 Jan 21. 32. ciclo, Anno Accademico 2020. [10.13130/ficulle-elena_phd2021-01-21].","filename":"phd_unimi_R11693.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/807615/1682125/phd_unimi_R11693.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1003768"},"title":"TITANIUM DIOXIDE PHOTOACTIVITY: EFFECTS OF COMBINED STRUCTURAL, SURFACE AND MORPHOLOGICAL MODIFICATIONS","internalauthor":"MONTALBANO, MARCO","type":"Tesi di dottorato","year":"2023","abstract":"Titanium dioxide is the most widely used and studied photocatalyst for a variety of applications. However, its performance as a photocatalyst is limited by two main drawbacks: i) the fast recombination of photogenerated charge carriers and ii) a high band gap energy, requiring UV light irradiation to promote its electronic excitation.   Several strategies have been investigated to overcome these limitations, such as surface modification with noble metal (NM) nanoparticles (NPs), Au, Pt, Pd, and doping with transition metals or p-block elements. The fine tuning of TiO2 crystal morphology represents another modification strategy that recently gained a lot of attention. By using suitable shape-controlling agents it is possible to modify the crystal habit of anatase, favoring the transition from its typical truncated bipyramidal structure, characterized by approximately 90% surface exposure of {101} facets, to the nanosheet-like morphology, mainly exposing the thermodynamically less stable (but potentially more reactive) {001} surfaces. At the same time, recent studies demonstrated that in-situ adsorption of fluoride ions has specific effects on the photocatalytic activity of TiO2, depending on the TiO2 crystal phase composition and on the mechanism of the photocatalytic reaction. A systematic evaluation of the combined effects produced on photoactivity by NM NPs deposition and in-situ TiO2 fluorination, as a function of the adopted deposition technique, the chosen NM and/or the semiconductor morphology, was still lacking.  In the present PhD thesis, the photocatalytic properties of doped and/or morphology-controlled anatase TiO2 samples modified by surface deposition of Au NPs was firstly investigated in both photocatalytic oxidation and reduction reactions. In particular, the effects induced by Au NPs deposited on the TiO2 surface by different techniques were investigated, as well as those of the in-situ addition of fluoride ions, to highlight possible synergistic effects on TiO2 photoactivity induced by coupling surface fluorination, specific morphology, and deposited NM NPs.  A systematic study was thus undertaken by studying at first the effects deriving from the use of two different Au NPs deposition methods, i.e., deposition-precipitation (DP) and photoreduction (P), on the photocatalytic activity of sol-gel prepared titanium dioxide samples bulk co-doped with different amounts of N and F. The photoactivity of the prepared composite Au/TiO2 materials was monitored in two different photocatalytic test reactions, i.e., formic acid oxidation and Cr(VI) reduction, each proceeding through completely different reaction paths. In particular, whereas in the case of formic acid oxidation no significant differences in the materials photoactivity was induced by the use of different Au NPs deposition techniques, regardless of the dopant content introduced in the TiO2 bulk structure, an outstanding photoactivity was instead attained in Cr(VI) to Cr(III) photoreduction upon coupling an optimal amount of bulk dopant in TiO2 with the photodeposition of NM NPS. The origin of such synergy between the use of a selective Au NPs deposition method (i.e., photodeposition) and the use of an optimal amount of dopant was then studied via Time-Resolved Photoluminescence Spectroscopy.  Next, the effects induced upon using the above-mentioned Au NPs deposition techniques on the photocatalytic activity of differently shaped anatase powders, eventually also coupled with in-situ surface fluorination, were evaluated mainly in three different photocatalytic test reactions, i.e., formic acid (FA) oxidation, rhodamine B (RhB) bleaching and Cr(VI) to Cr(III) reduction. In particular, the deposition of Au NPs on TiO2 was beneficial in FA degradation only in the case of {101} facet-dominated materials, whereas coupling Au NPs photodeposition with a nanosheet-like morphology of TiO2 did not lead to better performing photocatalytic materials.  Similar results were also obtained in the case of rhodamine B photobleaching. In particular, whereas in the case of metal-free titanium dioxide a positive synergy was observed upon coupling a nanosheet morphology (i.e., materials mainly exposing {001} facets) with in-situ surface fluorination, a positive effect on photoactivity induced by coupling the deposition of Au NPs and in-situ surface fluorination was obtained only when the materials were mainly dominated by the exposure of {101} facets (thus bearing a pseudo-spherical shape).   Differently, the photoactivity of morphology controlled Au/TiO2 materials in Cr(VI) photoreduction was found to be only slightly affected by the deposition of NM NPs. Instead, the photoefficiency of anatase was largely improved upon shifting from a pseudo-spherical morphology towards nanosheet-shaped crystallites, producing materials which also significantly outperformed reference benchmark P25 TiO2. This is possibly due to an improved oxidative power of {001} facets which help to overcome the kinetically rate-determining anodic half-reaction in Cr(VI) reduction, i.e., water oxidation. Furthermore, an enhanced oxidative power of {001} surfaces in comparison to {101} facets was demonstrated by a higher production of HO• radicals in solution during the hydroxylation of terephthalic acid in the aqueous media. This effect was observed when the morphology of TiO2 was shifted from a pseudo-spherical shape to a nanosheet-like structure, providing further confirmation of the mentioned findings.  Lastly, the performance of the materials was assessed in hydrogen production via methanol photo steam reforming. Our results revealed significant enhancements in the photoactivity of the powders upon deposition of NM NPs and, notably, the utilization of pseudo-spherically shaped TiO2 materials. It is possible that the increased exposure of {101} facets, which act as reduction sites, facilitates a greater availability of reduction centres, thereby promoting H2 evolution.   The obtained photoactivity results in the investigated test reactions allowed us to hypothesize a reaction mechanism based on charge migration in differently shaped Au/TiO2 composite materials able to rationalize the effects on photoactivity induced upon coupling Au deposition with differently shaped TiO2 materials, also under in-situ fluorinated conditions.","language":"eng","citation":"TITANIUM DIOXIDE PHOTOACTIVITY: EFFECTS OF COMBINED STRUCTURAL, SURFACE AND MORPHOLOGICAL MODIFICATIONS / M. Montalbano ; tutor: M. V. Dozzi ; co-tutor: E. Selli ; coordinatore: D. Passarella. Dipartimento di Chimica, 2023 Oct 03. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12763.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1003768/2291189/phd_unimi_R12763.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1198677"},"title":"MULTI-ORGAN FAILURE DRIVEN BY TELOMERE UNCAPPING","internalauthor":"TRASTUS, LUCREZIA AURORA","type":"Tesi di dottorato","year":"2025","abstract":"The telomere-bound shelterin complex safeguards chromosome ends from being recognized as DNA double-strand breaks, a function mostly dependent on TRF2. Loss of TRF2 results in telomere uncapping, activation of the DNA damage response, and chromosomal end-to-end fusions, with dramatic consequences for genome integrity and cell fate. The impact of TRF2 depletion is context-dependent, causing distinct outcomes in different cell types, however the systemic effects of acute TRF2 loss have remained poorly characterized.  In this work, we adopted an inducible Trf2 knockout mouse model to investigate the consequences of telomere uncapping at the organismal level. Trf2 deletion was rapidly achieved across multiple tissues and this event was accompanied by DDR activation and multi-organ functional failure, ultimately leading to lethality within approximately one week. Trf2 knockout elicited a syndrome resembling that occurring upon exposure to high doses of ionizing radiation, including severe bone marrow hypoplasia, leukopenia, hematopoietic stem and progenitor cell dysfunction, and intestinal epithelium degeneration. Bone marrow transplantation failed to extend lifespan in Trf2 knockout mice, whereas it rescued the mortality caused by X-rays at low doses, highlighting the fact that lethality is not primarily dictated by the hematopoietic system, but the consequences of TRF2 loss extend to other organs.  Our study demonstrates the essential role of TRF2 in preserving the integrity of the hematopoietic and intestinal systems, presumably owing to their highly proliferative nature, and underscores the catastrophic outcomes of its loss at the organismal level, aligning the effects of telomere uncapping with the pathophysiology of acute radiation syndrome.","language":"eng","citation":"Multi-organ failure driven by telomere uncapping / L.a. Trastus ; tutor: F. d'Adda di Fagagna ; co-tutor: V. Costanzo ; internal advisor: S. Campaner ; external advisor: J. Gil  PhD coordinator: D. Pasini. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Dec 17. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13527.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 26-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/827721"},"title":"INVESTIGATION OF C9ORF72 MOLECULAR HALLMARKS AND DEVELOPMENT OF THERAPEUTIC STRATEGIES","internalauthor":"BIELLA, FABIO","type":"Tesi di dottorato","year":"2021","abstract":"The majority of genetic Amyotrophic Lateral Sclerosis (ALS) cases are  due to the expansion in the number of an hexanucleotidic repeat in a  non-coding site of the locus C9orf72. Many mechanisms for the  C9orf72-ALS are suggested, both loss of function and gain of function  due to RNA foci and Dipeptide Repeats (DPR) toxicity.  Research on C9orf72-ALS is hindered by the lack of satisfactory  models and by the difficult access to the target cell type. Animal  models fail to recreate all the pathological features and the situation is  further complicated by the presence of many disease modifying genes.  To overcome theseissues, this study takes advantages of the induced  Pluripotent Stem Cells (iPSCs) technology to investigate canonical as  well as more recent C9orf72 molecular hallmarks. The iPSCs carry the  same genetic background of patients and can be further differentiated  in motoneurons (MNs) to study neuronal specific alteration and  comparing C9orf72-expanded cell lines with their isogenic corrected  counterpart, the influence of disease-modifying genes can be  eliminated.  We analysed canonical RNA foci and DPR accumulation finding them  increased in C9orf72 samples in both models. DNA damage  accumulation, a recently discovered C9orf72-ALS feature, was also  increased.  Moreover, in iPSC-derived MNs expression of SEPT7, STMN1 and  STMN2 genes, cytoskeletal regulators with important function in  neuronal cells, has been found altered in C9orf72 background.  Taking advantage of these established models we could also evaluate  the efficacy of a morpholine (MO)-based antisense oligonucleotide  (ASO) therapy as a proof of principle for the feasibility of drug  screening in these models. We foundthat both our MO oligomers were  able to rescue DPR accumulation and DNA damage induction.  Global gene expression analysis has also been performed. From this  investigation a subtle alteration in genes related with neuronal function  in iPSC was detected, while C9orf72 MNs showed deregulation in  pathways related to inflammation and cell-to-cell communication  suggesting a non-cell-autonomous mechanism for the disease.  Interestingly, MOs treatment could rescue these alterations.  Moving forward we started the characterization of a 3D organoidbased model of C9orf72-ALS that can reproduce the complexity of  central nervous system. We found in organoids DPR accumulation  and other disease hallmarks which could not be detected in 2D  models, supporting the promising role of this 3D model.","language":"eng","citation":"INVESTIGATION OF C9ORF72 MOLECULAR HALLMARKS AND DEVELOPMENT OF THERAPEUTIC STRATEGIES / F. Biella ; relatrice: S. P. Corti ; co-relatrice: M.M. Taiana ; coordinatore del corso di dottorato: M. Samaja. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2021 Mar 26. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12051.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/827721/1746316/phd_unimi_R12051.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/914517"},"title":"MINIMALLY INVASIVE SURGERY TO FACILITATE MICRO-IMPLANT SUPPORTED MAXILLARY SKELETAL EXPANSION IN ADULT PATIENTS.","internalauthor":"CANTARELLA, DANIELE","type":"Tesi di dottorato","year":"2022","abstract":"Introduction  The aim of the present study is to evaluate the skeletal modifications induced by maxillary expansion supported by palatal micro-implants and localized osteotomies produced with minimally invasive surgical technique in young-adult and adult patients.  In the present investigation, osteotomies had a lower extension than the ones used in conventional surgically assisted rapid palatal expansion (SARPE), to adopt a minimally invasive surgical technique that can be performed with greater comfort for the patient and less post-operative sequelae. More in detail, the localized osteotomies were executed only in the anterior part of the midpalatal suture and bilaterally at the basis of the zygomatic process of the maxilla without involvement of the piriform rim. These areas represent a great resistance to the lateral maxillary movement. Furthermore, they are of simple surgical access and don’t present important arterial plexuses.  Patients requiring micro-implant supported maxillary expansion and/or SARPE routinely undergo a pre-treatment cone-beam computed tomography (CBCT) of the skull, to plan the surgical operation and, one month after treatment a secondary CBCT for a surgical and orthodontic control.  CBCT is a low radiation tomography, extensively used in maxillofacial surgery and in dentistry. For the implementation of this study, that aims at evaluating the efficacy of micro-implant-supported maxillary expansion in combination with localized osteotomies, only radiologic exams that are anyway needed for the planning and post-treatment evaluation were used.  Aim  The aim of the present study is to evaluate the advantages introduced in the treatment of maxillary constriction by the therapy with micro-implant supported Maxillary Skeletal Expander (MSE) and localized osteotomies in young-adult and adult patients.  The main objective is to evaluate the efficacy of the technique, by measuring the movement of skeletal landmarks in the midface, particularly on the maxillary and zygomatic bones, and on the lateral wall of the nose, by comparing the pre-treatment and post-treatment CBCT.  For this particular technique, a new methodology for digital planning of position of MSE and miniscrews on patient CBCT was developed. Furthermore, incorporation of 2 additional miniscrews to the original MSE design, which conventionally features only 4 miniscrews, was developed with the aid of computer aided design – computer aided manufactured (CAD-CAM) technology.  Methods  The study presented the following steps:  ▪ Development of a digital planning methodology for positioning the miniscrews and MSE appliance on pre-treatment CBCT  ▪ Development of a CAD-CAM methodology for incorporating 2 additional miniscrews to the original MSE design with 4 miniscrews  ▪ Selection of patients with age above 17 years, without congenital craniofacial syndromes, who require intervention of maxillary skeletal expansion  ▪ Acquisition of initial CBCT with 17 x 13.5 cm field of view (FOV)  ▪ Intervention of maxillary expansion supported by palatal micro-implants and localized osteotomies executed with minimally invasive surgical technique  ▪ One month after treatment, acquisition of post-treatment CBCT with 17 x 13.5 cm FOV  ▪ Analysis of skeletal modifications in the midface (maxillary bone, sphenoid bone, zygomatic arch, nasal cavity, etc.), by comparing the pre- and post- treatment CBCT with a 3D software (OnDemand software by Cybermed)  Results  The new methodology allowed the digital planning of MSE and miniscrews positioning on patients’ CBCTs, and the incorporation of two additional miniscrews to the original MSE design through CAD-CAM technology.  In the clinical trial, a total of four patients had an average age of 27.6 years (range 22.1 – 39.9 years).  MSE appliance was activated by an average of 6.0 mm and generated a parallel split of the midpalatal suture of 3.4 mm, 3.0 mm and 3.6 mm at anterior nasal spine (ANS), nasopalatine foramen (NPF) and posterior nasal spine (PNS), respectively.  Skeletal modifications were found in all CBCT sections evaluated in the study (axial palatal, upper nasal, coronal zygomatic, axial zygomatic), indicating that all midfacial bones are affected by maxillary expansion with MSE and localized osteotomies.  Particularly, skeletal changes were noticed also in CBCT sections above the lateral maxillary osteotomies (LMOs), in the maxilla, zygomatic bone, zygomatic arches, and nasal cavity. In the upper nasal section (UNS) the maxilla was laterally displaced by 2.4 mm and 0.9 mm, at its anterior and posterior extremities, respectively.  The frontozygomatic angle (FZA) increased by 1.9° (average of right and left side), while the lower interzygomatic distance increased by 2.9 mm, indicating a rotation of the zygomatic bone in a lateral direction.  The zygomatic arch was affected by bone bending phenomena and was deflected in an outward direction, with increase in the anterior intermaxillary distance by 1.7 mm and in the posterior inter-zygomatic distance by 1.6 mm.  The nasal width (NW) parameter increased by 2.9 mm with treatment: this anatomical finding is the basis for a potential improvement in nasal breathing for patients suffering from increased nasal airway resistance.  The cited modifications in skeletal structures above lateral maxillary osteotomies (LMOs) are most likely due to the fact that LMOs didn’t involve the piriform rim of the maxilla, and this point needs further investigations.  Regarding dentoalveolar modifications, the inter-molar distance increased by 7.4 mm, and molars underwent a small dentoalveolar tipping in a buccal direction by 1.1° (average of right and left side), as evidenced by the change in molar basal bone angle (MBBA).  No intra-operatory hemorrhage nor post-operatory bleeding was reported in treated patients, probably due to the lack of pterygopalatine suture surgical disjunction.  A limitation of the study is its small sample size, represented by 4 patients. A larger number of patients is required to confirm the above results.","language":"eng","citation":"MINIMALLY INVASIVE SURGERY TO FACILITATE MICRO-IMPLANT SUPPORTED MAXILLARY SKELETAL EXPANSION IN ADULT PATIENTS / D. Cantarella ; tutor: M. Del Fabbro; co-tutor: A. B. Giannì. Università degli Studi di Milano, 2022 Mar 16. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12170.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/914517/1997576/phd_unimi_R12170.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/965316"},"title":"CRYSTAL CHEMISTRY AND PHYSICAL-CHEMICAL BEHAVIOR OF REE-BEARING PHOSPHATES AND ARSENATES: THE CASE STUDY OF MT. CERVANDONE","internalauthor":"PAGLIARO, FRANCESCO","type":"Tesi di dottorato","year":"2023","abstract":"The crystal chemistry, crystal structure and behavior at non-ambient conditions of natural Rare Earth Elements-bearing phosphates [monazite-(Ce), nominally Ce(PO4), and xenotime-(Y), nominally Y(PO4)] and arsenates [gasparite-(Ce), nominally Ce(AsO4), and chernovite-(Y), nominally Y(AsO4)], from the hydrothermal quartz-bearing fissures outcropping at Mt. Cervandone (Lepontine Alps, Piedmont, Italy), have been investigated. The chemical and structural characterization, performed via electron microprobe analysis, Raman spectroscopy and single-crystal X-ray diffraction, showed that the zircon-type minerals chernovite-(Y) and xenotime-(Y) share a very similar (Y,HREE) composition and the same can be stated for the LREE content of the two monazite-type minerals [gasparite-(Ce) and monazite-(Ce)]. An almost complete solid solution has been found between xenotime-(Y) and chernovite-(Y), while a wide miscibility gap has been observed within the monazite series minerals of Mt. Cervandone. Moreover, both the unit-cell and the REE-coordination polyhedral volumes are strongly controlled by the cationic population at the T-site: an increase in As not only expands the volume of the TO4 tetrahedron, but even that of the REE-polyhedron, irrespective of the A-site population. An exception is provided by the relative abundance of Th and Ca at the A-site, which was found to expand the coordination polyhedron and unit-cell volumes irrespective of the T-site composition.  The comparative analysis of the thermo-elastic behavior of selected samples has been conducted by in situ high-P, high-T and combined HP–HT X-ray diffraction experiments using both single-crystals and polycrystalline samples at synchrotron or conventional lab facilities. The compressional behavior of the investigated minerals is compatible with the literature data on the synthetic endmember counterparts. The two zircon-type minerals undergo different phase transitions under compression, while the monazite-type minerals experience a change in the compressional behavior, likely induced by the increase in coordination number of the REE-bearing polyhedron. The thermal expansion behavior of monazite-(Ce) and xenotime-(Y) confirm the literature data available, while the studied chernovite-(Y) is significantly less expandable than the synthetic counterparts described in the literature. The phosphates were found to be less compressible, but more expandable than the isostructural arsenates. The structural analysis at non-ambient conditions has been carried out on the basis of the refined structure models, allowing the description of the deformation mechanisms accommodating the bulk compression or expansion at the atomic scale. Both are mainly accommodated by the REEOx coordination polyhedra, while the tetrahedra behave as a quasi-rigid units. In conclusion, all the experimental data confirm the central role played by the T-site in controlling the structural deformation and, in turn, the bulk thermal expansion and compression.","language":"eng","citation":"CRYSTAL CHEMISTRY AND PHYSICAL-CHEMICAL BEHAVIOR OF REE-BEARING PHOSPHATES AND ARSENATES: THE CASE STUDY OF MT. CERVANDONE / F. Pagliaro ; tutor: P. Lotti ; cotutor: A. Guastoni ; coordinatore: M. I. Spalla. Dipartimento di Scienze della Terra Ardito Desio, 2023 Apr 17. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12624.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/965316/2181391/phd_unimi_R12624.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1132756"},"title":"ETHNOBOTANICAL SURVEYS IN LOMBARDY (ITALY): A MULTIDISCIPLINARY APPROACH TO STUDYING THE PAST TO IMPROVE THE FUTURE.","internalauthor":"MILANI, FABRIZIA","type":"Tesi di dottorato","year":"2025","abstract":"In the thesis presented herein, three case studies, with focus on ethnobotanical investigations conducted in Lombardy (North of Italy), are described. Considering ethnobotany as a multidisciplinary and cyclic science, the main phases of an investigation (the field, the laboratory, and the return to the population phases) are considered and the case studies are designed to cover them all.  The case studies are the following:  1. Case study Milan: a peculiar historical investigation on the majolica jars preserved at the Ca' Granda Ospedale Maggiore Policlinico, once used to store plant ingredients and medicinal remedies administered to the patients of the hospital. The thorough analysis of the inscriptions of the jars and extensive research on literature of the time allowed to hypothesize the medicinal species once potentially cultivated in the Hortus simplicium (Garden of Simples) of the hospital. Research in current scientific literature represented a starting point for the theoretical validation or rejection of the ancient remedies of the jars.  2. Case study Valle Imagna (Bergamo): the starting point of this case is the previous analysis of an ancient 18th century manuscript containing medicinal remedies. The diachronic comparison of the medicinal uses retrieved from historical sources with the traditional ones recorded during an ad hoc ethnobotanical investigation conducted on the territory of upper Valle Imagna allowed for the selection of a plant species symbol of the territory. The subsequent a multi-step laboratory survey was aimed at the thorough examination of the selected species, Agrimonia eupatoria L. (Rosaceae), from a micromorphological, phytochemical, and pharmacological standpoints.  3. Case study Alpine Lombardy: the case was developed along different Alpine territories: Sondalo (Valtellina, Sondrio), Valmalenco (Sondrio), and the neighboring Valposchiavo (Canton of Grisons, Switzerland). The field investigations of the three territories are presented. Additionally, the case involved the laboratory phase conducted in continuity with a previous PhD project in Valmalenco on the species Achillea erba-rotta subsp. moschata (Wulfen) I.Richardson and the nutritional analyses on six wild edible species collected in Valmalenco. Finally, different strategies for the return to the population phase are outlined and discussed.  Finally, in the Appendix attached to the main thesis, all the activities of dissemination of the scientific results and third mission of the three-year PhD project are thoroughly described.","language":"eng","citation":"ETHNOBOTANICAL SURVEYS IN LOMBARDY (ITALY): A MULTIDISCIPLINARY APPROACH TO STUDYING THE PAST TO IMPROVE THE FUTURE / F. Milani ; tutor: G. Fico ; phd coordinator: G. Vistoli. - DISFARM - UNIMI - Milano. Dipartimento di Scienze Farmaceutiche, 2025 Jan 29. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13301_5.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1132756/2632972/phd_unimi_R13301_5.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1051809"},"title":"HIGH-PRESSURE BEHAVIOUR AND CRYSTAL-FLUID INTERACTION OF THE ABC-6 ZEOLITES: THE CASE OF ERIONITE, OFFRETITE AND BELLBERGITE","internalauthor":"BATTISTON, TOMMASO","type":"Tesi di dottorato","year":"2024","abstract":"Zeolites represent an important class of hydrated aluminosilicates, characterized by an open-framework structure formed by interconnection of channel and cage systems, hosting alkali/alkaline-earth cations and small molecules. The framework is composed of TO4 tetrahedral units. The International Zeolite Association (IZA) recognises the existence of more than 250 compounds with zeolitic structures, among those more than 50 found as natural species, highlighting the considerable crystallographic diversity and the scientific and industrial interest on zeolites. In the last decades, the scientific community showed a rising interest on the high-pressure behaviour (ranging from few kbar to GPa) of zeolites, both natural and synthetics, particularly concerning the crystal-fluid interactions mediated by pressure. Given the zeolites capacity to host and exchange H2O, other small molecules or monoatomic species (e.g., nobles gases), experiments involving hydrostatically compressed zeolites in potentially-penetrating mixtures of molecules can provide new insights about their potential role as carrier of geological fluids in the first kilometres of the upper Earth crust. On the other hand, these experiments may open new routes for tailoring novel functional materials through specific host-guest interaction, or enhancing the performance of specifics industrial catalytic processes, potentially leading to a relevant technological impact.  In this PhD thesis, after a general review about the zeolites applications and their high-pressure techniques and experimental findings reported so far (Chapters 1, 2 and 3), the high-pressure behaviour and the crystal-fluid interaction of three zeolitic species, belonging to the ABC-6 group, are resumed. In detail, natural erionite (ERI topology,), offretite (OFF,) and bellbergite (EAB) were investigated, along with a synthetic counterpart of bellbergite with EAB topology. The protocol involved a first crystallo-chemical characterization of the samples, using a multi-methodological approach, followed by in-situ high-pressure experiments aimed to assess the intrinsic compressibility of these species and the pressure-mediated crystal-fluid interaction. In details, the high-pressure characterization involved:  1. Experiments using ‘non-penetrating’ P-transmitting fluids, such as daphne oil or silicone oil, aimed at determine the compressibility path and the elastic parameters of the materials without any interference of the P-transmitting fluid, setting a benchmark for the second-step.  2. Experiments using ‘potentially-penetrating’ P-transmitting fluids, such as alcohols-water mixtures or noble gases (in their liquid state), to describe the P-mediated crystal-fluid interaction.  The results of the experiments, along with their protocols, are detailed in the Chapter 4, 5 and 6, for erionite, offretite and bellbergite (and its synthetic analogues), respectively. Chapter 7 provides an overall discussion with a comparative analysis of their P-response, unveiling similarities and differences of the high-pressure behaviour of the three frameworks and the parameters governing the crystal-fluid interaction.","language":"eng","citation":"\"HIGH-PRESSURE BEHAVIOUR AND CRYSTAL-FLUID INTERACTION OF THE ABC-6 ZEOLITES: THE CASE OF ERIONITE, OFFRETITE AND BELLBERGITE / T. Battiston ; tutor: G. D. Gatta ; coordinatore: M. I. Spalla. - Milano, Università degli Studi di Milano, Dipartimento di Scienze della Terra \"\"Ardito Desio\"\". Dipartimento di Scienze della Terra Ardito Desio, 2024 May 29. 36. ciclo, Anno Accademico 2023.\"","filename":"phd_unimi_R12881.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1051809/2414854/phd_unimi_R12881.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1198318"},"title":"FASTING-MIMICKING DIET AND STARVATION ESCAPE INHIBITION AS NOVEL LOW-TOXIC TREATMENT FOR RENAL CELL CARCINOMA","internalauthor":"LAZZERI, SAMUEL","type":"Tesi di dottorato","year":"2025","abstract":"Renal cell carcinoma (RCC) remains a major therapeutic challenge despite significant therapeutic progress in recent years. Current treatments prolong survival but are often undermined by resistance and systemic toxicity, underscoring the need for integrative approaches with improved efficacy and tolerability. Fasting-mimicking diets (FMD) have emerged as promising interventions that sensitize tumor cells while protecting normal tissues. In this project, I investigated the potential of combining FMD with the identification and pharmacological inhibition of starvation escape pathways (SEPs) in the context of RCC. Transcriptomic and metabolomic profiling revealed that under nutrient restriction, RCC cells become highly dependent on ERK-MAPK and mTOR-S6K signaling. Building on this observation, I developed a treatment strategy combining FMD with selective inhibition of these pathways. This regimen consistently induced cancer cell death in vitro across multiple RCC lines while sparing normal cells and proved effective in vivo in syngeneic and xenograft models by delaying tumor growth, promoting regression, and reducing metastatic spread. Not only the treatment was well tolerated, but it reduced the toxicity of the drugs administered. Mechanistically, my data point to a nucleotide-centered vulnerability: by simultaneously restricting extracellular nucleotides through FMD and impairing de novo synthesis via ERK-MAPK and mTOR-S6K inhibition, the treatment collapses intracellular dNTP pools, triggers redox imbalance, and leads to cell death. Although the precise chain of events remains to be fully elucidated, the convergence of transcriptomic, metabolomic, and functional evidence strongly supports this model. The results presented here are highly promising and provide a strong rationale for the development of novel therapeutic approaches in RCC. These may ultimately contribute to new stand-alone treatments, even though are more likely to serve as complementary platforms to be integrated with current standard therapies, with the potential to enhance efficacy while preserving a favorable safety profile. Moreover, the mechanisms uncovered in this work reveal differential metabolic vulnerabilities that are not unique to RCC and may extend to other malignancies. Altogether, these findings lay the foundation for innovative and reduced toxicity therapy that warrant further investigation and careful translation into clinical practice.","language":"eng","citation":"Fasting-mimicking diet and starvation escape inhibition as novel low-toxic treatment for renal cell carcinoma / S. Lazzeri ; tutor: V. Longo. - IFOM, Milano. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Nov 07. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13487.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 25-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/814594"},"title":"PERIODIC AND QUASI-PERIODIC ORBITS IN NEARLY INTEGRABLE HAMILTONIAN SYSTEMS","internalauthor":"DANESI, VERONICA","type":"Tesi di dottorato","year":"2021","abstract":"\"The study of periodic and quasi-periodic orbits in nearly integrable Hamiltonian systems is a long standing and challenging problem, that dates back to Poincaré.  Quoting Poincaré, they represent \"\"the only opening through which we can try to enter a place which, up to now, was deemed inaccessible\"\". The aim of this thesis is to find effective and constructive algorithms for constructing both periodic and quasi-periodic solutions via a modification of the normal form methods related to Kolmogorov's theorem.  The thesis is divided in two parts.  The first part concerns the classical problem of the continuation of periodic orbits surviving to the breaking of invariant maximal or lower dimensional completely resonant tori in nearly integrable Hamiltonian systems: we here propose a new scheme which allows to deal with the problem of degeneracy at any order of perturbation.  The second part regards the development of a variation of the Kolmogorov's normalization algorithm, by avoiding the so-called translation step at the price of fixing only the final frequency, while the initial one can only be determined a posteriori.\"","language":"eng","citation":"PERIODIC AND QUASI-PERIODIC ORBITS IN NEARLY INTEGRABLE HAMILTONIAN SYSTEMS / V. Danesi ; tutor: T. Penati ; co-tutor: M. Sansottera ; coordinatore: V. Mastropietro. Dipartimento di Matematica Federigo Enriques, 2021 Feb 22. 33. ciclo, Anno Accademico 2020. [10.13130/danesi-veronica_phd2021-02-22].","filename":"phd_unimi_R12024.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/814594/1704226/phd_unimi_R12024.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1218875"},"title":"TECHNOLOGICAL DEVELOPMENT AS NARRATIVE AND MORAL PRACTICE. CULTIVATING RESPONSIBLE INNOVATION IN AI-DRIVEN START-UPS","internalauthor":"INNOCENTI, MARCO","type":"Tesi di dottorato","year":"2026","abstract":"The thesis investigates how the notion of Responsible Innovation (RI), conceived for research institutes and established firms, can be applied to the context of start-ups, where resource constraints and uncertainty about the final technological product make ethical assessment more difficult.   The research unfolds through the analysis of the concept of responsibility in the innovation context and in the field of ethics and philosophy of technology. While presenting the taxonomy of its meaning in detail, I identify the aspects most suitable to the approach adopted in the thesis, and to address the hypotheses formulated. Then, the research draws on a study of the conceptual and hermeneutic aspects of technological development, which culminates in an empirical study conducted in the research and development laboratory of the Franco-Norwegian start-up Beefutures. I show how prospective scenarios of technological impact, and the corresponding responsibilities, generate opportunities for moral reflection for individuals and teams. Then, the analysis leads to frameworks in which responsibility is cultivated as a collective practice and conflicting responsibilities are addressed through dialogical and practical means, thereby aligning innovation with personal fulfilment and meaningful work.   Within this context, a significant role is played by the study of how these dynamics are influenced by recent developments in the field of Artificial Intelligence (AI). This technology constitutes one of the driving forces behind the most recent wave of innovations, guiding or complementing the research and development process in many of today’s start-ups. Beefutures, in particular, develops new AI-enhanced technologies for beekeeping and biomonitoring through bee colonies, and the case studies addressed in this research will therefore be linked to this innovation and to its potential applications.","language":"eng","citation":"TECHNOLOGICAL DEVELOPMENT AS NARRATIVE AND MORAL PRACTICE. CULTIVATING RESPONSIBLE INNOVATION IN AI-DRIVEN START-UPS / M. Innocenti ; supervisors: B. Grespi (University of Milan); B. Formis and E. Picavet (Paris 1 Panthéon-Sorbonne University). Dipartimento di Filosofia Piero Martinetti, 2026 Feb 17. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14742.pdf","fileformat":"Adobe PDF","fileversion":"preprint","fileaccess":"Open from 24-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1198757"},"title":"MOLECULAR RECOGNITION OF THYROGLOBULIN BY SORTILIN","internalauthor":"BONIARDI, IRENE","type":"Tesi di dottorato","year":"2025","abstract":"Thyroglobulin (TG) is a large glycoprotein essential for thyroid hormone synthesis and storage. Synthesised and secreted by thyrocytes, TG forms a dimeric structure within the thyroid follicle lumen, where it undergoes iodination and hormonogenesis before being retrieved through endocytosis for hormone release. Despite its central role in thyroid physiology, the mechanisms governing TG uptake remain poorly understood. Sortilin, a ubiquitous receptor involved in protein sorting and endocytosis, has been proposed as a key mediator of TG internalisation, particularly for its iodinated forms. However, the molecular basis of this interaction has remained elusive.  Here, we elucidate the mechanisms of TG recognition by sortilin using an integrated approach combining cryo-electron microscopy, crosslinking mass spectrometry, biophysical characterisation, and endocytosis assays in human thyroid cells. We demonstrate that sortilin preferentially binds the monomeric form of TG over its native dimeric state, suggesting a conformational selectivity in cargo recognition. Using an in vitro iodination assay, we show that iodination has no detectable effect on sortilin binding, indicating that the interaction is independent from the hormone content of TG and may instead reflect recognition of partially unfolded or degraded TG. Structural analysis of sortilin in complex with TG and a TG-derived C-terminal peptide (TGpep) reveals a binding mode conserved across other sortilin ligands relying on the peptide fit in sortilin β-propeller domain. Henceforth, performing sequence alignments and AlphaPulldown predictions we computationally derived a shared recognition motif by sortilin that may explain its broad ligand repertoire.  Overall, this work elucidates a molecular mechanism for TG endocytosis, identifies sortilin as a monomer-selective receptor, and provides a structural basis for their interaction. This knowledge opens new avenues in understanding thyroid physiology and its regulation, deepening our understanding of sortilin-mediated protein trafficking.","language":"eng","citation":"MOLECULAR RECOGNITION OF THYROGLOBULIN BY SORTILIN / I. Boniardi ; supervisor: F. Coscia. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Nov 03. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13464.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 26-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1021244"},"title":"CHARACTERIZATION OF DNA POLYMERASE ETA CONTRIBUTION TO GENOME STABILITY UNDER REPLICATION STRESS","internalauthor":"GRASSO, LAVINIA","type":"Tesi di dottorato","year":"2024","abstract":"pol η is a Y-family translesion DNA polymerase extensively characterized for its ability to bypass thymine dimers induced by UV light. More recently, pol η has also been demonstrated to perform numerous functions independent of DNA lesions. We have shown that in budding yeast pol η sustains genome duplication when dNTP pools are reduced by hydroxyurea, but this activity favors the inclusion/stabilization of RNA stretches in genomic DNA that become toxic if not removed by RNase H enzymes. The origin of such RNA substrates and the exact mechanism by which they trigger genome instability are still unclear. In this study, I found that, upon dNTPs shortage, pol η may act on R-loops to promote resolution of transcription-replication collisions, ultimately causing RNA moieties to remain embedded in DNA behind the replication fork.     The techniques developed to study ribonucleotides incorporated in DNA molecules, do not allow to directly identify pol η-dependent RNA stretches embedded in DNA. To develop a strategy to overcome such limitation, we assessed the feasibility of detecting ribonucleotides embedded in DNA exploiting direct sequencing with Oxford Nanopore Technologies (ONT). To this extent, I synthesized DNA molecules containing rNMPs at known positions and we elaborated appropriate data analysis pipelines to recognize ribonucleotides in DNA by ONT. We reported for the first time that ONT can identify all four ribonucleotides incorporated in DNA by capturing rNMPs-related alterations in base calling, current intensities, and dwell times.     Finally, I investigated how this novel activity of pol η may be regulated. We have  previously observed that budding yeast pol η can be mono-SUMOylated and that  SUMOylation levels drop in hydroxyurea. I found that this is independent of the  presence/absence of RNases H in cells and that pol η SUMOylation is maintained in different cell cycle phases. I also identified K603 as the main candidate residue for this modification.","language":"eng","citation":"CHARACTERIZATION OF DNA POLYMERASE ETA CONTRIBUTION TO GENOME STABILITY UNDER REPLICATION STRESS / L. Grasso ; scientific tutors: M. Muzi-Falconi, G. Pavesi. Dipartimento di Bioscienze, 2024 Jan 23. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12503.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1021244/2336652/phd_unimi_R12503.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1138735"},"title":"\"NOVEL \"\"NO-HAIR\"\" AND UNIQUENESS RESULTS IN GRAVITY\"","internalauthor":"SPINELLI, BENIAMINO VITTORIO MARIA","type":"Tesi di dottorato","year":"2025","abstract":"\"In this thesis we are going to study, employing techniques of Riemannian geom- etry and global analysis, the \"\"Cosmic No hair\"\" conjecture proposed by Boucher, Gibbons and Horowitz. This conjecture is a sub-conjecture of the more general \"\"No Hair conjecture\"\" and focuses on manifolds not containing black holes. This will be done by studying both compact Riemannian manifolds with boundary and complete Riemannian manifolds without boundary that support static so- lutions of Gravity coupled to a map between Riemannian manifolds φ equipped with a self-interacting potential V (φ).  We study the above in four situations:  • first employing the Kazdan-Warner formula with φ-curvatures we study  the case of compact μ-quasi-φ-Einstein manifolds with boundary, we do  this by producing some rigidity and uniqueness results for the half sphere,  remarkably we manage to provide in the same picture with α = − 2 non w2  constant, w being the gravitational potential, a uniqueness result for the half sphere in the case of Einstein-Maxwell theory;  • secondly, on one hand by considering a bound on kφ(∂M), a notion of surface gravity that allows for the presence of the map φ, we prove another uniqueness result for the half-sphere, while on the other hand we prove a generalization of the Boucher-Gibbons-Horowitz formula that yields an analogous result under a bound on the gradient of gravitational potential.  • third, we produce a no hair result for complete manifolds that support a static solution gravity coupled to a self-interacting map φ with possibly a negative or concave self-interacting potential V (φ);  • Last but not least we produce some other rigidity results for a related fam- ily of structures, where the map φ is not self-interacting, called Einstein- type structures, through more geometric conditions on the φ-tensors φ- Weyl and φ-Cotton.  The spirit of this approach is two pronged: on one hand we generalize re- sults in the literature by considering a more general system, that reduces to the previous ones whenever the map φ is constant, and on the other hand we es- tablish under what hypotheses the map φ is constant, thus providing \"\"no-hair\"\" results. Furthermore we have done this using multiple approaches which, in the compact case, always require positivity of the self-interacting potential, thus strongly suggesting the necessity of this condition in the compact case for the validity of the conjecture.\"","language":"eng","citation":"\"NOVEL \"\"NO-HAIR\"\" AND UNIQUENESS RESULTS IN GRAVITY / B.v.m. Spinelli ; M. Rigoli. - Dip. matematica. Dipartimento di Matematica Federigo Enriques, 2025. 35. ciclo\"","filename":"phd_unimi_R12673.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1138735/2646369/phd_unimi_R12673.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1161817"},"title":"OPTIMIZING DIAGNOSTIC ACCURACY IN CANINE URINARY TRACT INFECTIONS: FUTURE DIRECTIONS TO REDUCE ANTIMICROBIAL MISUSE IN VETERINARY PRACTICE","internalauthor":"TAGLIASACCHI, FILIPPO","type":"Tesi di dottorato","year":"2025","abstract":"The thesis addresses the optimization of diagnostic accuracy in canine urinary tract infections (UTIs), aiming to reduce the inappropriate use of antimicrobials in veterinary clinical practice. Following an epidemiological overview of canine UTIs, the work presents an analysis of the International Society for Companion Animals Infectious Diseases (ISCAID) guidelines, a document that provides the foundation for standardized classification, diagnosis, and treatment of canine and feline UTIs in veterinary medicine. An updated overview is subsequently provided on antimicrobial resistance, the one health approach, and the European and national recommendations regarding antimicrobial choice in veterinary medicine.  The main challenges of the diagnostic process for canine UTIs are explored, particularly the low specificity of lower urinary tract signs (LUTS) and the variability in diagnostic accuracy associated with urinary sediment analysis. The thesis highlights the need for accurate biomarkers to support the screening of canine patients with UTIs and reviews the most promising molecules identified in human medical literature. A brief section is dedicated to the clinical relevance of potential point-of-care (POC) tests as rapid diagnostic tools for patients with suspected UTI.  In the experimental part, the analysis begins with a ten-year retrospective local study aimed at identifying the main uropathogens involved in canine UTIs and detecting possible trends in antimicrobial resistance by comparing the five years before and after the publication of the ISCAID guidelines (2019). The importance of up-to-date local data to guide general practitioners towards more informed empirical antibiotic use is emphasized.  Subsequently, the diagnostic performance of several promising biomarkers for the diagnosis of canine UTI is evaluated, including urinary neutrophil gelatinase-associated lipocalin (uNGAL), urinary interleukins 8 and 6, urinary xanthine oxidase, and urinary myeloperoxidase. Among these, urinary interleukin-8 and urinary xanthine oxidase are identified as the most promising disease markers, highlighting the need for further research, particularly including comparison with subjects affected by subclinical bacteriuria. Finally, the clinical applicability of a POC test for the measurement of uNGAL is assessed, showing almost perfect agreement with the reference ELISA method.  Overall, the thesis emphasizes the need to integrate innovative biomarkers, antimicrobial stewardship strategies, and veterinary education in order to improve the management of canine UTIs and reduce antibiotic resistance from a One Health perspective.","language":"eng","citation":"OPTIMIZING DIAGNOSTIC ACCURACY IN CANINE URINARY TRACT INFECTIONS: FUTURE DIRECTIONS TO REDUCE ANTIMICROBIAL MISUSE IN VETERINARY PRACTICE / F. Tagliasacchi ; tutor: P. Scarpa ; coordinatore: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2025 May 28. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13649.pdf","fileformat":"Adobe PDF","fileaccess":"Open from 30-OTT-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1203560"},"title":"THE INTERPLAY BETWEEN HPCAL4 AND MECP2: IDENTIFICATION AND CHARACTERIZATION OF A NOVEL PUTATIVE TARGET FOR RETT SYNDROME THERAPY","internalauthor":"SANDAKLY, JAWDAT","type":"Tesi di dottorato","year":"2026","abstract":"Rett Syndrome (RTT) is a severe neurodevelopmental disorder and the leading cause of intellectual disability in females with 1 in 10,000 births being affected. The symptoms start to manifest in between 6 and 18 months of age and these include intellectual disability, epilepsy and impairments of social and motor skills. Most cases (90-95%) arise from sporadic mutations within the X-linked gene coding for the methyl-CpG binding protein 2 (MeCP2). It is an important epigenetic regulator that is ubiquitously expressed and particularly abundant in brain and important for proper neuronal maturation and function. In fact, MeCP2 deficiency in neurons is responsible for impairment of fundamental aspects of neuronal development and function including defects in dendritic arborization and spine density. Besides Mecp2, several other genes have been associated with RTT or RTT-like phenotypes and the number of disease-candidate genes has grown over the years. Therefore, identifying novel molecular players may provide new insights into RTT pathophysiology and uncover potential modifier genes that influence disease progression and severity. In this work, we investigated the neuronal calcium sensor hippocalcin-like 4 (Hpcal4), which encodes for a protein belonging to the visinin-like (VSNL) subfamily of EF-hand Ca2+-sensing proteins. Evidence in literature alongside previous transcriptomic data from our laboratory, consistently reported a downregulation of this gene in RTT patients and mouse models. However, HPCAL4 functions remain fully undisclosed; indeed, it belongs to the category of T-dark genes, which comprises of protein coding genes with limited or unknown function in literature. Therefore, we aimed in this project to clarify Hpcal4’s involvement in neuronal functions in physiological conditions and determine if it can be flagged as a modifier gene for RTT by contributing to the observed RTT phenotypes. We explored the expression of the protein in the wild type and RTT mouse brain and found that it is regionally modulated along brain development and deficiently expressed in the symptomatic RTT brain. We additionally analyzed the protein levels in primary neuronal cultures where they were found to be increased during neuronal maturation and reduced in Mecp2 KO neurons. By assessing its subcellular level, we found that HPCAL4 is present in the soma and dendrites, enriched in the pre-synaptic compartment, and localizes to the plasma membrane in an activity-dependent manner. Proteomic analysis revealed that HPCAL4 interacts with a set of proteins with well established synaptic functions, including synaptic vesicles recycling and neurotransmitter release. Finally, we characterized the phenotypes resulting from its downregulation in neurons and found similar defects that are present in RTT neurons, including reduction in dendritic arborization accompanied by impairments in neuronal maturation. In conclusion, our study highlights a putative novel function for HPCAL4 in neuronal maturation and synaptic processes. Its decreased levels in RTT models, together with the phenotypes observed upon its downregulation, suggest that it may contribute to RTT pathophysiology as a modifier gene.","language":"eng","citation":"THE INTERPLAY BETWEEN HPCAL4 AND MECP2: IDENTIFICATION AND CHARACTERIZATION OF A NOVEL PUTATIVE TARGET FOR RETT SYNDROME THERAPY / J. Sandakly ; tutor: N. Landsberger ; supervisor : M. Francolini ; director : N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2025 Jan 09. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13856.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 18-GIU-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/981468"},"title":"ERUDIZIONE ANTIQUARIA E RICERCA ARCHEOLOGICA NELLA LOMBARDIA NORDOCCIDENTALE OTTOCENTESCA","internalauthor":"ERBA, MARCO EMILIO","type":"Tesi di dottorato","year":"2023","abstract":"This research focuses on four little-known scholars directly involved in antiquarian studies in northwestern Lombardy during the 19th century: Carlo Annoni (1795-1879), amateur epigrapher and patriotic provost of Cantù; Giovanni Ranchet (1834-1907), explorer of the pile dwellings of the Varese area and leading figure in the founding of the Museo Patrio of Varese; Vitaliano Rossi (1833-1890), first inspector of excavations and monuments in the territories north of Milan; Achille Varisco (1840-1909), linked to the documentary heritage of Monza Cathedral.  The biographies are framed in the historical and cultural climate of the transition from the Lombardo-Veneto government to the state structure of post-unification Italy. Unpublished archival sources, preserved in Lombard and non-Lombard, public and private funds, support the research.  Against the backdrop of the centralist ministerial thrusts promoted throughout Italy, the descriptive framework offers a cue to reexamine and specify aspects of a more bluntly museographic, collecting, normative and methodological nature.","language":"ita","citation":"ERUDIZIONE ANTIQUARIA E RICERCA ARCHEOLOGICA NELLA LOMBARDIA NORDOCCIDENTALE OTTOCENTESCA / M.e. Erba ; tutor: F. Slavazzi ; coordinatore. F. Slavazzi. Dipartimento di Beni Culturali e Ambientali, 2023 Jul 17. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12243.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/981468/2237113/phd_unimi_R12243.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1045430"},"title":"GESTIONE DELLE SOPRAVVENIENZE QUANTITATIVE E MANUTENZIONE DEL CONTRATTO","internalauthor":"MICCOLIS, GIOVANNI","type":"Tesi di dottorato","year":"2024","abstract":"\"This dissertation's topic took my interest because of the 2020 pandemic crisis, but the pro-blem of contractual contingencies is much more complex.  This problem isn’t new to italian civil law scholars. It has been discussed since the 1990s whether more effective remedies for the management of contingencies should be found than the \"\"ordinary\"\" ones provided for in Articles 1463 ff. and 1467 Civil Code. These rules, ex-cept for the hypothesis of partial impossibility (Art. 1464 Civil Code), react to the problem of contractual contingency through remedies whose effect is the dissolution of the contractual relationship. But there is a need for such rules to be flanked by solutions providing for the modification of the relationship, which would remain in force.  This dissertation will deal only with hardship    To delimit the scope of the research, Chapter I will identify and define the concepts that are fundamental.  We will analyze the two principles that are relevant in the area under investigation, name-ly the prin-ciple of contract binding and the principle rebus sic stantibus.   We will define contingencies will be defined: they will be found to be disruptive events that affect the original balance between the performances. They alter it to an extent that ex-ceeds the limit, which differs from contract to contract, constituted by the \"\"normal risk\"\".   We will define the contractual category subject to the problem. These are durational con-tracts, which are characterized by a temporal distance between the conclusion of the contract and its execution.   Finally, we will analyze quantitative contingencies, particularly to the legislature's choices regarding their typification.  Chapter II will acknowledge how the legislature regulates hardship. There is the general remedy of a demolitory type (the termination for hardship referred to in Article 1467 of the Civil Code), but there are many \"\"special\"\" rules providing maintenance remedies for special contracts too.   Comparison with different, but related, legal systems of the Italian legal system will be ve-ry important.  Finally, Chapter III will outline the interpretive solutions that the doctrine has been propo-sing for nearly three decades now. These theories have not received the favor of the jurispru-dence. These are theories aimed at identifying conservative remedies that have the potential to find widespread application.  The result of the research is that the legal system under consideration is particularly confu-sing, heterogeneous, and problematic.  On one hand, as noted above, ordinary remedies are ineffective in adequately handling contingencies.  On the other hand, doctrinal interpretive proposals have critical profiles that, perhaps, ha-ve contributed to their lack of acceptance by the dominant jurisprudence.  The idea, and the hope, is that the legislature should intervene on the issue, through a sy-stematic reform of the Civil Code. In this latter respect, however, there is little cause for op-timism. The Italian legislature, on the subject. has remained essentially inert, despite the fact that some historical events (the economic/financial crisis of 2008, the pandemic) have occur-red in recent years, which could have incentivized regulatory interventions.   But beyond these considerations, the scholar's task must be to derive a \"\"system\"\" from the regulations actually in place. The hope is that the present work has nevertheless succeeded in this endeavor.\"","language":"ita","citation":"GESTIONE DELLE SOPRAVVENIENZE QUANTITATIVE E MANUTENZIONE DEL CONTRATTO / G. Miccolis ; tutor: F. Delfini ; coordinatore: G. Ludovico. - Università degli Studi di Milano. Dipartimento di Diritto Privato e Storia del Diritto, 2024 Apr 16. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R12987.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1045430/2398849/phd_unimi_R12987.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/948216"},"title":"DEVELOPMENT OF SMALL MOLECULES AS INHIBITORS OF FTSZ AND RNPA ACTING AS POTENTIAL ANTIMICROBIAL AGENTS","internalauthor":"SUIGO, LORENZO","type":"Tesi di dottorato","year":"2023","abstract":"The antimicrobial resistance (AMR) is nowadays one of the most worrying threats of   modern medicine. Recently, AMR has been also called “the silent pandemic” because is as   worrying as the COVID-19 outbreak, but without receiving the same public attention. The   most important organizations such as World Health Organization (WHO) and Centres for   Disease Control and Prevention (CDC) pointed out how the academic work on the   development of new chemical entities as antimicrobials able to interact with new   molecular targets remains one of the key actions to fight antimicrobial resistance (World   Health Organization, 2015).   Within the present work, two innovative bacterial targets have been considered to develop   new potential inhibitors: FtsZ and RnpA.  FtsZ is a 40 kDa protein with 40 -50% of conservation among all bacteria and archaea. This   protein represents the main actor of the bacterial cell division cycle, the essential process   that allows the parent cell to divide through binary fission into two daughter cells. At the   beginning of the cycle, FtsZ polymerizes at the centre of the cell, constituting the “Z-ring”.   This step serves as guide for the continuation of the process, therefore the inhibition of   FtsZ leads to cell filamentation and death. For these reasons, FtsZ arose as a potential target   for the development of new antimicrobials. In the first part of this work, starting from the  insights gained in the last years, new families of benzodioxane-benzamides have been   designed, synthesized, purified and evaluated as potential antimicrobials on S. aureus, B.   subtilis and E. coli. Moreover, FtsZ was validated as the target of these compounds. In   particular, S. aureus and B. subtilis FtsZs were validated as targets through specific cellular   assays, while the capability of these compounds to interact with E. coli FtsZ was   demonstrated through an in vitro study on the isolated protein. Moreover, the cytotoxicity   of all the derivatives was evaluated, and most of the derivatives are characterized by low   to non-detectable cytotoxicity on human cells.   RnpA is a small protein of S. aureus essential for two cellular processes: mRNA degradation   and precursor tRNA (ptRNA) maturation. Indeed, RnpA alone can catalyse the degradation   of bulk mRNA thus promoting mRNA turnover among different growth phases (exponential   and stationary). Furthermore, RnpA is able to associate with a ribozyme to form RNase P,   a riboprotein complex that promotesthe removal of the 5’ leader sequence from precursor tRNA, inducing tRNA maturation. Shortly after the discovery of the essentiality of RnpA, the   investigation of RnpA inhibitors as potential anti-staphylococcal compounds started.   Within the second main body of this work, the structure-activity relationship (SAR) of two   classes of known RnpA inhibitors was evaluated. Modifications of the structures of the two   main RnpA inhibitors, JC2 and RNPA2000, have been designed and applied. The resulting   compounds were tested as antimicrobials on S. aureus, both methicillin-sensitive and   methicillin-resistant. Also in this case, the in vitro profile of inhibition of RnpA as well as the   cytotoxicity of the obtained derivatives were assessed.   With the results obtained in the present work, the understanding of both FtsZ and RnpA   inhibitors was significantly increased, speeding up the development of these important   tools to fight antimicrobial resistance.","language":"eng","citation":"DEVELOPMENT OF SMALL MOLECULES AS INHIBITORS OF FTSZ AND RNPA ACTING AS POTENTIAL ANTIMICROBIAL AGENTS / L. Suigo ; coordinatore:  G. Aldini ; supervisor: E. Valoti. Dipartimento di Scienze Farmaceutiche, 2023 Jan 13. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12500.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/948216/2109087/phd_unimi_R12500.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1118628"},"title":"L'ADEGUATEZZA DELLA RETRIBUZIONE NEL CROCEVIA TRA TUTELE, AUTONOMIA SINDACALE E REGOLAZIONE DEL MERCATO","internalauthor":"ROCCISANO, SARA","type":"Tesi di dottorato","year":"2024","abstract":"This thesis studies the adequacy of remuneration through the main jurisprudential, legislative and contractual junctures that have enveloped it.  After framing the problem of poverty despite work in the national and European scenario, the study takes its starting point from the analysis of Article 36 of the Constitution. and from the jurisprudence which, in the aftermath of the Constitution's entry into force, contributed, on the one hand, to giving it a ‘unique normative vitality’ and to consecrating the role of trade union organisations as the privileged wage authority in our system; on the other hand, however, it consolidated a ‘reductionist’ interpretation of Article 36 of the Constitution, which today, following the phenomenon of the proliferation of collective agreements, is much criticised.  The study then focuses on the regulatory interventions on remuneration that followed one after the other in Italy for three lustra starting in the 1970s and that led to the progressive dismantling of the automatic wage indexation system, until its definitive abandonment by the social partners in 1992. This phase was characterised by a strong tension that arose between heteronomy and collective autonomy in the regulation of workers' pay (also with regard to public workers, which, however, are not the subject of this paper). The impetus for these interventions stemmed from the realisation that pay is not an independent variable of the economic system, but a real constituent element of it. To replace the escalator, interconfederal agreements of 1993 and 2009 introduced a number of mechanisms to protect the purchasing power of wages, which, however, partly due to external circumstances, did not have the expected effects (the case of the collective agreement for fiduciary services is an emblematic example, on which we will dwell at length).   A change of pace seems to be represented by Directive (EU) 2022/2041 on adequate minimum wages in the Union. While sharing the - uncontroversial - assumption that wages are a variable dependent on the economic environment, the European Union adopts a conception of these as an element capable of regulating the market with a view to upward convergence.   On the basis of this consideration, the paper finally proposes to illustrate, in light of the legal nature of the directive, which is the best way to transpose it.","language":"ita","citation":"L'ADEGUATEZZA DELLA RETRIBUZIONE NEL CROCEVIA TRA TUTELE, AUTONOMIA SINDACALE E REGOLAZIONE DEL MERCATO / S. Roccisano ; tutor: M. T. Carinci ; coordinatore: G. Ludovico. Dipartimento di Diritto Privato e Storia del Diritto, 2024 Nov 21. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13319.pdf","fileformat":"Adobe PDF","fileaccess":"Closed"}
,{"handle":{"url":"https://hdl.handle.net/2434/1208144"},"title":"TRANSCORONARY COOLING AND DILUTION FOR CARDIOPROTECTION DURING REVASCULARISATION FOR ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION: THE STEMI-COOL PILOT STUDY.","internalauthor":"CARULLI, ERMES","type":"Tesi di dottorato","year":"2026","abstract":"Background: The effectiveness of primary percutaneous coronary intervention (pPCI) in ST-elevation myocardial infarction (STEMI) is limited by reperfusion injury (RI), for which no therapy has yet proven beneficial. Transcoronary hypothermia has shown good tolerability and safety but with a neutral effect on outcomes in previous clinical trials. Potential reasons include complex protocols that prolong ischaemia and transient reperfusion prior to cardioprotection. Transcoronary haemodilution may also reduce RI by effectively slowing reperfusion. We developed a novel, simple method combining transcoronary cooling and dilution (TCCD) to reduce RI during pPCI.   Methods: STEMI-Cool is a pragmatic, registry-based randomised pilot assessing recruitment, feasibility, and safety of a simplified TCCD strategy for cardioprotection. Sixty STEMI patients (1 drop out) presenting within 12 h of symptom onset, regardless of infarct territory, were randomised 1:1 to standard of care (SOC) pPCI or pPCI with TCCD. Patients in cardiogenic shock or resuscitated after cardiac arrest were also included. Up to 750 mL of room temperature normal saline (NS) was infused through the guiding catheter in the culprit vessel using a pressure bag, starting before crossing the occlusion, with pressure adjusted to reduce proximal coronary temperature by 6-8°C. A pressure/thermistor wire was used as a guidewire or placed proximally for monitoring. Post-procedure index of microvascular resistance (IMR) was measured. A subgroup underwent cardiac magnetic resonance (CMR) at 1-7 days. Clinical follow-up was at 6 weeks (completed) and 1 year (ongoing). Continuous variables were compared using the Student’s t-test or Mann–Whitney U test, as appropriate. Categorical data were analysed using the chi-square test or Fisher’s exact test.  Results: An average of 549±229 mL of room temperature NS was infused at a rate of 61±29 mL/min, achieving a coronary temperature reduction of 6.37±1.22°C. Steady-state recruitment rate was ~5 patients/month at a single centre. Establishing TCCD protection before crossing the occlusion was feasible in 24/30 (80%) cases. The following data are presented as treatment vs SOC arms: there was no periprocedural mortality, while there were 2 vs 4 postprocedural deaths (p=0.37). There was an increase in ventricular fibrillation (VF): 10 vs 2, p=0.01, mainly occurring on reperfusion, however all patients were successfully defibrillated. CMR area at risk was similar: 23.69±11.01% vs 22.70±14.79%, p=0.87, with a trend towards infarct size reduction: 11.73±10.40% vs 17.74±12.39%, p=0.24. Further favourable trends in mechanistic outcomes are summarised in the table. We built a linear regression model linking diastolic blood pressure (DBP) to pressure required in the infusion bag to achieve target temperature (=DBP×4–100 mmHg).   Conclusions: Preliminary results from STEMI-Cool suggest good recruitability and feasibility of the combined cooling and dilution cardioprotective strategy. There was an increased incidence of reperfusion arrhythmia in the intervention arm with no associated difference in clinical outcomes. NS was chosen for its reported safety in other studies, but the high incidence of VF may be related to lack of physiological plasma electrolytes. Harmann’s solution was safe in our previous proof-of-concept study and might be preferred for future investigation. We demonstrated a relationship linking DBP to infusion pressure that may eliminate the need for a thermistor wire facilitating widespread adoption of this therapy if effective. The encouraging trends in mechanistic outcomes suggest the need for a multicentre, efficacy-powered trial to detect infarct size reduction.","language":"eng","citation":"TRANSCORONARY COOLING AND DILUTION FOR CARDIOPROTECTION DURING REVASCULARISATION FOR ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION: THE STEMI-COOL PILOT STUDY / E. Carulli ; tutor: P. Agostoni ; co-tutor: D. Magrì ; coordinator: M. Clerici. - Milano. Dipartimento di Scienze Biomediche per la Salute, 2026 Jan 22. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14066.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1208144/3222063/phd_unimi_R14066.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/956982"},"title":"THE MATERIALITY OF KNOWLEDGE: THE COLONIAL ROOTS OF THE KNOWLEDGE ECONOMY","internalauthor":"PACI, BERNARDO","type":"Tesi di dottorato","year":"2023","abstract":"The present work aims to draw on the theoretical legacy of postcolonial critique, which includes the assumption of a fundamental continuity between colonial history and our postcolonial world, in order to rethink the current configuration of the relationship between capital and knowledge (usually analysed in terms of “knowledge society”, “knowledge economy”, and so on), in light of and in continuity with the history and structures of colonial capitalism. For this purpose, in the first place, the main neoliberal and critical theories concerning this relationship are discussed with a focus on the histories and temporalities they assume or entail, also including human capital theories and their connections with developmentalism, eugenics, and scientific racism. In the second place, a materialist conception of knowledge, of its relations with human labour and capital, and of its functions within capitalist production and reproduction is proposed in order to re-read its role in the history of capitalism during the long colonial modernity and to analyse the historical construction of Eurocentric modern knowledge. In the third place, the conclusions thus reached are used to “displace” the previously discussed theories, histories, and temporalities through the examination of significant cases from colonial history, mainly but not exclusively taken from early modern New Spain.","language":"eng","citation":"THE MATERIALITY OF KNOWLEDGE: THE COLONIAL ROOTS OF THE KNOWLEDGE ECONOMY / B. Paci ; tutor: G. Mormino ; coordinatore: A. Pinotti. Dipartimento di Filosofia Piero Martinetti, 2023 Apr 12. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12535.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/956982/2152807/phd_unimi_R12535.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1216735"},"title":"¿MÁS VALE UN AÑO DE REY QUE VEINTE DE GUËY¿. GIOVANI, VIOLENZA, RECLUTAMENTO CRIMINALE E SOCIETÀ CIVILE IN MESSICO TRA VULNERABILITÀ E RESISTENZA:IL CASO DEL CENTRO JUVENIL PROMOCIÓN INTEGRAL A.C. (CEJUV, A.C.)","internalauthor":"DE TUGLIE, ANNACLARA","type":"Tesi di dottorato","year":"2026","abstract":"The thesis investigates the relationship between youth and violence in contemporary Mexico, a context marked by chronic, structural, and multifaceted forms of violence that particularly affect children and adolescents. In this scenario, the material precarization of life, exclusion from social protection systems, the erosion of rights and citizenship, and processes of stigmatization and criminalization of young people can generate specific forms of vulnerability situated between the status of victims and that of perpetrators of violence, as in the case of the criminal recruitment of minors by organized crime. Alongside these dynamics, however, practices of resistance emerge that create spaces of protection, recognition, and emancipation, opening up possibilities for escaping contexts and experiences shaped by violence. Adopting a qualitative approach, the research analyzes the narratives, practices, and strategies developed by civil associations and organizations engaged in preventing, countering, and transforming the conditions of youth overexposure to violence, while also highlighting the limits and potential of their interventions in highly vulnerable settings. The analysis focuses in particular on a case study – the work of the Centro Juvenil Promoción Integral A.C. (CEJUV A.C.) in Mexico City – through which it seeks to show how the creation of safe spaces, the building of meaningful relationships, and the promotion of opportunities for active participation can serve as central levers for generating concrete alternatives in the lives of the most vulnerable young people.","language":"ita","citation":"\"\"\"MÁS VALE UN AÑO DE REY QUE VEINTE DE GUËY\"\". GIOVANI, VIOLENZA, RECLUTAMENTO CRIMINALE E SOCIETÀ CIVILE IN MESSICO TRA VULNERABILITÀ E RESISTENZA:IL CASO DEL CENTRO JUVENIL PROMOCIÓN INTEGRAL A.C. (CEJUV, A.C.) / A. De Tuglie ; tutor: M. Massari ;  co-tutor: R. Cammarata ;  coordinatore: F. Basile. Dipartimento di Studi Internazionali, Giuridici e Storico - Politici, 2026 Mar 06. 38. ciclo, Anno Accademico 2024/2025.\"","filename":"phd_unimi_R13721.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 20-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1155317"},"title":"ANALYSIS OF THE ECONOMIC AND ENVIRONMENTAL BENEFITS OF PRECISION VITICULTURE. A CASE STUDY FROM MONTEFALCO SAGRANTINO DOCG","internalauthor":"GRAZIA, DIEGO","type":"Tesi di dottorato","year":"2025","abstract":"The concept of terroir is fundamental for viticulture, as it highlights the connection between soil, climate, and human intervention, as well as the role each of these factors plays in wine production. This concept is particularly important for high-quality wines, which are closely associated with a specific location and community. This relationship is best exemplified by the development of Geographical Indication (GI) legislation in the European Union.   However, the accelerating pace of climate change presents a challenge to viticulture worldwide and, consequently, to the geographically fixed concept of terroir. This also affects rural communities that rely on local wine production. Therefore, this thesis aims to analyse the wine sector from both an environmental and socio-economic perspective.   The first chapter presents a bibliometric analysis of the scientific literature, published between 2000 and 2022, that investigates the relationship between viticulture and climate change. This allowed to identify the main actors (including authors, countries, institutions, and journals) leading the research in this domain. Moreover, co-citation analysis and bibliographic allowed to determine the dominant thematic clusters in previous and current scientific literature, and to reveal emerging research trajectories in this field. The main thematic clusters found include the assessment of climate change effects on viticultural regions worldwide, climate change’s impact on grape composition and phenology.   The second chapter focuses on the economic impacts of climate change on Italian wineries, through a Ricardian analysis. The aim is to assess how long-term climatic factors influence net revenue per hectare of Italian grape-growing and wine producing farms. When considering a +1°C increase in temperatures, results indicate a decrease in net revenue per hectare in Northern and Southern Italy (-5.95% when all Italy is considered).   The third chapter presents a qualitative analysis that illustrates how a wine GI in the Umbria region (Montefalco Sagrantino DOCG) may have influenced local socio-economic development and, if so, its perceived magnitude among local stakeholders.   Finally, the fourth chapter presents an analysis of three wine regions located in France and Italy, and, through a qualitative approach based on semi-structured interviews, we are able to identify the main factors influencing the successful (or unsuccessful) outcome of a wine GI in a rural area.","language":"eng","citation":"ANALYSIS OF THE ECONOMIC AND ENVIRONMENTAL BENEFITS OF PRECISION VITICULTURE. A CASE STUDY FROM MONTEFALCO SAGRANTINO DOCG / D. Grazia ; tutor: C. Mazzocchi ;  co-tutor: S. Corsi ;  coordinatore: S. R. Pilu. - Università degli Studi di Milano. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2025 Mar 21. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13590.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1155317/2720019/phd_unimi_R13590.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1045601"},"title":"IMPACT OF STRESS CARDIAC COMPUTED TOMOGRAPHY MYOCARDIAL PERFUSION ON DOWNSTREAM RESOURCES AND PROGNOSIS IN PATIENTS WITH SUSPECTED OR KNOWN CORONARY ARTERY DISEASE: A MULTICENTRE INTERNATIONAL STUDY - THE CTP-PRO STUDY","internalauthor":"BAGGIANO, ANDREA","type":"Tesi di dottorato","year":"2024","abstract":"Background: Stress computed tomography perfusion (Stress-CTP) is a CT-based functional technique that can be added to coronary computed tomography angiography (cCTA) to improve management of patients with suspected coronary artery disease (CAD).  The aim of the study is to evaluate the usefulness of combined evaluation of coronary anatomy and myocardial perfusion in intermediate to high-risk patients for suspected CAD or with known disease in terms of clinical decision-making, resource utilization and outcomes. The purpose of the substudy on circulating biomarkers is to identify, in the population of patients evaluated with CCTA, transcriptional biomarkers in peripheral blood of different CAD subtypes, with the aim of refining clinical decision making.  Methods: CTP-PRO study is a cooperative, international, multicentre, prospective, randomized controlled study evaluating the cost-effectiveness of a CCTA+CTP strategy (Group A) versus usual care (Group B) in intermediate-high risk patients with suspected or known CAD who undergo clinically indicated diagnostic evaluation. Data regarding downstream testing, hospitalizations, revascularizations, major adverse cardiac events (MACE) as unstable angina, non-fatal myocardial infarction and cardiovascular death after index test were collected at 1-year follow-up and 2-year follow-up. Patients randomized to Group A at Centro Cardiologico Monzino received blood sampling for peripheral blood gene expression assessment.  Results: At June 15th 2023, 805 consecutive patients were prospectively enrolled at 9 sites and uploaded in eCRF, of which 453 (56%) had previous revascularization. 413 patients were randomized to Group A, 246 of them with obstructive CAD and 143 of them, according to CTP performance, with inducible ischaemia. Remaining 392 patients were randomized to Group B (278 to Stress CMR, 56 to Exercise Echocardiography, 17 to Exercise ECG and 41 to SPECT), 90 of whom with inducible ischaemia according to test results.  At 1-year follow-up, no significant differences were found between two groups in terms of downstream non-invasive testing (p: 0.382), while more hospitalizations, invasive assessment (both p: 0.021) and revascularization (p: 0.003) were recorded in patients randomized to Group A. No significant differences were found between two groups in terms of MACEs.  At 2-year follow-up, no significant differences were found between two groups in terms of downstream non-invasive and invasive testing, hospitalization, revascularization and MACEs.  At whole-blood transcriptome analysis, highly significant differences in the circulating transcriptome were found between patients with non-obstructive CAD compared to those with obstructive CAD at cCTA, and in the subset of patients with obstructive CAD, between those with and without inducible ischaemia at Stress-CTP.  Conclusions: CT-based management of high-risk patients for CAD is associated with comparable rate of downstream non-invasive testing compared to standard of care. Good prognosis is warranted if clinical decision-making is based on combined anatomical and functional information.  Whole-blood transcriptome is able not only to accurately discriminate between subjects with and without obstructive CAD at cCTA, but also to identify subjects with obstructive CAD and inducible ischaemia at Stress-CTP.","language":"eng","citation":"IMPACT OF STRESS CARDIAC COMPUTED TOMOGRAPHY MYOCARDIAL PERFUSION ON DOWNSTREAM RESOURCES AND PROGNOSIS IN PATIENTS WITH SUSPECTED OR KNOWN CORONARY ARTERY DISEASE: A MULTICENTRE INTERNATIONAL STUDY - THE CTP-PRO STUDY / A. Baggiano ; tutors: P. Agostoni, G. Pontone ; PhD program coordinator: C. Sforza. Dipartimento di Scienze Cliniche e di Comunità, 2024. 36. ciclo","filename":"phd_unimi_R13175.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1045601/2399279/phd_unimi_R13175.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1123715"},"title":"MENINGES AS AN OVERLOOKED TARGET FOR GLOBOID CELL LEUKODISTROPHY","internalauthor":"AMENTA, ALESSIA","type":"Tesi di dottorato","year":"2025","abstract":"Globoid cell leukodystrophy (GLD), also known as Krabbe disease, is a severe neurological disorder caused by the deficiency of galactocerebrosidase (GALC) enzyme, leading to the accumulation of toxic metabolites and ultimately resulting in progressive demyelination and neurodegeneration. The only treatment option currently available is the hematopoietic stem/progenitor cell transplant (HSPC-T), although this is not effective if administered after diseases onset. Thus, there is no cure for GLD emphasizing the need for novel approaches.   While most of the GLD neurodegenerative clues in the brain have been clarified, the underlying mechanisms of neuroinflammation are not yet fully understood. GLD brain shows an important inflammatory infiltration including the accumulation of unique and often multinucleated macrophages (“globoid cells”). However, the role in GLD pathogenesis and progression of all other non-parenchymal components of the brain, potentially contributing to the inflammatory process and diseases progression, has not been elucidated yet.  Recently, new and important interactions between brain and meninges have been described. Meninges appeared as a highly heterogeneous tissue with trophic, immune and neurogenic properties. Recently it has been identified a neurogenic stem/progenitor cell (NSPC) population present in meninges. In vivo, meningeal NPCs can migrate to the brain and, without proliferation, differentiate into functional integrated neurons of the cortex. Following brain pathological conditions, meninges are activated increasing their immune function and neural stem cell properties. However, the potential involvement of meninges during GLD pathogenesis and progression is completely unknown.   In this project, I have studied the involvement of meninges in the pathogenesis and progression of GLD in the Twitcher mouse model that resembles the early infantile form in humans. I have used mice at four different time points that represent the disease stages, including early pre-onset, pre-onset, onset and disease progression. I have found an increase of immune cells, including neutrophils, macrophages and T cells in TWI meninges starting from very early pre-onset GLD stage and persisting throughout the disease. Moreover, neuronal committed NSPCs appeared to be present in meninges at pre-onset and onset stages of GLD. These findings reveal, for the first time, the early GLD-induced response of meninges that start perinatally, well before the pathological involvement of the brain and the appearance of the clinical symptoms are detectable in CNS.   Then, I have exploited meninges as a new complementary and less invasive site for in vivo gene therapy (GALC lentiviral transduction). Post natal day 1 (P.1) pup mice have been injected in meninges with lentiviral vector (LV) overexpressing GALC gene and then analyzed at P.30 when the GLD is severe. Of note, GALC transduction in meninges at P.1 induced at P-30 a significant improvement on motor function and a large reduction of inflammatory infiltrate in the brain. Moreover, GALC overexpressing NSPCs at P.1 meninges have been found in P.30 mice with neuronal morphology into the second layer of the cortex expressing the neuronal marker NeuN, suggesting that they migrated from meninges to the cortex and differentiated into cortical neurons.   Finally, I have assessed the proof of concept of efficacy and safety of LV-GALC overexpression in somatic adult human meningeal NSPCs as potential therapeutic target for meningeal-directed in vivo gene therapy. These results showed that GALC overexpression in human meningeal neurons derived from NSPCs showed no toxicity and alteration in stem cells and neuronal properties.  Overall, these data highlight the importance of early meningeal involvement in GLD pathogenesis, opening the opportunity to find in meninges newly GLD-modifier therapeutic targets. Moreover, meninges could be exploited as novel, safe and effective site for gene therapy, which is less invasive than current intraparenchymal gene transfer approaches. This work paves the way for new therapeutic strategies for GLD, changing the focus from brain toward its stromal component.","language":"eng","citation":"MENINGES AS AN OVERLOOKED TARGET FOR GLOBOID CELL LEUKODISTROPHY / A. Amenta ; tutor: F. Bifari ; director: N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2025 Jan 21. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13413_2.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1123715/2606038/phd_unimi_R13413_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/957822"},"title":"THE INFLUENCE OF THE MICROENVIRONMENT OF HEALTHY AND TUMORAL CELLS","internalauthor":"HOLUIGUE, HATICE ZOHRA MICHELE","type":"Tesi di dottorato","year":"2023","abstract":"Cells use the extracellular matrix (ECM), a part of their microenvironment, as a scaffold for their anchorage, and interact with it in a reciprocal way. The ECM is mainly composed of a three-dimensional network of collagen and crosslinked proteins, such as fibronectin and laminin; ECMs from various tissues can have strong differences in their composition and biophysical properties. The study of  reciprocal interactions between cells and their microenvironment pertains to the fields of mechanobiology and mechanotransduction.    Different techniques are used to study cellular interactions, among which Atomic Force Microscopy (AFM), for its versatility and robustness, stands as a reliable biosensor. This thesis reports in three main chapters the study of the cell-microenvironment interplay mainly through adhesion force spectroscopy techniques based on AFM.     The main objective of this work was to develop novel native ECM probes to investigate early mechanotransductive cellular interactions by means of AFM-based force spectroscopy measurements. ECM probes reproduce faithfully the structural and compositional complexity of the ECM; selection of patient derived ECMs and cells allows to perform personalized experiments with potential applications in the clinic. Murine bladder ECM probes have been produced using a combination of decellularization procedures and Laser Microdissection (LMD) and tested against tumoral rat cell line. As reference, we also performed force spectroscopy experiments using AFM spherical probes functionalized with the two main ECM proteins, laminin and fibronectin. Native ECM probes have been successfully produced, characterized and tested. The integrin-related adhesive pattern measured in the force spectroscopy experiments depends on the mechanical and chemical properties of the native ECM used to produce the probe, which demonstrates the specificity of this approach. Finally, as cellular intercommunication relies on forces in the order of pN, we assessed the reliability of different calibration methods (standard thermal noise, Sader’s, and Laser Doppler Vibrometry).","language":"eng","citation":"THE INFLUENCE OF THE MICROENVIRONMENT OF HEALTHY AND TUMORAL CELLS / H.z.m. Holuigue ; director of the school: M.Paris ; supervisor of the thesis: A. Podestà ; co-supervisor of the thesis: M. Chighizola. Dipartimento di Fisica Aldo Pontremoli, 2023 Mar 13. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12473.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/957822/2157869/phd_unimi_R12473.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/827428"},"title":"DESIGN AND SYNTHESIS OF NOVEL ENZYME INHIBITORS AS ANTIPROLIFERATIVE COMPOUNDS WITH ANTIPROTOZOAL AND ANTICANCER ACTIVITY","internalauthor":"GALBIATI, ANDREA","type":"Tesi di dottorato","year":"2021","abstract":"This dissertation describes the research carried out as part of a PhD program in Chemistry  from the 1st October 2017 until 30th November 2020. The PhD project investigated the  development of inhibitors of enzymes involved in important metabolic pathways, with the   final aim to produce an antiproliferative effect. The present thesis combines the works  performed at the University of Milan and Vrije Universiteit of Amsterdam.  Part A describes the research performed in Amsterdam, NL during my period abroad from  January to September 2019 in the research group of Professor Rob Leurs, at the Division of   Medicinal Chemistry of the Amsterdam Institute for Molecules, Medicines and Systems,  Vrije Universiteit of Amsterdam. In particular, this part outlines the design, synthesis and   pharmacological evaluation of two novel series of potent antitrypanosomal agents,   identified through SAR exploration and scaffold hopping approach starting from cyclic   nucleotide Trypanosoma brucei phosphodiesterase (PDE) inhibitors. PDE enzymes provide   a fine control on several biochemical pathways and have recently been demonstrated to   be essential for parasite proliferation. Their disruption by RNA interference (RNAi)   dramatically increase intracellular cAMP and, consequently, causes complete mortal   trypanosome cell lysis.  Part B describes the research done at the Department of Pharmaceutical Sciences,  University of Milan, under the supervision of Professor Paola Conti, on the design and   synthesis of novel covalent inhibitors targeting the glycolytic enzyme Glyceraldehyde-3-  phosphate dehydrogenase (GAPDH). Due to its pivotal role in the glycolysis, GAPDH   represents a rate-limiting enzyme in those cells that mostly, or exclusively rely on this   pathway for energy production. In this context, GAPDH inhibition represents a valuable   approach for the development of anticancer and antiparasitic drugs. Due to the presence   of a druggable nucleophilic cysteine residue in the catalytic pocket of the target, I focused   my attention on the development of covalent GAPDH inhibitors, presenting an electrophilic   warhead with a finely tuned reactivity. In particular, Section B2 reportsthe work conducted   on the development of Plasmodium falciparum GAPDH inhibitors and the in vitro  antiplasmodial activity. Section B3 shows the work performed on the design and synthesis   of human GAPDH inhibitors, with in vitro antitumor activity.","language":"eng","citation":"DESIGN AND SYNTHESIS OF NOVEL ENZYME INHIBITORS AS ANTIPROLIFERATIVE COMPOUNDS WITH ANTIPROTOZOAL AND ANTICANCER ACTIVITY / A. Galbiati ; supervisor: P. Conti. Dipartimento di Scienze Farmaceutiche, 2021 Mar 18. 33. ciclo, Anno Accademico 2020. [10.13130/galbiati-andrea_phd2021-03-18].","filename":"phd_unimi_R11939.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/827428/1745303/phd_unimi_R11939.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1208797"},"title":"LA RIVOLUZIONE DALLA PALESTINA ALL¿ITALIA: L¿ATTIVITÀ DELLE ORGANIZZAZIONI PALESTINESI IN ITALIA DAL 1967 AL 1982","internalauthor":"KHARMA, BASEM","type":"Tesi di dottorato","year":"2026","abstract":"This research examines the activities of the Palestinian movement in Italy between 1967 and 1982, emphasizing Palestinians as active agents fully aware of Italian political and social dynamics. The investigation is based on a wide range of Italian and Arabic sources, including institutional and party documentation, newspapers and magazines, internal materials from Palestinian organizations, as well as oral interviews with former Italian and Palestinian militants. The comparative approach and the dialogue between different sources represent an element of originality compared to previous historiography, which has often favored exclusively Italian perspectives and, due to linguistic and methodological barriers, neglected Palestinian strategies and practices. This thesis adopts a three-phase periodization: 1967–1970, marked by the rise of Palestinian resistance after the Six-Day War and the first contacts in Italy; 1970–1973, characterized by the establishment and consolidation of the GUPS (General Union of Palestinian Students) and the activity of figures such as Wael Zwaiter; 1973–1982, the stage of political and diplomatic maturation of the PLO in Italy, with the arrival of Nemer Hammad, the strengthening of institutional relations, and Yasser Arafat’s visit to Rome.  By reconstructing the cultural, political, and symbolic activities of the Palestinian movement – from the dissemination of journals such as Rivoluzione palestinese, Palestina, and Al Sharara, to the organization of student networks and participation in the Italian political debate – the thesis highlights the ability of Palestinian organizations to adapt their language and tools to the Italian context, creating spaces of mobilization and consensus that involved both the extra-parliamentary and parliamentary left. The work aims to contribute in filling a historiographical gap by offering a more various and rich perspective on the relations between Italy and Palestine and by showing how Italy, during the 1970s, represented a crucial political laboratory for the internationalization of the Palestinian cause.","language":"ita","citation":"\"LA RIVOLUZIONE DALLA PALESTINA ALL'ITALIA: L'ATTIVITÀ DELLE ORGANIZZAZIONI PALESTINESI IN ITALIA DAL 1967 AL 1982 / B. Kharma ; tutor: P. Zanini, M. C. Rioli ; coordinatore: P. Grillo. Dipartimento di Studi Storici \"\"Federico Chabod\"\", 2025. 38. ciclo, Anno Accademico 2024/2025.\"","filename":"phd_unimi_R13833.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 15-GEN-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/888881"},"title":"DEVELOPMENT AND VALIDATION OF TARGET THERAPIES FOR PATIENTS WITH BRAIN CANCER, THROUGH THE MODULATION OF ANGIOGENESIS, INVASIVENESS, AND PHARMACOLOGICAL SENSITIVITY/RESISTANCE, IN THE ERA OF PRECISION MEDICINE","internalauthor":"GUARNACCIA, LAURA","type":"Tesi di dottorato","year":"2022","abstract":"Brain tumors represent a group of heterogeneous neoplasms which, despite originating in the same  anatomical region, differ in morphology, etiology, molecular biology, and especially in clinical  behavior. It has been estimated that brain tumors affect about 200,000 people worldwide every year,  representing approximately 2% of cancer deaths. Among all primary human brain tumors,  glioblastoma (GBM) is the most malignant and frequent (~70%), with a median survival of about 14  months and a 5-year survival rate at 5%, thus representing an extreme therapeutic challenge. GBM is  characterized by sustained proliferation and survival, immune system escape, intense angiogenesis,  invasion, cell infiltration, rapid progression, resistance to radio- and chemotherapies, with high  frequency of relapse. In cancer pathogenesis, particularly in high grade tumors as GBM, aberrant  neo-angiogenesis is a vital process for the mass growth: it is driven by neoplastic cells in order to  respond to the tumoral hypoxic environment in the necrotic core, which increases the demand for  oxygen and nutrients by neoplastic cells, and is, therefore, essential to carry out the metabolic  functions on which their survival is based. Several observations led to the knowledge that tumoral  neo-angiogenesis gives rise to ultra-structurally abnormal vessels, larger than their normal  counterparts, dilated, convoluted, irregularly branched and exceptionally permeable due to the  presence of fenestrations and the lack of a complete basal membrane. Due to these destructive  features, despite aggressive therapeutic treatment, consisting in surgical resection followed by  chemotherapy with temozolomide (TMZ), most patients experience tumor recurrence in less than one  year, suggesting the urgent need to implement clinical practice with novel prognostic and therapeutic  strategies. To this aim, this research project has been focused on: i) aberrant angiogenesis mediated  by endothelial cells (ECs), which promote tumor infiltration into surrounding tissues, with consequent  compromission of cognitive skills, and ii) genetic instability, which characterize GBM with a high  intra- and intertumoral heterogeneity. In particular, the underlying hypothesis is that a specific  molecular signature characterizes “resistant” and “sensitive” GBM, and it may be responsible for  patient overall survival. Indeed, although GBMs from short- and long-term survivors (STS and LTS)  are histologically the same, their biological and molecular characteristics are remarkably different,  suggesting that factors that contribute to patients’ longevity are important for precise diagnosis and  correct clinical management of the disease. The genetic profiling obtained by array CGH on STS and  LTS revealed a high number of copy number variation (CNVs) across chromosomes 1 to 22, among  which several novel potential prognostic and predictive biomarkers have been described and  discussed. In particular, aCGH highlighted the presence of an altered chromosomic pattern relative  to calpain family genes. Calpains are a conserved family of cysteine proteinases that catalyze the  controlled proteolysis of many specific substrates. Calpain activity is implicated in several  5  fundamental physiological processes, including cytoskeletal remodeling, cellular signalling,  apoptosis and cell survival. Alterations of the calpain activity balance has been observed in numerous  cancer types, as they can reduce apoptosis, increase cell proliferation and stimulate cell migration and  invasiveness. The characterization of calpain expression in primary GBM endothelial cells (GECs)  showed an upregulation of calpains and a positive correlation between expression level and patient  survival. The blockade of calpain activation with natural and synthetic inhibitors resulted in the  inhibition of GEC viability and proliferation, as well as in the promotion of caspase-induced cell  apoptosis. Further, calpain inhibition led to the arrest of tumor angiogenesis and migration in vitro.  Finally, the molecular investigation revealed a downregulation of proliferative signalling as MAPK  and anti-apoptotic regulators as Bcl-2, as well as an upregulation of proapoptotic mediators, as  Caspases and Bax-family. From this evidence, calpains may be considered as novel potential  therapeutic targets to treat cancer and to limit its progression.  Overall, the discovery of novel potential prognostic and predictive biomarkers, by the “omics”  approach, will allow to optimize patient’s management, as early prediction of those patients who are  likely to be STS or LTS, and a full understanding of their clinical course can thus assist clinicians in  providing tailored treatments and support patients and their families. However, beyond prognosis,  what will really impact clinical management of GBM is if genomic analyses can lead to customized  treatment and ultimately improved survival, following the concept of precision medicine.","language":"eng","citation":"DEVELOPMENT AND VALIDATION OF TARGET THERAPIES FOR PATIENTS WITH BRAIN CANCER, THROUGH THE MODULATION OF ANGIOGENESIS, INVASIVENESS, AND PHARMACOLOGICAL SENSITIVITY/RESISTANCE, IN THE ERA OF PRECISION MEDICINE / L. Guarnaccia ; supervisor: G. Mantovani ; co-supervisor: G. Marfia,  S. E. Navone  ; PhD coordinator: C. Sforza. Dipartimento di Scienze Cliniche e di Comunità, 2022 Jan 14. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12387.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/888881/1928582/phd_unimi_R12387.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1244869"},"title":"COMPUTATIONAL ENZYME ENGINEERING: FROM MOLECULAR MODELING TO MACHINE LEARNING","internalauthor":"WEI, YAO","type":"Tesi di dottorato","year":"2026","abstract":"The chemical, pharmaceutical, and materials industries increasingly rely on sustainable and efficient strategies for molecular synthesis, driving the growing importance of biocatalysis in modern life sciences. Enzymes, as highly selective and efficient natural catalysts, offer significant advantages for environmentally benign and carbon-neutral processes. However, their practical application is often limited by narrow substrate scope, insufficient stability, and incomplete understanding of structure–function relationships. This PhD research addresses these challenges by developing and applying advanced computational approaches for enzyme engineering, integrating molecular modeling and machine learning, collaborating with experimental expertise to improve enzyme design, predict biocatalytic behavior, and expand catalytic capabilities.  A main focus of this work is the prediction of cytochrome P450 (CYP450)-mediated metabolism and inhibition, which play critical roles in drug efficacy and toxicity. A systematic benchmarking study of machine learning models for CYP450 substrate and inhibitor prediction was conducted, followed by the development of two predictive frameworks. First, CypEGAT integrates protein embeddings with graph-based molecular representations to predict interactions across five major human CYP450 isoforms. Building on this, CypST was developed as a multimodal deep learning framework combining ESM-3 protein embeddings and MolBERT-derived chemical features through attention-based fusion strategies. CypST demonstrated improved predictive performance over existing methods across nine CYP450 isoforms. Additionally, a toxicity prediction module trained on Tox21 dataset enabled the identification of hepatotoxicity-related mechanisms, although prediction of non-hepatic toxicities remains challenging due to limited endpoint coverage.  To complement data-driven approaches, this work also investigates enzyme structure–function relationships through classical molecular modeling. The bacterial monooxygenase CYP153A6 was studied using homology modeling, ensemble docking, molecular dynamics simulations, and QM/MM calculations to elucidate substrate recognition and reactivity toward toluene derivatives. The results reveal key determinants of substrate orientation and reactivity, highlighting the importance of active-site geometry and electronic effects in catalytic selectivity.  In the context of protein design, two machine learning frameworks were developed to address critical challenges in mutation effect prediction and sequence prioritization. The ThermoFusion model combines structural and evolutionary representations to predict mutation-induced stability changes (ΔΔG), achieving improved generalization across diverse proteins. In parallel, a supervised consensus ranking framework based on learning-to-rank methods integrates outputs from multiple design models to enhance the selection of functional protein variants, demonstrating improved performance in large-scale benchmarks and real-world enzyme design applications.  The application of computational enzyme design strategies was further explored in the engineering of stilbene cleavage oxygenase NOV1 for the biotransformation of ferulic acid to vanillin. Despite the use of multiple approaches, including deep learning–based design, physics-based modeling, and free energy calculations, experimental results revealed the loss of enzymatic activity in designed variants, underscoring the complexity of enzyme redesign and the limitations of current computational methods.  Finally, the catalytic mechanism and substrate specificity of lysine cyclodeaminase (LCD) were investigated using extensive molecular dynamics simulations and experimental validation. While substrate access was not limited, well-tempered metadynamics simulations revealed that catalytic inefficiency toward bulkier substrates arises from unfavorable conformational dynamics and misaligned reactive geometries. These findings emphasize the critical role of enzyme dynamics in determining catalytic outcomes and provide a mechanistic basis for rational enzyme engineering.  Overall, this thesis investigated how integrated computational approaches can accelerate enzyme engineering, improve predictive modeling of drug metabolism and toxicity, and provide fundamental insights into enzymatic catalysis. The methodologies developed herein contribute to advancing next-generation biocatalyst design and support the broader goal of sustainable biochemistry.","language":"eng","citation":"COMPUTATIONAL ENZYME ENGINEERING: FROM MOLECULAR MODELING TO MACHINE LEARNING / Y. Wei ; tutor: I. Eberini, F. E. Molinari ; coordinator: G. D. Norata. Dipartimento di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti, 2026. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R14186.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 14-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/967565"},"title":"BETWEEN LIGHT AND DARKNESS: THE ROUND-TRIP OF SURFACE AND SUBTERRANEAN ANIMALS","internalauthor":"BARZAGHI, BENEDETTA","type":"Tesi di dottorato","year":"2023","abstract":"Caves are extreme environments, this definition is mostly due to the absence of sunlight that limits the abundance of trophic resources in this environment. The animals that live there, in order to exploit of this ecosystem, must show particular adaptations such as an extremely reduced metabolism, the absence of eyes and the lack of pigmentation. These adaptations are still considered by many authors as an evolutionary dead end. In practice; an animal that has evolved to exploit the cave environment can not perform the reverse process and will never re-colonize the external environment.  The main purpose of this thesis was to verify whether this theory was correct.","language":"eng","citation":"BETWEEN LIGHT AND DARKNESS: THE ROUND-TRIP OF SURFACE AND SUBTERRANEAN ANIMALS / B. Barzaghi ; tutor: R. Pennati ; co-tutor: R. Manenti ; coordinatore: M. Guarino. Dipartimento di Scienze e Politiche Ambientali, 2023 May 02. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12714.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 01-GEN-28"}
,{"handle":{"url":"https://hdl.handle.net/2434/946457"},"title":"A PERTURB-SEQ SATURATION MUTAGENESIS APPROACH TO DISSECT THE MOLECULAR BASES OF GENETIC DISEASES","internalauthor":"VACCARO, LORENZO","type":"Tesi di dottorato","year":"2022","abstract":"The improvement of novel sequencing technologies is quickly transforming the scientific investigation and the therapeutic treatments of rare genetic diseases, which research is hampered by the limited cohort of diagnosed patients and by the difficulty of evaluating the effect of Variants of Unknown Significance (VUS).  In silico predictors represent the gold standard of clinical bodies for interpreting mutations identified through sequencing approaches. Unfortunately, many of them are classified as VUS, leading to wrong diagnoses and inadequate treatment of patients. To address this point, MITEseq (Mutagenesis by Integrated TilEs) is a novel saturation mutagenesis technique that allows us to quickly test thousands of potentially pathogenic protein variants in a single high throughput biological assay. As proof of principle, we decided to apply it to mutagenize two regions of P63 (a portion of the DNA Binding Domain and the SAM domain), a transcription factor that, besides an oncogenic function, is mainly a regulator of skin development.  To follow the biological activity of each generated variant, we set up a very efficient conversion strategy from fibroblasts to keratinocytes-like-cells (through P63-KLF4 induction). Using the specific keratinocytes membrane antigen ITGβ4, we separated the converted and non-converted cells, studied the enrichment of each variant in the different populations and ranked them according to their pathogenic effect. To expand such method to any disease-driving gene, we developed a scRNAseq-based platform. Through this approach, we could associate each cell (i.e., each variant) to a specific physiological or pathological activity based on a specific transcriptional signature.  This approach could represent a milestone in the field of genetic disorders, providing the scientific community with a robust (and easy-to-use) functional tool to explore the molecular bases of rare diseases.","language":"eng","citation":"A PERTURB-SEQ SATURATION MUTAGENESIS APPROACH TO DISSECT THE MOLECULAR BASES OF GENETIC DISEASES / L. Vaccaro ; tutor: D. Cacchiarelli ; internal advisor: C. Missero ; external advisor: M. Ziller. Università degli Studi di Milano, 2022 Dec 06. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12416.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/946457/2100751/phd_unimi_R12416.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1207275"},"title":"IDENTIFYING (UN)COMMON PATTERNS OF DEMOCRATIC BACKSLIDING","internalauthor":"GANBAATAR, GESER","type":"Tesi di dottorato","year":"2025","abstract":"In the past decade, there has been growing alarm over the crisis of democracy worldwide. Scholars and international organizations widely agree that the trend of the third wave of democratization has reversed, and the concept of “democratic backsliding” has swiftly materialized. However, this phenomenon encompasses deteriorations in a wide range of attributes, such as civil liberties, the rule of law, the separation of powers, checks on the executive branch of government, the independence of the judiciary, and aspects related to the central pillar of democracy, which is free and fair elections.  The common tendency in the vast majority of backsliding literature is for scholars to focus on one aspect of deterioration and thus consider that process as democratic backsliding. Although this focus is incontestable, this research project argues that it causes an overgeneralization of the problem which tends to overlook the state of the democratic system as a whole and the condition of other attributes of democracy. There has been much less attention given to whether deteriorations in certain aspects of democracy are occurring commensurately with the other ones.  This project aims to examine democratic backsliding through mixed-method approach. Firstly, it aims to conduct a large-N quantitative analysis of the state of democracy through two dimensions: liberal and electoral. By investigating whether deteriorations in the liberal dimension (and its sub-dimensions) are accompanied by deteriorations in the electoral dimension (and vice versa), this research aims to systematically distinguish various interplays between the two dimensions. The study seeks to identify patterns of backsliding and assess whether democracies follow a common trajectory of decline, providing a comprehensive understanding of how the state of democracy is deteriorating worldwide.   Secondly, this research analyzes the trajectory of democracy in Mongolia as a case study, with a particular focus on its backsliding process. Mongolia is often overlooked in both political science and comparative constitutional scholarship, despite having made a remarkable transition to democracy following its authoritarian past. For over three decades, it has maintained a democratic status under challenging conditions marked by economic crises and geopolitical pressures. However, during the last decade, the country has experienced significant shifts, with growing signs of democratic backsliding. This study evaluates that backsliding through the framework of disaggregated democratic dimensions and aims to trace the pattern and nature of erosion across them.","language":"eng","citation":"IDENTIFYING (UN)COMMON PATTERNS OF DEMOCRATIC BACKSLIDING / G. Ganbaatar ; tutor: A.Baraggia, A.Cassani ; coordinator: D.U. Galetta. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2025 Dec 11. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13346.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1207275/3220200/phd_unimi_R13346.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/946458"},"title":"AN IMPROVED GENOMIC SURVEILLANCE APPROACH TO DISSECT THE SARS-COV-2 PANDEMIC","internalauthor":"GRIMALDI, ANTONIO","type":"Tesi di dottorato","year":"2022","abstract":"Genomic surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the only approach to rapidly monitor and tackle emerging variants of concern (VOC) of the COVID-19 pandemic. Such scrutiny is crucial to limit the spread of VOC that might escape the immune protection conferred by vaccination strategies.  It is also becoming clear now that efficient genomic surveillance would require monitoring the host gene expression to identify prognostic biomarkers of efficacy and disease progression. Here we applied an integrated workflow for RNA extracted from nasal swabs to obtain in parallel the entire genome of SARS-CoV-2 and host respiratory epithelium transcriptome, representing the majority of Italian processed genomic samples. In addition, we have matured and applied novel proof-of-principle approaches to prioritize possible gain-of-function mutations by leveraging patients' metadata and isolated patient-specific signatures of SARS-CoV-2 infection. The goals mentioned above have all been achieved in a cost-effective manner that does not require automation, in an effort to allow any lab with a benchtop sequencer and a limited budget to perform integrated genomic surveillance on premises.","language":"eng","citation":"AN IMPROVED GENOMIC SURVEILLANCE APPROACH TO DISSECT THE SARS-COV-2 PANDEMIC / A. Grimaldi ; tutor: D. Cacchiarelli ;  internal advisor: D. Di Bernardo ;  external Advisor: N. Elvassore. Università degli Studi di Milano, 2022. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12419.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/946458/2100746/phd_unimi_R12419.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/913590"},"title":"BIOCATALYTIC AND FERMENTATIVE APPROACHES FOR THE PRODUCTION OF ADDED VALUE COMPOUNDS USING WILD TYPE AND GENETICALLY MODIFIED ACETIC ACID BACTERIA","internalauthor":"CANNAZZA, PIETRO","type":"Tesi di dottorato","year":"2022","abstract":"This PhD thesis is divided into four chapters that report the development of different microbial biocatalysts aimed at the valorization of food and biotechnological industrial by-products. The experimental parts are preceded by an introduction aimed to give a background on the impact of biocatalysis   on green chemistry and, more generally on circular economy, together with a systematic review of the main molecular biology approaches employed to   genetically engineer acetic acid bacteria.   The second chapter reports the optimization of a biocatalytic system for the regioselective hydroxylation of different terpenes employing a Mycobacterium  sp. CYP153A6 monoxygenase. In chapter 3 and in chapter 4 is described the development of different recombinant acetic acid bacteria strains, aimed at   the production of highly added value products, such as perillic acid, starting from limonene, a cheap and highly available substrate derived from the agro-food industry.   Limonene was employed as a pure compound (chapter 3) or via fermentation of orange peel wastes (chapter 4). The last chapter deals with the isolation and characterization of a bacterial cellulose (BC) producer strain, namely Komagataeibacter rhaeticus ENS9b, able to produce BC from acetate and crude glycerol, a by-product from the biodiesel production process.","language":"eng","citation":"BIOCATALYTIC AND FERMENTATIVE APPROACHES FOR THE PRODUCTION OF ADDED VALUE COMPOUNDS USING WILD TYPE AND GENETICALLY MODIFIED ACETIC ACID BACTERIA / P. Cannazza ; tutor: Prof. Francesco Molinari ; dean: D. Mora. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2022 Mar 02. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12389.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/913590/1994729/phd_unimi_R12389.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1033128"},"title":"QUANTITATIVE STABILITY VIA THE METHOD OF MOVING PLANES: APPROXIMATE SYMMETRY FOR OVERDETERMINED AND RIGIDITY PROBLEMS","internalauthor":"POLLASTRO, LUIGI","type":"Tesi di dottorato","year":"2024","abstract":"Since its introduction thanks to the work of Alexandrov, the method of moving planes has seen a widespread use in various applications of geometric analysis. Brought to the attention of the PDE community with the seminal work of Serrin, it has been a useful tool to prove a large variety of results, including symmetry results for overdetermined and rigidity problems. This thesis investigates three such problems from a quantitative viewpoint, by employing the method of moving planes and developing tools and techniques to prove symmetry and approximate symmetry results.","language":"eng","citation":"QUANTITATIVE STABILITY VIA THE METHOD OF MOVING PLANES: APPROXIMATE SYMMETRY FOR OVERDETERMINED AND RIGIDITY PROBLEMS / L. Pollastro ; tutor: G. Ciraolo, M. Cozzi ; coordinator: D. Bambusi. Dipartimento di Matematica Federigo Enriques, 2024 Mar 06. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R13092.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1033128/2370401/phd_unimi_R13092.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/920424"},"title":"DEMOCRACY AND THE RULE OF KNOWLEDGE","internalauthor":"BODINI, PAOLO","type":"Tesi di dottorato","year":"2022","abstract":"Democracy and the Rule of Knowledge    The work starts from the analyses of epistocratic theorists, reconstructing their criticism to democracy in order to develop a broader reflection on the role of political knowledge (episteme) within democratic paradigm. The thesis aims to present knowledge as vital component of political agency that democracy assumes and institutionalizes. Nonetheless, epistocrats’ epistemic reductionism represents a misinterpretation of such an agency and, accordingly, the remedies they support are presented as a misunderstanding of episteme’s reach and function in political process.   Chapter 1 focuses on epistocrats’ account of citizens’ epistemic littleness, emphasizing how ignorance and irrationality characterize their participation to political decision-making. Chapter 2 deals with the notion of political knowledge assumed by epistocracy: episteme is understood as a body of factual information, which constitutes the cognitive background of political decision-making. Chapter 3 argues that epistocratic interpretation of democracy recalls instrumentalism and, with it, the questionable assumption of politics as a mere epistemic practice. On the contrary, the thesis collocates the role of episteme in a procedural understanding of democracy, asserting that democracy embodies an “enlightened procedure”. In this view, democracy institutionalizes people’s capacity to formulate and consider factual truths (“serviceable truths”) concerning the context in which they operate as decision-makers. Chapter 4 challenges epistocracy by proposing an alternative institutional approach to deal with political ignorance. Democratic institutions have the duty to empower citizens’ epistemic agency, transforming the assumption of that agency into the commitment to spread political knowledge in society.","language":"eng","citation":"DEMOCRACY AND THE RULE OF KNOWLEDGE / P. Bodini ; TUTOR: C. Del Bò, C. Chwaszcza ; COORDINATORE: C.R. Luzzati. Università degli Studi di Milano, 2022 Apr 08. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12298.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/920424/2014404/phd_unimi_R12298.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1118548"},"title":"\"BACTERIAL  PLAYERS IN CROP SYSTEMS: BENEFITS AND RISKS IN THE \"\" ONE HEALTH\"\" PERSPECTIVES.\"","internalauthor":"PATANIA, GIOVANNI","type":"Tesi di dottorato","year":"2024","abstract":"In recent years, agri-food ecosystems have recognized as crucial environment in the One Health approach, which deals with the intersections between human, animal and environmental health, recognising them as a unique interconnected system. The research conducted in the frame of this PhD thesis dealt with the investigation on the effect of bacteria entrance in agri-food ecosystems. In compliance with the ‘One Health’ concept, both the benefits and the risks given by the introduction, voluntary or accidental, of bacterial players in environmental habitats related to food production were considered.  An example of deliberate release of microbes in agricultural systems is the use of plant beneficial strains (i.e., biofertilizer and biostimulants). Experiments were designed to better clarify the interactions occurring between bacteria inoculants and the recipient plant microbiome and, additionally, the research was focused on the design of novel delivery system for the administration of plant probiotics. The knowledge improvement regarding these two aspects has the potential to promote the transition from the lab to the field of microbial based solution for sustainable agriculture, such as the replacement of chemical fertilizers or the use of strains to improve plant tolerance to biotic and abiotic stresses. We characterized for Plant Growth Promotion (PGP) activities a collection of endophytic strains established from grapevine and lettuce plants collected in the field. Among the most promising strains, Rhizobium sp. GR12 and Kosakonia sp. VR04 were tagged with genes coding for fluorescent proteins and used to inoculate micropropagated grapevine cuttings. Plantlets were grown in vitro under optimal growth conditions or on a diluted medium to mimic nutritional deficit. The measurement of plant biomass showed that Rhizobium sp. GR12 displayed PGP activity, when the plantlest were grown under nutritional deficit. The colonization of the plant tissues was confirmed for both Rhizobium sp. GR12 and Kosakonia sp. VR04 through qPCR amplification of the GFP and m-Scarlet protein, respectively. However, though both the strains were able to colonize root and lead endosphere of the treated plantlets, metataxonomic analyses revealed that the composition of the endophytic community was differently modulated by Rhizobium sp. GR12 and Kosakonia sp. VR04. The former had a minor impact on the endophytic bacterial community while Kosakonia sp. VR04 caused a major change in community composition, suggesting an opportunistic colonization pattern. The results of this study corroborate the importance of preserving the native endophytic community structure and functions during plant microbiome engineering. Moreover, for the first time, the structure of bacterial endophytic community of micropropagated grapevine cuttings was described, showing that it clearly differed from those generally associated to this plant species in the field.  Rhizobium sp. GR12 strain was included in a panel of plant-associated bacterial strains isolated from different host species and selected based on their PGP properties, abiotic stress tolerance and polysaccharides degrading activity. These strains were used to test the possibility to provide beneficial bacterial inoculant through the functionalization of a bio-based polymer, derived from food industry waste and designed with the final aim to obtain biodegradable nursery pots. Cell viability within the biopolymer was evaluated by embedding the strains into the liquid material and by isolating them after its solidification, drying and storage. The results showed that the approach was suitable only for the tested spore-forming Bacillus strains, which were able to cope the desiccation step during the production of the biopolymeric film. Thus, to improve the survival of non-spore-forming strains, we changed strategy and tested food waste derived materials, and other different molecules, as cryoprotective agents to obtain a lyophilised PGP inoculum. Using as model bacterium Rhizobium sp. GR12 strain, interesting results were observed using a residual fraction obtained from the extraction of proteins from okara, a soy-milk by-product, in comparison with other cryoprotectants.   The second pillar of the present PhD thesis concern i) the investigation of the resistome profiling of water-dwelling microbiomes in environments associated with water reuse practices in agriculture and ii) the studies of Horizontal Gene Transfer (HGT) on lettuce phylloplane. On one hand, we collected freshwater samples along a gradient of increasing distance from the effluent releasing point of a WWTP located in the Cremona municipality to the Po River. From these samples, bacterial collection was established on selective media for Enterobacteriaceae and Enterococcaceae, aiming to characterize the resistome in this natural environment and applying different techniques, like Minimum Inhibitory Concentration (MIC) analyses and disk diffusion test. Taxonomic identification showed that the established collection encompasses, besides faecal-indicator-bacteria, several genera known to be able to interact with plants (e.g., Acinetobacter, Klebsiella) and previously reported as potential human and animal opportunistic pathogens. The results of MIC analyses showed the presence of 5 multi-drug-resistant strains. Based on the antibiotic resistance profiling, different strains were selected for genome sequencing. Moreover, we tested the possible introduction and spread of ARB in the microbiome of plants of agricultural interest, by administering some of the detected multi-drug-resistant strains to lettuces plants under greenhouse conditions. Eight bacterial strains belonging to Acinetobacter, Klebsiella and Escherichia genera were tested for colonization ability and were able to establish in the lettuce plants’ rhizosphere with a concentration ranging between 104 to 106 CFU/g of soil. The conducted antibiotic resistance survey showed how a high percentage of isolates important under the ‘One Health’ frame carried AR traits and/or were MDR strains. Rhizospheric colonization of a plant of agricultural interest by MDR strains, could represent an important trigger for HGT events related to AR transmission. The genomes of 15 isolates chosen among the MDR strains are currently under analyses to get more knowledge about AR traits, in particular ARGs localization and possible diffusion mechanisms.   In this context, the possible acquisition of extracellular DNA (exDNA) on lettuce phylloplane by the model strain A. baylyi BD413 was characterized performing in planta experiments, to clarify the role of natural transformation as entrance pathway of ARGs into the epiphytic and/or endophytic bacterial communities associated to leafy vegetables. Furthermore, we investigated the effect of surfactants, which are chemicals widely used in agriculture, on exDNA acquisition by bacteria and plant tissues, and on the bacterium leaf endosphere penetration. Firstly, we demonstrated that A. baylyi BD413 was able to acquire extracellular DNA on lettuce leaf when DNA was provided at low quantity mimicking those detected in treated wastewater. Notably, natural transformation frequency in planta was comparable to that occurring under optimal conditions (i.e., temperature, nutrient provision, and absence of microbial competitors). The transformation frequency of A. baylyi BD413 was not enhanced by the presence of the surfactant, a data in agreement with no increase of the bacterial cell permeability when the surfactant was added in the growth medium. Interestingly, the concentrations of total and transformant A. baylyi BD413 colonies retrieved from the lettuce endosphere showed higher values in leaves treated with the surfactant and such difference was statistically significant for transformant colonies. In our experimental set, we could not totally exclude that the latter result could be related to a higher uptake of exDNA by plant tissues in the presence of surfactant resulting in the occurrence of transformation events directly in the endosphere. All in all, the work conducted on natural transformation events using A. bayily BD413 highlighted the importance to obtain more experimental data on HGT mechanisms directly in planta, since produces represent the possible entry point of ARGs and ARB into food production, especially if raw consumed.  The results of this PhD thesis research led to an improved knowledge of beneficial bacterial invasion outcomes in planta, linking the response of all the involved players in the holobiont, and provided novel information to design technological solutions aimed at improving beneficial bacteria delivery to plants. On the other hand, the data collected on bacterial resistome and HGT events in relation to water reuse scenario confirmed the importance to assess the possible impact of agricultural practices under the framework of the One Health approach.","language":"eng","citation":"\"BACTERIAL  PLAYERS IN CROP SYSTEMS: BENEFITS AND RISKS IN THE \"\" ONE HEALTH\"\" PERSPECTIVES / G. Patania ; tutor: F. Mapelli, S. Borin; coordinatore: D. Mora. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2024 Dec 18. 37. ciclo, Anno Accademico 2024.\"","filename":"phd_unimi_R13322.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1118548/2589538/phd_unimi_R13322.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/950653"},"title":"QUANTITATIVE PROTEOMIC APPROACHES TO STUDY DRUG MECHANISM OF ACTION","internalauthor":"CASTELLI, SILVIA","type":"Tesi di dottorato","year":"2023","abstract":"In recent years an increased number of covalent protein kinase inhibitors has been approved for cancer therapy and many more are undertaking clinical trials. Covalent binding is usually obtained by introducing in these drugs an electrophilic warhead able to bind specific nucleophilic sites in the protein target.  Covalent inhibition of oncogenic protein kinases allows to obtain a stronger and prolonged therapeutic effect compared to reversible inhibition; however, the choice of the dose to be administered to patients and the evaluation of the selectivity among the kinase family are mandatory to reach pharmacological results reducing possible side effects. From the DMPK perspective for covalent inhibitors, in vitro and in vivo data extrapolation, to obtain human pharmacokinetic projection, can be challenging and numerous efforts have to be undertaken in developing methods to accurately and quantitively determine inhibitor target engagement in preclinical and more importantly in clinical studies. Chemoproteomic approaches, taking advantage of the use of chemical probes, provide powerful tools to analyze binding characteristics between small molecules and proteins and validate the mode of action of these drug candidates. Click chemistry is a cycloaddition reaction between an azide and alkyne group to generate a 1,4-disubstituted 1,2,3-triazole ring. In this way, it is possible to functionalize the inhibitor under development with an alkyne moiety that could be labelled with a fluorescent-azide for target engagement detection and quantitation in native environments and a desthiobiotin-azide molecule for identification of the inhibitor off-target binders and proteome-wide selectivity. The functionalization of the inhibitor with a small group such as the alkyne group (the molecule obtained is called probe) allows the incubation of the compound directly in situ, with minimal alteration of inhibitor features (e.g. potency and permeability).  Thus, the aim of this project is the optimization and application of click chemistry reaction in order to study covalent mechanism of action of ibrutinib, a covalent inhibitor of the tyrosine protein kinase BTK, approved by FDA in 2013 for the treatment of B cell malignancies.  We used ibrutinib as case study, but the developed protocols can be applied to the study of other covalent inhibitors. Target engagement conditions were initially optimized on the recombinant BTK protein using an ibrutinib derivative, bearing an alkyne group, and then transferred to cell extracts.  Competition experiments were set up on extracts and then an in cell target engagement experiment was conducted, treating cells with 5 μM ibrutinib. The significant decreasing of the signal intensity of fluorescent probe labeled BTK, after pre-incubation of cells with ibrutinib, suggested a full target occupancy of BTK.  Nevertheless, with the aim to precisely calculate this target occupancy, a chemoproteomic workflow coupled to quantitative mass spectrometry analysis has been optimized and set.  In this case, click chemistry reaction was performed coupling to ibrutinib probe an azide functionalized with a desthiobiotin moiety in order to capture desthiobiotinylated peptides with a streptavidin resin, taking advantage of high affinity between streptavidin and desthiobiotin.  The developed protocols have been validated in cells treated with ibrutinib and, in addition to BTK, two additional protein kinases JAK3 and BLK have been identified modified on cysteine 909 and 319, respectively. These cysteines are located in the ATP-binding site of the two kinases in a position corresponding to the cysteine 481 in BTK. Interaction with ibrutinib for JAK3 and BLK was confirmed by additional analyses on recombinant protein and cell lysates.  Total proteome analysis, both in label free quantitation and TMT mode, has been undertaken to additionally characterize ibrutinib treated cells. The work allowed to better understand the preclinical profile of an oncological target therapy drug in term of potency and selectivity in living cells. The process is transferable to other covalent drugs and applied not only in preclinical models but also in clinical trials, helping in the definition of the optimal dose for patients to obtain the best efficacy, limiting side effects.","language":"eng","citation":"QUANTITATIVE PROTEOMIC APPROACHES TO STUDY DRUG MECHANISM OF ACTION / S. Castelli ; tutor: G. Aldini, B. Valsasina ; coordinatore: G. Aldini. Dipartimento di Scienze Farmaceutiche, 2023 Jan 13. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12583.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/950653/2118539/phd_unimi_R12583.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1026675"},"title":"MASS SPECTROMETRIC STRATEGIES TO IDENTIFY BIOACTIVE COMPONENTS FROM NATURAL EXTRACTS WITH ANTI-INFLAMMATORY ACTIVITIES","internalauthor":"FERRARIO, GIULIO","type":"Tesi di dottorato","year":"2024","abstract":"Oxidative stress and chronic inflammation are two conditions that can worsen various diseases, spanning metabolic, neurological disorders to tumour formation. In this context, a wide source of bioactive molecules exhibiting anti-inflammatory effects, combined with antioxidant potential, can be found in fruit and vegetables extracts. In particular, it has been reported that certain phytoconstituents are able to target two closely related systems within the cell, namely the NRF2 and NF-κB pathways. While the NRF2 pathway is responsible for regulating an extensive panel of antioxidant enzymes, NF-κB is the main effector pathway involved in inflammation. Phytochemicals in general mediate their effects by modulating the DNA-binding capacity of both these transcriptional factors and, in turn, correcting an unbalanced cellular state related to an uncontrolled inflammatory condition. Whereas previously, as a source of these phytochemicals, the focus was on the 'nobler' parts of the plant (i.e. the fruits, leaves and roots), today much more emphasis is placed on the analysis of industrial by-products. Specifically, this strategy aimed at the reuse of industrial by-products could reduce the impact of cultivation on waste production, minimizing disposal problems while obtaining a potential source of bioactive compounds. Even though there is general knowledge on the possible targets of these compounds, newer techniques combining different -omics approaches could better illustrate the biological impact of these extracts while identifying the phytochemical compounds responsible for it. Combining these different approaches to a concept of circular economy to valorise waste products could be a key to obtain useful health care products to prevent or even treat oxidative and inflammatory conditions.  In particular, in this thesis, I will explore the antioxidant and anti-inflammatory activities of different extracts obtained from by-products of grape and apple cultivation. This investigation will employ a multifaceted approach, integrating engineered cell cultures for phenotypic screening of bioactive extracts, Mass Spectrometric-based metabolomics to unravel the primary components of these extracts, and Mass Spectrometric-based proteomic studies to comprehensively analyse their impact on the cell proteome. The exploration of potential mechanisms of action will be conducted through both in-vitro and ex-vivo quantitative proteomic studies. Conclusively, the thesis will showcase the application of a MS-CETSA (Mass Spectrometry – Cellular Thermal Shift Assay) methodology to probe the direct target of a bergamot leaves polyphenols extract.","language":"eng","citation":"MASS SPECTROMETRIC STRATEGIES TO IDENTIFY BIOACTIVE COMPONENTS FROM NATURAL EXTRACTS WITH ANTI-INFLAMMATORY ACTIVITIES / G. Ferrario ; tutor: G. Aldini ; coordinatore: G. Vistoli. Dipartimento di Scienze Farmaceutiche, 2023 Feb 13. 36. ciclo","filename":"phd_unimi_R12827.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1026675/2354160/phd_unimi_R12827.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1213895"},"title":"MODERN AND INDIGENOUS KNOWLEDGE OF CLIMATE CHANGE AND GLACIER MARRIAGE IN GILGIT-BALTISTAN, PAKISTAN.","internalauthor":"KHAN, SALMA","type":"Tesi di dottorato","year":"2026","abstract":"This thesis investigates how local communities in Gilgit-Baltistan, Pakistan, interpret and respond to environmental crises, drawing on their unique indigenous knowledge systems. The region is highly dependent on glacier melt; therefore, it is the main source of water for both drinking and irrigation purposes. The altered precipitation patterns and climate hazards such as glacial lake outburst floods, flash floods, and extreme weather events have intensified water scarcity and disrupted livelihoods. Local communities understand these shifts through spiritual, ecological, and cultural lenses. For them, climate change is not just a physical phenomenon but a sign of the disturbance of harmony between human and non-human beings. Therefore, mountains, glaciers, rivers, and winds are regarded as living entities whose behaviour depends on human actions.  Various indigenous communities inhabit this region, and indigeneity is intertwined in legal obscurity, postcolonial marginalization, and competing narratives of belonging. Indigeneity is contested, and a multi-layered identity is connected to clan histories, ancestral lineage, spiritual relationships with the land, and historical resistance to external forces. It is expressed through ritual performances and other everyday actions that help assert autonomy and a sense of belonging in the face of political marginalization. Indigenous knowledge comprises two primary forms: shamanic and ecological. Shamanic knowledge is performed by spiritual agents such as bitan/dayal, daśhman, khalifa, and akhón, which includes trance, rituals, and prophecies. Using this form of knowledge, climate change is interpreted as a result of spiritual disruption, disrespect of spirits, and failure to observe taboos and rituals. Ecological knowledge is developed by farmers, pastoralists, herders, and shepherds who interpret weather patterns, manage resources, and practice agriculture. In these two systems of knowledge, human and non-human actors become part of a network that influences climate adaptation strategy. Both shamanic and ecological practices are facing challenges due to Islamic orthodoxy, modernization, and political structures.  This study employs qualitative ethnographic methods. To achieve the research objectives, the sample was selected through a combination of purposive and snowball sampling. Various methods, tools, and techniques were employed, including in-depth interviews, participant observation, and semi-structured questionnaires. The data was collected from Hunza, Nagar, Gilgit, Danyor, Yasin, Skardu, Kharmang, Ghanche, and Shigar. With the help of four key informants from Chalth, Karimabad, Skardu, and Kharmang, 34 in-depth interviews were conducted with shamans, tribal leaders, and other supernatural mediators. 21 interviews were conducted with farmers, herders, pastoralists, shepherds, glacier growers, and climate experts from government and non-governmental organizations. Additionally, six focus group discussions were conducted in Aliabad, Gulmit, Nagar Khas, Skardu, and Gilgit city.  Finding highlights that traditional weather forecasting, which utilizes birds' behaviours, wind patterns, and sun movement, has become unreliable due to unpredictable weather patterns. This has increased the vulnerability of farmers’ and pastoralists' livelihoods. Climate shifts have led to declines in crop yields, an increase in pest infestations, livestock diseases, droughts, and rising living costs. Increasing climate hazards, such as glacial lake outbursts, have damaged  i  infrastructure, leading to poverty, migration, and forcing many to abandon traditional agricultural practices and adopt tourism, mining, and other services.  Local communities are responding to these changes by employing strategies that blend ecological, spiritual, and technical knowledge. The strategies include glacier marriage, avalanche harvesting, and ice stupas or towers. All these adaptation strategies are designed to store water during the winter season for use in the spring. The local farmers also employ strategies such as adjusting planting seasons, introducing new varieties of seeds, and utilizing night irrigation to conserve water. Although women manage most agricultural activities, their roles are often excluded from discussions at making tables. The revival of the indigenous techniques is the act of quiet defiance against political marginalization and state extractive policies. However, these traditional interventions are constantly exploited and appropriated by outsiders.  The study findings suggest that the ecological practices in Gilgit-Baltistan are neither purely traditional nor entirely scientific. They are formed as a result of deep ecological interaction, political structures, and state negligence. The locals integrate multiple practices, belief systems, and strategies to address environmental crises and economic challenges. The study provides nuanced insights for planning and designing climate adaptation policies for high-mountain indigenous communities.","language":"eng","citation":"MODERN AND INDIGENOUS KNOWLEDGE OF CLIMATE CHANGE AND GLACIER MARRIAGE IN GILGIT-BALTISTAN, PAKISTAN / S. Khan ; supervisor: L Ciabarri ; coordinator: N. Guicciardini Corsi Salviati. - University of Milan. Dipartimento di Filosofia Piero Martinetti, 2026 Feb 04. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13293.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1213895/3245780/phd_unimi_R13293.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1022991"},"title":"EPIDEMIOLOGIA GENOMICA DELLE PRINCIPALI VARIANTI DI SARS-COV-2 CIRCOLANTI IN ITALIA PRIMA E DURANTE L'ERA OMICRON","internalauthor":"BERGNA, ANNALISA","type":"Tesi di dottorato","year":"2024","abstract":"\"GENOMIC EPIDEMIOLOGY OF THE MAIN VARIANTS OF SARS-CoV-2 CIRCULATING IN ITALY BEFORE AND DURING THE OMICRON ERA  Introduction  Since the beginning of the pandemic, SARS-CoV-2 has shown a great genomic variability, resulting in the continuous emergence of new variants that has made their global monitoring and study a priority. Phylodynamic analysis, which is based on the combination of evolutionary, epidemiological, and immunological characteristics influencing the shape of a viral phylogeny, has become an increasingly important tool in the molecular surveillance of infections, particularly those due to emerging viruses. The COVID-19 pandemic presented a unique opportunity to apply such analyses to molecular surveillance due to the availability of SARS-CoV-2 genomic sequences since early January 2020, which has reached the impressive number of more than 16 million complete genomic sequences stored in one of the most widely used databases (GISAID, https://gisaid.org/, as of September 2023). These kinds of approaches together with genomic epidemiology have made it possible to trace international pandemic flows, to reconstruct outbreaks and transmission networks, to estimate transmissibility and identify variants with higher transmissibility or immune escape capacity.   This thesis aimed to study the genomic heterogeneity, the temporal origin, the rate of viral evolution and the population dynamics of the main variants circulating in Italy before and during Omicron era, such as 20E.EU1, Alpha, Delta variants and Omicron BA.1, BA.2 and BA.5, respectively.   Material and methods  The nasopharyngeal swabs of COVID-19 patients attending more than 70 clinical centers distributed throughout whole Italy, participating in the collaborative SCIRE group, were collected and processed between August 2020 and December 2022. For the study of the main variants circulating between summer 2020 and winter 2021 (clade 20E.EU1, and Alpha and Delta variants), 3 national and 3 international datasets were set up using a total of 609 whole genomes characterized by our collaborative network (20E.EU1, n= 269; Alpha, n=164; Delta, n= 176). To study the major lineages of the Omicron variant circulating during 2022 (BA.1, BA.2 and BA.5), 3 national datasets were set up using 1,658 whole genomes characterized by the collaborative network (BA.1, n= 268; BA.2, n=677; BA.5, n=713).   Italian genomes obtained from GISAID (https://gisaid.org) with the same variant and collection period were added to the 6 Italian datasets. International genomes with the same variant and collection period were added to the 3 international datasets. Mutational analyses were conducted only on the Italian datasets.   Phylogenetic analyses were conducted on 3 international datasets for 20E.EU1, Alpha and Delta variants and 3 national datasets for Omicron BA.1, BA.2 and BA.5. The maximum likelihood (ML) trees were estimated using IQ-TREE v. 1.6.12 (http://www.iqtree.org/). The GTR + F + R4 (general time reversible + empirical base frequencies + four number of categories) model, selected by the program, was used for clade 20E.EU1, Alpha and Delta variants; the GTR+F+R3 (general time reversible + empirical base frequencies + three number of categories) for Omicron BA.1 and BA.2, and GTR+F+R6 (general time reversible + empirical base Frequencies + six number of categories) for Omicron BA.5. 1,000 parametric bootstrap replicates were performed to support the nodes (≥60% bootstrap support). The statistically significant clusters (including more than two sequences) were identified in the ML tree by Cluster Picker v.1.2.3. Cluster Matcher v.1.2.23 program was used to selected clusters containing at least one Italian sequence, classified as mixed (M) those that included more than one Italian isolate and non-Italian sequences, as pure Italian (IT) those that included only Italian isolates, and as singleton (S) those clusters containing only one Italian isolate together with non-Italian sequences.   To characterize the epidemiological and evolutionary history of the different SARS-CoV-2 variants/lineages in Italy during 2020 and 2021, for each dataset only clusters including at least 70% of Italian sequences, having sufficient size for the analysis (>10 sequences) were considered by using the coalescent Bayesian Skyline Plot and the birth-death models (BEAST v. 2.7 program). Italian clusters characterized by 10 or more isolates were selected for analysis of the Omicron variants.  Results  For variants circulating before Omicron era, characteristic mutations in the ancestral B.1 and B.1.1 lineages were observed in addition to mutations specific to the variant. In about 1/3 of the B.1 lineage sequences two additional mutations were found in the S gene (A262V and P272L), while for the Delta variant, many additional mutations were shown, especially in the ORF1a region.  The international datasets showed 26 (23% Italians, 23% singleton, 54% mixed), 40 (60% mixed, 37.5% Italians, 1 singleton) and 42 (85.7% mixed, 9.5% singleton, 4.8% Italians) clusters with at least one Italian sequence, in 20E.EU1 clade, Alpha and Delta variants, respectively. These clusters presented a tMRCAs (Time of the most recent common ancestor) between June 2020-September 2020, November 2020-February 2021 and March 2021-July 2021 for 20E.EU1 clade, Alpha and Delta variants, respectively.   In all the lineage/variant, the earliest clusters were the largest in size and the most persistent in time and frequently mixed. Isolates from the major Italian Islands tended to segregate in clusters more frequently than those from other part of Italy. The estimation of evolutionary rate gave a mean of 3.8×10−4 s/s/y (95%HPD: 3.35×10−4–4.39×10-4), 4.87×10-4 s/s/y (95%HPD: 4.18×10-4–5.54×10-4) and 7.57×10-4 s/s/y (95%HPD: 6.65×10-4–8.48×10-4) for 20E.EU1 clade, and Alpha and Delta variant, respectively.  The skyline plot of 20E.EU1 dataset showed a rapid increase of the effective number of infections (Ne) during July 2020, followed by a second increase in October 2020, when the curve reached the plateau. The decrease of infections started in February 2021 reaching the lowest values in April 2021. Consistent with the dynamics of infection, estimates of Re showed a value greater than 1 from the beginning of the circulation of 20E, reaching a peak around July 2020 (Re=1.12). The Re value started to decline in autumn 2020, falling around 1 between December 2020–January 2021 and decreasing below 1 in April 2021.  The effective number of infections due to Alpha variant rapidly increased in December 2020, reaching a plateau during the winter 2021. A decrease in infections was observed from April 2021. Similarly, a value of Re above 1 was observed since the origin of the Alpha epidemic in the autumn 2020, with a peak around a value of 1.13 in winter 2020–2021. A decrease in the curve was observed between March and April 2021 reaching values below the unit in May 2021. A slow rise in spring 2021 was observed for Delta variant, followed by a rapid increase of infections in July 2021. From August the number of infections reached a plateau that persisted until the end of the year 2021. Similarly, the Re value shows a growth above 1 in spring 2021, reaching a value of 1.17, followed by a gradual decrease to a value below 1 in the summer of the same year.  The Omicron variant datasets under investigation were characterized by numerous sub-lineages with a frequency greater than 1%, with a high proportion of BA.1.17.2 and BA.1.1 sub-lineages for BA.1 variant, BA.2.9 sub-lineage for Omicron BA.2, and BA.5.2 and BA.5.2.1 sub-lineages in the BA.5 dataset. A high number of sub-lineages with a frequency of less than 1% was also shown for each variant. All these variants showed the presence of a high number of variant-specific mutations and deletions in more than 10 percent of the isolates.   Bayesian analyses conducted on 12 (Omicron BA.1), 7 (Omicron BA.2) and 10 (Omicron BA.5) Italian clusters showed a tMRCA between September 2021-November 2021, November 2021-January 2022 and October 2021-May 2022 for BA.1, BA.2 and BA.5 variants, respectively. Overall, clusters of BA.1 and BA.2 variants were characterized by a high number of isolates from northern Italy. Differently, 60% of the clusters of BA.5 variant were characterized by isolates from every part of Italy. The estimation of evolutionary rate gave a mean of 4.84x10-4 s/s/y (95%HPD:3.76x10-4 – 5.98x10-4), 3.99x10-4 s/s/y (95%HPD: 2.70x10-4 -5.33 x10-4), and 4.56x10-4 s/s/y (95%HPD: 3.72x10-4-5.44x10-4) for BA.1, BA.2 and BA.5 Omicron variants, respectively.  The skyline plot analyses of BA.1 variants showed an initial, gradual increase in the number of infections between September and November 2021 followed by a further increase in December 2021 and January 2022 when the number of cases stabilized. Since the beginning of the epidemic, the value of Re remained around 1, increasing from September 2021 until reaching a peak of 1.45 in October. From January 2022 a decrease and stabilization of this value around unity was observed. For Omicron BA.2, an exponential increase in the number of infections was observed between January and February 2022 following which there was a plateau phase. There was an increase in the value of Re reaching the peak of 1.42 in January-February 2022. A first decrease was recorded between February and March 2022, followed by a further decrease between May and July 2022. This value remained stable below unity until the end of August 2022.  An initial increase in the number of infections for variant BA.5 was observed in January 2021, and a second exponential increase was recorded in May and June 2022. Following the achievement of plateau phase in August 2022, the number of cases decreased between October and November of that year. Re values remained above unity since the beginning of the epidemic, with peak reached in May 2022 (Re=1.28). A slight decrease was found in July 2022 to stabilize around unity starting in September.  Conclusions  The analyzed genomes of SARS-CoV-2 were included in over 100 clusters with a high frequency of mixed clusters (around 70%), which included strains circulating in different regions of the world, suggesting multiple introductions of these lineages/variants in Italy, probably due to international travels. The fact that the earliest clusters were the largest in size, the most persistent, and most frequently mixed could be related to pandemic containment measures, such as travel restrictions, which were relaxed during the summer 2020 but were then reintroduced in autumn, with the arrival of variants of concern, and gradually relaxed from May 2021. Pure Italian clusters, suggesting a local circulation of the virus, were more prevalent during periods in which restrictive measures were in place while, with the easing of containment measures, they have become increasingly less frequent. This could also be the reason why pure Italian clusters were observed with higher frequency for 20E.EU1 and Alpha variant, compared to Delta variant (<5% of all observed clusters) which circulated in Italy only later, when the restriction measures were largely relaxed.   Since the beginning of 2022, the Omicron variant has rapidly spread around the world, becoming the dominant variant to date with its derived sub-lineages. Rapidly the Omicron variant evolved giving rise to a succession of numerous different lineages and sub-lineages, with peculiar mutational profiles. This heterogeneity was also found in the analyzed datasets, with different sub-lineages with a frequency greater than 1%. Furthermore, analyzing the mutational profile of the BA.1, BA.2 and BA.5 variants, we found a high number of mutations, mainly located in the S gene.   Phenomena of neutral evolution, such as the \"\"founder effect\"\", have made it possible to identify transmission clusters only at the national level, unlike an international context where, due to the high degree of evolutionary correlation between strains of a single variant, it is difficult to identify clusters of more related sequences that share a recent common ancestor.  Higher Re values were observed for these variants than those estimated for the 20E.EU1, Alpha, and Delta variants, confirming the higher transmissibility of Omicron. Our estimates are like the official ones, except for the peak in January 2022, probably corresponding to the simultaneous circulation of Delta and Omicron variants.  Globally, the study of infection dynamics showed a positive correlation between the trend in the effective number of infections estimated by Bayesian Skyline Plot model and the Re curves estimated by birth-death skyline plot. The estimated evolutionary rates had values around 4x10-4 s/s/y for all the variants under study with the only exception of the Delta variant, whose value is double; this could be due to a longer persistence of this variant of almost one year and the generation of numerous derived lineages. Overall, these data provided an accurate description of the dynamics’ epidemiology in our country over a broad period from August 2020 to December 2022, characterized by a succession of different viral variants.\"","language":"ita","citation":"EPIDEMIOLOGIA GENOMICA DELLE PRINCIPALI VARIANTI DI SARS-COV-2 CIRCOLANTI IN ITALIA PRIMA E DURANTE L'ERA OMICRON / A. Bergna ; coordinatore: C. La Vecchia ; tutor: G. Zehender ; revisore esterno: M. Ciccozzi, F. Ceccherini-Silberstein.. Dipartimento di Scienze Biomediche e Cliniche, 2023. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13013.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1022991/2342185/phd_unimi_R13013.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/948169"},"title":"TECHNOLOGICAL BREAKTHROUGH TOWARDS THE USE OF A NOVEL VISUAL-INERTIAL ODOMETRY SYSTEM AS AN AID FOR THE DIGITALLY-GUIDED INTERVENTION","internalauthor":"FARRONATO, MARCO","type":"Tesi di dottorato","year":"2022","abstract":"Recent data availability of three dimensional imaging brought new possibilities for the guided intervention. The management of complex data requires the use of new tools and new technologies. We analyzed the use of algorithms for the automatic, ai-driven segmentation to extrapolate the best systems for the use of CBCTs. The tool improves the timing and precision of the segmentation and allows to give normal values for the cephalometry. The segmented data can be analyzed through three dimensional alignment, the new techniques will be explored for data synthesis. Finally three dimensional resulting datasets can be exported and used to virtually plan an intervention. After the plan is complete they can be used to bring the clinician a new powerful system for the AR guided intervention. Clinical and research data results and outcomes will be given, bringing both preliminary as well as multidisciplinary researchers in the field of: orthodontics, endodontics and oral surgery with clinical direct performances and results.","language":"eng","citation":"TECHNOLOGICAL BREAKTHROUGH TOWARDS THE USE OF A NOVEL VISUAL-INERTIAL ODOMETRY SYSTEM AS AN AID FOR THE DIGITALLY-GUIDED INTERVENTION / M. Farronato ; tutor: C. Maiorana ; coordinator: M. Del Fabbro. Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, 2022 Dec 14. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12479.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 14-DIC-30"}
,{"handle":{"url":"https://hdl.handle.net/2434/1124260"},"title":"GENETIC IMPROVEMENT OF CAMELINA SATIVA: DEVELOPMENT OF NEW VARIETIES AND EXPLORATION OF ITS POTENTIAL AS AN INTERMEDIATE CROP","internalauthor":"GHIDOLI, MARTINA","type":"Tesi di dottorato","year":"2024","abstract":"In recent years, Camelina sativa has gained considerable attention as a sustainable crop, known for its resilience under harsh conditions and low input requirements. It is being explored for its potential as a biofuel source and for the production of omega-3 rich oil. Furthermore, its role in improving soil health through crop rotation and its environmental benefits, such as reducing greenhouse gas emissions, have further increased its attractiveness. This doctoral thesis presents an overview of research on the allelopathic and agronomic benefits of Camelina, in particular its potential in integrated management. The thesis examines progress in camelina breeding through traditional methods, biotechnological approaches, evaluating its potential to improve the crop (improvements in yield, oil content and reduction of anti-nutritional compounds such as glucosinolates). He underlines the importance of genetic diversity and proposes two selection strategies: one that involves crossing spring varieties and the other that crosses spring and winter varieties. Breeding programs have shown that winter cultivation in Northern Italy led to significantly higher yields than spring cultivation. Furthermore, a synthetic population of Camelina sativa was identified as adaptable with a low glucosinolate content, making it resilient to different environments. Molecular analysis made it possible to identify genetic differences between winter and spring varieties. Finally, the promising new variety (C1244) shows early maturity, high seed weight and oil content, offering potential for use in several sectors.","language":"eng","citation":"GENETIC IMPROVEMENT OF CAMELINA SATIVA: DEVELOPMENT OF NEW VARIETIES AND EXPLORATION OF ITS POTENTIAL AS AN INTERMEDIATE CROP / M. Ghidoli ; tutor: S.R. Pilu ; cotutor: F. Adani ; coordinatore: S.R. Pilu ; supervisori: E. Cominelli, E. Nielsen. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2024 Dec 16. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13199.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1124260/2607838/phd_unimi_R13199.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/931625"},"title":"GIUDICI, ZANZOTTO, RABONI. AUTONOMIE ED ETERONOMIE DELLA PROSA","internalauthor":"CAPPELLO, MASSIMILIANO","type":"Tesi di dottorato","year":"2022","abstract":"\"This dissertation investigates the non-fiction production of three Italian poets of the second half of the twentieth century: Giovanni Giudici, Andrea Zanzotto, and Giovanni Raboni. Adopting a transdisciplinary approach, it shows how these writings, often considered a \"\"secondo mestiere”, according to Montale's definition, do not play a merely ancillary or vicarious role in the interpretation of the poetical work of their authors, but they prove crucial for the understanding of their intellectual figures. Following an Introduction that provides essential contextual details and describes the aims, scope, and method of the dissertation, Part One looks at the post-1991 non-fiction writings of these three authors, linking them to the end of a whole Weltanschauung. What emerges is a sense of the awareness that literary criticism and essay writing in general developed of political dynamics in the contemporary world. Part Two identifies and scrutinises this textual corpus from its beginnings, datable between the Liberation and the Economic Boom, considering Giudici, Zanzotto, and Raboni’s non-fiction and literary criticism books as macro-texts and a means of verification of the season they were written in. The Third and final Part analyses some newly-recovered unpublished, scattered, or unsigned essays and highlights their significance by framing them as part of the intellectual reflection of their authors.\"","language":"ita","citation":"GIUDICI, ZANZOTTO, RABONI. AUTONOMIE ED ETERONOMIE DELLA PROSA / M. Cappello ; tutor: L. Neri ; coordinatore: F. Slavazzi. Dipartimento di Studi Letterari, Filologici e Linguistici, 2022 Jul 01. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12391.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/931625/2044040/phd_unimi_R12391.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1024668"},"title":"MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN:LONGITUDINAL BODY COMPOSITION ASSESSMENT, INFLAMMATORY MARKERS, AND FATTY ACIDS PROFILE","internalauthor":"DI PROFIO, ELISABETTA","type":"Tesi di dottorato","year":"2024","abstract":"The Sars-Cov 2 pandemic mainly affected the adult population. However, a small portion of children were affected by Multisystem Inflammatory Syndrome in Children (MIS-C). The severity of the syndrome required patients to be hospitalised and, in some cases, admitted to pediatric intensive care units. A high risk of malnutrition was detected in children hospitalised for long periods. In addition, omega-3 fatty acids (ω-3 FA) were used in conjunction with drug therapy in adults hospitalised for Covid-19 to improve the inflammatory response.    The aim of this work was to assess the risk of malnutrition in the acute phase and body composition over time in a cohort of children diagnosed with MIS-C. For all the recruited children, inflammatory markers, metabolic parameters, and fatty acid levels were assessed both in the acute phase and six months after discharge, alongside anthropometric assessment. In half of the patients recruited, three months of docosahexaenoic acid (DHA) supplementation was also recommended. We observed a change in body composition in the acute phase, with a reduction in fat-free mass. In contrast, in the long term we detected a gain in fat mass, probably due to the limited spontaneous and structured physical activity on the part of the children.   The fatty acid levels detected in the acute phase were lower than in the healthy population, while the glucose profile was altered. At three and six months after discharge, the ω-3 FA values were higher than the acute phase, particularly in the group that received supplementation. The correlation between ω-3 FA levels and inflammatory indices at six months after discharge in the supplemented group, showed a positive correlation between ω-3 eicosapentaenoic acid (EPA) and erythrocyte sedimentation rate (ESR)and d-dimer, as well as a positive correlation between DHA and ferritin. Overall, the MIS-C children had a favourable disease course. However, nutritional status and loss of body weight should always be monitored in this type of disease during hospitalisation. In the long term, adherence to a balanced diet should be advised along with the resumption of spontaneous and planned physical activity. At the same time, ω-3 FA supplementation may facilitate optimal recovery. As a future perspective, the effectiveness of ω-3 supplementation in the acute phase and later, in seriously ill paediatric patients should be explored.","language":"eng","citation":"MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN:LONGITUDINAL BODY COMPOSITION ASSESSMENT, INFLAMMATORY MARKERS, AND FATTY ACIDS PROFILE / E. Di Profio ; tutor: E. Verduci ; coordinator: L. Pinotti. Dipartimento di Scienze della Salute, 2023. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12955_1.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1024668/2348394/phd_unimi_R12955_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1156536"},"title":"ESSERE ALLENATORE DI CALCIO OGGI - RUOLO, COMPETENZE E DISPOSITIVI FORMATIVI","internalauthor":"MORANDA, MATTEO MARIO","type":"Tesi di dottorato","year":"2025","abstract":"The continuous changes in the world of football have contributed to making the figure of the coach increasingly complex and multidimensional, requiring constant adaptation of skills. The research project fits into this framework, adopting a constructivist perspective in order to explore the identity and role of the football coach, observing the growing importance of the relational dynamics of the role and the need to adapt to a rapidly changing complex reality (Maulini et al., 2021; Ryba et al., 2022). Through a review of the literature, historical and contemporary changes in the perception of this figure have been analyzed, with particular attention to the necessary skills, which are now increasingly broad and articulated (Amicucci, 2017; Maggi, 2016; Otte et al., 2024).  The research, based on a qualitative methodology, included semi-structured interviews submitted to a sample of 14 coaches, with integrated workshops aimed at representing the self and the skills perceived as crucial, reflecting on the coach's learning methodologies and the effectiveness of training devices. The analysis of the data, conducted through the Template Analysis method (King & Brooks, 2017, in King, Brooks & Tabari, 2018), revealed the difficulty of defining the role of the coach in a unique way.  The second phase concerns the activation of the Action Research process. A team of experts re-read the results to start a discussion on the role of the coach, investigating perceptions and needs of the role and identifying four essential skills: collaboration, communication, decision-making ability and management of complexity. From the comparison, a training device was subsequently designed structured in five modules based on a constructivist approach that alternates theory and practice, promoting awareness of the role, skills and training methodologies.   The ultimate goal of this research work was to apply the training device to a group of 8 football coaches, who participated in the 5 theoretical-practical training modules lasting 4 hours each. The subsequent evaluation of effectiveness through a Mixed-Methods of quantitative and qualitative methods recognized a growth on four fundamental dimensions: role responsibility, complexity management, need for continuous training and reflection on practices.  The overall aim is to promote professional and personal growth of coaches, making their practices more aware and effective, without introducing tools extraneous to the sporting context. The project emphasizes the importance of building relationships of trust with athletes, consolidating an approach that integrates technique and relationships for an overall improvement of the coach's training function.","language":"ita","citation":"ESSERE ALLENATORE DI CALCIO OGGI - RUOLO, COMPETENZE E DISPOSITIVI FORMATIVI / M.m. Moranda ; tutor: C. Gozzoli ;  coordinatore: C. Gozzoli ;  supervisore: C. Gozzoli. Dipartimento di Scienze Biomediche per la Salute, 2025 Mar 26. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13445.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1156536/2736838/phd_unimi_R13445.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/820780"},"title":"EMERGENT PHENOMENA IN CONDENSED MATTER, SOFT MATTER AND COMPLEX SYSTEMS","internalauthor":"MAMBRETTI, FRANCESCO","type":"Tesi di dottorato","year":"2021","abstract":"Physical systems composed of a large number of reciprocally interacting constituents provide the natural context for the rise of emergent phenomena. Despite the intrinsic difficulty in providing a mathematical definition of what is meant for ‘emergence’ (see [Baas, in Langton, Alife III, Santa Fe Studies in the Sciences of Complexity, Proc. Volume XVII, Addison-Wesley, (1994)]), the intuitive notion of emergent property is that of a collection of interact- ing objects showing a novel collective behavior, qualitatively different from and not immediately attributable to the behaviors of the individual components. Non-linear interactions among elements of the system, or interactions between the system and the environment, or merely the large number of constituents are usually the motivations addressed to be responsible for emergent behavior. It is important to remark that emergent properties can only be inferred from a comprehension of the collective properties of the microscopic constituents [Kivelson et al, npj Quant. Mater. 1, 16024 (2016)].  In this regard, computer simulations provide a unique tool to support experimental observation, develop abstract models and investigate systems’ properties at a microscopic level. In general, condensed matter, particularly soft matter but also the complex systems studied in Physics, are necessarily described via simplified models, which include the key features of the corresponding real systems. On the one hand, this certainly represents a powerful approach when it finds its roots in the concept of universality, connected with critical phenomena, but this also turns into a limiting factor for the realistic description of the considered phenomena. On the other hand, it makes the properties of such abstract simulated systems calculable and investigable via computer simulations. As a consequence, the simulations assume a key role in complementing the comparison between experiments and theory [Frenkel and Smit, Understanding Molecular Simulations, Academic Press (2002); Allen and Tildesley, Computer simulation of liquids, Oxford University Press (2017)]. In this sense, simulations are often regarded as being computer experiments, in which materials properties and novel phases of matter can be investigated.  The present PhD thesis is a collection of the main results coming from four different research lines which I have been involved into in the last 3 years. The topics could appear to be rather diverse but they are all connected by the presence of emergent phenomena which were studied via computer simulations (Molecular Dynamics and Monte Carlo methods, mainly). Three of these four research lines are related to collaborations with as many experimental groups. The first group I started collaborating with is led by dr. R. Grisenti, at the University of Frankfurt (https://www.atom. uni-frankfurt.de/hhng-grisenti/index.html). As reported in Chapter 1 and in a recent paper which I contributed to as first co-author [Schottelius, Mambretti et al., Nat. Mat. (2020)], we studied the crystal growth of supercooled Ar–Kr liquid mixtures by means of a micro–jet experiment, Molecular Dynamics simulation and thermodynamic analysis. The second ongoing collaboration is with the group of prof. P. Milani, which is the leader of the CIMaINa laboratories (http://cimaina.unimi.it/) at the Università degli Studi di Milano. We developed an abstract stochastic model of resistive switching devices that they are characterizing for neuromorphic applications (see Chapter 3). More recently, I started a collaboration with the group led by prof. T. Bellini at the Università degli Studi di Milano (https://sites.google.com/site/unimisoft/), in order to investigate the spinodal decomposition of mixtures of DNA nanostars via light scattering experiments and Monte Carlo simulations, as described in Chapter 4. I will now provide a brief overview of the contents of each Chapter, where each Chapter corresponds to a different research line.  Crystal growth from a supercooled melt is of fundamental theoretical and practical importance in many fields, ranging from materials science to the production of phase–change memories. To date, the temperature dependence of the growth rates of many materials, including pure metals, metallic alloys, colloids and many others are still under intense scrutiny (see e.g. Tang et al., Nat. Mat. (2013) and Sun et al., Nat. Mat. (2018)). The majority of systems display a maximum growth rate at a temperature located between the melting point and the glass transition [Orava et al., J. Chem. Phys. (2014)]. Several materials are characterized by a range of many orders of magnitude between this maximum value and the crystal growth rates measured in other regimes. We still lack a deep comprehension of the mechanism underlying this phenomenology, which emerges from experiments and simulations both. Classical models of crystal growth from a melt hypothesize either a diffusion-limited process, or a collision–limited one, but for a lot of materials them both fail to fit the available data. This situation claims for further investigation about the key elements that tune the crystal growth rates from supercooled liquids, extending the current theoretical framework. Jointly with the experimental group of dr. Grisenti (which performed measurements at the EU-XFEL facility https://www.xfel.eu/), we studied the crystallization of supercooled mixtures of argon and krypton via Molecular Dynamics. Our results showed that their crystal growth rates (obtained from the analysis of simulated configurations exploiting Steinhardt angular order parameters) can be reconciled with existing crystal growth models only by explicitly accounting for the non–ideality of the mixtures. Our theoretical and computational contribution aided in highlighting the importance of thermodynamic aspects in describing the crystal growth kinetics, yielding a substantial step towards a more sophisticated theory of crystal growth.  A second project concerns the study of soft matter systems in one dimension (1D), detailed in Chapter 2. Soft matter systems are made of particles which can overlap by paying a finite energy cost and they are renowned for being able to display complex emerging phenomena. Some of them, for example, are characterized by the presence of clustering phases [Prestipino, Phys. Rev. E (2014)]. Recently, a surprising quantum phase transition has been revealed in a 1D system composed of bosons interacting via a pairwise soft potential in the continuum. It was shown that the spatial coordinates undergoing two-particle clustering could be mapped into quantum spin variables of a 1D transverse Ising model [Rossotti et al., Phys. Rev. Lett. (2017)]. Extending the description and the results provided in a very recent paper I contributed to as first author [Mambretti et al., Phys. Rev. E (2020)], in the second Chapter we investigate the manifestation of an analogous critical phenomenon in 1D classical fluids of soft particles in the continuum. In particular, we studied the low–temperature behavior of three different classical models of 1D soft matter, whose inter–particle interactions allow for cluster- ing. The two–particle cluster phase is largely explored, by simulating the systems at the commensurate density via Monte Carlo and Simulated Annealing methods. The same string variables exploited in the aforementioned quantum case highlight that, at the right commensurate density, the peculiar pairing of neighboring soft particles can be nontrivially mapped onto a 1D discrete classical Ising model. We also observe a related phenomenon, i.e. the presence of an anomalous peak in the low–temperature specific heat, thus indicating the emergence of Schottky phenomenology in a non–magnetic fluid.  The third Chapter presents the case of an electrical resistor network featuring novel emergent properties, such as memristivity and the possibility to be used as a self–assembled logic gate; an article on this topic is currently in preparation. The growing difficulties arising in the improvement of the performance of standard computing architectures encouraged the quest for different approaches aiming at reproducing the computational capability and energy efficiency of the human brain, by mimicking neurons and synapses as probabilistic computing units [Markovic et al., Nat. Rev. Phys. 2, 499–510 (2020)]. Networks based on the bottom–up assembling of nanoscale building blocks and characterized by resistive switching (RS) activities are becoming increasingly popular as possible solutions for a straightforward fabrication of complex architectures with neuromorphic features [Wang et al., Nat. Rev. Mat. 5, 173-195 (2020)]. Specifically, it has recently been demonstrated that metallic nanostructured Au films, under certain conditions show a non–ohmic electrical behavior and complex and reproducible resistive switching, which can be exploited for the innovative realization of logic gates. In these devices, the nonlinear dynamic switching behavior resulting from an applied input voltage can be exploited for developing hardware for reservoir computing applications. In Chapter 3, I show how it is possible to simulate a complex model (Stochastic Resistor Network Model, SRNM) able to imi- tate the phenomenology and give hints for the development of experiments ongoing at the CIMaINa research laboratories, regarding the electrical current passage through nanostructured cluster gold films [Mirigliano et al., Nanotechnology, 31, 23, (2020)]. To this purpose, I personally contributed to develop from scratch a C++ code, parallelized via the Armadillo library (http://arma.sourceforge.net/). To study the electrical transport properties of this system, we modeled the experimental sample as a network of interconnected resistors whose effective resistance under a given voltage can be determined using spectral graph theory. The network state evolves stochastically via random physically–inspired update moves, and its effective total resistance (and the related Power Spectral Density) has been analyzed. The structure and the topology of the network were studied via the investigation of the shortest path connecting the source and the sink of the system, thus exploring the possible paths in which the current could flow. Moreover, we also applied Information Theory entropy–based tools to investigate the time evolution of network resistance at a local, coarse–grained, scale. We observed that specific input signals corresponding to 2 logical ‘bits’ pro- duce rich outputs associable to a logical NAND gate, which posses functional completeness. Given that relevant differences could be detected between the behavior of the network at low voltage before and after the so called ‘writing’ step (where the system is under a high applied voltage), memristive effects naturally emerge in the study of network properties. These results encourage further investigations, both experimental and via the innovative SRNM approach we developed, in order to exploit these RS devices in hardware computing applications as self–assembled logic gates.  Last, in Chapter 4 I focus on another soft matter system, that I have started to investigate during my PhD research activity, regarding Monte Carlo simulations of low valence DNA–based colloidal particles. This last Chapter is mainly devoted to the description of the simulation method I have been developing during my more recent PhD research activities, while the preliminary results presented obviously need to be confirmed and extended by further studies. Particles with a limited number of attractive spots (patches) on their surface are generally characterized by non–crystalline low energy states; they rather generate a disordered 3D network in which all the sticky sites are engaged in (mutually exclusive) patch–patch bonds [Bianchi et al., Phys. Rev. Lett. (2006)]. One of the most promising experimental realizations of such peculiar colloids is extremely recent: laboratory synthesized DNA nanostars (NS) with fixed valence [Bi et al., PNAS (2013)]. In this field the landmark is represented by our collaborators from the group led by prof. T. Bellini. Recently, they started to investigate the behavior of mixtures of nanostars with leftwise or rightwise chirality of the DNA strands, characterized by a merely repulsive interspecies interaction. To date, our contribution mainly consisted in the development of an abstract model of these DNA nanostars, schematized as limited valence soft patchy particles, whose equilibrium configurations are sampled via a canonical Monte Carlo program. Their different chirality is represented by a mixed interaction which only comprises excluded volume terms. Our goal in this project is twofold: on the one hand, we aim to reconstruct the temperature–density phase diagram of such mixtures, also depending on the mixing ratio. Experiments revealed a critical behavior and a phase separation processes for dilute mono–component DNA solutions; the properties of a mixture of two components, each found in critical conditions, are studied in this work. In this Chapter, after a detailed overview of the experimental, computational and theoretical studies regarding low valence particles, the simulation code is described and it is presented a comparison between the simulation results and the experimental measurements at equilibrium. The peculiar structures found in the patchy particles network claim for further analysis, as well as the interesting behavior near the critical point for mono–component and bi–component systems both. The second perspective of this research regards the unexplored aggregation and cluster growth process of such particles. In this concern, part of the future research effort will be devoted to the transformation of our custom code into a Brownian Monte Carlo in order to unveil the mechanisms underlying the dynamics of such particles during their aggregation stages.  The conclusions and further perspectives concerning each of the four topics addressed in this work can be retrieved at the end of each Chapter.","language":"eng","citation":"EMERGENT PHENOMENA IN CONDENSED MATTER, SOFT MATTER AND COMPLEX SYSTEMS / F. Mambretti ; supervisor: D. E. Galli. Dipartimento di Fisica Aldo Pontremoli, 2021 Mar 24. 33. ciclo, Anno Accademico 2020. [10.13130/mambretti-francesco_phd2021-03-24].","filename":"phd_unimi_R11853.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/820780/1723029/phd_unimi_R11853.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/943369"},"title":"PEIRCE'S INQUIRY ON HABITS. A CONTEMPORARY PERSPECTIVE","internalauthor":"BERNARDI DELLA ROSA, SIMONE","type":"Tesi di dottorato","year":"2022","abstract":"This thesis’ aim is to analysis the concept of habit from the point of view of the philosophy of  American thinker Charles Sanders Peirce (1829-1914). In particular, my goal is to treat habit  as a general principle, examining its structure, its “mode of being” and the consequences it  entails for cognition and human subjectivity. My thesis analyses and focuses on certain aspects  of Peirce’s vast and complex account of habit, starting from broad ontological questions.  Habit appears as a constitutive feature of his categorical system, one of the American  philosopher’s most important contribution to the history of thought. From there, moving  thematically in the complex architecture of his thought, I highlight the important role habit  plays in a pragmatist perspective.  My work is inserted in a wider conceptual framework and it is born out of some unsolved  question in contemporary secondary literature concerning Peirce and habit. On one hand, I took  into consideration the history of habit and its theoretical implications. In the last decade we  have witnessed a newfound interest in habits as a fundamental philosophical principle form its  very beginning, after almost a century of neglect in our discipline. On the other, the pragmatist  perspective has become of noteworthy importance in contemporary thought, and the peculiar  reading of habit inherent to this tradition is certainly one of its strengths. Peirce plays a peculiar  role in this wider context, and even though his thought on this matter has been somehow  thoroughly analysed, it has become necessary to show the richness of his theoretical  propositions and the contribution that a Peircean philosophy could give to a philosophy of  habit.  Given this context, my guiding insight was to analyse the concept of habit in its broadest  possible sense, in its mode of being. To do so, this work considers two factors. Firstly, it pays  special attention to accurately frame Peirce’s propositions, isolating some thematic cores I  deem central on which I based my own perspective, and, secondly, highlighting, in the  unfolding of the project, the differences, affinities and peculiarities that these thematic cores  bring up in relation to the contemporary debate concerning the concept of habit. Peirce  develops a wide and multifaceted concept across the entirety of his thought’s evolution,  underpinned by a clear structure: habit is a general principle, triadic and serving as a mediating  function, that constructs a tendency to act in a certain way given a certain situation in the future.  Taking heed from this general structure, I divided my work in three main sections. In the first  part, I highlight the philosophical particularity of the concept of habit (in a Peircean  perspective) and I show what vision of the concept of habit I’m going to uphold in my  argument, in contrast with some contemporary views of habit. In the second part, the  conceptual core of my thesis, I’ll examine the ontological features of habit and I’ll underline  its main metaphysical properties. My work will consider several areas of Peirce’s thought,  trying to show a philosophical position that could be confronted with other ontologies of habit,  that run through the whole history of this concept, albeit, at times, in disguise. My primary goal  is to demonstrate the peculiarity and originality of Peirce’s views on habit, that stems out of  habit’s secular history and captures some interesting implications entailed since the concept’s  inception. Peirce treats habit as a fundamental attribute of being, the central structure of one of  his categories. My theoretical aim is then to make one step further: habit is not just a categorical  state, but on the basis of Aristotelian interpretation, it is configured as the middle term between  the modes of potency and act, forming a dynamic principle that “enables” from the various  categories and modes of being, in a topological and temporal perspective. Only from this  assumption can we begin to appreciate the richness of a proper philosophy of habit, which  informs, albeit not in an explicit manner, all of Peirce’s philosophy. In fact, in the third part,  after having described the general architecture and the properties that define habit’s mode of  being, I will take into account which effects this renewed vision of habit could have on human  cognition and the self. I will observe that the concept of habit, as I have conceived it, as a  mediating and triadic structure among being’s categories, gives rise to a different way of seeing  our idea of intelligence and subjectivity, forcing us to revise some “substantialistic”  assumptions regarding our way of conceiving our mind, our faculty of reasoning and what we  are “used” to call “self”.  In conclusion, I will defend the idea uphold in much secondary literature (not exclusively  regarding habit) that we could be defined as “creatures of habit”. I will do it starting from the  considerations amassed in the first part of my work: my argument in support of this is that we  share with the principle of habit certain fundamental properties, which shape our mode of being  and place us in a precise ontological and temporal position. Habit not only influences deeply  the human being and play a fundamental role in various aspects of our life. Peirce shows us  further developments and I believe, with Peirce, that our perspective on the concept of habit  should be completely upended: we are the ones who navigate in an environment structed by  habits, and with participate in the same mode of being, that constitutes the real essence of being  alive in the world.","language":"eng","citation":"PEIRCE'S INQUIRY ON HABITS. A CONTEMPORARY PERSPECTIVE / S. Bernardi Della Rosa ; tutor: R. Fabbrichesi ; coordinatore: A. Pinotti. Università degli Studi di Milano, 2022 Sep 30. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12184.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/943369/2088081/phd_unimi_R12184.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1138655"},"title":"HYDROGELS FOR GROWTH OF LIVING MICRO-ORGANISMS","internalauthor":"KANG, HUIXUAN","type":"Tesi di dottorato","year":"2025","abstract":"In this work, I successfully achieved the goals of my PhD project on culturing diatoms, structural colored bacteria, and microalgae in different hydrogels, as well as co-culture bacterial and microalgal cells in the same hydrogel system.   In our first project, we developed an innovative approach to study diatoms embedded in hydrogels with controlled conditions, resulting in a straightforward technique to investigate species-specific photo-regulation of benthic diatoms. This work opens an opportunity for further research to better understand how individual diatom species respond to different light conditions and the mechanisms that regulate their endogenic rhythms.   In the second project, we have synthesized and characterized various hydrogels with different morphologies as matrices to grow three structural colored bacterial strains. By changing hydrogel compositions and studying their mechanical and physical properties, we successfully developed several methods for the bacteria to form bacterial biofilm with structural color, both in 2D and in 3D hydrogel matrix, which may contribute to further production of sustainable living pigmentations. The co-culture of microalgae and bacteria suggested the microalgal cells can contribute to bacterial growth thanks to the oxygen they produce from photosynthesis.  In our last projects, we developed two advanced methods to culture microalgal cells. Microalgal growth in 3D granular hydrogels provides a possible solution for cell aggregation problem in bulk hydrogels. The granular hydrogels are made of fully degradable and highly biocompatible polymers with a facile synthesis method. Due to the interconnected microporous structure, microalgae are able to migrate and proliferate within the hydrogels, enabling faster cell growth, higher photosynthetic efficiency, and less self-shading effect. We also embedded nutrients-encapsulated silica nano-capsules into GelMA hydrogels and used them to culture microalgae, higher cell density and biomass production were achieved by using this culture method, suggesting a potential application to use silica nano-capsules to provide essential nutrients for microalgal cultivation. This work has provided a promising technique for harvesting renewable microalgal bio-resources and have potential applications in both laboratory and industry.","language":"eng","citation":"HYDROGELS FOR GROWTH OF LIVING MICRO-ORGANISMS / H. Kang ; tutor: L. De Cola ; phd coordinator: G. Vistoli. - Via Mangiagalli, 25, Milano. Dipartimento di Scienze Farmaceutiche, 2025 Jan 29. 37. ciclo, Anno Accademico 2024. [10.17605/OSF.IO/WQDU6].","filename":"phd_unimi_R13296_1.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1138655/2645581/phd_unimi_R13296_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/812627"},"title":"MOLECULAR MECHANISMS OF THE SEXUALLY DIMORPHIC INFLAMMATORY RESPONSE INDUCED BYNEURODEGENERATIVE SIGNALS","internalauthor":"MORNATA, FEDERICA","type":"Tesi di dottorato","year":"2021","abstract":"Parkinson’s disease (PD) is a progressive, neurodegenerative disease characterized by motor symptoms linked to different pathogenic mechanisms, among which a deranged activation of innate immunity and neuroinflammation play a key role. The sexual dimorphism in PD, that results in men being more frequently affected than women, has been associated with genetic as well as sex steroid hormone-mediated mechanisms. New evidence suggests that the disease may start in the enteric nervous system and spread to the CNS only at later stages.  My working hypothesis is that the sexual dimorphism in PD is due to a distinct ability of macrophages of the two sexes to drive inflammatory and neuromodulatory actions, resulting in a sexually dimorphic onset and progression of PD. The aim of my research is to study the extent to which neurotoxic molecules, that are typically associated with PD pathogenesis, or neuronal signals generated in response to them, could modulate macrophage cells and induce immune, metabolic and oxidative stress responses that influence PD progression. In addition, my goal is also to assess whether these specific functions of macrophages could be different in male and female mice. In the laboratory where I performed my PhD thesis, engineered reporter animals were available which allowed assessment of the transcriptional activity of NRF2 and NFkB, two transcription factors deeply involved in antioxidant and inflammatory responses, respectively. Primary cultures of peritoneal macrophages obtained from these mice allowed me to highlight the key function of NRF2, and not NFkB, in the macrophage response to neurotoxic and oxidant molecules, such as MPP+ and tBHQ, respectively. Moreover, I observed that the activation of NRF2 allows macrophages to acquire a protective immune phenotype through changes in cell metabolic and inflammatory functions under homeostatic as well as inflammatory conditions, which were mimicked by LPS administration to cells. In fact, the simultaneous administration of tBHQ+LPS alters the effects of each individual pathway in a target gene-specific manner. Importantly, I observed that both NRF2 and NFkB activation and function are sexually distinct in macrophages. In fact, NRF2 transcriptional activity and  5  NRF2-target gene expression were induced at higher levels by NRF2 activating stimuli in female macrophages. Moreover, NRF2 activation correlated also with a stronger anti-inflammatory response against LPS activity on inflammatory genes in female cells. On the other hand, NFkB activation and the expression of pro-inflammatory cytokines, such as L-1b, IL-6 and TNFa were higher in LPS- treated male compared to female cells. By demonstrating the key role for NRF2 in the sex-specific reactivity of macrophages these results indicate possible molecular and cellular mechanisms to explain the sexual differences in PD onset and progression.  Altogether, our results show that the activation of NRF2 redirects the metabolic, immune and proliferative response of peritoneal macrophages to inflammatory signals in a sex-dependent manner, with relevant consequences for the pharmacological treatment of diseases that are associated with unopposed inflammatory responses, such as neurodegenerative diseases and PD.","language":"eng","citation":"MOLECULAR MECHANISMS OF THE SEXUALLY DIMORPHIC INFLAMMATORY RESPONSE INDUCED BYNEURODEGENERATIVE SIGNALS / F. Mornata ; tutor: A. C. Maggi ; co-tutor:  E. Vegeto ; coordinatore:  A.  L. Catapano. Università degli Studi di Milano, 2021 Feb 16. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12019.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/812627/1698316/phd_unimi_R12019.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1209826"},"title":"INTER-COMPARISON AND VALIDATION OF GLOBAL AND REGIONAL REANALYSES PRODUCTS FOR THE STUDY OF EXTREME WEATHER EVENTS OVER ITALY","internalauthor":"CAVALLERI, FRANCESCO","type":"Tesi di dottorato","year":"2026","abstract":"The increasingly severe impacts of extreme weather events, driven by climate change, are pushing an urgent need for reliable tools to understand, monitor, and predict the evolution of atmospheric phenomena. Meteorological reanalyses, blending observations with dynamical models, respond to this need by providing gridded datasets that reconstruct past atmospheric conditions at high temporal resolution, typically hourly, over several decades. These products are essential for planning mitigation strategies against climate change and extreme events in key sectors such as renewable energy development, electric system resilience, water resource management, urban planning, and many others. However, given the wide range of reanalysis datasets developed for Italy in recent years, inter-comparison and validation against observations are crucial to support their informed use and to maximize their potential applications, both in scientific and applied research.    During the first part of my PhD, I focused on the validation and the intercomparison of reanalyses 2-meter air temperature (t2m), with particular attention to daily mean values. An accurate representation of t2m is essential, as it is a variable directly relevant to evaluating the effects of warming weather conditions. Moreover, t2m is a fundamental driver of atmospheric dynamics, with a significant influence on other variables. I inter-compared and validated against observations multiple reanalyses available over Italy during the 1991–2020 period, evaluating performances of both climatological averages and daily anomalies (Paper I). In particular, I developed a new validation method which accounts for the biases arising from different representations of orography between reanalysis and observations. In this way, dynamical ability of reanalyses is evaluated separately from their static orographic description.    My research subsequently concentrated on the assessment of total precipitation (tp) variable, which presents significant challenges in a correct model representation because of its intermittent nature and high spatial variability. I assessed the ability of reanalyses to reproduce precipitation at different spatial and temporal scales, and I validated them against both station-based and gridded observational datasets (Paper II). A multi-scale approach, ranging from climatological to daily values, was adopted, including the use of wavelet analysis to investigate the role of the finer spatial scales and the potential of convection-permitting reanalyses in describing convective precipitation. In parallel, I contributed to a study on long-term precipitation trends derived from global reanalyses over Italy and the Alpine region (Paper III). In this work, I assessed the temporal stability of reanalyses against homogenized observations.     The results of these studies were disseminated across multiple scientific communities, with a major interest among reanalysis developers and users. I therefore actively contributed to the evaluation of new reanalysis products, both collaborating with research institutions already involved in this PhD project (MERIDA HRES, Paper IV) and with external partners (MORE, Paper VI, under review), specifically supporting the validation and intercomparison sections of their publications. In addition, I extended the outreach of my PhD studies to a broader audience through the publication of a science communication article in the Rivista di Meteorologia Aeronautica. Since this contribute was originally in Italian language, an English version is provided in this thesis (Paper V).    The final phase of my PhD focused on precipitation extremes over Italy. Building on the  awareness of reanalysis strengths and limitations acquired in the previous studies, I develop a method to identify precipitation events from hourly reanalysis fields. Finer temporal scales posed additional methodological and interpretative challenges. Understanding such extremes is particularly important given their significant socio-economic impacts, especially in the context of risk management and climate change adaptation strategies. The study revealed increases in the occurrence of hourly extreme precipitation events during the summer and autumn seasons in some Italian regions. The results are currently under review (Paper VII).","language":"eng","citation":"INTER-COMPARISON AND VALIDATION OF GLOBAL AND REGIONAL REANALYSES PRODUCTS FOR THE STUDY OF EXTREME WEATHER EVENTS OVER ITALY / F. Cavalleri ; supervisor: M. Maugeri ; tutor: V. Manara, F. Viterbo ; coordinator: M. P. Guarino. - Milano. Dipartimento di Scienze e Politiche Ambientali, 2026 Jan 30. 38. ciclo","filename":"phd_unimi_R13787.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1209826/3230414/phd_unimi_R13787.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1149095"},"title":"DESAFIOS DE LA PROTECCION JURIDICA A LAS PERSONAS TELETRABAJADORAS: UNA MIRADA CRITICA AL CONCEPTO DE SUBORDINACIN.","internalauthor":"CORREA GOMES CARDIM, TALITA","type":"Tesi di dottorato","year":"2025","abstract":"Remote work and, specifically, teleworking are addressed in this study from a socio-legal and multi-level approach, finding in the Italian legal system a reference to contribute to the analysis of the main issue: the concept of subordination in accordance with the current work reality. In this way, under the title “Challenges of legal protection for teleworkers: a critical look at the concept of subordination”, the prominence of teleworking during the last five years is taken advantage of to investigate whether the scope of application of Labor Law is adapted to labor relations, frequently characterized by the use of information and communication technologies, which allow the worker to develop their work performance with a high degree of autonomy, in its various manifestations. In this sense, it is finally examined whether it is necessary to update the main Spanish labor regulations, and especially the first article of the Workers' Statute, to specify and, in turn, make more flexible the notes of third-party and subordination. The core of the thesis is structured in five chapters. The first of them presents the main characteristics of a labor market sector where ICT predominates, delving into the sociological dimension of teleworking. The second and third chapters condense the basic legal and conceptual framework of teleworking, which makes it easier, in the fourth chapter, to delve deeper into the complex debate on the borders of Labor Law in general and, finally, in the fifth, to highlight the issues that this raises in the specific context of teleworking. The first chapter is dedicated to introducing the context of work in the digital age, current technologies and the digital skills required for the new profile of the teleworker. This chapter has a predominantly sociological aspect, which will address important aspects of the importance of teleworking today, dealing with identifying and reflecting on the advantages and disadvantages of teleworking for the three affected groups, that is, the worker, employer and society, around the issue of the digital divide (or, better, digital divides) and the need for professional training of the teleworker regarding this type of work. It is considered necessary to first address an important sociological review of the topic and then delve deeply into the legal aspects that involve teleworking. The second chapter contextualizes in the legal systems of Spain and Italy the important historical-normative evolution of the employment contract, from remote work, until reaching the figure of teleworking, with due analysis of the important distinction between these figures. The third chapter analyzes the notion of teleworking in labor doctrine. To do this, we start from a necessary delimitation and conceptualization of this work organization model, as well as the analysis of the different modalities in which teleworking can be developed. Having established the above, the fourth chapter of the thesis is dedicated to the complex issue of the current borders of Labor Law, with the protection of teleworkers and the analysis of subordination and alienation in teleworking, the labor notes in this context and the tenuous border with self-employed work and the vulnerable self-employed, as a consequence of the evolution of labor markets and the advance of NICT. Given the complexity and specificity of the topic, it is necessary to resort to descriptive analysis at certain moments to offer the essential notions, so that the reader can understand and evaluate the critical points that will be addressed. Once these essential bases have been established, we enter the complex task of the study proposed by the thesis. In this sense, the last chapter contains an investigation that delves into the notion of subordination, as well as the uncertainties that arise in issues directly related to teleworking as a form of organization of subordinate work, dealing with the reality of this organizational model, its complexity and need for a dynamic notion, also identifying a gray area with autonomous teleworking and the risks that it entails of escape from Labor Law. It is based on the premise that there is no single form of organization and provision of services within the teleworking modality, as we currently know it, and therefore there is no single rigid concept for the notion and indications of subordination and dependency notes, which can lead to the exclusion of certain groups from Labor Law. Finally, a reflection is made about the future and perspectives regarding the protection of Labor Law for vulnerable groups, taking into consideration the various issues that force us to rethink the current role of labor law in this issue, and the necessary protection that must be granted to certain groups that are currently on the margins of labor protection. Finally, the general and specific conclusions of the study will be addressed, capable of providing a satisfactory legal response to what the research proposes. However, although the variables for the questions raised are diverse and do not present only one direction, this research work seeks to investigate the challenges posed by the protection of those who provide their services in a teleworking regime, with the intention of reducing the legal risks derived from the differences in the levels of subordination presented by those who provide their services in a teleworking regime, as well as those that arise from the legal framework in the different figures of teleworking.","language":"spa","citation":"DESAFIOS DE LA PROTECCION JURIDICA A LAS PERSONAS TELETRABAJADORAS: UNA MIRADA CRITICA AL CONCEPTO DE SUBORDINACIN / T. Correa Gomes Cardim ; diretta da: F. Fita Ortega, G. Ludovico. - Valencia, Spagna. Dipartimento di Diritto Privato e Storia del Diritto, 2025 Mar 13. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R14146.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1149095/2688608/phd_unimi_R14146.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1032671"},"title":"AGRONOMIC AND ECO-PHYSIOLOGICAL RESPONSES OF BRASSICACEAE SUBJECTED TO BIOSTIMULANT TREATMENT AND ABIOTIC STRESS","internalauthor":"PETRINI, ALICE","type":"Tesi di dottorato","year":"2024","abstract":"\"The European Union is committed to achieving climate neutrality by 2050 through its Green Deal, focusing on sustainable agriculture to secure an eco-friendly food supply. The strategy involves \"\"producing more while consuming less,\"\" emphasising efficient resource utilisation and fair compensation in the supply chain by 2030. In this context, biostimulants can be represent an environmentally friendly alternatives, optimising fertiliser and pesticide use while enhancing crop productivity and supporting the Green Deal's objectives.   The aim of this thesis is the agronomic and eco-physiological evaluation of potential biostimulant products applied to horticultural crops. Biostimulants are substances which can promote the nutrient uptake and assimilation, thus maximise the action of fertilisers, resulting in higher yields with fewer inputs. Additionally, biostimulants have demonstrated positive effects in resisting abiotic stress, such as drought, salinity, heat, and cold.   Developing new biostimulant products involves a complex process involving several steps, including screening, investigating the mode of action, and efficacy validation. Determining the appropriate dosage and timing for applying biostimulants ensures their efficacy.   Since biostimulants can stimulate plants differently, studies on physiological, biochemical, and molecular effects are pivotal to deepening the knowledge of their mode of action. Fast and economical methods to evaluate physiological responses in vivo, such as the evaluation of photosynthetic capacity and gas changes, are essential tools for preliminary trials. After an initial screening, more sophisticated and specific trials can be designed to investigate plant changes at the molecular level. It is possible to deepen the view of the mode of action by analysing the differentially regulated genes by adopting several bioinformatic tools, and understand which biological processes are the most interesting. The data obtained can be helpful to determine in which situation a specific product can be used. For example, if genes for heat stress are activated in non-stressed conditions, in a sort of priming mechanism, it could be interesting to try that product in a stressful situation for the plants.   A step-by-step approach, which corresponds to the thesis's four chapters, is proposed to evaluate the potential application of biostimulants:  - Characterisation of novel biostimulant from raw materials: Screening for dosage optimisation and characterisation of the transcriptomic response.  - Efficacy validation of a biostimulant prototype in a model plant to contrast heat stress, testing application before and after the temperature increase.  - Identify the best timing for applying a biostimulant product before a heat stress period.  - Validation of the efficacy of a biostimulant as a curative application to counteract heat stress events.  In the first chapter, three different biostimulant products were tested on wild rocket (Diplotaxis tenuifolia L.): two of them derived from brewery and bakery yeast, while the latter is a botanical hydrolysate obtained from corn. Two different trials were conducted: the first investigated plants' physiological response to different doses of the three treatments, while the second looked into both physiological and molecular responses of the most promising dose of each treatment. All the products resulted in attractive biostimulant candidates. The stimulation of transcriptome regulation is explicit, with interesting effects on photosynthesis and secondary metabolism, partially confirmed by physiological analysis.  In the following three chapters, several biostimulant products at different development stages (one prototype and two commercial products) were tested in different times to verify their efficacy against heat stress. In all trials, plants were exposed to cycles of supra-optimal temperatures, matching the maximum (37°C ± 1 °C) corresponding to the photoperiod peaks. The heat treatment was applied for up to 4 days for 4 hours to induce a stressful condition.   The second chapter aimed to understand better the molecular and physiological responses of a model plant, Arabidopsis thaliana (L.) Heynh., subjected to heat stress and to the application of a biostimulant prototype, obtained from bacterial fermentation of sugarcane. Two distinct trials were designed to investigate the efficacy of counteracting the adverse effects of heat stress: in the first trial, the aim was to establish the possibility of a priming effect by applying a biostimulant before the stress period. In the second experiment, the biostimulant was applied after high-temperature exposure to determine its possible curative effects. The product was found to be an effective biostimulant in both cases; however, its preventive application showed more promise in mitigating the effects of heat stress. We found that the preventive application of the biostimulant helped maintain a higher leaf functionality and nitrate metabolism and led to the accumulation of heat shock proteins (HSPs).  The third chapter aimed to evaluate the effect of the different application times of a commercial biostimulant product, based on Ascophyllum nodosum extracts, applied to wild rocket plants prior to a heat stress period. After identifying the most promising application time as 24 hours before heat stress, the trial investigated the different molecular responses to underline the product's mode of action. The biostimulant maintains the photosynthetic activity in stressed and biostimulated plants, thanks to the protective effects of the product on photosystems efficiency and the photosynthetic machinery in general. The positive and protective effects are probably due to the overexpression of HSP genes, which directly regulate heat shock proteins responsible for ensuring proper protein folding and preventing cellular damage.  In the last chapter, a physiological and transcriptomic evaluation was carried out to assess the impact of an amino acid-based biostimulant product applied to wild rocket plants subjected to heat stress. The experimental objective was to investigate the different physiological and molecular responses and highlight the product's mode of action as a curative application when applied following stress. The analysis confirmed the positive effect of biostimulants on plant recovery: the application of the biostimulant reduced the energy dissipated during the photosynthetic process, contributed to maintaining the nitrate metabolism in stressed plants and promoted the transcription of heat shock regulatory elements.  In the presented approach, certain aspects, such as utilising varying crop types and conditions different from the protected environment, have yet to be fully explored. Nonetheless, the methodologies employed in this research can be adapted and applied to other products grown in diverse settings and exposed to varied forms of stress.   In conclusion, biostimulant products hold great promise for agriculture and have the potential to provide solutions to the challenges of sustainable farming. The development and application of new biostimulant products must be based on a targeted approach involving a thorough understanding of the product's mode of action and the optimum dosage and timing of application. The proposed protocol outlined in this thesis constitutes a flexible framework that can be tailored to suit specific applications.\"","language":"eng","citation":"AGRONOMIC AND ECO-PHYSIOLOGICAL RESPONSES OF BRASSICACEAE SUBJECTED TO BIOSTIMULANT TREATMENT AND ABIOTIC STRESS / A. Petrini ; tutor: A. Ferrante, G. Cocetta ; coordinatore: P. A. Bianco. Università degli Studi di Milano, 2024 Mar 08. 36. ciclo","filename":"phd_unimi_R12912.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1032671/2369374/phd_unimi_R12912.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/848088"},"title":"WILDLAND SURFACE FIRE BEHAVIOUR: A SPATIAL SIMULATION MODEL FOR OPERATIONAL EMERGENCY MANAGEMENT","internalauthor":"VOLTOLINA, DEBORA","type":"Tesi di dottorato","year":"2021","abstract":"Wildfires affect vegetation dynamics, geomorphological processes, biogeochemical cycles, atmospheric chemistry, and climate, posing a severe threat to human lives and activities interacting with the natural system. As both fire activity and wildland-urban interface exposure are expected to increase under future climate projections, the improvement of our ability to promptly predict wildland fire behaviour, in terms of expected intensity and geographic patterns, has become a tangible need.  The general purpose of this research is to investigate on wildland surface fire behaviour simulation models and to support disaster managers in optimising decision making processes in wildfire risk management in a Mediterranean-type climate region, namely Sardinia, Italy. This project is intended to pursue two major objectives: (i) develop and validate a predictive spatially distributed wildland surface fire behaviour simulation model intended for operational use; (ii) design and implement a geospatial decision support system to provide decision makers with appropriate strategies and tools for an integrated wildland fire risk management.  Predicting wildland surface fire behaviour requires a deep understanding of the influence of environmental parameters that act as drivers of the fire spread, including geomorphometrical variables, meteorological conditions, and fuel characteristics, on fire descriptors, such as the rate and direction of the maximum fire spread, the eccentricity of the ellipse approximating the fire shape, the intensity of the fire front, and the flame length. The Rothermel’s mathematical model for predicting surface fire spread in wildland fuels is currently the most extensively used method to estimate fire descriptors, especially for operational purposes. The application of the Rothermel’s model for simulating the behaviour of ongoing wildfires calls for the need of a technique for continuous monitoring of the spatiotemporal variability of weather conditions and fuel characteristics, such as fuel height, loading, and moisture content, in the pre-fire environment. Firstly, freely available data sources and remote sensing products and datasets have been investigated to define a pre-processing methodology for the near real-time estimation of the drivers of fire spread. Secondly, the need for flexibility in handling the equations of the Rothermel’s and associated models, together with the necessity of integrating corrections and updates, have led to an original implementation of a computer algorithm that evaluates the fire descriptors as defined by the extended Rothermel’s mathematical model. Then, a proxy model of this implementation has been developed using a machine learning ensemble method in order to analyse the interdependence of the drivers and to understand their relative importance in predicting fire descriptors. Furthermore, the proxy model for predicting fire spread across heterogeneous landscapes has been integrated into an agent-based simulation model developed to predict the surface fire behaviour and growth with the aim of providing fire management authorities with timely information on the expected progress of the fire front. Finally, the developed simulation model has been applied to and validated against historical wildfire events recorded in Sardinia, Italy, to evaluate its performance in terms of predictive capacity. The effects of fire suppression activities have also been simulated according to the availability of accurate information on timing and location of interventions that effectively extinguished the fire’s spread.  As a whole, the developed wildland surface fire behaviour simulation model, together with the pre-processing methodology, have resulted in a satisfying accuracy in terms of quantitative agreement between modelled and observed patterns of fire growth. The adoption of the proxy model instead of its original implementation has guaranteed a significative reduction of the computing time in the face of a limited loss in accuracy at the scale of the analysis if compared with the original implementation of the Rothermel’s equations. Results of the validation suggest the model’s suitability for operational uses for predicting wildland surface fire behaviour. The predictive ability of the simulation model could reasonably benefit from the inclusion of some additional mathematical models simulating the potential evolution of the surface fire towards passive or active crown fires or spotting fires. Moreover, major improvements could be granted by implementing in the agent-based simulation model a wider range of fire suppression activities and techniques, ranging from ground to aerial interventions.  The proposed predictive model could become a valid tool for the optimization of risk planning, prevention, and management activities. Within the context of this project, three modules of a geospatial decision support system have been designed and implemented with the aim of improving the efficiency of risk management strategies and reducing expected impacts and potential damage. The first module is a dynamic workflow of actions and represents the core of the decision support system. This module aims to guide decision makers in carrying out the procedures of the intervention model compliant with the legislative framework. The workflow is then supported by a second module, a customised version of a geographic information system with dynamic forms designed to support users with limited expertise in geodatabase management. This module will incorporate a structured relational geodatabase storing (i) scenarios of wildfire events, produced by means of the developed predictive wildland surface fire behaviour simulation model, (ii) existing institutional wildfire susceptibility, hazard, and risk maps, (iii) available resources and socioeconomic exposed values, and (iv) real-time data from field surveys. Finally, the decision support system will provide authorities and technicians with a third module composed by web applications for mobile field data collection and sharing.  This research strived to investigate principles and accepted theories on the complex dynamics of wildland surface fire behaviour and to shed light on the need for a better understanding of the difference between real and simulated fire behaviour in terms of the importance of the drivers of fire spread in predicting fire spread and growth. The project also tried proposing solutions integrating remote sensing and machine learning techniques with the aim of improving the applicability of near real-time simulation models as well as the effectiveness of decision-making strategies.","language":"eng","citation":"WILDLAND SURFACE FIRE BEHAVIOUR: A SPATIAL SIMULATION MODEL FOR OPERATIONAL EMERGENCY MANAGEMENT / D. Voltolina ; tutor: T. Apuani, S. Sterlacchini, G. Cappellini ; coordinatore: F. Camara Artigas. Dipartimento di Scienze della Terra Ardito Desio, 2021 Jun 07. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11976.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/848088/1814717/phd_unimi_R11976.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1122081"},"title":"INDUSTRY 4.0 IN THE AGRI-FOOD SECTOR: INNOVATIVE SENSORS AND SMART LOGISTICS TO SUPPORT THE SUSTAINABILITY OF THE SUPPLY CHAIN","internalauthor":"PAMPURI, ALESSIA","type":"Tesi di dottorato","year":"2024","abstract":"The agri-food sector is undergoing significant transformations in measurement technologies, with traditional laboratory-based analytical techniques increasingly being replaced by rapid, non- destructive, and environmentally friendly methods. Visible and Near-Infrared (vis/NIR) spectroscopy and imaging techniques are highly regarded for their non-destructive sampling, real- time results, and ability to perform quality controls throughout the production process. However, these techniques typically involve expensive, complex instruments often impossible to use outside of a specialized laboratory. To overcome these problems, low-cost prototypes are being created that maintain the reliability of laboratory instruments, although with significantly lower performance. The aim is to ensure high-quality products that meet customer demands for healthiness and sustainability through meticulous quality controls. Chemometrics plays a crucial role in interpreting data, predictive modeling, and variable selection, which can simplify these devices. This project aims to meet the needs of high value-added supply chains by implementing simplified spectroscopic devices utilizing a limited number of wavelengths. Over the three years, not only were prototypes of portable instruments used, but several studies also involved the use of benchtop instruments. These served as a reference for the optical acquisitions obtained using the prototypes, as well as for conducting feasibility studies and with the aim of implementing this type of instrumentation in-line within the food industry. Commercial instruments used included Aurora NIR, (Grainit), ASD Quality SpecTrek, Jaz (Ocean Optics), Corona Process® (Zeiss), and Unity® (Hellma). Data analysis followed a specific procedure involving spectra exploration, chemometrics analyses and modeling, using Microsoft Excel, Matlab® and the PLSToolbox package as the main software.  A first prototype, which also led to the filing of a patent, was developed and tested on olives, tomatoes and wine grapes and it has been designed specifically for use on small-sized matrices. The optical device was used to evaluate table tomatoes' quality features and then to quantify qualitative parameters of Chardonnay grapes directly in the field. Regarding wine grapes, Life Cycle Assessment (LCA) methodology was also applied to evaluate the sustainability of the optical analysis compared to traditional laboratory analyses, demonstrating the environmental advantages of spectroscopy. Research activities continued with grape matrices during post-harvest phases, using benchtop instruments to measure key parameters at consignment. The feasibility of vis/NIR spectroscopy for rapid polyphenol content determination in grapes was assessed and the final models provided valuable information on phenolic parameters, with promising results that require further testing in wineries.  Another experiment focused on evaluating the environmental and economic performance of an automated system for managing yeast nutrition and monitoring the fermentation process. In line with the principles of 4.0 winemaking, another simplified prototype was developed with the aim of analyzing non-solid matrices, such as wine, must, or other liquids, for detecting adulterations and measuring qualitative parameters. This prototype was used to monitor wine must fermentation and craft beer production, testing its applicability to different liquid matrices and fermentation types. Another experiment was conducted using benchtop instruments for the determination of acrylamide in cocoa biscuits, yielding promising results that align perfectly with Industry 4.0 and the in-line implementation of spectrophotometric analyses. A third prototype has been developed and tested but is still in the pre-prototype stage (Technology Readiness Level, TRL of 3 out of 9) and requires further experimentation before reaching the performance of the other two prototypes (TRL 4). Experiments were conducted on larger agri-food matrices, such as apples and pears, always using commercial instruments as references, given the early stage of development of the prototype. The goal was to monitor qualitative parameters and create predictive models for ripening and senescence. Visible/Near-Infrared spectroscopy is a valuable technology for rapidly, non-destructively, and sustainably assessing quality parameters of several food and agricultural products. The prototypes developed showed promise for certain applications but require further experimentation. Further development and testing are necessary to enhance the applicability of these prototypes in the agri- food sector.","language":"eng","citation":"INDUSTRY 4.0 IN THE AGRI-FOOD SECTOR: INNOVATIVE SENSORS AND SMART LOGISTICS TO SUPPORT THE SUSTAINABILITY OF THE SUPPLY CHAIN / A. Pampuri ; tutor: R. Beghi; co-tutor: L. Limonta ; coordinator: D. Mora. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2024 Dec 20. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13415.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1122081/2600998/phd_unimi_R13415.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/961738"},"title":"MODERN ANIMAL NUTRITION IN THE ERA OF SUSTAINABLE DEVELOPMENT GOALS","internalauthor":"FUMAGALLI, FRANCESCA","type":"Tesi di dottorato","year":"2023","abstract":"The livestock sector faces several challenges for 2050: the growth of the human population and the consequent greater demand for products of animal origin, the reduction of the environmental impact and the use of natural resources, as well as the reduction of feed/food competition. In this scenario, animal husbandry offers the environment ecosystem services, and the supply of protein and essential micronutrients for populations, especially in developing countries. The sector of feed production and livestock breeding is constantly evolving, numerous technologies are being developed in the field of animal nutrition, for example, nutrigenomics and omics techniques to evaluate feed ingredients for animal diets. In particular, metabolomics, i.e. the study of all the metabolites present in the bio-fluids of an organism, is under development since it offers the advantage of carrying out matrice samplings in a non-invasive way and offering a complete analysis of the animal metabolic profile. As far as the challenges of the feed sector are concerned, the keyword remains feed safety, which refers mainly to mycotoxin contamination. Mycotoxins are ubiquitous, and it is impossible to prevent their development, but it is essential to apply preventive and risk management protocols throughout the entire feed production chain. In a scenario of climatic changes, it is essential to study their effects on mycotoxin contamination in crops. Climate changes are to be considered another challenge for the livestock sector which is often labeled as responsible for greenhouse gas emissions, including methane, nitrous oxide, and carbon dioxide. It is essential to accurately assess emissions from the livestock sector and feed production. As efforts need to be made to mitigate environmental emissions and enhance food industries' by-products ensuring the transition to a circular economy, one proposal is the use of alternative sources for  animal nutrition, such as former foodstuffs and by-products and co-products derived from food industries. Evaluating the quality and nutritional characteristics of new ingredients is one of the current challenges in the feed industry. The application of new technologies in the field of animal nutrition research is one of the future objectives, with the aim of improving the quality of animal origin products, ensuring animal health and welfare as well as the ongoing development of the livestock sector from a precision nutrition perspective to face modern challenges.","language":"eng","citation":"MODERN ANIMAL NUTRITION IN THE ERA OF SUSTAINABLE DEVELOPMENT GOALS / F. Fumagalli ; tutor: F. Cheli, L. Pinotti ; coordinatore: L. Pinotti. Università degli Studi di Milano, 2023 Apr 13. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12540.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open from 01-GEN-28"}
,{"handle":{"url":"https://hdl.handle.net/2434/1135635"},"title":"LIGHT AND ELECTRICITY: POWERFUL TOOLS FOR NEW SUSTAINABLE STEREOSELECTIVE SYNTHESIS","internalauthor":"RESTA, SIMONETTA","type":"Tesi di dottorato","year":"2025","abstract":"Aimed from the increasing need to identify new reactions, exploiting green energy sources, three different synthetic routes have been developed and analysed during this thesis work: the electrochemical dehydrogenative homo-coupling of β-Naphtylamines derivatives; the stereoselective cyclization of aryl-enones under homogeneous and heterogeneous conditions and the late-stage C-H iron (III) catalyzed electrophotochemical perfluoroalkylation. Chapter 1 provides a detailed description of the synthetic techniques employed. Chapter 1.1 explains how electrochemistry emerged in the field of organic chemistry thanks to technological development, underlining the principles of electrochemical reactions and its application in stereoselective transformations. The physical properties of light are reported in Chapter 1.2, as starting point to introduce Photoredox catalysis under homogeneous, heterogeneous and flow conditions. In addition, Chapter 1.3 shows a concise overview of electrophotocatalysis focusing on the difference between electrochemical mediated photoredox catalysis (e-PRC) and interfacial photoelectrochemistry (i-PCR). Chapter 2 concerns the electrochemical dehydrogenative homo-coupling of β-Naphtylamines derivatives: first, Chapter 2.1 reports a comprehensive description of the electrochemical homo- and cross- coupling between phenols and naphthols depicted in literature. Also, the behaviour of anilines and β-naphtylamines under electrochemical oxidative conditions is well analysed. With this literature in hands, we explored the possibility to carry out a stereoselective version of electrochemical homo-coupling using β-Naphtylamines bearing chiral auxiliaries. Chapter 2.2 is focused on the discussions of the results obtained for the intermolecular and intramolecular homo-coupling of chiral β-Naphtylamides and amines. Moreover, the possibility to remove the chiral auxiliary is also investigated and a proposed mechanism is well depicted. A brief resume of the data collected is reported in the conclusion (Chapter 2.3). The stereoselective cyclization of aryl-enones under homogeneous and heterogeneous conditions is outlined in Chapter 3. In particular, Chapter 3.1 consists in an historical background of the aryl-enones cyclization starting from the preliminary studies on the metal-catalysed cyclization to the metal-free photocatalyzed approaches. Considering the results reported, we envisioned to develop stereoselective methods for the metal-free photocyclization in order to synthetize trans-cyclopentane rings and functionalized bicyclo[3.2.0]heptane. Chapter 3.2 shows all the results obtained for the synthetic routes designed. First, we explored the enantioselective version of the photocyclization for the synthesis of trans-cyclopentane rings under homogeneous conditions. In order to address the stereochemical outcome from the reaction, a chiral auxiliary has been introduced on the aryl-enones to be cyclized and removed after the photocyclization. Then, with the aim to recover and reuse the catalyst, Eosin Y has been immobilized onto a sold support and the photocyclization carried in a heterogeneous environment. Lastly, at the end of the chapter, it is depicted the deep study on the stereoselective synthesis of bicyclo[3.2.0]heptanes. A concise resume of the results analysed is then reported in Chapter 3.3. The last part of this thesis, Chapter 4, is related to the topic explored during the visiting research period at University of Gӧttingen. In particular Chapter 4.1 points out on the role of fluorinated groups in medicinal chemistry. Moreover, electrochemical, photochemical and electrophotochemical approaches for the monofluoromethylation, difluoromethylation, trifluomethylation and perfluoroalkylation reported in literature have been selected and explained. Taking into account the advantages and the powerful of electrophotocatalysis, it is developed a versatile strategy to generate fluorinated radicals (both electrophilic and nucleophilic) through decarboxylative Iron (III) electrophotocatalysis. The discussions of the obtained results is shown in Chapter 4.2. After a brief description of the electrophotochemical set-up, this chapter presents the electrophotochemical method developed for the fluoroalkylation of xanthines derivatives and other bioactive molecules. In addition, the perfluoro C-H functionalization of Pirimidine and Purine analogues is carefully detailed. Chapter 4.3 collects the main results of the previous chapter giving a concise conclusion. Lastly, Chapter 5 provides all the experimental part of the PhD thesis including the synthetic procedures, 1H-NMR, 19F-NMR and 13C-NMR of the unknown compounds and the HPLC traces of the enantiomeric excess of the asymmetric transformations. Also, all the information regarding DFT calculations and kinetic studies are here reported.","language":"eng","citation":"LIGHT AND ELECTRICITY: POWERFUL TOOLS FOR NEW SUSTAINABLE STEREOSELECTIVE SYNTHESIS / S. Resta ; tutor: S. Rossi ;  co-tutor: M. Benaglia ; coordinatore del corso di dottorato: L.  Prati. - Dipartimento di Chimica-Università degli Studi di Milano. Dipartimento di Chimica, 2025 Jan 20. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13345_2.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1135635/2636255/phd_unimi_R13345_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1074668"},"title":"AS HIGH AS EYES CAN SEE: A MODERATE LIBERALISM FOR THE ADMISSIBLE CONTENTS OF PERCEPTION","internalauthor":"COUDRAY, QUENTIN","type":"Tesi di dottorato","year":"2024","abstract":"A philosophically crucial question within contemporary philosophy of perception is to determine what things we can perceive, as opposed to things we can only think about. In this thesis, I defend a “liberal” view of perception which accepts that we can perceive some kinds of high-level contents. I propose an original argument based on describing a relevant psychological mechanism that grants such representational capacity that I call schematization. Schematization describes a process by which perceptual systems (I focus on vision) representationally structure their sensory inputs, prioritizing certain feature dimensions, and implicitly activate (or prime) similar representations stored in perceptual memory. Schematization is a purely perceptual process that allows us to represent contents that are not reducible to low-level contents: aspects. Aspects represent some high-level kind properties of particulars. They represent particulars as having some physical body form that makes them belong to a superficial kind, such as the superficial kind of cat-form or chair-form. Crucially, I argue that aspects cannot represent natural or functional kind properties like cat-hood or chair-hood, since such properties depend on below-surface, non-visible characteristics of objects. I thus argue that careful empirical considerations about the representational capacities of perception vindicate a moderate Liberalism that only admits aspects representing superficial kind properties as the higher-level contents of perception. Aspects are as high as eyes can see.","language":"eng","citation":"AS HIGH AS EYES CAN SEE: A MODERATE LIBERALISM FOR THE ADMISSIBLE CONTENTS OF PERCEPTION / Q. Coudray ; tutors : C. Sinigaglia, J. Dokic ; coordinator : F. Guala, J. Dokic, M. Aymes. - Università degli Studi di Milano Statale. Dipartimento di Filosofia Piero Martinetti, 2024 Jul 26. 36. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R12853.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1074668/2471815/phd_unimi_R12853.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1209195"},"title":"INVASION DYNAMICS OF FRESHWATER CRAYFISH IN A MAN-DOMINATED LAND: SPATIO-TEMPORAL, ECOLOGICAL AND HUMAN DIMENSIONS","internalauthor":"MESSINA, VALERIA","type":"Tesi di dottorato","year":"2026","abstract":"Biological invasions are among the leading threats to freshwater biodiversity, yet predicting their dynamics and mitigating their impacts remains challenging, especially in human-dominated landscapes where human-aided dispersal is highly possible. This thesis in particular advances understanding of freshwater crayfish invasion dynamics in Lombardy (Northern Italy) by integrating spatio-temporal modelling, impact assessment on native fauna, and socio-managerial perspectives.  As the latest comprehensive assessment in the region was carried out in 1994–2006 by Fea et al., Chapter 2 aimed first to update invasive crayfish distribution, compiling occurrences from scientific and grey literature. Moreover, using Maximum Entropy (MaxEnt) modelling, high-suitability areas were identified, while both linear regression and Bayesian diffusion–growth models quantified Procambarus clarkii expansion rates and revealed environmental drivers of dispersal and local population growth. Compiled historical records indicate multiple probable introduction events for both Faxonius limosus, mostly found in major lakes, and for the more widespread P. clarkii. The latter had a steady early-stage (1997–2006) spread of approximately 3.8 km per year near Pavia, strongly facilitated by urbanized low-slope areas and irrigation networks acting as dispersal corridors, whereas forests and natural river margins slightly limited diffusion and offered less suitable habitat for establishment.  Second, the field study presented in Chapter 3 warns on the possible negative effects of P. clarkii on native amphibians living at the border of today’s distribution in hilly and mountain areas. The research compares ecological impacts of the native crayfish Austropotamobius pallipes complex and the alien P. clarkii on fire salamander (Salamandra salamandra) larvae. Significantly lower body condition was found in larvae from sites with P. clarkii than those co-occurring with A. pallipes, suggesting stronger predation pressure or indirect effects of the invasive species on resource availability, due to the contrasting functional roles of native versus alien crayfish.  Finally, the human dimension in protected areas was explored through visitor surveys in Chapter 4 and management assessments in Chapter 5 to evaluate how the general public behavior and institutional actions influence conservation outcomes. In Monte Barro Regional Park (Chapter 4), surveys revealed low public awareness regarding native and invasive crayfish, with widespread misidentification and limited understanding of actions that could support conservation. Risky behaviors were detected, such as unauthorized fishing, illegal stocking, or entering creeks with potentially contaminated equipment, highlighting the role of human-mediated dispersal in spreading alien species. Importantly, awareness and knowledge were strongly linked to attitudes toward conservation, with better-informed visitors more likely to support eradication of alien species and the protection of native crayfish. At Monza Park (Chapter 5), long-term monitoring showed the local extinction of the Italian agile frog (Rana latastei), likely driven by habitat modification, severe droughts, and predation pressure from invasive P. clarkii, compounded by fragmented management responses. These results underline that effective conservation requires not only ecological interventions, such as habitat protection and species reintroduction, but also proactive engagement with stakeholders and coordinated, consistent management by authorities. Integrating socio-ecological perspectives therefore emerges as essential to anticipate human-driven threats, enhance compliance with conservation measures, and safeguard vulnerable freshwater species in human-dominated landscapes.  In conclusion, this thesis demonstrates how combining distribution models, ecological impact assessments, and socio-managerial research can generate useful insights for invasive species management. The findings inform proactive strategies to protect native crayfish and amphibians, particularly through early detection, prioritization of high-risk areas, and integration of public engagement into conservation planning.","language":"eng","citation":"INVASION DYNAMICS OF FRESHWATER CRAYFISH IN A MAN-DOMINATED LAND: SPATIO-TEMPORAL, ECOLOGICAL AND HUMAN DIMENSIONS / V. Messina ; tutor: R. Manenti ;  co-tutor: G. F. Ficetola ;  coordinator: M. P. M. Guarino. - Milano. Dipartimento di Scienze e Politiche Ambientali, 2026 Jan 09. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R14006.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 15-LUG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1038969"},"title":"OPTIMISATION AND THERAPEUTIC-TARGET-DISCOVERY ORIENTED ANALYSIS OF CRISPR-CAS9 SCREENS","internalauthor":"VINCETI, ALESSANDRO","type":"Tesi di dottorato","year":"2024","abstract":"The emergence of CRISPR-Cas9 technology has revolutionized cancer research by enabling targeted genome modifications in tumour cells, offering insights into cancer biology and potential treatment targets. My PhD research focuses on developing tailored tools and pipelines to enhance the analysis of CRISPR-Cas9 screens for identifying cancer therapeutic targets.  CRISPR-Cas9 screens are vital in cancer research, allowing precise gene knockout and unveiling genes critical for cancer cell survival. However, challenges persist in experimental setup optimization and data analysis. My work addresses these challenges by optimizing CRISPR-Cas9 screens and developing advanced analysis tools.  Key challenges include addressing biases from copy number alterations and distinguishing between core-fitness and context-specific fitness genes. Identifying context-specific genes is crucial for personalized cancer treatments.  Additionally, cancer dependency datasets derived from CRISPR-Cas9 screens on large cell line panels offer valuable insights into cancer vulnerabilities, guiding cancer and fundamental biology research.  In conclusion, optimised methods and analytical tools for CRISPR-Cas9 screens are pivotal in cancer research. My research aims to overcome challenges in experimental setup and data analysis, facilitating the identification and validation of novel therapeutic targets. These tools not only enhance screen accuracy but also provide valuable resources for the scientific community, advancing cancer treatment and fundamental biological understanding.","language":"eng","citation":"OPTIMISATION AND THERAPEUTIC-TARGET-DISCOVERY ORIENTED ANALYSIS OF CRISPR-CAS9 SCREENS / A. Vinceti ; tutor: F. Iorio ; co-tutor: G. Testa ; coordinatore: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2024 Apr 11. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12758_2.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1038969/2382874/phd_unimi_R12758_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1172305"},"title":"LA SUPERFICIE DI MEZZO. L¿ECOSISTEMA DELLE INTERFACCE DIGITALI: UNA TASSONOMIA CRITICA","internalauthor":"COSTELLA, ALESSANDRO","type":"Tesi di dottorato","year":"2025","abstract":"Although part of our daily lives for decades, interfaces are a hard to define technology. Whileas many different disciplines and approaches have tried to give a definition of it, little effort has been done to classify, distinguish and define different categories of interfaces. The present work aims to investigate different definitions and mechanisms pertaining to the concept of interface through philosophy, media archaeology and disability and critical studies to structure a critical taxonomy of the computer interface. The grand set computer interfaces constitute has been divided in three main ontological classes, each associated with a strong norm that defines all other categories in the same class. Furthermore, the work proposes to observe how the normalizing mechanisms and the processes of exclusion, descending from different devices and previous technology, contribute to the definition of the norm itself on the bodily, cultural, social and political levels.","language":"ita","citation":"LA SUPERFICIE DI MEZZO. L' ECOSISTEMA DELLE INTERFACCE DIGITALI: UNA TASSONOMIA CRITICA / A. Costella ; tutor:  A. Pinotti ;  cotutor: A. Ferrara ;  coordinatore: N. Guicciardini. Dipartimento di Filosofia Piero Martinetti, 2025. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13543.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1172305/3096050/phd_unimi_R13543.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/816287"},"title":"STANDARDIZATION OF MINIMALLY INVASIVE SURGICAL AND PERI-SURGICAL PROCEDURES IN POND SLIDERS (TRACHEMYS SCRIPTA)","internalauthor":"BARDI, EDOARDO","type":"Tesi di dottorato","year":"2021","abstract":"North American pond sliders (Trachemys scripta) are invasive alien species that, following the release of pet specimens in the wild over the decades, have established breeding populations outside their native habitat, with detrimental effects on local biodiversity. Their commerce and breeding have been recently banned in the European Union, and national programs are being introduced by Union Members to eradicate and control their presence. Aims of the present PhD project were to elaborate on this species’ minimally invasive ovariectomy regarding surgical, anesthesiologic and analgesic aspects, and to dwell on the concept of population control, possibly providing means alternative to surgical gonadectomy.  The first study included in the present thesis is a comparison between dorsal and lateral recumbency during endoscope assisted oophorectomy. Ovariectomy via the prefemoral fossa, with or without endoscopic assistance, is a well-described technique for elective and therapeutic sterilization in chelonians. The choice between lateral and dorsal recumbency is generally left to the surgeon’s preference, with no data supporting an objective superiority of one over the other. Twenty-four sexually mature female pond sliders were enrolled for this study, and were randomly divided in two groups: 12 animals were placed in right lateral recumbency with a left fossa approach (Group A), and 12 in dorsal recumbency with a right fossa approach (Group B). Scoring systems were applied to assess the ease of access to the coelomic cavity, and the ease of identification of the ovary opposite to the surgical incision; total surgery times and necessity to perform bilateral access were recorded. A negative correlation was found between the body weight of the animals and the ease of access to the coelom (p = 0.013), making the access easier in smaller animals. No significant difference was found between the two groups in terms of ease of access to the coelomic cavity, first ovary removal time, ease of identification of the second ovary, second ovary removal time, or total surgery time. It can be concluded that endoscope-assisted prefemoral ovariectomy in mature pond sliders can be indifferently performed in lateral or dorsal recumbency, depending on the preference of the surgeon, on the animal’s pathophysiologic status, or on the necessity to perform concurrent procedures.  The second study is the description and comparison of two totally intramuscular anesthetic protocols. Chelonian anesthesia is a challenge for reptile practitioners: the capability of these animals to hold their breath for a considerable amount of time, and the ability of the chelonian heart to perform right-to-left shunts, make inhalant maintenance less predictable and reliable. Intravenous administration of anesthetic drugs can pose problems as well, since the difficulty of obtaining and maintaining IV catheters in non-complying patients. Anesthetic induction and maintenance by the intramuscular (IM) route circumvent these problems, but the number of multimodal protocols available for this purpose is limited. Twenty-six sexually mature female pond sliders undergoing elective prefemoral ovariectomy were enrolled for this study, and were randomly divided in two groups: Group A received a IM combination of ketamine 3 mg/kg + dexmedetomidine 0.1 mg/kg + midazolam 0.5 mg/kg + alfaxalone 8.5 mg/kg; Group B was premedicated with morphine 1 mg/kg IM 1 hour prior to induction, which was achieved via ketamine 3 mg/kg + dexmedetomidine 0.1 mg/kg + midazolam 0.5 mg/kg + alfaxalone 5 mg/kg IM. Time of loss of and recurrence of spontaneous movement, muscle and cloacal tone, and limb withdrawal latency, time to intubation, heart rate (HR), need for isoflurane administration, recovery time and total anesthesia time were recorded and compared between the two groups. Results indicate that IM administration of dexmedetomidine/ketamine/midazolam/alfaxalone alone (Group A) or in combination with morphine (Group B) provided an adequate anesthetic depth for surgical purpose respectively in 76.9% and 100% of animals, witnessed by the lack of reaction to skin incision and organs manipulation and resection. No marked cardiovascular effects were recorded but, if compared to basal values, Group B displayed a significantly lower HR in the first 15 minutes of surgery, likely determined by the cardiorespiratory effects of morphine. Protocol B showed quicker loss of measured parameters, shorter mean induction time (11 ± 5 vs 22 ±5 minutes, p = 0.00001), quicker recurrence of measured parameters and shorter recovery time (21 ±12 vs 36 ±22 minutes, p = 0.04). Both protocols were safe and provided quick induction and recovery time; premedication with morphine allowed to lower the dosage of alfaxalone, and the resulting protocol provided surgical anesthesia suitable for the whole length of the procedure without requiring inhalant maintenance.   The third study evaluated the role of differentially expressed plasmatic micro RNAs (miRNAs) as possible biomarkers for surgical pain in pond sliders. Plasma of female turtles that underwent surgical gonadectomy were collected 24 hours pre-surgery, and 2.5 hours and 36 hours post-surgery; the expression of miRNAs was profiled by Next Generation Sequencing and the dysregulated miRNAs were validated using RT-qPCR. The diagnostic value of miRNAs was calculated by ROC curves, and the pointed out that, out of 14 differentially expressed miRNAs, miR-499-3p and miR-203-5p were effectively modulated. MiR-203-5p was fair (AUC: 0.7934) in discriminating pre-and 36h post-surgery samples and poor for other time points, while miR-499-3p was excellent (AUC: 0.944) in discriminating pre-surgery and 2.5h post-surgery samples, and fair in discriminating pre-surgery and 36h post-surgery (AUC:0.7292) and 2.5h and 36h post-surgery (AUC:0.7569) samples. In conclusion, it was demonstrated for the first time that miRNAs profile changes in plasma of turtles underwent surgical oophorectomy and identified miR-203-5p and miR-499-3p as potential candidate biomarkers.   The last study investigated the efficacy of single and double IM 4.7 deslorelin acetate implant in suppressing fertility in female pond sliders. The use of long-acting GnRH-agonists has been poorly investigated in reptiles, and the few available studies show inconsistent results. Twenty sexually mature turtles were divided into three groups: one single-implant groups (6 animals), one double-implant group (6 animals) and one control group (no implant). During one reproductive season (March to October), plasmatic concentration of sexual hormones (estradiol, progesterone and testosterone) and ovarian morphometric activity via computed tomography were monitored about every 30 days. A significative (p = 0.011) decrease in the number of phase-II ovarian follicles was detected in the double-implant group when compared with the control group, but no significant difference was noted regarding the number of phase-III and phase-IV follicles, egg production, and sexual hormones plasmatic concentration. Results show that neither a single or double deslorelin acetate implant can successfully inhibit reproduction in female pond sliders during the ongoing season, but the lower number of phase-II follicles in the double-implant group can possibly be associated to a reduced fertility in following seasons.  The present PhD project confirms the poor feasibility of non-surgical sterilization in chelonians and improves the knowledge on endoscopic-assisted ovariectomy, providing useful insight regarding not only the surgical procedure, but also regarding anesthesiologic concerns and pain management in these animals. Obtained results confirm this surgery as a highly specialistic procedures, and its massive application in the context of population control programs is questionable.","language":"eng","citation":"STANDARDIZATION OF MINIMALLY INVASIVE SURGICAL AND PERI-SURGICAL PROCEDURES IN POND SLIDERS (TRACHEMYS SCRIPTA) / E. Bardi ; tutor: S. Romussi ; coordinatore: V. Grieco. Dipartimento di Medicina Veterinaria, 2021 Mar 30. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11917.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/816287/1708995/phd_unimi_R11917.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1125196"},"title":"EXPOSURE TO STRESS EARLY IN LIFE AND ENHANCED RISK TO DEVELOP MOOD AND METABOLIC DISORDERS LATER IN LIFE: IDENTIFICATION OF THE COMMON PERIPHERAL AND CENTRAL MECHANISMS","internalauthor":"D'APRILE, ILARI","type":"Tesi di dottorato","year":"2024","abstract":"The intricate relationship between mental and physical health, particularly the co-occurrence of psychiatric disorders and metabolic conditions, has become a focus of recent research. Early-life stress (ELS) is recognized as a key factor that heightens the risk of developing mood and metabolic disorders, often resulting in comorbidities during adolescence and adulthood. This study investigates the role of ELS in contributing to psycho-metabolic comorbidities, with a focus on disruptions in the brain-liver axis, which is crucial for regulating metabolic and inflammatory processes.  Using a rat model of prenatal stress (PNS), we explored five biological questions. First, we examined whether dysregulation of the inflammatory state within the brain-liver axis could mediate vulnerability to PNS exposure in adolescence by assessing microglial activation and pro-inflammatory cytokine expression in the dorsal and ventral hippocampus and liver, focusing on leptin's role in inflammation. We found strong microglia activation in the dorsal hippocampus of animals vulnerable to PNS exposure, along with increased transcription of pro- inflammatory markers in the liver. Moreover, an upregulation of leptin receptor expression was found in the same animals and it correlates with the inflammatory status in the liver. Second, we explored other biological mechanisms involved in PNS-induced vulnerability in adulthood, investigating disruptions in the hypothalamic-pituitary-adrenal (HPA) axis and metabolic functions and identifying candidate genes associated with psycho-metabolic comorbidities. Vulnerable males showed more pronounced metabolic issues, including weight loss, inflammation and insulin resistance, as well as upregulation of stress-related markers (FoxO1, 11β- HSD1) in the brain and liver. In contrast, resilient males demonstrated better metabolic and anti-inflammatory responses, such as increased ADIPOR1 and IL4R expression, indicating effective stress management. Additionally, the liver of vulnerable males exhibited upregulated insulin and leptin signaling, alongside decreased glucocorticoid receptor expression, linking stress response to metabolic dysregulation. Third, we assessed potential sex differences in central and peripheral responses to PNS, considering the different developmental trajectories of mood and metabolic disorders in males and females. Females do not respond to PNS exposure in the same way as males; a less pronounced effect was observed, at least in the systems analyzed. This difference in stress response could be attributed to sex hormones and their ability to buffer stress consequences. Fourth, we investigated whether PNS leads to common molecular alterations in the liver and brain of male adult offspring by conducting transcriptomic analyses to identify commonly altered differentially expressed genes and modulated pathways. Molecular analyses showed that vulnerable animals had significant disruptions in neurotransmission and inflammatory signaling pathways, particularly downregulation of CREB signaling, which is crucial for memory and synaptic plasticity. This may contribute to cognitive and behavioral vulnerabilities, such as depression-like symptoms. Lastly, we evaluated the long-term metabolic impact of PNS by analyzing glucose metabolism and plasma biomarkers, hypothesizing potential dysregulation in PNS-exposed animals. PNS-exposed animals showed different glycemic levels after glucose or insulin injection, indicating a possible dysregulation in the insulin system and in glucose metabolism. Moreover, levels of metabolic hormones in plasma of PNS exposed animals, such as leptin, insulin, ghrelin and incretins, were significantly different compared to controls. Taken together, these results could suggest a possible dysregulation of insulin signaling and glucose metabolism, hallmark of metabolic syndrome.  Our findings shed light on the biological mechanisms linking ELS to increased vulnerability to psycho-metabolic comorbidities, underscoring the importance of the brain-liver axis as a critical mediator.  Overall, the study highlights the central role of inflammation in the comorbidity of mental and physical health conditions following early life stress and underscores the importance of sex-specific approaches in understanding and addressing these vulnerabilities.","language":"eng","citation":"EXPOSURE TO STRESS EARLY IN LIFE AND ENHANCED RISK TO DEVELOP MOOD AND METABOLIC DISORDERS LATER IN LIFE: IDENTIFICATION OF THE COMMON PERIPHERAL AND CENTRAL MECHANISMS / I. D'aprile ; tutor: A. Cattaneo ; co-tutor: M. A. Riva ; coordinatore: G. D. Norata. Dip. di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti, 2024 Dec 18. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13271.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1125196/2609490/phd_unimi_R13271.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1032989"},"title":"COMPREHENSIVE WHOLE GENOME SEQUENCING UNRAVELS THE COMPLEX GENOMIC LANDSCAPE OF NEUROBLASTOMA","internalauthor":"D'ALTERIO, GIUSEPPE","type":"Tesi di dottorato","year":"2024","abstract":"Neuroblastoma (NBL) is a clinically and biologically heterogeneous pediatric malignancy characterized by a broad spectrum of clinical outcomes. Although the genome of this tumor has been extensively studied through the last decades, a comprehensive analysis of NBL mutational landscape – which may expain its complexity – is still lacking. Moreover, while the role of germline variants in the predisposition of NBL is well established, little is known about their contribution to the onset of specific tumor phenotypes.  In this dissertation we used publicly available Whole Genome Sequencing data from two NBL databases i) to provide a full compendium of NBL genomic alterations (point mutations and structural variants or SVs) and ii) to investigate the correlation between germline Small Nucleotide Variants (SNVs) and the genomic instability of NBL, a well-established marker of poor prognosis.   We found unreported pathogenetic point mutations in 3 cancer-related genes, ESR1, MYH9 and SKI, the latter under-expressed in high-risk tumors. Focal and numerical copy number alterations associated with high and low risk tumors, respectively. Genomic rearrangement analysis revealed novel and recurrent translocations. Patients carrying at least one SV showed different tumor phenotypes in terms of genetic instability, mutational patterns and gene expression with respect to those without SVs. Finally, these patients also carried germline pathogenic variants in genes involved in double-strand break DNA repair.  The results of this dissertation may improve the clinical stratification of NBL, help the development of novel personalized therapies and finally increase the knowledge about the germline contribution of tumor phenotypes.","language":"eng","citation":"COMPREHENSIVE WHOLE GENOME SEQUENCING UNRAVELS THE COMPLEX GENOMIC LANDSCAPE OF NEUROBLASTOMA / G. D'alterio ; tutor: M. Capasso ; phd coordinator: S. Minucci. - TIGEM, Pozzuoli (NA). Università degli Studi di Milano, 2024. 35. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R12769_1.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1032989/2370009/phd_unimi_R12769_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/885836"},"title":"HOSPITAL-ACQUIRED BACTERIAL INFECTIONS IN SARS-COV-2 INFECTED PATIENTS. WASN¿T COVID-19 COMPLICATED ENOUGH? PROSPECTIVE STUDY ON NOSOCOMIAL BLOODSTREAM INFECTIONS AND DESCRIPTION OF NDM-1-PRODUCING KLEBSIELLA PNEUMONIAE OUTBREAK IN COVID-19 UNITS","internalauthor":"CONA, ANDREA","type":"Tesi di dottorato","year":"2021","abstract":"Introduction Bacterial superinfections may complicate the clinical course of hospitalized SARS-CoV2 infected patients. However, the exact burden of bacterial complications and their impact on mortality in COVID-19 is not fully understood yet.   Aim of the first study included in this dissertation is to evaluate the burden and epidemiology of hospital-acquired bloodstream infections (HA-BSIs) in patients hospitalized with COVID-19 pneumonia, exploring in particular risk factors associated with HA-BSIs and impact of HA-BSI on mortality.  In the second study it will be described an outbreak due to NDM-1-producing Klebsiella pneumoniae (NDM-Kp) involving SARS-CoV-2 infected patients in ICU and non-ICU Units. Epidemiological and clinical characteristics of the outbreak, including molecular characterization of the micro-organism, will be discussed as well as the infection control measures implemented to control the outbreak.   Methods Prospective observational cohort study conducted at San Paolo Hospital in Milan, Italy. All patients admitted to hospital for symptomatic SARS-CoV-2 infection from 24 February 2020 to 31 March 2021 were included in the study. HA-BSI defined as infections occurring ≥48 hours after hospital admission. Incidence of HA-BSI was estimated as the numbers of HA-BSI episodes over 1000 patients-day of hospitalization with 95% confidence interval calculated by Poisson distribution. Factors associated with the development of HA-BSI were analysed using an unadjusted and adjusted logistic regression model. The impact of HA-BSI on in-hospital mortality and hospital discharge has been evaluated with a 1:1 matching nested study using competing-risk analysis.     The main objectives of the study were: (i) description of microbiological and clinical characteristics of HA-BSIs; (ii) assessment of the incidence and prevalence of HA-BSIs; (iii) evaluation of risk factors for the development of HA-BSIs; (iv) evaluation of the impact of HA-BSIs on length of stay and in-hospital mortality.  Results Among 1,950 consecutive patients hospitalised with COVID-19, 121 episodes of HA-BSI were observed in 101 (5.2%) patients. The incidence rate of HA-BSI was 3.5/1000patient-days (95%CI 2.3–4.3). 1,077/1,950 (55%) patients received corticosteroid therapy and 93/1,950 (5%) immunomodulators. 29% and 7% received continuous positive airway pressure (C-PAP) or non-invasive mechanical ventilation (NIMV) while 5.5% of patients received invasive mechanical ventilation (IMV). No difference in the distribution of therapies and oxygen support was noted between the HA-BSI and non-BSI groups except for a higher consumption of steroids (73% vs 54%, p=0.001) and higher use of NIMV/IMV (44% vs 12%, p<0.001) in the HA-BSI group. At multivariate analysis, NIMV/CPAP (aOR 1.82, 95%CI 1.15–2.90, p=0.010), IMV (aOR 4.75, 95%CI 2.32–9.72, p<0.001) and corticosteroid treatment (aOR 2.15, 95%CI 1.27–3.65, p=0.005) were confirmed as independent factors associated with HA-BSI. Concerning clinical outcomes, patients with HA-BSI compared to no-BSI groups, had a longer hospital stay (28 vs 10 days, p<0.001) but a similar in-hospital mortality (HA-BSI 33% vs non-BSI 25%, p=0.091). At competing-risk analysis, an increased risk of death in patients with HA-BSI was observed (p=0.030). However, after fitting a multivariable competing-risk regression model, a trend toward an increased risk of death in patients with HA-BSI was observed even tough statistical significance was not reached (aSHR 1.80, 95%CI 0.98-3.30, p=0.057). Regarding length of stay, the 30 days cumulative incidence of hospital discharge was 54% and 75% in patients with and without HA-BSI, respectively (p=0.019); this finding was confirmed after multivariable competing-risk regression model adjusted (aSHR 0.65, 95%CI 0.43-0.85, p=0.003).  The outbreak of NDM-Kp described in the second study was observed from February 2021 to March 2021 at the San Carlo Hospital. It involved 4 Units, including COVID-ICU, for a total of 12 patients. Five of these patients developed an infection caused by NDM-Kp while the rest of them had an asymptomatic colonization. 7 out of 12 patients died. Genomic sequencing has confirmed that all the cases were due to the same strain, ST-945. The outbreak was controlled thanks to the implementation of additional infection control measures.  Conclusions In our cohort the incidence of HA-BSI was relatively low. Development of HA-BSI did not significantly affect mortality but was associated with a longer hospital stay. Patients treated with corticosteroid therapy had double the risk of developing BSI.    Concerning the outbreak, the additional infection control measures implemented, in association with those already in force, made possible the containment of the NDM-Kp outbreak. No more cases have been reported; recently few more cases of NDM-Kp have been identified in non-COVID-19 patients; epidemiological and molecular analysis are currently ongoing.","language":"eng","citation":"HOSPITAL-ACQUIRED BACTERIAL INFECTIONS IN SARS-COV-2 INFECTED PATIENTS. WASN¿T COVID-19 COMPLICATED ENOUGH? PROSPECTIVE STUDY ON NOSOCOMIAL BLOODSTREAM INFECTIONS AND DESCRIPTION OF NDM-1-PRODUCING KLEBSIELLA PNEUMONIAE OUTBREAK IN COVID-19 UNITS / A. Cona ; tutor: A. d.Arminio Monforte, G. Marchetti ; coordinatori: E. Berti, M. Del Fabbro. Dipartimento di Scienze della Salute, 2021 Dec 14. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12378.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/885836/1920270/phd_unimi_R12378.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/974188"},"title":"TRANSLATIONAL APPROACH TO NEUROMUSCULAR FUNCTION AND ITS RECOVERY: EFFECT OF LIMBS, AGING, AND DISEASE.","internalauthor":"COLOSIO, MARTA","type":"Tesi di dottorato","year":"2023","abstract":"Several factors can determine changes along the pathway from the brain to the muscles, and the  interaction of different processes during exercise can ultimately determine neuromuscular function  fatigability. Furthermore, the time course of neuromuscular function recovery after exercise is  essential for planning repeated daily activities and sports. My PhD work aimed to compare the effects  of different fatiguing exercises, populations, and interventions on neuromuscular function fatigability  and recovery.  Daily-living and sporting activities have different physical requirements, and the fatigability of  different muscle groups is of interest. As a result, comparisons of the fatigability of upper- and lowerlimb  muscles have been investigated, but there is a lack of information about muscle force loss and  recovery following dynamic multi-joint exercise involving elbow flexors and knee extensors. The  aim of the first study was to evaluate the magnitude and etiology of neuromuscular function changes  in elbow flexors and knee extensors from dynamic multi-joint maximal incremental exercise. For this  study 10 young, healthy, and physically active men were enrolled. Each participant completed one  familiarization session and two experimental sessions consisted of a maximal incremental exercise to  task failure on either an arm-cranking ergometer or a cycle ergometer. Before, exactly 1 min and 20  min after exercise cessation, neuromuscular function evaluation was conducted. The results showed  that both maximal voluntary isometric force loss and decreases in evoked forces were not different  between elbow flexors and knee extensors 1 min after task failure. However, 20 min after task failure,  maximal voluntary isometric force, and low-frequency fatigue were greater in elbow flexors than  knee extensors. These results suggest that exercise-induced recovery is muscle-specific.  The neuromuscular function is affected by age and the changes within the neuromuscular system are  associated with a decline in both muscle strength and mass. Since aging affects functional  performance tasks such as stair climbing, ambulation, and rising time from a chair, affecting  neuromuscular function, it is of interest to investigate muscle force and power fatigability.  Sarcopenia, a highly prevalent disease in older than 65 years, exacerbates age-related changes in the  neuromuscular system. The second study aimed to determine the mechanistic bases of the knee  extensor muscles fatigability in healthy and sarcopenic old men and women elicited by high-velocity  concentric contractions. Fifty-seven healthy old, 14 sarcopenic, and 21 young adults were recruited.  Neuromuscular function assessment was performed before and immediately after an intermittent  isotonic fatiguing exercise. Sarcopenia was associated with a reduction in knee extensor contractile  properties, isometric torque, and power. Exercise-induced loss of isometric torque was not different  between healthy and sarcopenic adults whereas power reduction resulted higher in sarcopenic  III  suggesting that the age-related changes in fatigability are contraction-specific and exacerbated by  sarcopenia. Since no differences were observed for voluntary activation, the greater power reduction  during exercise in sarcopenic adults may be due to intrinsic muscle impairment of contractile and/or  metabolic nature.  Many research activities have been addressed in counteracting the muscle weakness observed in older  people. Since, aging seems to negatively affect plasma nitrate concentration [NO3-] and the potential  benefits of dietary NO3- supplementation on skeletal muscle contractile function and muscle fatigue  have been recently suggested, the third study aimed to evaluate the effects of prolonged NO3-  supplementation on contractile properties and fatiguability of ankle plantar-flexor muscles in elderly  subjects. Eleven elderly and 11 young men were recruited. Two main experimental sessions were  performed after a 7-day supplementation period with either nitrate-rich beetroot juice or nitratedepleted  beetroot juice. Neuromuscular function evaluation, comprising voluntary and electrically  evoked isometric contractions of the plantar flexors, was performed on the dominant and nondominant  leg. Our results report that after beetroot juice supplementation, young and elderly increased  the plasma concentration precursors of nitric oxide. Improving nitric oxide bioavailability had  potentially beneficial effects on fatigue resistance, calcium handling and skeletal muscle force  production at submaximal forces in elderly people. Thus, the impairment in muscle contractile  properties observed with aging can be positively affected by the increase in plasma concentration of  nitric oxide precursors.  Finally, independent of age, neuromuscular function can be affected by different diseases. Following  acute Covid-19, a substantial proportion of patients showed symptoms and sequelae for several  months, namely the post-acute sequelae of Covid-19 (PASC) syndrome. Major phenomena were  exercise intolerance, muscle weakness, and fatigue. The aim of the fourth and last study of my thesis  was to investigate the physiopathology of exercise intolerance in patients with PASC syndrome by  structural and functional analysis several months after recovery. At least 3 months after infection, 11  non-hospitalized PASC patients and 12 patients without long-term symptoms visited the laboratory  on four non-consecutive days. Spirometry, lung diffusion capacity and quality of life were assessed  at rest. Muscle oxidative capacity recovery rate constant was assessed by repeated arterial occlusion  by near-infrared spectroscopy. The cardiopulmonary incremental exercise test was performed.  Neuromuscular function as knee extensor rate of torque development, maximal voluntary isometric  contractions torque and electrically-evoked single and doublet twitches were assessed before,  immediately and 10 minutes after 80 maximal velocity contractions with 20 % of the maximal  isometric torque load. Histochemical analysis, quantification of key molecular markers of  IV  mitochondrial biogenesis, dynamics, and mitochondrial respiration were performed in vastus lateralis  biopsies. Finally, specific isometric force and the no-load shortening rate of chemically skinned single  isolated muscle fibers were measured. PASC patients showed reduced force-generating capacity and  slower recovery after a dynamic fatiguing task compared to control subjects. These results seemed  attributable to mild muscle atrophy and impairments in the recovery of excitation-contraction  coupling, while actin-myosin bridge formation was not affected. Exercise intolerance of PASC  patients was primarily due to impaired mitochondrial function as suggested by both functional invivo  indexes of muscle oxidative metabolism and ex-vivo measurements. Finally, impairment in  neuromuscular function recovery, along with mitochondrial dysfunction, suggests a delayed  restoration of metabolic homeostasis after exercise in PASC.  Overall, the work in this thesis shows how the combination of in-vivo measurements and ex-vivo  analyses can be utilized to investigate impairments along the pathway from the central nervous system  to the muscles, elucidating potential sites of alterations in both upper and lower limbs. Moreover, the  results suggest that changes within the neuromuscular system are exacerbated by sarcopenia and  disease (i.e. COVID) but can be counteracted by interventions such as dietary nitrate  supplementation.","language":"eng","citation":"TRANSLATIONAL APPROACH TO NEUROMUSCULAR FUNCTION AND ITS RECOVERY: EFFECT OF LIMBS, AGING, AND DISEASE / M. Colosio ; supervisors: G. Vernillo, R. Codella, S. Porcelli; coordinatore: C. Sforza. Dipartimento di Scienze Biomediche per la Salute, 2023 Jul 14. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12602.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/974188/2214810/phd_unimi_R12602.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1159559"},"title":"THE ALTERNATIVE SPLICING OF NF-YA REGULATES MOUSE EMBRYONIC STEM CELLS DIFFERENTIATION","internalauthor":"POLETTINI, SOFIA","type":"Tesi di dottorato","year":"2025","abstract":"Embryogenesis is governed by a fine balance between pluripotency and differentiation controlled by a handful of Transcription Factors (TFs). Some are implied in the maintenance of self-renewal and pluripotency of Embryonic Stem Cells (ESC), others drive cell lineage decisions which give rise to the entire organism. An example of these factors is NF-Y, a heterotrimeric pioneer TF promoting chromatin accessibility to other TFs to regulate gene expression. The regulatory subunit of NF-Y, NF-YA, recognizes and binds the CCAAT box motif, one of the most enriched DNA elements in enhancers and promoters of genes specifically active in ESCs. NF-YA exists in two different isoforms generated by Alternative Splicing of Exon 3. The short (NF-YAs) and the long (NF-YAl) isoforms differ from a stretch of 28-29 amino acids in the N-terminal Q-rich activation domain. Although they display identical DNA-binding properties in vitro, the two isoforms have distinct roles in several biological processes. Regarding embryogenesis, NF-YAs is the predominant isoform in undifferentiated mouse ESCs, being crucial for the regulation of pluripotency and stemness maintenance. By contrast, during Embryoid Bodies (EB) formation process, NF-YAl prevails, suggesting an implication of this specific isoform in the differentiation of mESCs. Our data strengthen the stem-related function of NF-YAs and propose a novel role of NF-YAl in mesoderm formation to shed light on the distinct functions of NF-YA isoforms in the equilibrium between pluripotency and differentiation.","language":"eng","citation":"THE ALTERNATIVE SPLICING OF NF-YA REGULATES MOUSE EMBRYONIC STEM CELLS DIFFERENTIATION / S. Polettini ; tutor: D. Dolfini. Dipartimento di Bioscienze, 2025 Apr 17. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13457.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 14-OTT-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1205255"},"title":"MUSCLE-SPECIFIC MECP2 MISEXPRESSION INDUCES SKELETAL AND VISCERAL MUSCLE DEFECTS RESCUED BY BUTYRATE SUPPLEMENTATION IN DROSOPHILA","internalauthor":"CONSONNI, GAIA","type":"Tesi di dottorato","year":"2026","abstract":"Summary  Background   MeCP2 is a chromatin-associated protein whose dosage alterations cause two severe neurodevelopmental disorders: Rett syndrome (RTT), linked to loss-of-function mutations, and MECP2 duplication syndrome (MDS), linked to overexpression. Although widely studied for their neurological symptoms, these disorders also display prominent non-exclusively neurological features, including gastrointestinal dysmotility and muscle hypotonia - suggesting that MeCP2 dysfunction may also impact peripheral tissues. Since MECP2 is expressed in muscle, yet its role outside the nervous system remains poorly defined, this work explores the tissue-autonomous effects of MECP2 misexpression in muscle.  Aims   This project aims to establish a Drosophila model to investigate the impact of MECP2 misexpression in muscle tissue and its role in muscle development, assess whether the resulting phenotypes are autonomous or secondary to neuronal dysfunction, and test the therapeutic potential of short-chain fatty acids (SCFAs) - specifically butyrate - as chromatin-targeting interventions.  Results   Because Drosophila lacks an endogenous MECP2 gene, we used transgenic lines overexpressing either wild-type or mutant human MECP2. Using the Gal4/UAS system, tissue-specific expression revealed that muscle-targeted MECP2 overexpression led to the strongest phenotypes, such as reduced viability, disorganized skeletal and visceral muscle, impaired locomotion, and delayed gut transit. In addition, mitochondrial abnormalities - increased organelle number and altered cristae structure - were observed by electron microscopy in muscle fibers. Visceral muscle defects were most pronounced when MECP2 was expressed during gut development, suggesting interference with tissue maturation.  We also employed the model to functionally classify MECP2 variants. Alleles were scored based on their ability to enhance or suppress wild-type MECP2 phenotypes. R106W suppressed lethality and caused mild muscle disruption, consistent with loss of function. Δ166 enhanced lethality but caused minimal pathology, suggesting a benign effect. R294X produced strong muscle phenotypes and variable lethality across tissues, indicating partial function.  To determine whether these effects were secondary to neural dysfunction, we expressed MECP2 in neurons but observed no impact on muscle structure or gut function. Similarly, MECP2 expression in muscle did not disrupt synaptic architecture. These findings support a tissue-autonomous mechanism.  With a clear muscle-specific phenotype and considering their energetic and epigenetic functions, we next tested whether SCFAs supplementation could reverse these defects. High-dose propionate reduced survival. In contrast, acetate, sodium butyrate, and the butyrate-rich postbiotic Lalbaay® improved viability and development, with Lalbaay® showing the strongest effects.  Motor function was also enhanced, supporting the beneficial role of butyrate molecule. Indeed, supplementation with sodium butyrate, an HDAC inhibitor with energetic role, specifically restored muscle structure and gut motility. Valproic acid, a pan-HDAC inhibitor without metabolic properties, produced similar improvements, suggesting an epigenetic mechanism of action.  Finally, we began dissecting genetic interactions. Since Drosophila lacks endogenous MECP2, it provides a clean background to identify functional modifiers. Recent work implicated PHF14 - a MeCP2 interactor mutated in a Rett-like syndrome - as a candidate modifier. Given its conservation in flies, we initiated a mutagenesis screen via transposon excision. To date, 22 candidate mutant lines have been isolated and are being validated, paving the way for future genetic interaction studies.  Conclusions   This thesis demonstrates that MECP2 misexpression in Drosophila muscle leads to autonomous morphological and functional defects, which can be partially reversed by SCFAs such as butyrate and Lalbaay®, likely via chromatin remodeling and possibly metabolic support. Disease-associated MeCP2 variants reproduce the pathogenicity reported in patients, showing distinct tissue-specific behaviours and underscoring the validity of this model for functional interpretation. These findings highlight the systemic nature of MECP2 disorders and advocate for therapeutic strategies that extend beyond the nervous system to include peripheral tissues such as muscle.","language":"eng","citation":"MUSCLE-SPECIFIC MECP2 MISEXPRESSION INDUCES SKELETAL AND VISCERAL MUSCLE DEFECTS RESCUED BY BUTYRATE SUPPLEMENTATION IN DROSOPHILA / G. Consonni ; tutor: E. Borghi ;  co-tutor: T. Vaccari ;  altro supervisore: A. Galeone ;  collaboratori: A. Mineo, I. Miguel-Aliaga coordinator: M. Clerici. - Milano. Dipartimento di Scienze della Salute, 2026 Jan. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13986.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1205255/3214126/phd_unimi_R13986.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/886195"},"title":"CONFIGURATION MIXING INVESTIGATION IN GERMANIUM ISOTOPES","internalauthor":"PORZIO, CARLOTTA","type":"Tesi di dottorato","year":"2021","abstract":"Protons and neutrons of atomic nuclei can arrange in both spherical and non-spherical configurations. Nuclei can also exhibit configurations which lie close in energy, yet present different deformations. Such phenomenon is referred to as shape coexistence and its occurrence in nuclei is thought to pervade the entire nuclear chart. Excited states with similar energies and same spin and parity can also mix, so that the observed states are the result of mixing of different configurations.  In this context, the structure of Ge isotopes has been widely investigated over the years. Previous transfer reaction experiments pointed to the occurrence of configuration mixing between the ground state and first excited 0+ state in 72Ge (N = 40). Furthermore, they indicated a weakening of such mixing moving away from N = 40, in correspondence with the increase of the excitation energy of the 0+[2] state. However, the nature of the configurations that mix and their evolution along the Ge isotopic chain is still elusive.   In this thesis, a study of configuration mixing in the even-even Ge isotopes at and near stability (A = 72, 74, 76, 78) has been carried out through the measurement of electric monopole (E0) transition strengths, which have been identified as a sensitive probe of configuration mixing. In particular, the focus has been set on the transitions with I = 2, 2+[2]→2+[1].   The experiments presented in this thesis have been performed at the TRIUMF laboratory (Vancouver, Canada). The isotopes of interest have been populated via the β decay of radioactive ion beams of 72,74,76,78Ga, which were implanted at the center of the GRIFFIN decay station. The GRIFFIN spectrometer, combined with the PACES silicon array, enabled us to perform both γ-ray and electron spectroscopic investigations, to measure E0 strengths between states with I = 2.","language":"eng","citation":"CONFIGURATION MIXING INVESTIGATION IN GERMANIUM ISOTOPES / C. Porzio ; supervisor: S. Leoni ; co-supervisor: A. Garnsworthy ; coordinatore: M. Paris. Università degli Studi di Milano, 2021 Dec 13. 34. ciclo, Anno Accademico 2021. [10.13130/porzio-carlotta_phd2021-12-13].","filename":"phd_unimi_R12370.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/886195/1921250/phd_unimi_R12370.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1089668"},"title":"BIOINFORMATIC PIPELINES AND MICROBIAL DATABASES FOR THE ANALYSIS OF DAIRY COWS 16S RRNA-GENE SEQUENCING DATA: A BENCHMARKING STUDY.","internalauthor":"GINI, CHIARA","type":"Tesi di dottorato","year":"2024","abstract":"Background    Understanding the microbiomes in different organisms is crucial across various   scientific fields. To achieve this, specialized computer programs called bioinformatic   pipelines have been developed to convert raw data into meaningful biological results.   However, the rapid growth of this field in dairy cows’ research has led to a lack of   guidelines on how these pipelines differ and what they can do.    Methods    This study aims to benchmark four different software – MICCA, QIIME (versions 1.9   and 2), and VSEARCH – by examining their features and evaluating their outputs using   three different databases, two of which in two different releases. The performances of   these combinations will be assessed using two mock communities and four dairy cows-related datasets: milk, skin, rumen, and feces.    Results     Mock communities’ analysis outcomes focus on evaluating the pipelines' ability to   accurately predict the composition of bacterial communities previously documented in   the literature. Real-life dataset instead allow to investigate the influence of pipelines   and databases on dataset analysis at 3 stages: firstly, a pilot experiment with 1 dataset   (milk), 1 pipeline (QIIME version 1.9), and 1 database (SILVA version 132) was used to   compare with the results of the same pipeline on the same dataset using other 3 different databases, of which 1 in double release and 1 as the updated version of the one previously used. Then, the application of 4 pipelines (of which 2 with the 2 different approaches) and 4 databases (of which 2 in a double release, for an overall of 36 combinations) on the same dataset, and later, the benchmarking of the same 36 combinations on other datasets will allow to gain a broader view of the effects of the pipelines of analysis and microbial databases available for dairy cows 16S rRNA-gene sequencing data.    Conclusions    Ultimately, this study aimed to establish a standardized approach and enhance decision-making in 16S sequencing analysis, thereby improving the scientific rigor of microbiome   analysis studies in dairy cows. MICCA and QIIME version 2, in conjunction with the SILVA   version 138 database, demonstrated the most promising results in achieving this goal.","language":"eng","citation":"BIOINFORMATIC PIPELINES AND MICROBIAL DATABASES FOR THE ANALYSIS OF DAIRY COWS 16S RRNA-GENE SEQUENCING DATA: A BENCHMARKING STUDY / C. Gini ; tutor: F. Ceciliani ; coordinatore: F. Ceciliani. - Lodi. Università degli Studi di Milano, 2024 Sep 16. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12929.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1089668/2511992/phd_unimi_R12929.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1273604"},"title":"ESSAYS IN MACROECONOMICS AND MONETARY POLICY: TOPICS AND CHALLENGES FOR CENTRAL BANKS","internalauthor":"MURAKAMI, DAVID HIROYUKI","type":"Tesi di dottorato","year":"2026","abstract":"This dissertation comprises six essays in macroeconomics, the culmination of my studies of monetary policy, financial frictions, and international macroeconomics. It is perhaps an orthodox view, but I have come to believe that the primary purpose of macroeconomics is to understand economic fluctuations and to inform the design of policy. I hope these essays serve as an ode to this view; at the core of each, readers will find an application of the New Keynesian framework.    The New Keynesian framework has come under much scrutiny in recent years, and understandably so: my fellow doctoral students and I have witnessed not one but two macroeconomic crises during our most formative years. As I write this foreword, a third may well be brewing, driven by a combination of factors including another episode of financial market overvaluation, high public debt, continual global supply chain disruptions, and ongoing geopolitical tensions. I understand, perhaps more than most, the scepticism about the New Keynesian framework's ability to explain these phenomena.    Nevertheless, I believe the New Keynesian framework remains invaluable. It is remarkably adaptable to new empirical evidence and theoretical developments. Like most paradigms, in economics or elsewhere, it is a powerful tool that must be applied appropriately. My concern is that we, as macroeconomists, risk throwing the baby out with the bathwater: abandoning the framework because of its poor performance when misapplied in the 2010s and early 2020s would be a mistake. Over the past few years, I have met many doctoral students who express no interest in the New Keynesian framework or lack even an intermediate understanding of it. I find this odd and troubling. It is precisely because these are such turbulent times that we must remain vigilant and keep a firm grasp of the intuition the New Keynesian framework offers about the macroeconomy. It cannot speak to, say, recent developments driven by micro data, but it remains a powerful tool for understanding aggregate prices, output, and interest rates.    I should make clear that my views on the function of macroeconomics and the strengths of the New Keynesian model differ from how I view the core purpose of economics as a discipline. While it may seem at odds with my orthodox view of macroeconomics, I believe that we – as economists more broadly – must avoid dogmatism when confronting the more fundamental and pressing questions of our time: global wealth and income inequality, fascism and the shortcomings of capitalism in the 21st century, racial and sexual justice, and peace and the sanctity of human life and rights. Economists have not been vocal enough on these issues, and I think this has created a vacuum for nefarious political actors to exploit.    I now briefly describe each chapter. The chapters are ordered chronologically, by when I wrote them or completed a first draft, and each is self-contained and can be read independently:    Chapter 1: Gone with the Wind: Monetary Policy and the Global Financial Cycle. This chapter grew out of my MPhil dissertation at the University of Oxford. The core research question is unchanged: how important is the exchange rate regime in buffering the domestic economy from global financial cycles? The approach and methodology, however, have been substantially updated. I build a small open economy New Keynesian model to inform the Mundellian Trilemma versus Dilemma debate and, as a key contribution, estimate it on South Korean data with an occasionally binding constraint. I also use nonlinear solution methods that allow agents to behave precautionarily to avoid hitting the constraint, in stark contrast to other papers, which typically estimate models with ‘always-binding’ constraints. To the best of my knowledge, this is the first paper to study the interaction among global financial cycles, the Mundellian Trilemma, and occasional episodes of financial crisis or stress. I find that the Mundellian Trilemma remains relevant, and that the economy's dynamics depend not only on the exchange rate regime but also on whether it is in a crisis or stress regime.    Chapter 2: Cryptocurrencies in Emerging Markets: A Stablecoin Solution? (co-authored with Ganesh Viswanath-Natraj; published in the Journal of International Money and Finance, June 2025). Motivated by El Salvador's 2021 experiment in making Bitcoin legal tender, which increased financial inclusion at the cost of a volatile medium of exchange, we study the macroeconomic effects of introducing cryptocurrencies in a workhorse small open economy model. The model builds on my experience with the bank financial frictions of Aoki, Benigno, and Kiyotaki and of Akinci and Queralto in open economy settings. Relative to an economy without cryptocurrency, introducing a low-volatility currency such as a stablecoin yields net welfare gains for the unbanked population, whereas a high-volatility currency such as Bitcoin yields net welfare costs. Cryptocurrency adoption attenuates the transmission of both domestic and foreign monetary policy, and flexible exchange rates provide an effective buffer against cryptocurrency price shocks. Our findings rationalise the growing use of stablecoins in emerging markets as a hedge against macroeconomic uncertainty.    Chapter 3: CBDCs, Financial Inclusion, and Optimal Monetary Policy (co-authored with Ganesh Viswanath-Natraj and Ivan Shchapov; revision requested at Macroeconomic Dynamics). This chapter is a natural follow-up to the previous one, written as I became more familiar with the Gertler–Kiyotaki–Karadi financial frictions framework and the heterogeneous agent literature. We study the interaction between monetary policy and financial inclusion in an economy that introduces a central bank digital currency (CBDC). Using a two-agent New Keynesian framework with banked and unbanked households, we show that a CBDC gives the unbanked a more efficient savings device with which to smooth consumption, raising welfare. Under Ramsey optimal policy, the CBDC rate is set at a constant spread to the policy rate. We identify a policy trade-off: a higher CBDC rate benefits the unbanked but disintermediates banks and reduces the welfare of banked households. Taken together, our findings highlight the importance of tailoring CBDC design to an economy's level of financial inclusion.    Chapter 4: Productivity over the Life-Cycle and its Effects on the Interest Rate (co-authored with Momo Komatsu and Ivan Shchapov; published in the Japanese Economic Review, special issue on Heterogeneity and Macroeconomics, February 2025). This chapter builds on the Blanchard–Yaari–Gertler overlapping generations framework and began as my master's dissertation at Keio University. That early version was quite simple, with almost no role for fiscal transfers. Given the pressing challenges of demographics and fiscal sustainability, however, my co-authors and I rewrote the paper and extended it substantially. Japan has faced rapid ageing, persistently low interest rates, sluggish growth, and deflation for decades, while the productivity of young and elderly workers has gradually converged. Using an overlapping generations two-agent New Keynesian (OTANK) DSGE model, we explore the relationship between productivity, demographic shifts, and interest rates in Japan during the post-bubble era. The narrowing productivity gap between younger and older cohorts puts upward pressure on interest rates, whereas longer life expectancy and negative population growth push them down; the latter effect dominates. A central bank that fails to account for this when setting monetary policy may induce deflationary pressure. Two policy implications emerge: raising productivity over workers' entire life-cycle and bridging the gap between younger and older workers can help offset the decline in interest rates, and monetary policy ought to account for shifting demographics.    Chapter 5: Restoring Existence and Uniqueness at the Effective Lower Bound with Simple Fiscal Policy (co-authored with Ivan Shchapov and Yifan Zhang; second-round revision requested at the Journal of Economic Dynamics and Control). My interest in the nonexistence and multiplicity of equilibria began when I worked as a research assistant for Guido Ascari and Sophocles Mavroeidis on their paper ‘The Unbearable Lightness of Equilibria in a Low Interest Rate Environment’, later published in the Journal of Monetary Economics. Around the same time, I began researching nonlinear solvers – most notably OccBin – and the numerical difficulties posed by the effective (or zero) lower bound (ELB). In New Keynesian models, the occasionally binding ELB constraint often leads to multiple equilibria or none. The problem stems from a strong feedback loop between expectations of inflation and output and current outcomes at the ELB. We show that simple fiscal policy rules can introduce additional stabilising forces that dampen this loop, thereby ensuring the existence and uniqueness of a minimum state variable (MSV) solution.    Chapter 6: Global Determinacy According to HANK (co-authored with Ivan Shchapov and Yifan Zhang). A natural follow-up to the previous chapter, this chapter builds on the approach of Ascari and Mavroeidis (2022) to test whether Bilbiie's workhorse tractable heterogeneous agent New Keynesian (HANK) model exhibits multiplicity or nonexistence of MSV solutions in the presence of an occasionally binding constraint – in this case, the ELB. We show that the HANK model generally suffers from the same nonexistence or multiplicity problem as the representative agent New Keynesian model. However, when calibrated to have procyclical income and consumption inequality, such that aggregate demand is inverted, the HANK model has a unique MSV solution and satisfies local determinacy conditions – a property we term global determinacy.","language":"eng","citation":"ESSAYS IN MACROECONOMICS AND MONETARY POLICY: TOPICS AND CHALLENGES FOR CENTRAL BANKS / D.h. Murakami ; tutors: G. Ascari, A. Ferrero, F. Zanetti ;  coordinator: F. Iacone, M. Nicolini. Università degli Studi di Milano, 2026 Sep 30. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13729_4.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1273604/3410204/phd_unimi_R13729_4.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/933926"},"title":"THE LANDSCAPE OF AFFECTIVE MEANING","internalauthor":"CARRANZA PINEDO, VICTOR RAFAEL","type":"Tesi di dottorato","year":"2022","abstract":"Swear words are highly colloquial expressions that have the capacity to sig-  nal the speaker’s affective states, i.e., to display the speaker’s feelings with  respect to a certain stimulus. For this reason, swear words are often called  expressives. Which linguistic mechanisms allow swear words display affective  states, and, more importantly, how can such ‘affective content’ be character-  ized in a theory of meaning? Even though research on expressive meaning  has produced models that integrate the affective aspects of swear words in a  compositional framework, there is extensive evidence that swear words can-  not be assigned a single or stable affective interpretation across contexts. For  example, even though expletive adjectives (e.g., 'damn'), particularistic insults  (e.g., 'bastard') and slurs (e.g., 'wop') typically express (and elicit) negatively  valenced affective states, they can also be interpreted positively in some con-  texts. Thus, inspired in recent developments in formal sociolinguistics, I  propose an 'indexical' approach to affective meaning. Under this approach,  an affective expression is associated with a set of affective qualities, anyone  of which may emerge at a given context depending on the interpreter’s prior  assumptions about the speaker’s affective states and/or relation with the tar-  get of the swear word. To define this set, also called 'indexical field', I will  use the dimensions pleasure, arousal and dominance, standardly employed in  cognitive psychology to characterize and measure affective episodes. In this  dissertation, thus, the affective meaning of an expression is given by the set  of affective states it typically conveys within a linguistic community, but its  interpretation at a given context is established by taking into account the  interpreter’s prior assumptions about the speaker’s affective states and/or  attitudes with respect to the target of the affective expression.","language":"eng","citation":"THE LANDSCAPE OF AFFECTIVE MEANING / V.r. Carranza Pinedo ; coordinatore: A. Pinotti ; supervised by E. Paganini and M. Abrusan. Università degli Studi di Milano, 2022 Jul 11. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12356.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/933926/2052172/phd_unimi_R12356.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1158995"},"title":"IL PARTENARIATO PUBBLICO-PRIVATO E L¿ENERGY PERFORMANCE CONTRACT NEL PROCESSO DI TRANSIZIONE ENERGETICA","internalauthor":"VERRENGIA, MORENA","type":"Tesi di dottorato","year":"2025","abstract":"The legal analysis undertaken begins by exploring the precise placement of energy efficiency within the broader objectives of environmental sustainability as identified by the supranational framework. It specifically focuses on the complex scenario resulting from the intersection between environmental and energy dimensions.  Chapter I addresses the complexities inherent in the legal regulation of the energy sector, emerging from an examination of public law sources (both European and national), the division of competencies, regulatory instruments, and the forms through which public authorities intervene in the market. The analysis reveals how the interplay of public and private interests, which governs the energy transition process, reflects the inherent complexity of regulating and governing – by means of traditional administrative law instruments – new models of development aimed at harmonising environmental protection goals with economic systems. Within this framework, having outlined the boundaries of public intervention in the productive system, the analysis particularly investigates what may spontaneously arise from the market and what degree of freedom should be reserved to private autonomy for achieving energy-related objectives. The focus is placed on the regulatory function that could, at least in theory, be transferred to the new actors active in the energy market, and on the legal implications stemming from attributing “public relevance” to these operators in pursuing objectives related to energy efficiency. In examining the public-private dialectic in depth, negotiated and consensual measures are analysed as legal tools capable of aligning individual interests of private operators with the broader public interest in energy efficiency, thus facilitating the emergence of innovative solutions from the market. The collaborative phenomenon, which revolves around the concepts of “negotiability of power” and “contractualism”, serves, on the one hand, as a means of guiding private-sector activities without imposing market rules excessively restrictive of individual legal autonomy. On the other hand, it provides a way to harness private autonomy (alongside resources such as know-how or economic capital), thus aligning the market’s goal of economic development with the pursuit of sustainable development.  Chapter II then analyses the collaborative frameworks identifiable within the paradigm of public-private partnership (PPP). It begins by conceptually and legally framing PPP through an analysis of definitional profiles at both European and national levels, and by exploring the reasons underlying the development and implementation of this institution. Following reflections on the current economic role assigned to public contracts – and specifically to public-private collaboration – in light of objectives outlined in Italy’s National Recovery and Resilience Plan (PNRR) and the revised legal framework introduced by Legislative Decree No. 36 of 31 March 2023 (Procurement Code), the analysis highlights critical issues that must be overcome to enable PPP to fulfill the “strategic” role envisioned by new European and national policy frameworks. The analysis subsequently provides a detailed examination of the new PPP regulation (with specific attention given to the planning phase, operational risk, economic-financial equilibrium, and accounting aspects), carefully considering the role assigned to the private partner. This serves to assess whether the rationale underlying effective collaboration necessitates a deeper integration of public and private functions. In this context, the suitability of the new regulatory framework – emerging from innovations introduced by the new Procurement Code – is evaluated with respect to its ability to encourage PPP as an effective tool for addressing the challenges of the energy transition. The chapter concludes with an analysis of project financing, focusing particularly on the most debated contemporary issues. Among the procedural aspects considered are the promoter’s role, the central position of the private partner, and the safeguarding of competition.  Finally, considering that PPP instruments are fundamental for achieving goals related to the energy transition (both in terms of promoting new-generation renewable energy sources and accelerating the energy efficiency of public infrastructures), Chapter III explores the potential benefits derived from the appropriate implementation of Energy Performance Contracts (EPCs) through the PPP model. After presenting the legal framework governing EPCs, the analysis investigates, on the one hand, the potential of this contractual instrument to establish a robust energy efficiency system while simultaneously meeting environmental protection requirements. On the other hand, it identifies and discusses critical aspects currently hindering the wider implementation of this model.  In conclusion, the effectiveness of PPPs and EPCs depends decisively on the degree of active and strategic involvement of the private sector, as well as on the precise intersection of tasks and clear delineation of responsibilities among the parties involved. Only through fruitful interaction of the respective roles within these limits and a balanced consideration of competing interests can synergistic cooperation be fostered, thus optimising the distribution not only of risks but, above all, of benefits.  This way, it becomes possible to ensure the compatibility of energy efficiency projects with energy transition objectives, while simultaneously safeguarding both private economic interests and the collective interests in environmental sustainability. It is, therefore, evident that the strategic use of the EPC, by pursuing an interest worthy of protection such as energy efficiency, ensures not merely a reconciliation of opposing interests between contracting parties, but proves itself to be an instrument aligned with the broader and more complex interests underlying sustainable development.","language":"ita","citation":"IL PARTENARIATO PUBBLICO-PRIVATO E L'ENERGY PERFORMANCE CONTRACT NEL PROCESSO DI TRANSIZIONE ENERGETICA / M. Verrengia ; tutor: W. Troise Mangoni, cotutor: L. Bertonazzi, coordinatore: F. Biondi. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2025 May 14. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13629.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open from 10-OTT-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/927922"},"title":"CHARACTERIZATION OF STAPHYLOCOCCI AND STREPTOCOCCI ISOLATED FROM BOVINE MASTITIS:GENOTYPES, VIRULENCE PROFILES AND ANTIMICROBIAL RESISTANCE PATTERNS OF STAPHYLOCOCCUS AUREUS STRAINS AND STREPTOCOCCUS UBERIS STRAINS","internalauthor":"MONISTERO, VALENTINA","type":"Tesi di dottorato","year":"2022","abstract":"Mastitis is the most expensive disease in dairy production. Among mastitis causative agents, Staphylococcus aureus and Streptococcus uberis are recognized as the major pathogens responsible for contagious and environmental IMIs, respectively. Both S. aureus and Strep. uberis strains can acquire antimicrobial resistance and can express a multitude of factors strongly linked to the outcomes of the disease, but only few genetic lineages, characterized by specific resistance phenotypes and molecular characteristics, are responsible for the spread of infections within bovine population.  The principal aims of this project were to investigate the genotypic variability, the virulence and the antimicrobial resistance in S. aureus and Strep. uberis isolates collected from bovine mastitis cases.  The study on S. aureus determined the phenotypic antimicrobial susceptibility, the occurrence of selected antimicrobial resistance genes and other virulence genes in 93 isolates from clinical mastitis collected in different countries and previously genotyped by RS-PCR. The results revealed the low prevalence of the IEC genes and of the multidrug resistance in S. aureus, with the detection of only two MRSA strains. The occurrence of AMR genes did not always correspond with their actual expression.  The studies on Strep. uberis firstly developed 2 low-cost and fast multiplex PCRs to detect simultaneously 10 housekeeping and virulence Strep. uberis genes. These molecular assays were subsequently used for a 4-month epidemiological investigation of a Strep. uberis clinical mastitis outbreak on an Italian dairy farm. We explored the genotypic (RAPD) patterns, the virulence and the phenotypic antimicrobial resistance profiles of 71 Strep. uberis isolates. The same combination of virulence-associated genes was present in all the strains analyzed and a conserved RAPD pattern was detected within the herd, confirming the genetic similarity of Strep. uberis strains and suggesting their contagious transmission. Strep. uberis strains belonging to the same genotypic cluster differed in their resistance phenotypes. Most of them were resistant to at least one of the drugs tested and 25% were not inhibited by three or more antimicrobial classes, but the majority were susceptible to β-lactams, including cephalosporins.  The last aim of this thesis was to provide an overview of the pathogens involved not only in the development of bovine IMI but also in foodborne human diseases, presenting further information on their characteristics. Different identification and detection techniques were reported and could be prospectively used to analyze other mastitis causative agents than S. aureus and Strep. uberis.  The relevance of this research would consist in filling the gap between the phenotypic and genetic traits of bovine mastitis pathogens and could help to set up control measures and treatment strategies based on their specific epidemiological and pathogenic properties.","language":"eng","citation":"CHARACTERIZATION OF STAPHYLOCOCCI AND STREPTOCOCCI ISOLATED FROM BOVINE MASTITIS:GENOTYPES, VIRULENCE PROFILES AND ANTIMICROBIAL RESISTANCE PATTERNS OF STAPHYLOCOCCUS AUREUS STRAINS AND STREPTOCOCCUS UBERIS STRAINS / V. Monistero ; TUTOR: P. MORONI ; COORDINATORE: F. CECILIANI. Università degli Studi di Milano, 2022 May 19. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12187.pdf","fileformat":"Adobe PDF","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/927922/2033698/phd_unimi_R12187.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1064928"},"title":"DIGITALISING HEALTHCARE: A COMPARATIVE ANALYSIS OF THE ITALIAN AND GERMAN SYSTEMS","internalauthor":"RE FERRE', GIULIA","type":"Tesi di dottorato","year":"2024","abstract":"This works adopts a comparative law approach to analyze the process of healthcare digitalisation in two EU countries, Italy and Germany. The selection of the cases and the legal systems object of the comparison was based on several factors, which respectively relate to a (infra-)structural precondition - the level of overall digitalisation in the two countries - and two institutional dimensions - the territorial structure of the state and the model of healthcare protection. The precondition is that Italy and Germany have a comparable level of overall digitalisation: in fact, a large gap between the two countries would have made a comparison in the field of healthcare digitalisation ineffective. However, along the institutional dimension, the constitutional arrangement of the two countries is different, since Italy is a unitary regional state while Germany is a federal republic. Finally, with respect to the second institutional dimension, the Italian and the German healthcare systems differ substantially, the former presenting a  Beveridgean model based on a universalistic national healthcare system, whereas the latter is organized in accordance with the Bismarckian model of social insurance.   Both similarities and substantial differences allow to assess whether the development of the digitalisation process follows similar trajectories, or whether it is intimately dependent on the chosen healthcare model, as well as the possible role played by the different constitutional arrangements.  Within this framework, the study has several objectives: to identify which digital health tools have been introduced in the two jurisdictions; to identify what obstacles have been encountered in the process of legislative introduction and subsequent implementation; to outline future perspectives. Thus, the purpose is to determine whether there is a common matrix with respect to the challenges that have characterized the process of digitalisation of healthcare which - although benefiting from considerable momentum due to the pandemic - has been underway in   both countries for more than a decade, and consequently whether the solutions implemented follow a common trajectory or are on the contrary attributable to specific institutional conditions in the two countries. In addition, since Germany has recently introduced “pioneering” legislation in the area of mHealth, the research sought insights into that legislation   for possible future development in Italian legislation.   The dissertation consists of four chapters. The first is introductory in nature and it aims to outline both the key concepts needed to understand the characteristics of the two health systems analyzed, and the challenges and opportunities related to digitalisation in health. After a brief consideration of the concept of health and its protection at the supranational and international levels, the main features of a universalistic and an insurance-based healthcare models are outlined. The final part of the chapter is then devoted to the definition of digital health in its various declinations and the benefits it can bring, as well as the challenges it poses to legal systems.  The two central chapters are dedicated to the two national systems under comparison and follow a similar structure, being divided into three parts: the first is dedicated to the constitutional principles underlying the right to health and the corresponding obligations of protection on the part of the state; the second is aimed at reconstructing the main characteristics of the health systems, centered on the National Healthcare System (NHS) in the Italian case (SSN) and thebGKV in the German case; finally, the third part is dedicated to digitalisation tools and their implementation. This last part is the core of the research, to which the other two are preparatory and functional. Particular attention is paid in both Chapter II and Chapter III to the Electronic Health Record tool, that is the pivot of the digitalisation process in both countries. With regard to the Italian system, interest then shifts to telemedicine guidelines, focusing on their historical evolution and current implementation; differently, the German legislation has also offered the opportunity for an in-depth analysis of mHealth and the prescription and reimbursement mechanism of apps for medical use.   The fourth Chapter Four is comparative and it contains the final reflections along the analytical lines followed in the previous chapters. It moves from a comparison of the framework of constitutional principles, which leads to the recognition that although the constitutions of Italy and Germany protect the right to health through different techniques, they establish an equal level of protection. The common goal of protecting this fundamental right is reflected in the different healthcare systems. The final part of the chapter focuses on the main elements of comparison that have emerged in relation to the digitalisation of healthcare, starting with an explicit comparison of the levels of digitalisation in the two states, based on the DESI index, and moving on to a reflection on the points of contact and differences in the legislation and implementation of the Electronic Health Record and telemedicine. A reflection is then devoted to the possible development of an administrative process for the introduction within the Italian SSN of mHealth solutions inspired by the German model . Finally, it is highlighted how the common matrix underlying the obstacles and slowdowns encountered by the two countries in the process of healthcare digitalisation relate to the fragmentation of the legal systems, albeit   with different declinations, and how the current development is characterized by a common tendency toward centralization, both at the legislative and administrative levels.","language":"eng","citation":"DIGITALISING HEALTHCARE: A COMPARATIVE ANALYSIS OF THE ITALIAN AND GERMAN SYSTEMS / G. Re Ferre' ; tutor: D. U.Galetta, K. P. Sommermann ; coordinatore: F. Biondi. - Milano. Università degli Studi di Milano, 2024 Jun 27. 36. ciclo","filename":"phd_unimi_R12958.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open from 20-DIC-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1035708"},"title":"NF-YA ISOFORMS ROLES IN CLAUDIN LOW CANCERS","internalauthor":"LONDERO, MICHELA","type":"Tesi di dottorato","year":"2024","abstract":"NF-Y is a pioneer transcription factor that regulates the expression of genes involved in cell cycle progression and metabolism. It is composed of: NF-YA, NF-YB and NF- YC subunits. NF-YA recognizes and binds to the CCAAT box, a DNA element found enriched in the promoters of cancer-specific genes in several tumor gene expression profiles analyzed, including those of breast, colon, thyroid, prostate, and leukemia cancers. NF-YA is present in two major isoforms called NF-YAl (long), and NF-YAs (short), which alternative splice exon 3. NF-YAl/NF-YAs ratio changes in different tissues, cell lines and differentiational stages. A robust increase in mRNA levels of NF- YA has been observed in different tumors of epithelial origin, among which BRCA and STAD. In human breast and gastric cancers and cell lines, NF-YAs isoform is highly expressed in all subtypes except in Claudinlow in which NF-YAl isoform is predominant. Recently it has been identified a 158 genes signature defining Claudinlow tumor subclass common to BRCA and STAD, correlating with high NF-YAl/NF-YAs ratio.  For the first part of my PhD project, I worked with two different BRCA Claudinlow cell lines that mainly express NF-YAl. Through CRISPR/Cas9n genome-editing I obtained homozygous exon 3 deleted clones (NF-YAl-KO). NF-YAl-KO clones had an impaired ability to form compact aggregates, their migration, extravasation, invasion, and metastasis formation abilities were significantly impaired both in vitro and in vivo compared to negative controls. RNA-seq data underlined pathways downregulated in all NF-YAl-KO clones, among which EMT and angiogenesis, corroborating in vitro and in vivo data.  In parallel, I have investigated the role of different RNA-binding proteins in driving NF-YA alternative splicing, among which RBFOX2, QKI and CELF2 both in BRCA and in STAD cell lines. Through transient overexpression, I validated RBFOX2 as splicing factor promoting the maturation of NF-YAl.  Finally, through a frameshift mutation in NF-YA gene, I have investigated the effect of NF-YA alternative translation initiation sites (TISs) usage in HeLa cells and its impact at cellular and molecular levels.","language":"eng","citation":"NF-YA ISOFORMS ROLES IN CLAUDIN LOW CANCERS / M. Londero ; tutor: R. Mantovani. Dipartimento di Bioscienze, 2024 Mar 08. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13018_1.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1035708/2376209/phd_unimi_R13018_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1126635"},"title":"NEW PERSPECTIVES ON POSTURAL CONTROL IN CHILDREN AND ADULTS","internalauthor":"FARINELLI, VERONICA","type":"Tesi di dottorato","year":"2025","abstract":"\"Background:  The main objective was to explore how the central nervous system (CNS) regulates the different neural mechanisms aimed at maintaining static and dynamic posture. The research activity RA-1 involved the postural analysis of children with neurological or neuromuscular diseases with the aim of differentiating the pathologies under study; the others (RA-2 and RA-3) focused on gait initiation (GI). Specifically, I started a study (RA-2) to assess the existence of Anticipatory Postural Adjustments (APAs) in healthy toddlers that could be relevant in anticipating the diagnosis of paediatric diseases. Finally, I looked at how APAs may change after fatigue (RA3-A) or following toe amputation (RA3-B) to understand what changes our CNS enacts according to circumstances and needs.  Methods:  Data in RA-1 and RA-3 were acquired using an optoelectronic system, dynamometric platforms and electromyographic probes while, in RA-2, data were obtained from a locomotion database collected at the Vrije Universiteit (VU) in Amsterdam.  RA-1 involved twenty-five patients with clinical diagnosis of Duchenne Muscular Dystrophy (DMD), Charcot-Marie-Tooth disease (CMT), Hereditary Spastic Paraparesis (HSP) or Cerebral Palsy (CP), and twelve healthy children as a control group (HC). During static posturography, participants stood quietly for 30 s with their eyes open (EO) and closed (EC), while during dynamic assessment participants walked barefoot, choosing their speed.  The RA-2 included seventeen children who performed \"\"voluntary\"\" GI. This analysis is stopped at data processing, pending the normalization data to be provided by VU.  For RA-3, the participant stood on the force plate for 10 s and then start walking, at will. In RA3-A, sixteen healthy male adults and trained, wearing their sports shoes performed GI before and after one minute of uninterrupted countermovement jump. In RA3-B, a professional mountaineer whit all toes of his feet amputated performed GI barefoot and after wearing ad-hoc prosthetic shoes, which restored the foot original length.  Results:  In RA-1, static posturography revealed an imbalance in weight distribution between feet in DMDs compared to the HC, with a greater base of support. Instead, eye x pathology interaction showed a better performance of HSPs with EC than with EO. Moving to kinematics, the time courses of pelvic, spinal and trunk variables highlighted distinctive strategies adopted by groups. In RA3-A, the effect of fatigue reached significance in the Erector Spinae (ES) of the trailing side and in the Obliquus Abdominis of the leading while all muscles were significantly delayed in APA activity after fatigue. In RA3-B, when barefoot, ES showed reciprocal activity between body sides. When shod, ES were bilaterally inhibited. This different behaviour was accompanied respectively by a rotation toward the trailing side (“turning” strategy) and by a forward projection of scapular girdle and pelvis (“diving” strategy).    Conclusions:  This multivariate approach highlighted the idea that each movement can be associated with a range of postural commands, each adapted to a specific context. Indeed, different postural strategies have been identified not only because of pathology but also based on the different conditions in which the self-confidence seems to be the switch for the change of strategy.\"","language":"eng","citation":"NEW PERSPECTIVES ON POSTURAL CONTROL IN CHILDREN AND ADULTS / V. Farinelli ; tutor: R. Esposti ; coordinator: C. Sforza. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2025 Jan 23. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13288.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1126635/2614468/phd_unimi_R13288.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/959016"},"title":"TARGETING METABOLIC PLASTICITY OF GLIOBLASTOMA TUMOR INITIATING CELLS TO RESTORE SENSITIVITY TO LSD1-DIRECTED THERAPY","internalauthor":"MAROTTA, GIULIA","type":"Tesi di dottorato","year":"2023","abstract":"Despite all progresses, we are still far away to reach effective treatments for patients  with glioblastoma (GBM). It remains up to date an unmet clinical need. GBM  malignant traits are sustained by the existence of tumor-initiating cells (TICs) that  are able to adapt and survive in the different GBM microenvironments. TICs  plasticity is under the control of epigenetic modifications that, among others,  regulate metabolic genes' expression. We have recently shown that Lysine Specific  Demethylase 1 (LSD1) genetic and pharmacological inhibition employing the  selective LSD1 inhibitor (LSD1i) impairs TICs ability to restore homeostasis after  ER stress or nutrient starvation by hindering a proper Activating transcription factor  4 (ATF4)-dependent integrated stress response (ISR). In line with the GBM intertumor heterogeneity, a cohort of patient-derived TICs displayed resistance toward LSD1i. LSD1i reduces the growth, survival, stem cell-like traits and in vivo  tumorigenicity of LSD1i-sensitive cells, but it exerts no effects in LSD1-resistant  cells. Indeed, we measured no modifications in in vitro proliferation, even upon  exposure to a prolonged treatment, survival, self-renewal and in vivo tumorigenicity.  Our data demonstrate that LSD1i provokes a dysregulation of ER homeostasis  leading to physical and metabolic rearrangements of mitochondria in LSD1isensitive  cells. This activates the pro-apoptotic pathway thus leading to cell death.  None of this is observed in LSD1i-resistant TICs. LSD1i non-responsive cells display  metabolic flexibility which allow them to face LSD1i-dependent perturbations, thus  efficiently restoring cellular homeostasis after stress.  By performing a high-throughput synthetic lethal shRNA screening, we discovered  that Post-GPI Attachment to Proteins 1 (PGAP1), a protein involved in the quality  check of proteins’ folding in the ER, is a mediator of such resistance. Targeting  PGAP1 in LSD1-resistant TICs sensitizes refractory cells toward LSD1i treatment  reshaping their metabolic features.  This project pioneers a new approach to precision medicine by exploiting metabolic  weaknesses as points of vulnerability to sensitize LSD1i-resistant patients.  Unveiling novel aspects of the epigenetic-metabolic interplay that sustains both  GBM-TICs plasticity and tumorigenicity will be of further translational impact.","language":"eng","citation":"TARGETING METABOLIC PLASTICITY OF GLIOBLASTOMA TUMOR INITIATING CELLS TO RESTORE SENSITIVITY TO LSD1-DIRECTED THERAPY / G. Marotta ; tutor: S. Minucci ; co-tutor: G. Pelicci ; phd coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2023 Apr 13. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12425.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/959016/2161146/phd_unimi_R12425.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/956878"},"title":"CRYOGENIC DETECTION OF SCINTILLATION LIGHT WITH LARGE AREA SIPM ARRAYS FOR NEXT GENERATION NEUTRINO AND DARK MATTER EXPERIMENTS","internalauthor":"GALLICE, NICCOLO'","type":"Tesi di dottorato","year":"2023","abstract":"The collection of scintillation light is a fundamental technique for the detection of neutrino or dark matter interactions in cryogenic environments. The continuous development and deeper understanding of such technique are fundamental to advance the results in these fields.  In the present work, a development for the photon detection modules of the DUNE experiment (horizontal drift TPC – Time Projection Chamber) is successfully carried out. The design of electronic boards for the readout of such modules, as well as the successful test of the largest functional unit to be installed in the detector, is presented.  To enhance the response of the photon detection system in liquid argon TPCs, the very first large-scale xenon doping of liquid argon was performed in the DUNE prototype ProtoDUNE-SP. It allowed measuring the fundamental rate constants governing the scintillation, and for the first time with such granularity at low xenon concentrations. It was proved that the increased Rayleigh scattering length improves light collection uniformity, and that a few parts per million of xenon can recover most of the light quenched by nitrogen.  The second module of DUNE (vertical drift TPC) will host the photon detection system on its cathode plane, at -300 kV, therefore requiring the use of power over fiber technology instead of copper cables. To bias silicon photomultipliers (SiPM) in such environment, a novel DC-DC boost converter working in cryogenics was designed. First, a proof-of-concept prototype was tested and characterized at liquid nitrogen temperature, then a full prototype integrated with the DUNE electronics was successfully realized.  Scintillation light detection is also the technique used by dark matter direct-search experiments using NaI(Tl) crystal. The best example is DAMA, the only detector reporting a long-standing positive observation of dark matter. To confirm and to extend the physics reach of NaI(Tl)-based experiments, a new generation of dark matter detectors is needed. The ASTAROTH project is presented, highlighting how using SiPM at cryogenic temperatures could overcome current limitations. Two main results are reported: the characterization of a crystal at cryogenic temperatures, and the development of a dedicated SiPM array with its relative front-end electronics for crystal readout.","language":"eng","citation":"CRYOGENIC DETECTION OF SCINTILLATION LIGHT WITH LARGE AREA SIPM ARRAYS FOR NEXT GENERATION NEUTRINO AND DARK MATTER EXPERIMENTS / N. Gallice ; tutor: D. D'Angelo, P. Sala ; coordinatore: M. Paris. Dipartimento di Fisica Aldo Pontremoli, 2023 Mar 13. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12638_02.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/956878/2152563/phd_unimi_R12638_02.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/924462"},"title":"NEW RESEARCH ON AGROTECHNICS FOR ORGANIC RICE PRODUCTION AND THEIR SUSTAINABILITY ASSESSMENT","internalauthor":"VAGLIA, VALENTINA ADA ROSA","type":"Tesi di dottorato","year":"2022","abstract":"\"This thesis studies and evaluates the agronomical techniques associated with organic rice cultivation in the Northern Italy area. The study funding is from the Italian MIPAAF project \"\"Risobiosystems\"\", which started in 2017 and ended in 2020.  The studies presented are connected to the European sustainable food production strategy \"\"Farm to Fork,\"\" which is the core of the European Green Deal to make food systems fair, healthy and environmentally friendly, encouraging the expansion of the organic agriculture sector (European Commission 2020). As reported in the literature, organic farming is capable of reducing the environmental impact of agriculture by avoiding the use of synthetic compounds (e.g. fertilisers, pesticides) and by promoting practices (e.g. crop rotation, leguminous cultivation, organic fertilisers, green manure crops, green mulching.) able to increase the soil carbon stock, and prevent the indirect environmental impacts due to the industrial production of inputs (Acuna et al. 2018). Focusing on the rice sector, the organic system was observed able to increase the soil carbon storage capacity (Komatsuzaki and Syuaib, 2010) and organic matter content, facilitating the soil preparation (Mendoza, 2004) and promoting the ecological succession and temporal heterogeneity of the macrophyte communities into the soil (Martínez- Eixarch et al.; 2017). The thesis is a collection of articles published or under review associated with the organic rice production connected with Risobiosystems project results. Each paper explains my work and contribution, and each Chapter gave rise to new and ongoing studies.  Chapter I (https://doi.org/10.1016/j.agsy.2019.102739) reveals the lack of scientific research and information about organic rice farming, especially in Europe and Italy. The studies mainly propose three different weed management techniques in the paddy field that can be considered models that can be standardised on farms specialising in their use. These models are the basis of a sustainable fight against ecological and environmental problems thanks to the strict avoidance of chemicals such as herbicides. Value is given to methodologies whose effectiveness has been widely tested. The green mulching technique uses cover crops that effectively control weeds thanks to four main mechanisms. The first consists of the partial inhibition of weeds' germination thanks to competition for water, nutrients, and shading, which are phenomena caused by the presence of cover crops. The second consists of the mulching effect when the crops are chopped or placed on the ground with rice sowing. The third is represented by the phenomena of allelopathy that arise between cover crops and weeds (this aspect will be further explored in Chapter II, https://doi.org/10.3390/plants9030324, https://doi.org/10.1007/s11356-020-10140-4 ). At the same time, the fourth mechanism is linked to the accumulation of phytotoxic compounds following the fermentation caused by the submersion water of the paddy field: the anaerobic environment that is created leads to the formation of organic acids such as acetic acid, butyric and propionic acid. Allelopathy is an interesting aspect offered by plants in this particular agrotechnical. Allelopathy generally produces and releases secondary metabolites, generating inhibitory effects against nearby plant species. The germination, growth and reproduction of target plants can thus be impaired; these aspects were deepened in Chapter II, starting from the organic farmers' experience. The study aimed to define the inhibitory action of Lolium multiflorum Lam., used as a cover crop before rice sowing against Echinochloa oryzoides (Ard.) Fritsch is one of the main rice weeds. Chapter III focuses on evaluating the environmental impact of organic rice cultivation through LCA considering the production scenarios and the agrotechnics described in Chapter I. The LCA approach was adopted because it is largely used to assess the environmental impact of the agriculture process. However, from an LCA viewpoint, organic agriculture is not an obvious answer to environmental problems because LCA defines the function of the studied system using a 'functional unit', which should be a precise measure of what the system delivers but is not able to consider for example indirect effects. Furthermore, LCAs express impacts per unit of a product by default. However, organic agriculture generally emits fewer pollutants per unit of land occupied than conventional agriculture (an area-based approach); it may have higher impacts per unit of product due to its lower yields per unit area (van der Werf, 2020).\"","language":"eng","citation":"NEW RESEARCH ON AGROTECHNICS FOR ORGANIC RICE PRODUCTION AND THEIR SUSTAINABILITY ASSESSMENT / V.a.r. Vaglia ; supervisori: S.Monaco Ph.D, C. Bertora PhD ; tutor: S. Bocchi ; coordinator: P. A. Bianco. Dipartimento di Scienze e Politiche Ambientali, 2022 Apr 27. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12291_04.pdf","fileformat":"Adobe PDF","fileversion":"capitolo","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/924462/2024925/phd_unimi_R12291_04.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1018417"},"title":"LINE1 EXPRESSION DYNAMICS IN COLORECTAL CANCER SENSITIVITY TO DNA DAMAGE","internalauthor":"GASPAROTTO, ERICA","type":"Tesi di dottorato","year":"2023","abstract":"Transposable Elements (TEs) are repetitive DNA sequences that make up approximately 45% of the human genome. Among these TEs, LINE1 (autonomous interspersed nuclear elements, constituting 18% of the genome) have been reported to exert crucial epigenetic regulatory functions, and their expression is specific to the type of cancer. In this context, it has been found that p53 represses LINE1 transcription. TP53 mutations are associated with a higher mutation burden and LINE1 retrotransposition in various tumors, with the exception of Colorectal cancer (CRC), which displays a low degree of genome instability despite having a microenvironment characterized by high concentrations of free radicals, well-known inducers of DNA oxidation and damage. Thus, we have investigated LINE1 expression and possible function in CRC genome stability. Our initial observations revealed that LINE1 is specifically expressed in p53 mutated CRCs. This was determined by conducting RNA in situ hybridization (ISH) on formalin-fixed paraffin-embedded samples from CRC patients and normal-like colon tissues (n=17 patients). LINE1 is actively transcribed and remains associated with chromatin in p53 mutated CRC cell lines. Notably, LINE1 expression exhibits an inverse correlation with the abundance of CD3+ T Lymphocytes, indicative of tumor immunogenicity.  Subsequently, we formulated the hypothesis that LINE1 transcription could contribute to genome stability in CRCs. We have assessed that CRCs with high LINE1 expression are less sensitive to ROS-like DNA-damaging agents compared to CRCs not expressing LINE1, and we addressed that downregulation of LINE1 could reverse this phenotype. We hypothesize that LINE1 RNA could act as scavenger for free radicals to protect CRC genome integrity. Thus, we found that H2O2 treatment induce DNA oxidation only in CRC in which LINE1 expression is repressed. Finally, we performed RNA immunoprecipitation and sequencing analyses detecting oxidation of LINE1 RNA in p53 mutated CRC cell lines exposed to ROS.   Currently our current research is focused on determining the mechanism mediated by LINE1 RNAs in safeguarding the genome against DNA damage and we sought to understand if LINE1 expression could be a marker to predict resistance to chemotherapy, which is known to induce oxidative stress.","language":"eng","citation":"LINE1 EXPRESSION DYNAMICS IN COLORECTAL CANCER SENSITIVITY TO DNA DAMAGE / E. Gasparotto ; tutor: B. Bodega, S. Abrignani ; internal advisor: F. d'Adda di Fagagna ; phd coordinator: S. Minucci. Dipartimento di Bioscienze, 2023 Dec 12. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12692.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1018417/2327917/phd_unimi_R12692.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1047994"},"title":"FROM DG-CATEGORIES OVER K TO K-LINEAR STABLE INFINITY-CATEGORIES","internalauthor":"DONI, MATTEO","type":"Tesi di dottorato","year":"2024","abstract":"The purpose of this thesis is to prove that “idempotent-  complete pretriangulated dg-categories over k are stable k-linear idempotent com-  plete ∞-categories”. This result is a meeting point between algebraic topology  and algebraic geometry.  In 2013 L. Cohn proved it in a preprint, and in 2016, he updated the preprint to  its latest version.  Since then the ∞-category theory and the spectral algebraic geometry theory  have made progress: therefore, we think that a reproof can be useful in make  this result clearer for more mathematicians.  The first four chapters are devoted to laying the groundwork for the next chapter  where linear category theory can finally be presented. In the fifth chapter, we  tackle for the first time the problem of defining the theory of k-linearization using  enriched ∞-category theory (Lurie has previously addressed this topic but with  a different setting [1, Spectral Algebraic Geoemetry]). This chapter comprises three parts: the first two run  almost in parallel, while the third compares them. In the first part, we delve  into the theory of dg-categories over a fixed ring k, which serves as the algebraic-  geometric setting for k-linearization. One significant result is the demonstration  that M odHk-enriched categories are left Hk-module objects in CatSp  ∞ . This result  elucidates why the two parallel sections converge, prompting an additional section  to present it in a categorical setting. This finding enables k-linear Morita theory  to be explored using nonlinear theory.  In the second part, we investigate linearization from the viewpoint of spectral  algebraic geometry (or algebraic topology). We provide a conceptual overview of  linearization and define Morita theory for k-linear ∞-categories. In this part, we  will come to realize that there exists an incredible number of equivalent definitions  of k-linear ∞-categories, and the main outcome of this section is to demonstrate  their equality. In the final part of the fifth chapter, we achieve our goal and prove  the main results. The thesis concludes with a brief chapter outlining possible  directions for future research following this work.","language":"eng","citation":"FROM DG-CATEGORIES OVER K TO K-LINEAR STABLE INFINITY-CATEGORIES / M. Doni ; tutor: P. Stellari. Dipartimento di Matematica Federigo Enriques, 2024. 36. ciclo","filename":"phd_unimi_R12806.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1047994/2405715/phd_unimi_R12806.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1020889"},"title":"WORDS AS DEEDS: GENDER AND FEMINIST DISCOURSE IN BRITISH SUFFRAGE PERIODICALS (1907-14)","internalauthor":"GUZZETTI, MARTINA","type":"Tesi di dottorato","year":"2023","abstract":"The movement for women’s enfranchisement carefully exploited the press in order to convey its message and as a further help for its campaign, despite the fact that the Suffragettes’ motto was ‘deeds, not words’. The publication of their own periodicals, aimed at a new type of female readership, was significant, as it led to the creation of a true counter-discourse that also meant to overcome biased views on the matter of  votes for women. Lately, scholarly research has focused on re-investigating the suffrage movement in a sort of revisionist emphasis which has also followed a new wave of national interest in the story of the Suffragettes; however, scholars have tended to concentrate more on the fields of feminist and media history. My attempt will be a linguistic analysis of Suffragette periodicals: the main aim is to study the language strategies used for their propagandistic goals, how they significantly challenged the   representation of suffrage activists in mainstream press and their relevance for their campaign. This will result in a description of common linguistic practices used by the Suffragettes; moreover, through the use of critical discourse analysis, I will be able to interpret these linguistic choices, to place them in context and to go beyond the text itself by looking at issues of (hidden) ideologies, power relations and gender representation.","language":"eng","citation":"WORDS AS DEEDS: GENDER AND FEMINIST DISCOURSE IN BRITISH SUFFRAGE PERIODICALS (1907-14) / M. Guzzetti ; tutor: L. Pinnavaia ; coordinatore: M. V. Calvi. Dipartimento di Lingue, Letterature, Culture e Mediazioni, 2023. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12819.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1020889/2335395/phd_unimi_R12819.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/961276"},"title":"METABOLIC ADVERSE EFFECTS INDUCED BY SECOND GENERATION ANTIPSYCHOTIC DRUGS IN PEDIATRIC PATIENTS: PHARMACOGENETIC PROFILING AND MECHANISTIC ANALYSIS OF GENETIC VARIANTS EFFECT IN VITRO MODELS","internalauthor":"NAPOLI, ALESSANDRA","type":"Tesi di dottorato","year":"2023","abstract":"Second-generation antipsychotics (SGAs) are increasingly used in pediatric patients both in and offlabel. The rise in SGA prescription rates may be due to the perception of improved safety compared with first-generation antipsychotics. However, SGA use is often associated with rapid weight gain and metabolic syndrome as adverse drug reactions (ADRs). Interestingly, these side effects are not observed in all SGA-treated children, suggesting that some underlying genetic factors may predispose an individual to develop these adverse conditions. Recent studies have identified single nucleotide polymorphisms (SNPs) in genes encoding for enzymes involved in drug metabolism (CYP450) and SGA receptors in the central nervous system (CNS), which partly explain the inter-patient variability in ADR development. With this project, we intend to define the role of SNPs in genes related to the pharmacodynamics of SGA, expressed in peripheral tissues, to evaluate their involvement in the mechanisms responsible for weight change and metabolic ADRs. To this end in a cohort of 209 paediatric patients affected by disruptive behavioural disturbance who are prescribed SGAs (risperidone and aripiprazole), we have assessed the association of pharmacodynamics genetic variants with the occurrence of changes in body mass index (BMI) Zscore. This allows us to evaluate if the presence of specific variant alleles increases or decreases the risk of weight changes and metabolic adverse events. Tested SNPs will be selected from a comprehensive meta-analysis by Zhang e al (2016) of associated gene variants with antipsychotic-related weight gain. Between the 15 SNPs studied, the variants statistically significant associated with BMI changes are rs6318, rs3813929, rs5181147 in 5- Hydroxytryptamine Receptor 2C (HTR2C), rs1799732, rs6275, rs7131056 in D2 dopamine receptor (DRD2) and rs489693 in melanocortin-4-receptor (MCR4). We consider that the identification of these SNPs might provide useful input for personalized and individualized early intervention. Another goal of this project is to examine the direct effect of SGAs and validate the role of selected SNP at the peripheral level by performing in vitro experiments. Dysregulation in adipose tissue homeostasis has been suggested as a plausible mechanism by which antipsychotics induced metabolic alteration. To investigate the impact of SGAs on dysfunctional adipose tissue we decided to use the SW872 liposarcoma cell model. 6 First, we performed a detailed characterization of the model establishing the cell culture condition for the adipogenic differentiation process. Then, to clarify the mechanisms by which SGAs induce weight gain we studied the risperidone effect on the adipogenesis of SW872. We observed that risperidone directly promoted adipocyte differentiation and lipid accumulation. To better understand the phenotype of risperidone-induced adipocytes, next we assess its impact on some mitochondria parameters. We observed that risperidone's effect on mitochondrial phenotype can more faithfully recapitulate the white adipocyte profile observed in human adipose tissue. In line with this, our data also showed that Hoxc4, a key marker of white adipocytes, is highly expressed in risperidone adipocytes. From these results, we hypothesize that the induction of white adipocytes may be a possible mechanism by which risperidone induces weight gain as a side effect. Finally, to validate in the adipocyte cell line the impact of SNPs on differentiation, we have set up an in vitro model system for the expression of the genetic variants, by choosing the site-directed mutagenesis approach to modified the DNA sequence of the genes of interest . We selected two SNPs: rs6318 for the 5-HT2C gene and rs6275 for the DRD2 gene, identified in our population study as related to BMI changes after SGAs administration and already evaluated in correlation with weight gain, metabolic ADRs, and antipsychotic treatment with a focus on SNC expression . Using our adipocyte differentiation protocol, we showed that the modified cells could be differentiated into adipocytes therefore providing a relevant model for studying the SNP role in SGAs-induced adipogenesis.","language":"eng","citation":"METABOLIC ADVERSE EFFECTS INDUCED BY SECOND GENERATION ANTIPSYCHOTIC DRUGS IN PEDIATRIC PATIENTS: PHARMACOGENETIC PROFILING AND MECHANISTIC ANALYSIS OF GENETIC VARIANTS EFFECT IN VITRO MODELS / A. Napoli ; tutor: E. Clementi ; correlatrice: C. Perotta, S. Zecchini, S. Cheli. Dipartimento di Scienze Biomediche e Cliniche, 2023 Apr 04. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12615_1.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/961276/2167971/phd_unimi_R12615_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1211196"},"title":"CANCERHUBS: A NETWORK-CENTRIC FRAMEWORK FOR CANCER GENE PRIORITISATION","internalauthor":"FERRARI, IVAN","type":"Tesi di dottorato","year":"2026","abstract":"\"Cancer is a complex disease that originates from genetic mutations, which represent the primary triggering events of neoplastic transformation. Nevertheless,  such lesions alone are not sufficient to account for the full complexity of tumour  development, which also arises from epigenetic and regulatory alterations that remodel cellular networks and molecular circuits. In this framework, conventional  single-gene approaches risk overlooking key elements that, although not frequently  mutated or differentially expressed, play a critical role as network hubs. In this thesis, \"\"CancerHubs\"\" is presented, a systematic data mining and integration pipeline  that combines mutational data, clinical outcome predictions (via PRECOG meta-Z  scores), and protein-protein interaction networks to identify cancer-related protein  hubs. The method computes a composite Network Score that integrates mutational  profiles, prognostic associations, and interactome connectivity, thereby prioritising  genes that may not be strongly mutated or differentially expressed, but are central to the cancer network structure. This approach moves beyond conventional  mutation-centric strategies and provides a network-informed perspective on cancer  gene discovery. Alongside the computational method, \"\"CancerHubs Data Explorer\"\",  a Shiny web application that allows users to interactively explore mutation-enriched  hubs across 11 tumour types was developed. The application provides ranked tables, global interactomes, and neighbourhood visualisations of user-defined genes,  with filtering options for mutational and prognostic data. This ensures that the  results of the pipeline are not only reproducible but also broadly accessible to researchers with varying computational expertise. As a proof of principle, predictions  generated by CancerHubs were validated both in silico and experimentally. These  analyses demonstrated that TGOLN2 displays tumour suppressor features in Multiple Myeloma, Breast, and Prostate Cancer, while EFTUD2 exhibits oncogene-like  behaviour specifically in Multiple Myeloma. This validation highlights the ability  of the framework to uncover genes of clinical and mechanistic relevance that may  be missed by mutation- or expression-centric approaches. Altogether, CancerHubs  provides a exible and extensible framework for interactome-based cancer gene prioritisation. By integrating heterogeneous data layers into a unied network-aware  metric, and by complementing predictions with functional validation and accessibility through the CancerHubs Data Explorer, this work contributes to the advancement of systems oncology. The tools and ndings described here aim to support  hypothesis generation, biomarker discovery, and the identification of novel therapeutic targets, ultimately bridging the gap between large-scale cancer genomics and  translational applications.\"","language":"eng","citation":"CANCERHUBS: A NETWORK-CENTRIC FRAMEWORK FOR CANCER GENE PRIORITISATION / I. Ferrari ; tutor: S. Biffo. Dipartimento di Bioscienze, 2026. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13707_3.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 11-FEB-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1044629"},"title":"DISSECTING THE MOLECULAR MECHANISMS RELATED TO THE ONSET OF NEUROLOGICAL COMPLICATIONS IN THREE CELLULAR MODELS OF SARS-COV 2 INFECTION: IPSC-DERIVED MOTO R NEURONS, IPSC-DERIVED DOPAMINERGIC NEURONS, IPSC DERIVED-HUMAN CORTICAL ORGANOIDS.","internalauthor":"CAPPELLETTI, GIOIA","type":"Tesi di dottorato","year":"2024","abstract":"Although COVID‐19 typically leads to respiratory disorders, recent evidence show that acute and sub-acute neurological complications are reported in patients not only with severe disease, but also in otherwise minimally symptomatic or asymptomatic people [1–3]. Notably, up to 65% of COVID-19 affected patients reported a wide range of neurological conditions, such as decreased sense of smell or hyposmia, dizziness, headache, nausea, vomiting, impaired consciousness, as well as cases of encephalopathy, but also peripheral disorders including Guillain-Barre syndrome and myositis-like muscle injury [2, 4–8], suggesting detrimental effects of SARS-CoV-2 on both the central and peripheral nervous system (CNS, PNS). Multiple studies have shown neuroinflammation in patients with COVID-19, which may underlie these neurological and neuropsychiatric symptoms [7, 9–17]. In addition, as with other viruses, the hypothesis that SARS-CoV-2 infection may accelerate neurodegeneration and the risk of neurodegenerative diseases is gaining increasing attention. [18–21]. However, the molecular mechanisms responsible for these disfunctions, as well as the potential neurotropism of SARS-CoV-2, are still under investigation. To date it remains unclear whether the neurological symptoms are a consequence of direct neural infection, para-infectious or post-infectious immune-mediated disease, or sequalae of systemic disease [1, 22]. It has been hypothesized that SARS-CoV-2 might affect the dopamine pathway [23–28] which in turn would interfere with neuronal activities.  In this frame, it has been demonstrated both in-vivo and in-vitro that SARS-CoV-2 is able to infect different neuronal cell types with different degrees of success [29–37]. Further, considering that human brain tissue is difficult to access, particularly from patients with a contagious pathogen due to safety concerns [38], 2D and 3D in vitro models can provide a viable and safe alternative and represent a suitable model system to test the neurotoxic effects of SARS-CoV-2 [32, 34–37, 39].   In this context, during my PhD training I’ve been involved in different projects in collaboration with different research groups, whose general purpose was to assess the relationship existing between SARS-CoV-2 infection and the alteration of the nervous system. Thus, I was given the chance to work with three different neuronal models, including dopaminergic neurons, iPSC derived motor neurons, and human cortical organoids, in order to investigate this extremely current and concerning condition. Each of these projects, addressed below in the text, has independently contributed to broadening knowledge about the relationship between SARS-CoV-2 and the nervous system.  From this scenario, using human iPSC differentiated to dopaminergic neurons (DA neurons) we found that. Infection with EU and Delta variants results in a reduced intracellular content and extracellular release of dopamine, while tyrosine hydroxylase was upregulated at the mRNA level and downregulated at the protein level. DOPA-decarboxylase and dopamine transporter were downregulated at both mRNA and protein levels, and in addition, in vitro SARS-CoV-2 infection was associated with altered MAP2 and TAU expression and increased neuronal stress markers. These results suggest that SARS-CoV-2 affects dopamine metabolism and production, partially explaining the neurological symptoms.    In parallel, for the very first time, we found that SARS-CoV-2 can productively infect human iPSC-derived MNs probably by binding CD147 and NRP1 receptors. Furthermore, SARS-CoV-2 infection in iPSC-MNs significantly altered the expression of genes (IL-6, ANG, S1PR1, BCL2, BAX, Casp8, HLA-A, ERAP1, CD147, MX1) associated with cell survival and metabolism, as well as antiviral and inflammatory response. Such information will be important to unveil the biological bases of neuromuscular disorders characterizing SARS-CoV-2 infection and the so called long-COVID symptoms.    At the same time, we observed that iPSC-Human Cortical Organoids (HCO) were productively infected by SARS-CoV-2, probably by binding CD147 receptor. Furthermore, SARS-CoV-2 infection as well as Spike exposure of MNs were accompanied by the activation of apoptotic and stress pathways (caspase 3, caspase8, Bcl2) (S100B), inflammatory process (CCL2, NLRP3) and induce expression of both Interferon Stimulated Genes (IFITM1, IFITM3, STAT1, NFkB) and the antigen presentation pathway (ERAP1, ERAP2, HLA-A and TAP). Overall, the results obtained suggest that HCO organoids may be infected by SARS-CoV-2 and their homeostasis may be significantly altered even following S-exposure.  These three independent projects contributed to partially explain some of the neurological symptoms, characterizing the Long COVID symptomatology. Further analyses are ongoing to unveil the molecular mechanisms responsible for the neuronal disorders characterizing SARS-CoV-2 infection and the so called long-COVID symptoms in these neuronal models.","language":"eng","citation":"DISSECTING THE MOLECULAR MECHANISMS RELATED TO THE ONSET OF NEUROLOGICAL COMPLICATIONS IN THREE CELLULAR MODELS OF SARS-COV 2 INFECTION: IPSC-DERIVED MOTO R NEURONS, IPSC-DERIVED DOPAMINERGIC NEURONS, IPSC DERIVED-HUMAN CORTICAL ORGANOIDS / G. Cappelletti ; tutor: M. Biasin ; coordinator: C. Sforza. Università degli Studi di Milano, 2024 Jun 04. 36. ciclo","filename":"phd_unimi_R12939_1.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1044629/2969411/phd_unimi_R12939_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1205226"},"title":"PRINTING MUCOADHESIVE AND ORODISPERSIBLE FILMS FOR THE PERSONALIZATION OF THERAPY","internalauthor":"MEAZZINI, CHIARA","type":"Tesi di dottorato","year":"2026","abstract":"Customizable oromucosal dosage forms such as orodispersible films (ODF) and mucoadhesive films (MAF) are increasingly recognized as valuable tools for addressing unmet therapeutic needs in populations requiring flexible, easy-to-administer medicines, such as paediatric and dysphagic patients. Among the proposed manufacturing techniques, extrusion-based 3D printing technologies, specifically direct powder extrusion (DPE) and semisolid extrusion (SSE) 3D printing, appear to be the most promising for the on-demand point-of-care preparation of personalized dosage forms, since they are simple processes that only require a desktop 3D printer and can potentially be carried out in a pharmacy setting. The aim of this PhD project is therefore to demonstrate the suitability of such techniques for the extemporaneous compounding of MAF (via DPE 3D printing) and ODF (via SSE 3D printing). Using DPE, MAF containing clobetasol propionate and lidocaine were obtained, achieving uniform drug loading, suitable mucoadhesive properties, controlled drug release, and favourable mucosa penetration of the loaded drug, supporting their suitability for oral inflammation and local analgesia. Then, since DPE entails exposure of the formulation components to high temperatures, hot-melt ram-extrusion (HMRE) 3D printing was tested as a milder alternative in the preparation of ODF containing the enzyme β-galactosidase, and compared with solvent casting. While HMRE resulted in the thermal degradation of the protein, enzymatic activity was completely preserved in the ODF obtained by solvent casting, which were able to digest lactose contained in milk in simulated gastric media. The attention was therefore directed toward prototyping a 3D printer that could print slurries similar to those used for solvent casting operating at room temperature, making it compatible with heat-sensitive molecules. The versatility of the resulting SSE printer was tested by preparing ODF loaded with β-galactosidase, CBD oil, and diclofenac-loaded lipid microparticles. In all cases, ODF with satisfactory properties were obtained and the payload was not negatively impacted by the process. Finally, to test the feasibility of obtaining sustained-release ODF by SSE 3D printing, a trihexyphenidyl/clay hybrid was prepared and successfully loaded into ODF, resulting in a controlled release of the drug over a 6-hour period. In conclusion, this work demonstrates the versatility of extrusion-based 3D printing technologies and their potential for the extemporaneous preparation of personalized dosage forms.","language":"eng","citation":"PRINTING MUCOADHESIVE AND ORODISPERSIBLE FILMS FOR THE PERSONALIZATION OF THERAPY / C. Meazzini ; tutor: F. Cilurzo ; co-tutor: U. M. Musazzi ; coordinatore: G. Vistoli. Dipartimento di Scienze Farmaceutiche, 2026 Jan. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13930.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1205226/3213826/phd_unimi_R13930.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1165855"},"title":"POLITICAL BELIEF SYSTEMS AS NETWORKS OF ATTITUDES: CONCEPTUALIZATIONS AND IMPLICATIONS","internalauthor":"BERTERO, ARTURO","type":"Tesi di dottorato","year":"2025","abstract":"This thesis advances the study of political belief systems by integrating network-based approaches from political science, sociology, and psychometrics. The research is grounded in Philip Converse’s seminal work, which conceptualized political belief systems as interconnected networks of attitudes. Despite the foundational importance of this framework, the field has been slow to empirically embrace this networked perspective. This thesis seeks to fill this gap by employing innovative methods to study belief systems. The research is centered around two core questions: First, how can political attitudes be conceptualized as a belief system? This involves refining the construct of a belief system and investigating the implications deriving from considering attitudes as parts of a broader cognitive structure. Second, how can existing network methodologies be integrated to study belief systems? By combining Belief Network Analysis (BNA), Correlational Class Analysis (CCA), and Pairwise Markov Random Fields (PMRFs)—previously isolated within distinct research domains—the thesis promotes cross-fertilization between disciplines. Chapter 2 presents the theoretical and methodological foundations of the belief system literature. Following Converse, I define political belief systems as networks of causally interacting political attitudes. I then discuss why the dominant view on measurement in social   sciences — the latent variable model— is limited in studying these constructs. Next, I motivate why network approaches can provide new insights in this field. Finally, I conduct a scoping review of all papers adopting these approaches to study socio-political attitudes. Chapters 3, 4, and 5 present three empirical analyses. Chapter 3 contributes to the growing literature on subjective inequality by applying CCA and Exploratory Graph Analysis (EGA) to survey data from the U.S. and the Netherlands (n = 2,501 and 1,618). These methods uncover distinct cognitive structures in both countries, with CCA identifying groups sharing similar   construals and EGA modeling these as belief systems. The analysis shows that the two belief systems of each country have distinct sociodemographic correlates and that attitudes toward inequality are more socially patterned in the U.S. Moreover, we show that belief systems might represent independent factors in determining different levels of support for redistribution. These findings highlight that ignoring the structural organization of attitudes limits our understanding of public opinions on inequality and redistributive policies. Chapter 4 extends the inquiry by examining how multiple political attitudes coalesce to form a political belief system. Using original data from the 2022 Italian general election, this chapter applies three network models to explore variations in belief system structures across different social groups. The results show that political interest increases the interdependence of attitudes, leading to tighter belief systems, while education levels do not have a similar effect. Interestingly, despite ideological differences, voters from Italy’s two main coalitions (left and right) organize their attitudes similarly, whereas Movimento 5 Stelle voters display   significantly different belief structures. This chapter addresses a significant gap by showing how distinct political groups organize their support for parties and issues. Chapter 5 introduces a novel approach to Propensity to Vote (PTV) data, conceptualizing PTV as behavioral intentions embedded in a belief system regarding vote choice. Rather than using traditional data reduction techniques, this chapter models PTV data as networks, where items are connected by weighted edges representing their unique shared variance. Using data from   the European Election Studies (1989–2019; 28 countries, n = 121,959), this chapter shows that national political contexts influence the structure of PTV networks. Higher levels of party institutionalization are linked to higher network connectivity, while higher affective polarization correlates with the negativity of PTV belief systems (i.e., the higher ratio of negative to positive edges). Furthermore, increased negativity in these networks is associated with higher voter turnout in both EU and national elections, suggesting that PTV belief systems might have important downstream effects on political behavior.   In conclusion, this thesis offers both conceptual and methodological dvancements in the study of political belief systems. By integrating network-based approaches, it provides new tools to understand how political attitudes are organized and how they vary across different sociopolitical contexts and sociodemographic segments. The findings underscore the importance of accounting for the structural features of belief systems and highlight the need for further research into their causal dynamics.","language":"eng","citation":"POLITICAL BELIEF SYSTEMS AS NETWORKS OF ATTITUDES: CONCEPTUALIZATIONS AND IMPLICATIONS / A. Bertero ; supervisor: C. Vezzoni, co-supervisor: R. Vacca ; co-authors (Chapter 3): G. Franetovic, J. J. B. Mijs  Co-Authors (Chapter 5): M. J. Brandt ; coordinator: M. Jessoula. Dipartimento di Scienze Sociali e Politiche, 2025 May 23. 37. ciclo","filename":"phd_unimi_R13221_02.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1165855/3075277/phd_unimi_R13221_02.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1253996"},"title":"INSIGHTS ON THE CROSSTALK BETWEEN THE IMMUNE SYSTEMAND CANCER: IMMUNE CHECKPOINT MOLECULES AND LYMPHOIDPOPULATIONS ASSESSMENT IN CANINE ROUND CELL TUMORS","internalauthor":"UBIALI, ALESSANDRA","type":"Tesi di dottorato","year":"2026","abstract":"The crosstalk between the immune system and cancer represents a fundamental aspect of oncology, since a better understanding of disease mechanisms could lead to the development of novel therapeutic strategies.    This PhD project focused on three main topics: (1) the expression and prognostic role of programmed death-ligand 1 (PD-L1) in canine lymphoma, (2) the expression and prognostic role of CD47 in canine leukemias, and (3) the characterization of lymphocyte populations in peripheral blood and sentinel lymph nodes (SLNs) of dogs with mast cell tumors (MCTs).    Regarding PD-L1, the project evaluated the expression of the surface membrane protein (mPD-L1) by means of flow cytometry (FC), mRNA by real-time qPCR, and soluble protein (sPD-L1) plasmatic concentrations by competitive ELISA in dogs with nodal lymphoma. Their potential prognostic role was also investigated. B-cell lymphomas showed the highest frequency and level of mPD-L1 expression, aggressive T-cell lymphomas exhibited the lowest one, and T-zone lymphomas displayed frequent but overall low expression. No correlation was identified among mPD-L1, mRNA levels, and sPD-L1, although the latter was increased in FC-negative dogs. No statistically significant influence on prognosis was found. However, trends suggested longer survival in mPD-L1-negative cases in both B-cell and T-cell lymphomas, and all progressing T-zone lymphomas were mPD-L1-positive. These findings indicate a potential, although not definitive, prognostic role of mPD-L1, warranting further investigation in larger cohorts.    In the second part of the project, CD47 was assessed in peripheral blood cells of healthy dogs to establish baseline values and support interpretation in pathological conditions. It resulted consistently expressed across all leukocyte populations and red blood cells, with low intra-assay variability but notable inter-individual differences, particularly in lymphocytes and erythrocytes. Subsequently, CD47 expression was evaluated in canine leukemias. No differences were observed between acute and chronic leukemias, but myeloid acute leukemias exhibited significantly higher expression compared to lymphoid forms. Although not statistically significant, survival was lower in dogs with acute leukemia and CD47 overexpression, suggesting a possible prognostic implication that requires confirmation in larger studies.    In the third part of the project, we investigated lymphocyte populations in SLNs and peripheral blood of dogs with mast cell tumors. Variations in nodal T/B and CD4/CD8 ratios were influenced by tumor grade, metastatic status, and glucocorticoid pre-treatment, highlighting a complex interplay between tumor biology and immune response, whereas no significant changes were observed in circulating lymphocytes. As part of this project, the impact of SLN mapping dyes on FC fluorescence measurements was assessed. Results demonstrated that commonly used dyes can significantly alter baseline fluorescence across channels, potentially introducing bias in quantitative FC analyses.     In conclusion, this PhD project provides further insights into tumor-immune system interactions while also addressing critical technical aspects of FC. PD-L1 appears to be overall low expressed in canine lymphoma, while CD47 emerges as a more promising marker. As expected, different tumor characteristics influenced the composition of lymphoid population in SLNs.","language":"eng","citation":"INSIGHTS ON THE CROSSTALK BETWEEN THE IMMUNE SYSTEM AND CANCER: IMMUNE CHECKPOINT MOLECULES AND LYMPHOID POPULATIONS ASSESSMENT IN CANINE ROUND CELL TUMORS / A. Ubiali ; tutor: V. Martini ; co-Tutor: D. Stefanello ; coordinatore: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2026 May 05. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13673.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 11-DIC-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/844440"},"title":"TRAIT-BASED FUNCTIONAL CHARACTERIZATION OF PLANT SPECIES AND COMMUNITIES: TRENDS AND ADAPTIONS TO ENVIRONMENT IN ALPINE AND EUROPEAN VEGETATION","internalauthor":"ZANZOTTERA, MAGDA","type":"Tesi di dottorato","year":"2021","abstract":"Over the last few decades, plant functional traits (morphological, physiological or phenological features, measurable at the individual level, with a direct or indirect effect on whole-plant fitness) have become widely applied to plant ecology; they provide many insights into plant responses to ecological factors, plant resource acquisition and use, plant assemblages and relations within and between communities, from individual to ecosystem scale. A small set of traits that co-vary recurrently among environments has been used to globally identify certain axes of variation, representing the different plant strategies of resources acquisition and use. In particular, plant species have been classified within a three-way strategy model (CSR) proposed by Grime, according to the distinct trait combinations the are selected under conditions of competition (C), abiotic limitation to growth (S) and periodic biomass destruction (R). Variation in plant functioning (captured by variation in trait values) and species distribution depend on variation in environmental factors that can change gradually through space and time identifying gradients which can be determined by different variables such as altitude, latitude, successional stage, resource availability, soil composition, disturbance events (grazing, fire, trampling, floods etc.) and many others.  In this study, plant functional traits and Grime’s CSR adaptive plant strategies were applied in order to gain a functional characterization of plant communities of European vegetation at different levels (within and between communities), to highlight functional similarities and/or differences and to identify common patterns and responses to environmental factors.   In details, was investigated the role of an additional trait associated to leaf nutrient content (i.e. leaf sulfur content) within the framework of both global spectrum of plant form and function and the CSR plant adaptive strategies, which resulted to be a consistent addition to the acknowledged and commonly used trait set as it was related to other traits identifying the leaf economics spectrum. Plant inter-specific trait variation in response to changes in single ecological factors was also assessed by considering gradients of different Ecological Indicators referring to key environmental drivers, demonstrating that temperature, light conditions and nutrients were associated with clear effects on plant traits, underlining that responses to changes in land use and increased soil nutrient loading could trigger and strengthen responses to climate alteration. CSR plant strategies were also applied to investigate alien species success and adaption to different habitats, showing that alien species occupy the same CSR space and, therefore, the same niches of native species, being also particularly competitive and associated to relatively productive habitats which are highly prone to invasion.   Plant functional traits variation was then studied at the community level considering a topographic sequence in in an alpine pasture, in relation to a variety of abiotic and biotic factors, which showed a strong relationship between vegetation, soil properties, topography, and grazing supporting the ability of plant strategy variation to reflect ecological parameters. In alpine environment, multiple plant communities (floristically and ecologically defined, corresponding to Habitat of EU Commmunity interest) were also functionally characterized along a successional gradient at a regional scale, finding a clear pattern of community-level trait variation that reflected the plant economics spectrum (from acquisitive and fast-growing characteristics in pioneer succession stages, to conservative and stress-tolerant features toward the succession climax) demonstrating that plant trait trade-offs can undergo adaptation at the regional scale caused by local environmental conditions. Finally, the functional characterization of classes of European vegetation using their woody diagnostic species was applied to investigate whether traits and CSR strategies reliably indicate plant-environment relations underpinned by the phytosociological classification method, suggesting a solid link between the two main approaches to vegetation description and classification, phytosociology and functional ecology.  This Ph.D. project allowed an overall better insight into plant ecology and functioning, starting from the species-level and then moving to the community-level, analysing plant adaptive strategies and trait interactions, and identifying trends and responses to environmental factors.","language":"eng","citation":"TRAIT-BASED FUNCTIONAL CHARACTERIZATION OF PLANT SPECIES AND COMMUNITIES: TRENDS AND ADAPTIONS TO ENVIRONMENT IN ALPINE AND EUROPEAN VEGETATION / M. Zanzottera ; tutor: M.Caccianiga, B.E.L. Cerabolini ; supervisori: R. Ambrosini, S. Pierce. Università degli Studi di Milano, 2021 Mar 12. 33. ciclo, Anno Accademico 2020. [10.13130/zanzottera-magda_phd2021-03-12].","filename":"phd_unimi_R12099.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/844440/1803462/phd_unimi_R12099.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1201251"},"title":"TRUSTED RUNTIME ENVIRONMENTS FOR EMBEDDED SYSTEMS: FROM MEMORY PROTECTION TO SECURE VIRTUALIZATION","internalauthor":"ZOIA, MATTEO","type":"Tesi di dottorato","year":"2025","abstract":"The proliferation of embedded systems and IoT devices has introduced critical security challenges, particularly in environments constrained by limited computational and memory resources. This thesis addresses these challenges by proposing lightweight, scalable mechanisms for runtime memory protection and secure execution, with an emphasis on minimizing device overhead through remote verification. To strengthen spatial memory safety, the thesis introduces a fat pointer–based monitoring system that detects errors across heap, stack, and global memory regions. By combining detailed crash reporting with root-cause vulnerability localization, the system enables precise identification of the code responsible for violations and provides developers with clearer diagnostic information to support efficient patching. For temporal memory safety, a novel remote attestation protocol is presented to model heap state and detect use-after-free vulnerabilities. The approach relies on a precomputation analysis to identify a minimal set of control-flow checkpoints that encapsulate sequences of pointer operations. Instrumentation at these semantically meaningful points reduces runtime and communication overhead. A remote verifier reconstructs execution traces and emulates memory state, enabling accurate detection of temporal violations with minimal impact on constrained devices. Since all proposed mechanisms depend on Trusted Execution Environments (TEEs), the thesis also introduces VS-TEE, a secure virtualization framework that extends ARM-based TEEs to multi-tenant cloud environments. VS-TEE enables multiple virtual machines to securely share TEE resources, overcoming the limitations of current hardware-backed confidential computing solutions. It integrates hypervisor-level communication and driver support, ensuring compatibility with legacy ARM TrustZone software and libraries, while addressing challenges of memory isolation, resource management, and interoperability.  Overall, this thesis demonstrates that carefully designed architectural approaches can deliver effective security in highly constrained embedded environments. The proposed solutions achieve precise vulnerability detection, efficient runtime protection, and scalable secure execution across both IoT devices and cloud infrastructures.","language":"eng","citation":"TRUSTED RUNTIME ENVIRONMENTS FOR EMBEDDED SYSTEMS: FROM MEMORY PROTECTION TO SECURE VIRTUALIZATION / M. Zoia ; relatore: D. Bruschi ; co-supervisor: A. Lanzi ; coordinator: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2025 Dec 05. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13895.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1201251/3199959/phd_unimi_R13895.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1110188"},"title":"AUTOMATION AND NATIONALISM: THE MICROFOUNDATIONS OF THE MIDDLE-CLASS POLITICAL REALIGNMENT?","internalauthor":"BUZZELLI, GREGORIO","type":"Tesi di dottorato","year":"2024","abstract":"\"This dissertation provides a microfoundational analysis of automation’s political consequences, particularly focusing on mid-skill routine workers exposed to technological replaceability. Extant literature shows that this group of workers has become a core constituency of the radical right parties, raising two key puzzles. First, a mismatch emerges between the limited job losses associated with automation and the radical political reactions of the expected “losers”. Second, current explanations fail to adequately address why automation \"\"losers\"\" embrace postmaterialist political demands, crucial drivers of radical right support.  In response to the first puzzle, Paper 1 empirically links automation risk to worsening employment conditions across Western European labor markets, particularly after the Great Recession (2007-2009). In response to the second puzzle, the following two papers provide a sound empirical test of the “misattribution” hypotheses, although undermining the expectation of an authoritarian shift of routine workers’ postmaterialist values.  Paper 2 shows that automation \"\"losers\"\" misattribute their economic concerns to migration rather than technology, driven by sociocultural concerns rather than material hardship. Against the expectations, Paper 3 shows that the distributional impacts of automation are not associated with relevant attitudinal shifts, suggesting that the former might have contributed to a change in individuals’ priority over public issues.\"","language":"eng","citation":"AUTOMATION AND NATIONALISM: THE MICROFOUNDATIONS OF THE MIDDLE-CLASS POLITICAL REALIGNMENT? / G. Buzzelli ; supervisor: S. Sacchi ; co-supervisor: F. Nicoli ; coordinatore programma dottorato: M. R. C. Jessoula. Università degli Studi di Milano, 2024 Oct 17. 36. ciclo","filename":"phd_unimi_R12920.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1110188/2562192/phd_unimi_R12920.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1222596"},"title":"ON-FARM APPLICATION OF PLF TECHNOLOGIES TO DETECT EARLY BEHAVIOURAL AND PHYSIOLOGICAL INDICATORS OF DISEASE AND WELFARE IN PAIR - HOUSED DAIRY CALVES BEFORE WEANING.","internalauthor":"PESENTI ROSSI, GAIA","type":"Tesi di dottorato","year":"2026","abstract":"This thesis investigates the welfare implications of pair housing for pre-weaned dairy calves, evaluated through the lens of Precision Livestock Farming (PLF) technologies. The aim was to assess whether behavioural and physiological indicators collected by non-invasive sensors could provide insights into welfare status and disease risk, with a particular focus on accelerometer-based monitoring and infrared thermography.  Study 1 applied triaxial accelerometers to monitor lying behaviour and synchronisation in calves reared individually or in pairs during the pre-weaning phase, under commercial conditions. Results demonstrated that pair housing improved growth without compromising health and promoted behavioural synchronisation, supporting its value as a positive welfare indicator. While the first study relied on continuous data provided by accelerometers, Study 2 explored the use of infrared thermography to measure ocular temperature and asymmetry at selected timepoints in pre-weaned dairy calves housed individually or in pairs. The aim was to investigate ocular asymmetry as potential measure of positive emotional states linked to social housing. While no evidence of lateralisation emerged, pair-housed calves exhibited higher absolute eye temperatures, suggesting subtle physiological differences associated with higher arousal states. Whereas lying synchronisation appeared more promising for the assessment of positive welfare in pair-housed calves, Study 3 further investigated rest and sleep quality, reported as positive welfare indicators, and to sensor-based approaches for their assessment. A systematic review was conducted on the application of PLF technologies to monitor lying, rest, and sleep in calves. The review highlighted the widespread use of accelerometers for lying behaviour, while identifying critical gaps in assessing rest and sleep, behaviours essential for development and welfare. Since previous studies found significant changes in cattle heart rate variability with sleep stages, Study 4 validated a wearable smart-textile sensor for measuring heart rate variability (HRV) against a standard ECG in calves. The device showed strong agreement across key HRV parameters, supporting its potential as a low-stress tool for assessing calf welfare and, prospectively, sleep quality.  Together, these studies demonstrate that pair housing supports calf growth and social cohesion, while PLF technologies provide novel opportunities for continuous, non-invasive welfare assessment. By integrating behavioural, physiological, and sensor-based perspectives, this thesis contributes to advancing management practices that align animal welfare with the goals of sustainable and cage-free dairy production.","language":"eng","citation":"ON-FARM APPLICATION OF PLF TECHNOLOGIES TO DETECT EARLY BEHAVIOURAL AND PHYSIOLOGICAL INDICATORS OF DISEASE AND WELFARE IN PAIR-HOUSED DAIRY CALVES BEFORE WEANING / G. Pesenti Rossi ; tutor e co-tutor: E. Canali, S. Barbieri ; coordinatore del corso di dottorato: F. Ceciliani. - Lodi. Universita' degli Studi di MILANO, 2026 Mar 11. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13830.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 04-MAR-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1161658"},"title":"AUTOCRATIZATION AND PUBLIC OPINION ONDEMOCRACY: INSIGHTS FROM TURKEY","internalauthor":"ASLAN, REMZIYE GUL","type":"Tesi di dottorato","year":"2025","abstract":"In recent years, Freedom House (2023) and the Varieties of Democracy (V-Dem) Institute (2023) have documented a significant global surge in autocratization. While much research addresses the drivers of this wave, its consequences—especially for public opinion—remain underexplored. This gap is critical, given that regime types and transitions shape citizens' public opinion on democracy, ultimately affecting the long-term stability and consolidation of autocratizing regimes.    This dissertation examines how autocratization, through changes in political and informational environments, shapes citizens’ understanding of democracy, evaluations of regime democraticness, and support for democracy, using Turkey’s recent shift from a flawed democracy to a competitive authoritarian regime as a case study. The analysis draws on diverse data sources, including the World Values Survey, V-Dem and Freedom House indices, national statistics, and Justice and Development Party’s (AKP) electoral manifestos.    Regarding citizens' understanding of democracy, the findings highlight how diminishing opportunities for meaningful democratic engagement have significantly eroded the liberal-procedural understanding of democracy among the populace. Notably, this erosion suggests that direct experiences with shifting political environments exerted a more substantial influence than the regime's mediated portrayals of democracy. Despite the AKP's increasing rhetorical emphasis on procedural legitimacy, citizens' emphasis on procedural aspects of democracy has declined. Concerning the social understanding of democracy, the early discourse and reform initiatives undertaken by the AKP initially bolstered citizens' understandings of social democracy. However, this influence receded as the regime reduced its focus on these themes.    Concerning evaluations of regime democraticness, the study identifies a paradoxical positive correlation between autocratization and citizens' evaluations of democratic performance. Autocratization narrows experiences with democratic norms and strengthens governmental control over information. Consequently, misinformation accentuating regime achievements—combined with narrower democratic expectations aligned with official democratic claims—obscures observable democratic erosion. This effect is especially pronounced among older citizens socialized before significant autocratization, highlighting the importance of critical thinking skills and alternative media—often byproducts of modernization—in helping younger cohorts resist authoritarian narratives. Additionally, the regime’s procedural democratic rhetoric resonates strongly with individuals prioritizing procedural democracy, amplifying positive evaluations among them.    Finally, regarding democratic support, the findings demonstrate a negative impact of autocratization. By disrupting democratic institutions and creating cognitive dissonance among citizens familiar with democratic norms, autocratization contributes to the perception of democracy as increasingly unattainable, diminishing democratic support across generational cohorts. Importantly, evaluations of regime democraticness moderate this effect: recognizing democratic backsliding promotes adaptive preference formation. Meanwhile, a strong liberal understanding of democracy serves as a protective factor—citizens prioritizing liberal and political rights are more resistant to accepting nondemocratic governance.    Overall, this dissertation enriches our understanding by illuminating autocratization’s nuanced impacts on public opinion, offering critical insights into the dynamics of democratic stability and regime resilience in contemporary autocratizing contexts.","language":"eng","citation":"AUTOCRATIZATION AND PUBLIC OPINION ONDEMOCRACY: INSIGHTS FROM TURKEY / R.g. Aslan ; supervisor: A. Cassani ; coordinator: F. Franchino. Dipartimento di Scienze Sociali e Politiche, 2025 Jun 20. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13286.pdf","fileformat":"Adobe PDF","fileaccess":"Open from 28-OTT-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1075769"},"title":"UNCOVERING IMMUNE EVASION MECHANISMS FOR THE PROGNOSIS AND THERAPY OF ENDOMETRIAL AND OVARIAN CANCERS","internalauthor":"CAZZETTA, VALENTINA","type":"Tesi di dottorato","year":"2024","abstract":"Gynecologic malignancies are a heterogeneous group of solid tumors which include endometrial cancer (EC) and ovarian cancer (OC). EC is the most common gynecological neoplasm and the only gynecologic cancer with increasing incidence and mortality. It is generally diagnosed at an early stage and is well managed with surgery, radiation, and/or chemotherapy. However, EC patients with advanced/recurrent disease have poor outcomes and respond poorly to current management treatments. On the other hand, OC is a devastating disease since the majority of patients, when first diagnosed, are at advanced clinical stages (III/IV). Furthermore, relapse occurs in more than 70% of patients and the 5-year survival rate is lower than 40%. Thus, it is important the development of novel therapeutic approaches. In this context, remarkable progresses have been made in immunotherapy. In fact, several preclinical and clinical studies are ongoing with immunotherapeutic strategies combined or not with classic treatments. To date, the efficacy is not satisfactory, thus a detailed understanding of the biology and interactions between cancer and the immune system is essential for the recognition and development of potential new immunotherapeutic strategies and targets as well as the optimization of existing immunotherapies. Therefore, the aim of this thesis was to characterize the molecular profile, frequency, phenotype and function of immune cells in EC and OC patients.  In particular, considering that the presence of activated tissue-resident gamma delta (γδ) T cells, recognized for their favorable response in various human malignancies, has been associated with a beneficial response to immunotherapies, and that their role in EC progression has not been elucidated yet, we performed a characterization of γδ T cells in EC. Flow cytometry analysis reveals that Vδ1 is the primary subset of γδ T cells infiltrating EC lesions in both early and advanced stages. Upon in vitro stimulation, these cells maintain their functional activity by producing cytokines, such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α. However, within the tumor, they exhibit increased expression of PD-1, compared to their blood-matched circulating counterparts. Single-cell RNA-sequencing (scRNA-seq) analysis confirmed the upregulation of PD-1 expression in γδ T cells, exhibiting a progressive increase from peritumor to tumor specimens, in contrast to healthy tissue. Crucially, tumor-infiltrating Vδ1 T cells expressing PD-1 retain their immune competence, which can be enhanced by PD-1 blockade. Indeed, their cytotoxic response against autologous tumor cell targets significantly increases in the presence of the specific blocking anti-PD-1 monoclonal antibody compared to controls. Moreover, scRNA-seq analysis associated the presence and the specific activation of Vδ1 T cells with the response to anti-PD-1 therapy. These data not only emphasize the specific anti-tumor response of Vδ1 T cells in EC but also indicate the feasibility of targeting γδ T cells to enhance current immunotherapeutic strategies.  As few studies have been conducted on the early stages (stage I) of OC due to the difficulty in diagnosing this disease, we performed a deep characterization through scRNA-seq of stage I high-grade serous ovarian cancer (HGSOC) tumor microenvironment (TME), the most common subtype of OC, to assess the impact of the TME in OC progression and to identify potential immunotherapeutic targets. Within the HGSOC lesions we detected high enrichment of CD4 regulatory T cells (Tregs) that displayed a spectrum of states linked to their naïve, effector, proliferating and destabilized transcriptomic profiles. The presence of FOXP3+ Tregs associates with a permissive, immune-suppressive TME, characterized by the prevalence of CD4 Th2 cells, exhaustion of cytotoxic CD8 T cells, and pro-tumoral states of natural killer (NK) cells and tumor-associated macrophages (TAMs). Cell-to-cell communication analysis predicted multiple molecular mechanisms underlying Treg inhibition of T and myeloid immune responses, along with the establishment of reciprocal interactions between Tregs and tumor cells, promoting tumor progression. Trajectory analysis revealed two differentiation paths for Tregs, both leading to immunosuppressive Treg profiles. While the FOXP3high profile converges with proliferating Tregs, the second path of cytotoxic FOXP3+ Tregs converged with FOXP3-KLRB1+ ex-Tregs, distinguished for their anti-tumoral CXCL13+IFNG+ transcriptomic profile. These findings highlight the pivotal role of Tregs in the early establishment of the immunosuppressive TME conducive to HGSOC, also highlighting the potential of manipulating Treg cell fate and their de-stabilization as a promising target for therapeutic interventions.","language":"eng","citation":"UNCOVERING IMMUNE EVASION MECHANISMS FOR THE PROGNOSIS AND THERAPY OF ENDOMETRIAL AND OVARIAN CANCERS / V. Cazzetta ; tutor: D. Mavilio ; supervisor: J. Mikulak ; director: N. Landsberger. Università degli Studi di Milano, 2024 Jul 22. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12866.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1075769/2475194/phd_unimi_R12866.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/919437"},"title":"L'ORDINE EUROPEO D'INDAGINE PENALE: DISCIPLINA NORMATIVA E PRIME ESPERIENZE APPLICATIVE","internalauthor":"DE LUCA, CARLOTTA","type":"Tesi di dottorato","year":"2022","abstract":"The European criminal investigation order, introduced by Directive 2014/41/EU, is  an instrument of judicial cooperation in the field of evidence, which has become  necessary, given the growing transnational dimension of crime as a result of the  sublimation of geographical boundaries in the European Union's Area of Freedom,  Security and Justice. The supranational directive, implemented by Italian Legislative  Decree no. 108 of 2017, has given rise to a construct of hybrid nature, inspired by the  principle of mutual recognition, which maintains, at the same time, certain features  typical of traditional mutual legal assistance, in an attempt to combine investigative  efficiency and protection of fundamental guarantees.  In an underlying backdrop still characterized by the absence of harmonization of  national procedural and evidentiary rules, the mechanism for adducing evidence in a  foreign country revolves around the principle of proportionality, which in turn takes  shape in the context of a balancing judgement - to be conducted in the actual case and  taking into consideration the specificities of such case - between the needs related to  the detection of crime and the sacrifices imposed on the rights of the persons  involved, for various reasons, in the procedures aimed at issuing and executing the  relevant order. This doctoral thesis intends to provide a comprehensive analysis of the  European Investigation Order, beginning with its legal framework, for the purposes  of highlighting the main problems that have emerged in its early-stage enforcement  and of identifying solutions capable of shorten the gap between theory and practice.  To this end, a large space is firstly dedicated to the analysis of the early case-law  rendered by the Court of Justice and by the Italian Court of Cassation on this theme,  which reveals the overall tendency to prefer purposes of investigatory efficiency to  the detriment of defense rights; secondly, this thesis critically evaluates some  practical cases selected at the Public Prosecutor's Office of Milan and Monza.","language":"ita","citation":"L'ORDINE EUROPEO D'INDAGINE PENALE: DISCIPLINA NORMATIVA E PRIME ESPERIENZE APPLICATIVE / C. De Luca ; tutor: L. Camaldo ; coordinatore: C. Luzzati. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2022 May 17. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12282.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/919437/2011697/phd_unimi_R12282.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/964879"},"title":"CHARACTERIZATION OF EPCAM IN THYROID CANCER BIOLOGY BY THREE-DIMENSIONAL SPHEROIDS IN VITRO MODEL.","internalauthor":"GHIANDAI, VIOLA","type":"Tesi di dottorato","year":"2023","abstract":"Thyroid cancer (TC) is the most common Endocrine malignancy. Currently, the mechanisms responsible for insensitivity to therapeutic treatments, tumor aggressiveness and tumor relapse described in undifferentiated thyroid cancers (UTCs) haven’t been fully elucidated yet. The insurgence of therapy resistance and disease relapse is believed to be due to a subpopulation of cancer cells within the tumor bulk that shows stem-like phenotype and specific tumor-initiating abilities. These cells are called tumor-initiating cells (TICs), and a comprehensive understanding of how to specifically isolate and target them is necessary. In thyroid cancer, TICs have been identified using specific in vitro and in vivo assays, variations of enzymatic activities, expression of well-known stemness markers and expression of membrane markers. Among the possible membrane markers described in literature to identify TICs, Epithelial Cell Adhesion Molecule (EpCAM) has already been defined as a marker for cancer cells with tumor-initiating properties in many solid tumors, where its possible role in tumor progression and aggressiveness has been described. However, this protein is poorly studied in TC and its role in TC pathology, especially in the undifferentiated forms, needs further comprehension. Hence, the aim of my PhD project was to: 1) characterize EpCAM as a putative thyroid TICs marker on poorly differentiated and anaplastic thyroid cancer cell lines, applying both classical monolayer cultures and 3D spheres cultures; 2) establish if the 3D model is a valid in vitro approach to study the expression and role of EpCAM in the context of TC; 3) observe whether TC cell lines respond differently when treated as adherent cells or as 3D spheres. Our data demonstrated that EpCAM is subjected to an intense cleavage process in FRO-derived 3D tumor spheres and that the 3D model is representative of the variability of EpCAM expression and cleavage that we observed in patient-derived tissue samples, with the different gradient of EpCAM cleavages corresponding to different areas of the tumor sections. We also observed that the expression of EpCAM can be modulated by the regulation of its cleavages and that the integrity of the protein seem to be a crucial factor for the initial phase of the generation of 3D spheres in FRO, while the cleavage of the protein may occur in a subsequent phase, induced by the ability of cells to adapt to variations in growth conditions and/or to the microenvironment within the spheres. Moreover, we demonstrated that EpCAM+ and EpCAM- subpopulations respond differently to treatment with a well-known drug commonly used in clinical practice, Vemurafenib (PLX-4032), both in FRO and HTCC3 adherent cells, and EpCAM+ cells appeared to be more resistant. Finally, the 3D sphere model is also a valid in vitro approach to assess cell response to PLX-4032 and we observed that FRO-derived 3D spheres seemed to be more resistant than HTCC3-derived spheres upon PLX-4032 treatment. In conclusion, we believe that EpCAM expression and its cleavage in 3D spheres could play a significant role in putative TC TICs biology and may partially explain the therapeutic failure observed in the more undifferentiated TCs, concomitantly to other mechanisms of resistance and/or escape that may occur.","language":"eng","citation":"CHARACTERIZATION OF EPCAM IN THYROID CANCER BIOLOGY BY THREE-DIMENSIONAL SPHEROIDS IN VITRO MODEL / V. Ghiandai ; Tutor: L. Persani; Supervisor: E. S. Grassi; Coordinatore: N. Landsberger; Revisore esterno: E. Puxeddu; Revisore esterno: C. Nucera. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2023 Apr 19. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12639.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/964879/2180418/phd_unimi_R12639.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1203516"},"title":"LINKING HISTONE LACTYLATION TO THE EPIGENETIC REPROGRAMMING OF CD4+ T REGULATORY LYMPHOCYTES IN THE TUMOR ECOSYSTEM","internalauthor":"BENEGGI, ANNA","type":"Tesi di dottorato","year":"2026","abstract":"Tumor infiltrating regulatory T cells (TI-Tregs) exhibit a complex interplay with various cell types, including tumor cells, immune cells, and stromal cells thereby promoting tumor growth and invasion. TI-Treg are transcriptionally and epigenetically adapted to the hostile tumor microenvironment (TME), which is characterized by nutrient- deprivation, hypoxic conditions and accumulation of lactic acid. Here we describe our findings on epigenetic and metabolic reprogramming of TI-Treg, mediated by lactic acid which fuels their suppressive function. Using integrated single-cell RNA-seq and spatial transcriptomics datasets, we first correlated the expression of lactate metabolism–related genes in TI-Tregs with highly glycolytic and hypoxic regions of colorectal cancer. We then demonstrated that Tregs maintained strong suppressive activity under glucose-restricted, lactic-acid rich environments, which correlates with a global increase in protein lactylation signal in TI-Tregs isolated from human colorectal and breast tumors and is further enhanced by concomitant exposure to hypoxia. Since we are particularly interested in the role of histone lactylation in Treg cells epigenetic rewiring, we performed comprehensive post-translational modification mass spectrometry (PTM-MS) experiments and discovered three previously undescribed key lactylated histone lysine residues, H3K122la, H4K91la and H2AK9la induced by TME- like cues. To further explore their functional relevance, we are generating monoclonal antibodies against these lactylated lysine residues. Consistent with our hypothesis, ChIP-seq analyses revealed precise deposition of histone lactylation around transcription start sites (TSS) of Treg genes involved in synergistic transcriptional responses to lactic acid and hypoxia, thereby linking lactylation with gene activation in Tregs for the first time. Overall, these findings suggest histone lactylation as a key mechanism underlying TI-Tregs adaptation to the TME. Ongoing mechanistic studies of lactylation are expected to uncover novel therapeutic opportunities to dampen Treg suppressive activity through metabolic and epigenetic modulation.","language":"eng","citation":"LINKING HISTONE LACTYLATION TO THE EPIGENETIC REPROGRAMMING OF CD4+ T REGULATORY LYMPHOCYTES IN THE TUMOR ECOSYSTEM / A. Beneggi ; supervisor: M. Pagani ; tutor: G. Rossetti ; director: N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2026 Jan 21. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13969_1.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 18-GIU-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1149636"},"title":"GREEN SENSORS AND SMART SERVICES FOR THE OPTIMIZATION OF AGRI-FOOD SUPPLY CHAINS IN A VIEW OF INDUSTRY 4.0: GREATER SUSTAINABILITY OF PRODUCTION, BUSINESS COMPETITIVENESS AND REDUCTION OF FOOD WASTE","internalauthor":"VIGNATI, SARA","type":"Tesi di dottorato","year":"2025","abstract":"The 12th Sustainable Development Goal (SDG) focuses on the concept of sustainable consumption and production, with a particular focus on reducing food loss and waste (Goal 12.3) by 2030. In order to achieve this in the fresh-cut chain, it is necessary to implement systemic improvements, including advanced agronomic practices, optimised harvest timing, effective post-harvest storage and innovative packaging. Green technologies such as optical sensing have the potential to enhance quality, extend shelf life and reduce environmental impact. However, their high costs present a significant barrier to adoption, as multiple devices are often required to address the complexities of supply chains. Research is addressing this challenge by developing compact, and low-cost imaging solutions for both pre- and post-harvest monitoring.  This doctoral research project concerns the application of non-destructive imaging techniques to assess the quality of some fresh and fresh-cut products, in terms of freshness and shelf life. Additionally, it involves the development of customized optical devices in a view of Industry 4.0, with the objective of enhancing the sustainability of the supply chain and reducing food loss and food waste. Two distinct measurement configurations were employed at laboratory scale, each with a different application objective. The first configuration concerned a cost-effective IoT hyperspectral prototype, that has been designed and successfully tested. The prototype operated within the spectral range of 400 nm to 1000 nm and has been developed using commercial equipment and a 3D-printer. It has reached satisfactory results for the current stage of technology development, which is estimated to be at a TRL (Technology Readiness Level) of 2. The prototype exhibited the capacity to differentiate between healthy and damaged tissue and to be sensible to variations in leafy vegetables over time, thereby demonstrating the capability to detect changes in the product as it undergoes decay. The prototype was designed for future integration at critical points in the production chain. Instead, the second configuration was proposed with the aim of monitoring the quality level of packaged products, thereby improving their management at the sales point and providing consumers with information on the true quality level of the products. This study demonstrated the potential of multispectral imaging for non-destructive monitoring of fresh-cut lettuce deterioration through packaging. The application of chemometric methods enabled effective identification and classification of fresh samples. However, the classification accuracy for subsequent days was found to be variable due to differences in decay rates between sample groups and light reflections from packaging.   In conclusion, this PhD project has demonstrated the benefits and potential of imaging systems as an effective and sophisticated tool for quality assessment in the food industry throughout the production chain, as well as one of the key tools for reducing food loss and waste. However, continued research and development is essential to refine these technologies and make them accessible and adaptable for wider applications. By integrating these tools into sustainable practices, the agri-food sector can make significant progress towards achieving global sustainability goals.      Keywords: Green technology, food quality, imaging, industry 4.0, sensor design, cost-effective, chemometrics.","language":"eng","citation":"GREEN SENSORS AND SMART SERVICES FOR THE OPTIMIZATION OF AGRI-FOOD SUPPLY CHAINS IN A VIEW OF INDUSTRY 4.0: GREATER SUSTAINABILITY OF PRODUCTION, BUSINESS COMPETITIVENESS AND REDUCTION OF FOOD WASTE / S. Vignati ; tutor: R. Guidetti ; co-tutor: R. Beghi ; coordinatore: D. Mora. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2025 Mar 04. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13616_1.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1149636/2693481/phd_unimi_R13616_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1125775"},"title":"METABOLICALLY HEALTHY AND UNHEALTHY OBESITY IN CHILDREN AND ADOLESCENTS: DIETARY IMPLICATIONS AND NEW OPPORTUNITIES FOR GUT MICROBIOTA MODULATION","internalauthor":"FIORE, GIULIA","type":"Tesi di dottorato","year":"2025","abstract":"This doctoral dissertation aimed to evaluate strategies for modulating gut microbiota composition in children and adolescents with metabolically healthy and unhealthy obesity. Three main projects were carried out: (1) a systematic review and metanalysis on the role of dietary intervention in modulating gut microbiota, and two clinical trials (2) the DAMOCLE study and (3) the PolyMets Study, both oriented towards investigating the efficacy of bioactive compounds as complementary strategies to act on gut microbiota composition.  A systematic review and meta-analysis were conducted to assess the effects of dietary interventions on gut dysbiosis in pediatric obesity. After screening 47 studies, five were included, focusing on calorie-restricted or low-sugar diets. Meta-analysis revealed significant improvements in gut microbiota alpha diversity following calorie restriction, including an increase in butyrate-producing bacteria, namely Faecalibacterium and Roseburia, which are linked to improved cardiometabolic health.  The DAMOCLE study evaluated the impact of docosahexaenoic acid (DHA) supplementation in 18 obese children. Results showed that DHA supplementation (500 mg/day) helped restore the Firmicutes/Bacteroidetes ratio, with sustained effects even after discontinuation. DHA supplementation drove a depletion in Ruminococcaceae and Dialisteraceae, and enrichment in Bacteroidaceae, Oscillospiraceae, and Akkermansiaceae. At genus level, Allisonella was the most decreased by DHA supplementation. In vitro, DHA demonstrated anti-inflammatory properties by reducing oxidative stress and modulating cytokine production in Caco-2 cells.  The PolyMets study examined the effects of a polysaccharidic macromolecule supplement (5 g/day of mixed fibres) combined with dietary and lifestyle interventions in 36 children with metabolically unhealthy obesity (MUO). Intervention led to improvements in BMI, biochemical parameters, and gut microbiota composition. The supplementation itself reduced obesity-associated bacterial families such as Monoglobaceae and Erysipelatoclostridiaceae. A non-significant reduction in the Firmicutes/Bacteroidetes ratio was also observed, and polysaccharidic macromolecules also contributed to a significant reduction in total fat mass and increases in fat-free mass.  Overall, dietary interventions alone can improve gut microbiota diversity, yet bioactive compounds such as DHA and polysaccharide macromolecules represent a tool that can optimise changes in the gut microbiota and effects on cardio-metabolic parameters in paediatric obesity.","language":"eng","citation":"METABOLICALLY HEALTHY AND UNHEALTHY OBESITY IN CHILDREN AND ADOLESCENTS: DIETARY IMPLICATIONS AND NEW OPPORTUNITIES FOR GUT MICROBIOTA MODULATION / G. Fiore ; tutor: E. Verduci ; coordinator: F. Cheli. - Università degli Studi di Milano. Dipartimento di Scienze della Salute, 2025 Jan 13. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13311.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1125775/2612076/phd_unimi_R13311.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/951591"},"title":"PROFILI DEL GIUDICATO SU QUESTIONI DI MERITO","internalauthor":"CORRARO, DAVIDE","type":"Tesi di dottorato","year":"2023","abstract":"The study aims to investigate the concept of the “res judicata on issues” beyond the narrow limits imposed by Article 34 of the Italian Civil Procedure Code. Given the mismatch between the res judicata and the operative part of the judgment, the scope of the civil process in light of its “progressive establishment” is assessed.   To do so, the research firstly analyzes the main theories focusing on extending the res judicata to some of the grounds of judgment. Among others, the Begründungstheorie as elaborated by Albrecht Zeuner was object of an in-depth analysis. Zeuner, in particular, extended the ruling to the grounds of judgment by adopting a coherent approach that could be implemented into the Italian system. However, for the implementation to be successful, some adjustments are needed: on the one hand, the enforcement of the right of defense and, on the other hand, the implementation of the cross examination, as widely established in common law systems through the English “issue estoppel” (or “issue preclusion” in the United States) doctrine.  In regard to the latter, the Supreme Court has recently recognized a sort of issue estoppel in tax law cases. Against this backdrop, the study will focus on the future development of the Supreme Court civil judgments as inspired by the functioning of the res judicata on tax issues.","language":"ita","citation":"PROFILI DEL GIUDICATO SU QUESTIONI DI MERITO / D. Corraro ; tutor: M. Marinelli, E.S.C. Marinucci, S.A. Villata; coordinatore: G. Ludovico. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2023 Mar 29. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12630.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/951591/2124675/phd_unimi_R12630.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1032052"},"title":"ORIGEN Y ANALISIS DEL TURISMO ESCOLAR: EL TOUR DIDACTICO COMO PRODUCTO TURISTICO Y ACTIVIDAD COMPLEMENTARIA PARA POTENCIAR LAS COMPETENCIAS CLAVE DEL ALUMNADO","internalauthor":"ROMERO SANCHEZ, FRANCISCO MANUEL","type":"Tesi di dottorato","year":"2023","abstract":"Pre-university education offers students a unique opportunity for tourism through the complementary and extracurricular activities programmed by the departments of primary and secondary schools, initiatives previously approved by the school council and which teachers use as a didactic resource to motivate their students in their subjects. These school trips become real tourist experiences by offering pupils a fun and educational moment with a well-defined product, supported by experts in the sector who can benefit economically by providing services adapted to the nature of the group and even directly, in collaboration with the teacher, by coordinating, accompanying and interpreting the different tourist attractions in the areas close to the school premises.  From a methodological point of view, the research has been approached through an empirical approach using mixed descriptive techniques with the intention of justifying a tourist typology focused on school trips. By creating a travel agency specialised in educational guided tours, favouring the dynamic use of the participant-observation methodology, resulting in a tourist-educational product validated and tested by the schools.  The purpose of this research is: (1) to unravel school tourism as a sub-segment of educational and cultural tourism from its origins to the present day. To this end, the market generated is analysed, well defined in a network of trips and products designed by tourism professionals, materialised in school outings, excursions, trips, cultural exchanges, workshops and activities. (2) To promote initiatives outside the classroom as a didactic strategy and socio-economic activity that creates synergies between the school community and tourism service providers. (3) To create an educational tour validated by teachers and applied to groups of schoolchildren as a complementary, transversal activity that helps to strengthen the key competences decreed by the European Commission and implemented in the education systems of the member countries, as in the case of Spain and Italy. (4) Include in the last part of the work the business plan of a tourism company, set up during the research process, to serve as an example for those professionals in the sector who want to revitalise this type of tourism-educational activities aimed at schools to discover their territory with the help of a heritage interpreter specialised in school groups.","language":"spa","citation":"ORIGEN Y ANALISIS DEL TURISMO ESCOLAR: EL TOUR DIDACTICO COMO PRODUCTO TURISTICO Y ACTIVIDAD COMPLEMENTARIA PARA POTENCIAR LAS COMPETENCIAS CLAVE DEL ALUMNADO / F.m. Romero Sanchez ; directores: E. Asenjo Rubio, D. Gavinelli. Università degli Studi di Milano, 2024. 30. ciclo","filename":"phd_unimi_R11491.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1032052/2367861/phd_unimi_R11491.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/807862"},"title":"EFFICIENCY AND REALISM IN STOCHASTIC BANDITS","internalauthor":"CELLA, LEONARDO","type":"Tesi di dottorato","year":"2021","abstract":"This manuscript is dedicated to the analysis of the application of stochastic bandits to the recommender systems domain. Here a learning agent sequentially recommends one item from a catalog of available alternatives. Consequently, the environment returns a reward that is a noisy observation of the rating associated to the suggested item. The peculiarity of the bandit setting is that no information is given about not recommended products, and the collected rewards are the only information available to the learning agent. By relying on them the learner adapts his strategy towards reaching its learning objective, that is, maximizing the cumulative reward collected over all the interactions.  In this dissertation we cover the investigation of two main research directions: the development of efficient learning algorithms and the introduction of a more realistic learning setting. In addressing the former objective we propose two approaches to speedup the learning process. The first solution aims to reduce the computational costs associated to the learning procedure, while the second's goal is to boost the learning phase by relying on data corresponding to terminated recommendation sessions. Regarding the latter research line, we propose a novel setting representing use-cases that do not fit in the standard bandit model.","language":"eng","citation":"EFFICIENCY AND REALISM IN STOCHASTIC BANDITS / L. Cella ; tutor: N. Cesa-Bianchi ; coordinatore PhD program: P. Boldi. Dipartimento di Informatica Giovanni Degli Antoni, 2021 Jan 15. 33. ciclo, Anno Accademico 2020. [10.13130/cella-leonardo_phd2021-01-15].","filename":"phd_unimi_R11945.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/807862/1682771/phd_unimi_R11945.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/972608"},"title":"LE INTERAZIONI TRA ECONOMIA DIGITALE E ORDINAMENTI FISCALI: IPOTESI RICOSTRUTTIVE E PROSPETTIVE DI EVOLUZIONE, NEL RISPETTO DEI PRINCIPI EUROPEI E COSTITUZIONALI","internalauthor":"RATTI, JACOPO","type":"Tesi di dottorato","year":"2023","abstract":"The pervasive spread of digital technologies has brought about radical changes and fundamental innovations in all areas of everyday life.  In the market, the interaction of this new technology with the economy has not only helped to shape the reality in which transactions and trade take place, but, above all, it has disrupted the way in which businesses and users interact, revolutionising the ways in which, until then, business activities were conducted. But not only that.  With the proliferation of the digital economy - the synthesis of these new synergies and the demiurgic action of digitalisation being understood here - new forms of wealth have also manifested themselves, in the most varied forms and with the most diverse consistencies: immaterial ideas and creations have progressively replaced, quantitatively and qualitatively, material counterparts; there is also the increasing use of data, elements that are difficult to classify systematically and whose introduction into one legal category rather than another is hotly debated.  The advent of the digital economy has affected the entire production chain, going so far as to call into question the econometric reconstructions that, until recently, considered the structure of the balance sheet intangible, as well as the very idea of the value chain (Musgrave 1985); in fact, the companies that move in the digital ecosystem, that is, the place where subjects and the market merge inseparably to proliferate to the detriment of strict state regulation, act on a twofold level the immaterial one, in which the relevant economic activity is conducted, generating huge profits, and the material one, where, exploiting the constraints and asymmetries of the legal system, it is possible to craft an autonomous legal status, capable of increasing wealth disproportionately, regardless of state controls and wills.  From the fiscal point of view, this innovative wind has brought with it very significant consequences, on which, despite the interest and copious amount of work, there is still incessant work to be done. The present work, after dwelling at length on the identification of these new riches and outlining the relevant legal scenario (Chapter I), devoted to the study of the subject, will attempt to show how the classical categories used in international tax law (namely, income [Haig 1921, Hicks 1939, Simons 1938], as well as the binomial place of residence-place of source) are perhaps obsolete and therefore unsuitable to grasp the entirety of the tax effects of the digital phenomenon (Chapter II).  In carrying out this study, an attempt will nevertheless be made to dispel certain commonplaces, which have led the doctrine to speak, not without good reason of course, of a state 'crisis of sovereignty' in the digital world; in particular, it is true that the digital world disregards the physical territory, the privileged place of exercise of sovereign power; but it is equally true that, on the one hand, technological progress, as well as the incessant work of the doctrine and institutions that, for at least twenty years, have been dealing with the subject, make it possible today to tackle the subject with renewed vigour, new certainties and new hypothetical theoretical bases on which to design new tributes; on the other hand, the very exercise of sovereignty may be possible, though necessarily having to deal with an invisible reality.  Thus, analysing the different solutions provided by the various legal systems, and noting the dissatisfaction that nonetheless emanates from the adoption of one of those solutions (Chapter III), an attempt will finally be made to suggest the introduction of a new tax, complementary to the income tax, and specifically constructed on account of the peculiarities found in the digital context. On the sidelines of this theorisation, however, ample space will be given to the most recent solutions that, during the compilation of this paper, have nevertheless found their way into the corridors of supranational, international and community institutions (Chapter IV).","language":"ita","citation":"LE INTERAZIONI TRA ECONOMIA DIGITALE E ORDINAMENTI FISCALI: IPOTESI RICOSTRUTTIVE E PROSPETTIVE DI EVOLUZIONE, NEL RISPETTO DEI PRINCIPI EUROPEI E COSTITUZIONALI / J. Ratti ; tutor: G. RAGUCCI ; coordinatore: F. BIONDI. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2023 Jul 05. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12507.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/972608/2209903/phd_unimi_R12507.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/935711"},"title":"A TRIPLE FLORIGEN SYSTEM IS ESSENTIAL FOR FLOWERING AND PANICLE ARCHITECTURE IN RICE","internalauthor":"GIAUME, FRANCESCA","type":"Tesi di dottorato","year":"2022","abstract":"The transition from a vegetative phase to a reproductive one has always been deeply studied in plants and in particular in the cereals due to the relevance of this trait for seed yield. The transition occurs upon the arrival of a mobile flowering signal, the florigen, at the shoot apical meristem (SAM).  In rice (Oryza sativa), there are two different florigens: Heading Date 3a (Hd3a), that promotes flowering in short day (SD) conditions and Rice Flowering Locus T 1 (RFT1) that promotes flowering in both short and long- days (LD). They are transcribed and translated in leaves once environmental conditions are optimal, and then transported through the phloem to the SAM. After reaching the shoot they form a heterohexameric complex named Florigen Activation Complex (FAC) binding to two 14-3-3 proteins and to two bZIP transcription factors and activate conversion of the shoot apex into an inflorescence by promoting expression of inflorescence- identity genes.  Here, we show that Hd3a and RFT1 arrival at the SAM activates FLOWERING LOCUS T-LIKE 1 (FT-L1), encoding a third florigen-like protein showing atypical characteristics.  Expression data from qRT-PCR, in situ hybridization and transcriptional marker lines indicated that its mRNA is mainly expressed in the SAM and persists during all developmental stages of inflorescence development. Misexpression of FT-L1 from meristem- and tissue-specific promoters indicates that only when expressed in the SAM, FT-L1 has florigenic activity.  Isolation and analysis of EMS and CRISPR mutants showed that FT-L1 strengthens the effects of Hd3a and RFT1 during conversion of the vegetative meristem into inflorescence, in an addictive manner. Furthermore, it controls panicle branching by inhibiting secondary branching and promoting spikelet meristem differentiation.  Thus, we propose a triple florigenic module that promotes a balanced progression of inflorescence identity and determinacy.","language":"eng","citation":"A TRIPLE FLORIGEN SYSTEM IS ESSENTIAL FOR FLOWERING AND PANICLE ARCHITECTURE IN RICE / F. Giaume ; scientific supervisor: F. Fornara ; phd school coordinator: M. Kater ; revisore: G. Valè, S. Boden. Dipartimento di Bioscienze, 2022 Jul 21. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12317_1.pdf","fileformat":"Adobe PDF","fileversion":"preprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/935711/2059074/phd_unimi_R12317_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1123317"},"title":"THE ROLE OF ACTIN CYTOSKELETON IN REGULATING NEURONAL FUNCTION IN PHYSIOLOGY AND DISEASE:  ZOOM IN ON THE CYCLASE-ASSOCIATED PROTEIN 2","internalauthor":"STRINGHI, RAMONA","type":"Tesi di dottorato","year":"2024","abstract":"Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the deposition   of extracellular amyloid-beta (Aβ) plaques and intracellular accumulation of hyperphosphorylated tau   protein. Recent studies point out synaptic loss as the strongest indicator of cognitive impairment in AD,   leading to the classification of AD as a “synaptopathy”. The actin cytoskeleton plays a critical role in   synaptic plasticity, and disruptions in actin dynamics contribute to synaptic failure in AD. We focused   on cyclase-associated protein 2 (CAP2), an actin-modifier essential for spine architecture and synaptic   transmission and altered in AD patients. Indeed, CAP2 expression is reduced in AD and, thereby, the   synaptic availability of CAP2 dimer is decreased, having an impact of cofilin association with the CAP2   dimer/monomer. Additionally, actin and its associated proteins regulate mitochondrial dynamics,   therefore actin cytoskeleton dysfunction may further contribute to AD pathology, adding another layer   of complexity to the disease pathology.    Here, we reported that AD patients show higher CAP2 CSF levels compared to controls and non-AD   patients, that positively correlate with total and tau phosphorylated at Thr181 (p-tau181). CAP2 mRNA   levels are reduced in the hippocampus of AD patients. Therefore, to assess a potential biological link   between CAP2 and tau, we downregulated CAP2 expression in hippocampal neurons and we measured   a significant increase in p-tau181 and a concomitant increase of caspase-3 activation without affecting   cell viability. In addition, we demonstrated a higher variance, suggesting increased instability, of   dendritic spine actin cytoskeleton upon CAP2 down-regulation.    Moreover, we show the involvement of CAP2 in those mechanisms relevant for actin-dependent   mitochondrial dynamics. Indeed, the ablation of CAP2 triggers an evident alteration of mitochondrial   morphology, mediated by the suppression of Drp1-dependent fission dynamics, and a simultaneous   loss of mitochondrial mass caused by alterations in mitobiogenesis processes.    Given the downregulation of CAP2 in AD, we described that CAP2 gene delivery in AD mice restores   synaptic CAP2/cofilin and plasticity pathways, thus preserving cognitive function. CAP2 overexpression   reduces cofilin actin rods formation and mitigates tau abnormalities. CAP2 is accumulated within   cofilin-actin rods specifically induced by Aβ oligomers. Furthermore, CAP2 dimerization is required for   preventing Aβ-induced synaptic loss but not to protect neurons from cofilin-actin rods formation.    Taken together, these findings strengthen the role of synaptic pathology in the early stages of AD and   support the correlation of AD synaptic failure with actin cytoskeleton dysfunction, highlighting CAP2 at   the crossroad of multiple pathways underlying AD pathogenesis.","language":"eng","citation":"THE ROLE OF ACTIN CYTOSKELETON IN REGULATING NEURONAL FUNCTION IN PHYSIOLOGY AND DISEASE:  ZOOM IN ON THE CYCLASE-ASSOCIATED PROTEIN 2 / R. Stringhi ; tutor: E. Marcello; coordinatore: G. D. Norata. Dip. di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti, 2024 Dec 18. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13259.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1123317/2604983/phd_unimi_R13259.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1115344"},"title":"FAITHFUL ESTIMATION OF UNCERTAINTIES IN MODERN PDF EXTRACTIONS","internalauthor":"BARONTINI, ANDREA","type":"Tesi di dottorato","year":"2024","abstract":"The primary focus of this Ph.D. thesis is the precise determination and validation of the uncertainties associated with parton distribution func- tions (PDFs). We introduce and implement the theory covariance method within the NNPDF4.0 framework, enabling the incorporation of theoretical uncertainties into the PDF determination process. Additionally, we revisit and expand upon the closure tests framework, which serves as a tool for val- idating the PDF extraction methodology in a controlled environment. This framework is applied to a dataset that has been deliberately constructed to be inconsistent, allowing for a rigorous assessment of the methodology’s ro- bustness. Furthermore, we utilize this framework to validate the extraction of the strong coupling constant using the correlated replica method. Finally, we present a novel theoretical pipeline, which introduces several technical advancements and underpins all the results discussed in this thesis.","language":"eng","citation":"FAITHFUL ESTIMATION OF UNCERTAINTIES IN MODERN PDF EXTRACTIONS / A. Barontini ; supervisore: S. Forte ; coordinatore: A. Mennella. Dipartimento di Fisica Aldo Pontremoli, 2024. 37. ciclo","filename":"phd_unimi_R13428.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1115344/2577674/phd_unimi_R13428.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1132740"},"title":"EMISSIVE PEPTIDE NUCLEIC ACIDS (PNAS): POTENTIAL TOOLS FOR INNOVATIVE DIAGNOSTICS AND THERAPEUTICS","internalauthor":"DELL'ACQUA, ROSA MARIA","type":"Tesi di dottorato","year":"2025","abstract":"ABSTRACT  I. Introduction and aim of the thesis  Peptide nucleic acids (PNAs)1 are synthetic mimics of natural nucleic acids, in which the chiral and negatively charged sugar-phosphate backbone is replaced by achiral and neutral N-(2-aminoethyl)-glycine (aeg) units, where the four nucleobases (thymine, adenine, cytosine, guanine) are inserted through a carboxymethylene spacer. PNAs are able to bind complementary DNA and RNA single strands through Watson-Crick base pairing, with high sequence specificity and affinity2. Thanks to their synthetic nature, PNAs also display high chemical and enzymatic stability3. All these unique features make PNAs excellent candidates for diagnostic and therapeutic applications4,5, such as detecting genetic mutations and interfering with protein production in antigene and antisense therapies, for cancer and antibacterial treatments. However, despite their potential, PNAs face challenges in clinical applications due to their poor cell membrane penetration and water solubility. Therefore, the research in the field of PNAs is still ongoing to improve PNA delivery and fully exploit their potential especially for therapeutic purposes.  This Ph.D. thesis aimed to broaden the opportunities to employ PNAs in biomedical applications, developing new and attractive tools for diagnostics and therapy. To this purpose, this thesis focused on exploring and validating synthetic methodologies for the creation of modified PNAs. The work of the thesis was divided into four main research activities, with the common feature of creating emissive PNAs. Emissive molecules offer various advantages when paired with PNAs. Their luminescent properties enable cellular localization studies, while their ability to penetrate cells makes them potential carriers for PNAs. Additionally, emissive compounds could introduce new therapeutic capabilities to PNAs. Emissive PNAs could allow to handle the current limitations and propose valid alternatives from which both the diagnostic and the therapeutic fields can benefit. Finally, the study of unmodified PNAs for in vivo application through antisense strategy was also preliminary explored.  II. Intrinsically emissive PNAs containing isomorphic thieno[3,4-d]pyrimidine nucleobase  The isomorphic emissive nucleobase thieno[3,4-d]pyrimidine6 was inserted in different positions of a model PNA decamer to create intrinsically emissive PNAs. Such PNAs could elicit changes in their emission upon hybridization with complementary DNA or RNA strands, opening up new opportunities for diagnostic purposes.   Three novel modified PNAs (PNA1, PNA2 and PNA3) were synthesized manually through standard solid phase protocols and characterized through photophysical studies and melting temperature measurements, which were performed using UV absorption spectroscopy and micro differential scanning calorimetry (micro-DSC), in collaboration with Professor Fin (University of Turin).   These studies demonstrated that the nucleobase conferred emissive properties to the PNAs, which maintained their ability to bind complementary antiparallel DNA. Additionally, it was possible to verify the hybridization event between the emissive PNA and the DNA by monitoring the changes in the fluorescent properties of the PNA.  Although further research is required to better understand the results and optimize the photophysical and hybridization properties of these PNAs, the results of this study provided valuable insights for the development of emissive PNAs that could be employed in the diagnostic field.  III. Development of a luminescent bioorganometallic Ir-PNA conjugate as potential dual-action        system against cancer  Organometallic cyclometalated iridium (III) complexes, containing two phenylpyridine ligands and a phenathroline as third ligand, display excellent photophysical properties, and can act as photosensitizers (PSs) generating cytotoxic singlet oxygen (1O2) for applications in photodynamic therapy (PDT)7. Moreover, they show good cell permeability, for example towards cancer cells.  In this research activity, in collaboration with Professor Maggioni (University of Milan), the Ir-COOH and Ir-NH2 were investigated as carriers for delivering PNAs into cancer cells and create a potential dual-action system, which combines the therapeutic properties of both components of the conjugate.   This work introduced the first example of cyclometalated Ir(III) complexes conjugated to a model PNA tetramer. Two Ir(III) complexes with different functional groups (Ir-NH2 and Ir-COOH) were conjugated to the PNA tetramer, using a coupling reaction on solid phase, to investigate the conjugation method. The Ir-PNA conjugate retained the photophysical properties of the iridium complex, including its ability to generate singlet oxygen in solution, a feature that can be employed for PDT. Confocal microscopy studies confirmed the ability of the Ir(III) complexes to effectively deliver the PNA into HeLa cells and demonstrated that the intracellular localization of the system could be tracked using the luminescent features of the iridium component. Cytotoxicity tests in the absence of light showed that the Ir-PNA conjugate is non-toxic for HeLa cells, but its cytotoxicity increased under light irradiation, likely due to the generation of 1O2 by the Ir(III) complex, confirming its ability to act as a photosensitiser (PS) when conjugated to the PNA strand.  Therefore, this innovative bioorganometallic Ir-PNA conjugate offers promising features for the future development of dual-action anticancer agents, in which a microRNA target will be selected for the PNA, and its antisense effect will be combined with the PDT related to the iridium complex to synergically target tumors.  IV. Luminescent Pt(II) complexes as potential carriers for PNAs to bacteria  Neutral and planar N^C^N tridentate Pt(II) complexes have been widely investigated for bioimaging applications and in PDT, thanks to their outstanding photophysical features and ability to act as PSs8. Thus, their conjugation to PNAs could provide a novel approach for therapeutic applications. In particular, given the growing challenge of treating bacterial infections, the combination of Pt(II) complexes as antimicrobial PDT (aPDT) agents and PNAs as antisense oligonucleotides could offer several advantages for the development of new antibacterials.  In collaboration with Professor Colombo (University of Milan), two Pt(II) complexes with different spacers (Pt-1 and Pt-2) were conjugated to a model PNA decamer, using a coupling reaction on solid phase, validating the conjugaton method for this class of platinum complexes. The ability of the Pt-PNA conjugates (Pt-1-dPNA and Pt-2-dPNA) to hybridize with complementary single strand DNA (ss-DNA) and single strand RNA (ss-RNA) was assessed through melting temperature measurements and circular dichroism (CD) studies. The results suggested that the conjugation of the Pt(II) complexes to PNAs could affect the hybridization properties of the PNA sequence towards complementary ss-DNA and ss-RNA depending on the length of the spacer. The formation of stable duplexes was observed with the Pt-2-dPNA conjugate, bearing a longer spacer between the metal centre and the PNA sequence. Notably, the photophysical properties of the Pt(II) complex were conserved and the quantum yield of the conjugate Pt-PNA was even higher, suggesting that the conjugation with the PNA could be beneficial for the intrinsic features of the complex. This result also demonstrated that this class of Pt(II) complexes could be suitable for future intracellular localization studies, allowing the tracking of the PNA inside cells.     Next, in collaboration with Professor Trylska (Centre of New Technologies, University of Warsaw), the Pt-PNA conjugates targeting the mRNA of the essential acpP gene in E. coli9 were tested for their antibacterial activity. They inhibited the growth of E. coli strains with defective LPS membranes (AS19) but showed no effect on other strains, suggesting that the LPS layer plays a key role for their effectiveness.  Current research is focusing on understanding how Pt-PNA conjugates interact with bacterial membranes and optimizing their ability to penetrate cells. In future, these conjugates will be evaluated as dual-action antibacterial agents, combining the antisense activity of the PNA with the cytotoxic singlet oxygen production from the Pt(II) complex for a synergistic antimicrobial effects.  V. Cyclic triimidazoles as potential luminescent probes and carriers for PNAs  This project, carried out in the final part of this Ph.D. thesis, aimed to study the conjugation of PNAs to three different cyclic triimidazoles as potential luminescent carriers for PNAs to bacterial cells10, in a joint collaboration with Professor Cariati (University of Milan) and Professor Trylska (Centre of New Technologies, University of Warsaw). The conjugation of three different cyclic triimidazoles to PNAs designed to target the acpP mRNA was successfully accomplished via a coupling reaction on solid phase.  Melting temperature studies of cyclic triimidazole-PNA conjugates with the complementary antiparallel RNA strand revealed that the recognition properties of the PNA conjugates were affected with varying degrees by the different functionalizations.   Absorption and photoluminescence studies on the TT-Th-anti-acpP-PNA in water confirmed that its photophysical properties were in agreement with those typically observed for this class of cyclic triimidazoles. Indeed, the TT-Th-anti-acpP-PNA displayed an intense emission at 464 nm, which could be useful for the future development of new emissive probes.  Preliminary studies performed to evaluate the antibacterial activity of these conjugates showed that they were not effective in inhibiting the growth of E. coli AS19, meaning they were not able to penetrate the bacterial membrane. Future work will involve the evaluation of the cyclic triimidazoles on additional bacterial strains, such as Gram-positive bacteria, to further explore their potential as PNA carriers. Moreover, considering the versatility of functionalizing cyclic triimidazoles through synthetic techniques established in Professor Cariati’s group, upcoming research will also focus on developing new derivatives as carriers.  In summary, the initial findings highlight the promise of cyclic triimidazole-PNA conjugates, though further studies are necessary to confirm these preliminary results and fully realize the objectives of the project.  VI. Anti-miR124 PNAs for in vivo studies in ascidian embryos  Besides the work on emissive PNAs, a part of this Ph.D. thesis was also dedicated to the study of anti-miR124 PNAs for in vivo studies using ascidian embryos as animal model. Anti-miR PNAs have been employed for studying miRNA functions and interfere with their activity, potentially treating various diseases11-13. The goal of this research was to investigate the ability of PNA to target miR-124 and study the effects on the neural development of ascidian Ciona intestinalis embryos, in collaboration with Dr. Hitoyoshi (Laboratoire de Biologie du Développement de Villefranche-sur-mer, Sorbonne Université). By using this approach, it would be possible to investigate how miRNA-124 regulation could influence the neural development and gain deeper insights into the role of miRNA-124 in the CNS diseases. Two unmodified PNA sequences, the antiparallel complementary sequence to miRNA-124 (PNA-a124) and the scrambled PNA (PNA-sc124), were synthesized using manual solid phase synthesis.   Unfortunately, the unmodified PNA-a124 sequence did not seem suitable for this study, mainly due to its low solubility in the seawater used for the in vivo experiments, so in future the insertion in this sequence of some lysine- or arginine-based residues could be performed to improve its water solubility and potentially prevent their precipitation, which makes the injection in the embryos difficult. Additionally, the toxicity of the PNA-sc124 could arose from off-target binding. Thus, it could be mitigated rearranging its sequence.   VII. Conclusions  This Ph.D. thesis started and developed several projects within three years, leading to mostly preliminary results that require further optimization to fully unlock the potential of the newly developed PNAs. Despite this, the thesis achieved its goal of designing and creating novel emissive PNAs that combine the advantages of both PNAs and emissive molecules. These emissive PNAs represent a promising starting point for expanding their use in clinical applications, which has been limited by the poor cellular uptake displayed by PNAs. Notably, Ir(III) and Pt(II) complexes emerged as effective carriers for delivering PNAs into cancer and bacterial cells, respectively.   VIII. References  (1) Nielsen, P. E.; Egholm, M.; Berg, R. H.; Buchardt, O. Sequence-Selective Recognition of DNA by Strand Displacement with a Thymine-Substituted Polyamide. 1991, 254, 1497-1499. https://www.science.org/doi/10.1126/science.1962210.  (2) Egholm, M.; Buchardt, O.; Christensen, L.; Behrens, C.; Freier, S. M.; Driver, D. A.; Berg, R. H.; Kim, S. H.; Norden, B.; Nielsen, P. E. PNA hybridizes to complementary oligonucleotides obeying the Watson–Crick hydrogen-bonding rules. Nature. 1993, 365, 566–568.   https://doi.org/10.1038/365566a0.  (3) Demidov, V. V.; Potaman, V. N.; Frank-Kamenetskii, M. D.; Egholm, M.; Buchard, O.; Sönnichsen, S. H.; Nielsen, P. E. Stability of peptide nucleic acids in human serum and cellular extracts. Biochem. Pharmacol. 1994, 48, 1310-1313.   https://doi.org/10.1016/0006-2952(94)90171-6.  (4) Saarbach, J.; Sabale, P. M.; Winssinger, N. Peptide Nucleic Acid (PNA) and Its Applications in Chemical Biology, Diagnostics, and Therapeutics. Curr. Opin. Chem. Biol.  2019, 52, 112–124.   https://doi.org/10.1016/j.cbpa.2019.06.006.  (5) MacLelland, V.; Kravitz, M.; Gupta, A. Therapeutic and Diagnostic Applications of Antisense Peptide Nucleic Acids. Molecular Therapy Nucleic Acids. 2024, 35.  https://doi.org/10.1016/j.omtn.2023.102086.  (6) Srivatsan, S. G.; Weizman, H.; Tor, Y. A Highly Fluorescent Nucleoside Analog Based on Thieno[3,4-d]Pyrimidine Senses Mismatched Pairing. Org. Biomol. Chem. 2008, 6, 1334–1338. https://doi.org/10.1039/b801054d.  (7) Maggioni, D.; Galli, M.; D’Alfonso, L.; Inverso, D.; Dozzi, M. V.; Sironi, L.; Iannacone, M.; Collini, M.; Ferruti, P.; Ranucci, E.; D’Alfonso, G. A Luminescent Poly(Amidoamine)-Iridium Complex as a New Singlet-Oxygen Sensitizer for Photodynamic Therapy. Inorg. Chem. 2015, 54, 544–553. https://doi.org/10.1021/ic502378z.  (8) De Soricellis, G.; Fagnani, F.; Colombo, A.; Dragonetti, C.; Roberto, D. Exploring the Potential of N^C^N Cyclometalated Pt(II) Complexes Bearing 1,3-Di(2-Pyridyl)Benzene Derivatives for Imaging and Photodynamic Therapy. Inorganica Chim. Acta. 2022, 541, 121082-121095.  https://doi.org/10.1016/j.ica.2022.121082.  (9) Good, L.; Kumar Awasthi, S.; Dryselius, R.; Larsson, O.; Nielsen, P. E. Bactericidal Antisense Effects of Peptide-PNA Conjugates. Nat. Biotechnol. 2001, 19, 360–364.  https://doi.org/10.1038/86753.  (10) Previtali, A.; He, W.; Forni, A.; Malpicci, D.; Lucenti, E.; Marinotto, D.; Carlucci, L.; Mercandelli, P.; Ortenzi, M. A.; Terraneo, G.; Botta, C.; Kwok, R. T. K.; Lam, J. W. Y.; Tang, B. Z.; Cariati, E. Tunable Linear and Nonlinear Optical Properties from Room Temperature Phosphorescent Cyclic Triimidazole-Pyrene Bio-Probe. Chemistry - A European Journal. 2021, 27, 16690–16700. https://doi.org/10.1002/chem.202102839.  (11) Gambari, R.; Fabbri, E.; Borgatti, M.; Lampronti, I.; Finotti, A.; Brognara, E.; Bianchi, N.; Manicardi, A.; Marchelli, R.; Corradini, R. Targeting MicroRNAs Involved in Human Diseases: A Novel Approach for Modification of Gene Expression and Drug Development. Biochem. Pharmacol. 2011, 82, 1416–1429.   https://doi.org/10.1016/j.bcp.2011.08.007.  (12) Mercurio, S.; Cauteruccio, S.; Manenti, R.; Candiani, S.; Scarì, G.; Licandro, E.; Pennati, R. Mir-7 Knockdown by Peptide Nucleic Acids in the Ascidian Ciona Intestinalis. Int. J. Mol. Sci. 2019, 20, 5127-5137.   https://doi.org/10.3390/ijms20205127.  (13) Mercurio, S.; Cauteruccio, S.; Manenti, R.; Candiani, S.; Scarì, G.; Licandro, E.; Pennati, R. Exploring Mir-9 Involvement in Ciona Intestinalis Neural Development Using Peptide Nucleic Acids. Int. J. Mol. Sci. 2020, 21, 2001-2012.   https://doi.org/10.3390/ijms21062001.","language":"eng","citation":"EMISSIVE PEPTIDE NUCLEIC ACIDS (PNAS): POTENTIAL TOOLS FOR INNOVATIVE DIAGNOSTICS AND THERAPEUTICS / R.m. Dell'acqua ; tutor: S. Cauteruccio ; phd coordinator: D. Passarella. Dipartimento di Chimica, 2025 Jan 23. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13525.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1132740/2628816/phd_unimi_R13525.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/921478"},"title":"RAPPORTI SOCIALI E CONFLITTI DI CLASSE NELL'INGHILTERRA DEL XVIII SECOLO: VERSO UNA NUOVA TEORIA MATERIALISTA DELLA TRANSIZIONE AL CAPITALISMO","internalauthor":"BRUNAZZI, GIANMARIA","type":"Tesi di dottorato","year":"2022","abstract":"This work has two main aims: it wants, from one side, to revive the debate on the Transition to Capitalism, whereas, on the other side, it proposes a new political approach to historical materialism.  Triggered by social concerns about our times - which are characterised by growing inequality and poverty, by class polarisation, climate emergences, economic crises and new wars - the research devotes theoretical attention to the dialectics between political present and the writing of history.  While the world leaves behind thirty years of neo-liberal unipolarism, and History, in its magnitude, gets back into the scene, the paper, critically focusing on the origins of Capitalism and on the praxis of change, shakes the hypostatization of the present social system and, highlighting the specific features that make it finite and superable, historicises it.   The work challenges those academic studies which have dealt, in the wake of several cultural trends, with the history of economic and social development, counterposing to micro-specialisation, post-modern fragmentation and the multiplication of perspectives, a systematic contestation of the whole bulk of relations which Capitalism entails.    Devoting a new importance to class paradigm - even with respect to materialist traditional approaches - the essay contributes to Marxist historiography, originally investigating theoretical nodes such as the relationship between base and superstructure, history and theory, materiality and ideology, objectivity and subjectivity.  Group interests, class relations and conflicts in XVIII century England are inspected with the goal of defining a new method for historical investigation: the social praxis, as a methodological criterion, does not only permit us to reframe the dynamics relating economic (structural) and social transformations, but proves to be a valid guide to preserve the researcher’s writing from from the ideological influence of his time hegemony.","language":"ita","citation":"RAPPORTI SOCIALI E CONFLITTI DI CLASSE NELL'INGHILTERRA DEL XVIII SECOLO: VERSO UNA NUOVA TEORIA MATERIALISTA DELLA TRANSIZIONE AL CAPITALISMO / G. Brunazzi ; tutor: G. Maifreda ; coordinatore: M. Soresina ; coordinatrice D. Saresella ; supervisor (EHESS): J. Bourdieu ; supervisor (EHESS): J-Y Grenier. Dipartimento di Studi Storici, 2022 May 17. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12033.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/921478/2017269/phd_unimi_R12033.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/811891"},"title":"SYNTHESIS, SAR AND BIOLOGICAL STUDIES OF NATURAL AND NATURE-INSPIRED POLYPHENOLS","internalauthor":"MATTIO, LUCE MICHELA","type":"Tesi di dottorato","year":"2021","abstract":"Polyphenols represent a wide class of diverse natural products, largely present in our diet, which have attracted the interest of several scientists in the last decades because of their beneficial effects on human health. Despite of intensive research efforts, the mechanisms of action of these compounds are still largely mysterious. This is partially due to the lack of a systematic investigation of single pure compounds with respect to several studies on complex mixtures from plant extracts. In addition, polyphenols are well known to undergo extensive hepatic and intestinal metabolism, which is of particular interest since metabolites can be responsible for both beneficial and toxic effects of dietary polyphenols.   In this scenario, the purpose of this PhD thesis was to develop synthetic strategies to obtain pure natural polyphenols and their analogues for systematic studies on their biological activity and to investigate the metabolites of this class of compounds.  The first part of this PhD thesis focused on resveratrol-derivatives, known as stilbenoids, a class of phytoalexins, produced by plants as means of defence against pathogens invasion and stress factors. In spite of the huge number of scientific reports on resveratrol, systematic studies on resveratrol-derived compounds are quite scarce. This derives from the difficulty to isolate and purify these compounds by extraction procedures from natural sources. In order to address this issue, we aimed at developing efficient and versatile biocatalytic and synthetic approaches to obtain natural-resveratrol derivatives in substantial amounts for their biological evaluation. Moreover, design and synthesis of new stilbenoid analogues were carried out for structure-activity-relationship (SAR) studies in order to identify the molecular features of the most active compounds involved in the interaction with biological targets. In addition, the synthetic strategies developed would allow to obtain new chemical entities with improved pharmacodynamic and pharmacokinetic characteristics with respect to the natural precursors. In particular, the compounds were tested as antimicrobials and as inhibitors of α-amylase, fundamental enzyme in glucose metabolism.   The second part of this PhD thesis dealt with xanthohumol, the main prenylflavonoid found in hops and beer, endowed with several bioactivities. By LC-MS/MS, we identified and quantified xanthohumol metabolites in humans, which could be responsible for both beneficial and toxic effects of the natural precursor. The investigation of differences in xanthohumol metabolism in humans would reflect inter-individual differences in microbiota composition, and consequently in metabolic profiles. In addition, the last chapter described the development of a synthetic strategy to build a chemical probe of xanthohumol for the identification of its biological targets. In particular, efforts were made to selectively functionalize the prenyl chain of xanthohumol, without affecting the other parts of the molecule, which were supposed to be relevant to the interaction with the target.","language":"eng","citation":"SYNTHESIS, SAR AND BIOLOGICAL STUDIES OF NATURAL AND NATURE-INSPIRED POLYPHENOLS / L.m. Mattio ; tutor: S. Dallavalle ; coordinatore: A. Pagliarini. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2021 Feb 19. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12014.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/811891/1694794/phd_unimi_R12014.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1198077"},"title":"USE OF ON-FARM DATA AND MILK LEUCOCYTE COMPONENTS FOR MONITORING THE HEALTH OF DAIRY COWS","internalauthor":"MONDINI, SARA","type":"Tesi di dottorato","year":"2025","abstract":"The aim of this PhD project was monitoring cow health and welfare, using on-farm data and leucocytes components in milk. For this reason, the investigation focused on the two main diseases of dairy cows: mastitis and lameness. Critical aspects are linked with these diseases and some of them were considered and discussed in four different experiments.   The first experiment focused on the variability of leucocytes in milk, that affects its use as a detection tool for mastitis. For this reason, the factors that influence neutrophils, lymphocytes and macrophages of milk were analyzed. A total of 848 milk samples from 179 dairy cows bred in 6 farms of Northern Italy were collected and analyzed, with Vetscan DC-Q milk Analyzer (Advanced Animal Diagnostic) and DeLaval Cell Counter (DeLaval), to detect Total Leucocyte Count (TLC), Somatic Cell Count (SCC) and the concentration of neutrophils, macrophages and lymphocyte. The results of the Generalized Mixed Model highlighted that the three fractions of leucocytes were significantly influenced by parity, stage of lactation, and farm. The highest values of neutrophils (>60% of TLC) were found at the beginning and at the end of lactation, the two most critical moments for mastitis onset. In accordance, high level of neutrophils (>63% of TLC) was described as one of the risk factors of high SCC (>100,000 cells/ml), highlighting the possibility to apply neutrophils as indicators of udder issues, after accounting for parity, stage of lactation and management conditions.   The second experiment focused on the reduction of antimicrobials usage to treat and prevent the insurgence of intramammary infections, investigating one of the main critical periods for antimicrobial overuse: dry-off. This experiment proposed a Selective Dry Cow Therapy (SDCT) protocol based on SCC (thresholds 100,000 cells/ml for primiparous cows and 200,000 cells/ml for multiparous ones) and Differential Somatic Cell Count (threshold of 69.3%) to identify the cows to treat and not treat at dry-off, with the aim to investigate the effects on udder health (SCC value). 33% of 243 dairy cows were selected to not be treated at dry-off. The analysis of milk sample at the beginning of lactation highlighted similar udder conditions, SCC (P=0.5) and TLC (P=0.7) were not different between cows treated with or without antimicrobials. On the other hand, the abandonment of antimicrobial therapy at dry-off, together with poor hygiene conditions and long dry periods (> 55 days), was identified as a risk factor of high SCC (>100,000 cells/ml) at the beginning of the subsequent lactation. The proposed SDCT protocol permits to select cows to treat and not treat with antimicrobials at dry-off, reducing efficiently antimicrobials usage without compromising udder health, even if adequate hygiene conditions and proper management of dry period is requested for the successful of the procedure.  The last two experiments were focused on lameness and on-farm data were explored as early indicators of lameness onset. The aim was to produce a starting point for future studies investigating the possibilities of lameness detection without farmers needed to dedicate more work or incur in additional expenses.   In the first experiment, milking (e.g. milk production, milking flows) and behavioral (e.g. lying time, number of steps, lying bouts) data were collected for one year, using only on-farm sensors (Afimilk) in one farm of Northern Italy. From the starting dataset, 3459 daily observations of 67 lame cows were extracted. Generalized Additive Mixed Models were used to model the trends of milking and behavioral parameters in the 30 days before and after the detection of lameness, and derivatives were used to identify the changing points of the function. The results showed a change in most of the parameters before the lameness detection, with different magnitude for the three parity groups of cows considered. The reduction of average milk flow and yield in the first two minutes of milking suggested that the milk ejection is disturbed with lameness onset. Milk production and lying time reported changes, decrease and increase respectively, at least 12 days before lameness detection, emphasizing the possibility, in the future, to detect lameness in early stage using only on-farm data.  In the second experiment, Locomotion Score (LS) and Body Condition Score (BCS) were manually evaluated by two observers for 7 months in 3 farms of Northern Italy. The milking data were automatically collected for each udder quarter by sensors implemented in automatic milking systems (AMS) (e.g. milk production, milk conductivity, milk flows, milking duration). At first, the cows were divided into three classes of lameness using LS (not lame, mildly lame and severely lame). A Mixed Model was performed to evaluate the least squares means of milking parameters of the lameness classes (42,569 observations), and the contrast between groups showed differences in almost all the milking parameters, especially number of visits to AMS, milk flows and milk production. For this reason, an eXtreme Gradient Boosting machine learning algorithm was trained and tested to classify cows in the three LS classes, using as predictors only BCS and milking on-farm data. Balance accuracy, sensitivity and specificity higher than 0.9 were found, suggesting good predictive performances of the algorithm. Shapley values were used to identify the contribution in classification of the variables, and BCS, parity, days in milk, milk production, average and maximum milking flows were reported as the main contributors.  In conclusion, the use of on-farm data and leucocytes components of milk could be a supportive tool for farmers to detect diseases, to reduce antimicrobials usage and to monitor the health status of cows. This is important to guarantee a reduction of the negative consequences of mastitis and lameness on health and welfare of dairy cows, and consequently to preserve productivity of animals, promoting a sustainable dairy farm.","language":"eng","citation":"USE OF ON-FARM DATA AND MILK LEUCOCYTE COMPONENTS FOR MONITORING THE HEALTH OF DAIRY COWS / S. Mondini ; tutor: M. Zucali ; co-tutor: G. Gislon ; coordinatore: S. R. Pilu. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2025 Dec 16. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13685.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 24-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1220759"},"title":"SHAPING STUDENTS ACADEMIC PERFORMANCE: TWO ESSAYS ON THE ROLE OF SCHOOL-LEVEL INTERVENTIONS","internalauthor":"DALPONTE, FEDERICA","type":"Tesi di dottorato","year":"2026","abstract":"The thesis consists of two papers in the field of education economics, which make use of counterfactual econometric techniques to evaluate the impact of specific school-level interventions on students' academic performance in the Italian context. Education is universally acknowledged as a key determinant of human development, yielding substantial returns across economic, health, and social domains. However, substantial disparities in educational achievement and attainment persist, largely shaped by individual attributes and family background characteristics. Therefore, it is of particular interest to investigate if and how specific school-level interventions may foster improvements in students’ academic performance, while also contributing to shape existing inequalities in educational achievement.     The first paper examines the effects of the introduction of school canteens in Italian primary schools on students’ standardized test scores in Italian, mathematics and English. The results indicate that, while no effect is observed in grade 2, a positive and statistically significant effect is found in grade 5 for Italian and English listening. Findings also suggest that the mechanism of increased school time, which theoretically could be favored by the presence of the canteen, is not the one driving the effect of school canteens introduction on academic performance in grade 5. Rather, it is plausible that other mechanisms are at play, on which an hypothesis is made concerning the beneficial effect of socializing with peers during lunchtime. Results also indicate that the introduction of a school canteen contributes to narrowing some existing performance gaps among students, namely those related to gender and socio-economic and cultural status. These findings reveal that the introduction of school canteens in primary schools exerts a positive effect on students’ academic performance, also contributing to reducing some of the existing inequalities, thereby constituting a valuable investment.    The second paper reports the results of the evaluation of a two-year intervention --- implemented in lower secondary schools in Italy and aimed at fostering students’ digital skills through the creation of digital communication products --- on students’ standardized test scores in English, mathematics and Italian. Results indicate that the assignment to the project had a positive and statistically significant impact on digital skills. By contrast, a negative and statistically significant effect is found on academic performance in all subjects, only for students with a higher taste for digital activities. We interpret these findings as the potential result of a “crowding-out” effect on time allocation: the intervention may have increased the time devoted to digital activities outside school for more digitally-oriented individuals, which came at the expense of study time and ultimately reduced academic performance. These findings reveal potential trade-offs between improving digital skills and deteriorating student performance in core subjects, pointing to the necessity of understanding which types of activities at the core of digital skills acquisition initiatives may have the greatest potential to improve digital skills with minimal or no damage to academic performance.","language":"eng","citation":"SHAPING STUDENTS ACADEMIC PERFORMANCE: TWO ESSAYS ON THE ROLE OF SCHOOL-LEVEL INTERVENTIONS / F. Dalponte ; supervisor: G. d’Adda ; co-supervisor: M. Bratti; coordinatore: E. Damiani. Dipartimento di Economia, Management e Metodi Quantitativi, 2026 Feb 26. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14079.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 02-SET-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/932853"},"title":"NEW ADVANCES IN QUANTITATIVE RADIOLOGY: RADIOMICS IN NEURORADIOLOGY APPLIED TO PRIMARY BRAIN TUMORS USING A MACHINE LEARNING APPROACH","internalauthor":"DONISELLI, FABIO MARTINO","type":"Tesi di dottorato","year":"2022","abstract":"Arterial spin labelling (ASL) radiomics analysis to predict IDH mutation and MGMT methylation status in gliomas      Fabio M. Doniselli1,2, Riccardo Pascuzzo1, Eleonora Bruno3, Domenico Aquino1, Mattia Verri, Alberto Redolfi, Valeria Cuccarini1, Marco Moscatelli1,2, Maria Grazia Bruzzone1, Luca Maria Sconfienza2,4     Abstract   Objectives: To evaluate the strength and ability of radiomics features extracted from multiple tumor subregions on MR brain images to predict MGMT promoter (MGMT) methylation status and isocitrate dehydrogenase (IDH) mutation in glioma patients through a multiparametric MRI-based radiomics model, using arterial-spin labelling (ASL) perfusion imaging.   Methods: Retrospective single-institution study in a cohort of 52 glioma patients. Radiomics-based models with a minimal set of relevant features and clinical parameters were built for MGMT methylation and IDH-mutation prediction from a training cohort (31 patients) and tested on an validation cohort (13 patients).   Results: Feature selection methods (Boruta, RFE and LR-EL) identified age and 3 radiomics features for MGMT prediction and 3 features for IDH prediction. For IDH prediction, SVM classifier achieved average 96.8% accuracy and 0.929 AUC during the training phase, and 84.6% accuracy and 0.60 AUC on the test set. For MGMT methylation prediction, SVM classifier achieved average 67.7% accuracy and 0.765 AUC during the training phase, and 38.5% accuracy and 0.429 AUC on the test set.   Conclusions: The classification model based on both demographic (age) and radiomic ASL perfusion characteristics had the best performance in predicting the IDH mutational status of gliomas. This result suggests that the proposed method has promising efficacy in predicting IDH mutational status. We have not obtained a sufficient result trying to correlate radiomics with the MGMT mutational pattern.","language":"eng","citation":"NEW ADVANCES IN QUANTITATIVE RADIOLOGY: RADIOMICS IN NEURORADIOLOGY APPLIED TO PRIMARY BRAIN TUMORS USING A MACHINE LEARNING APPROACH / F.m. Doniselli ; tutor: L.M. Sconfienza ; coordinatore: M. Del Fabbro. Dipartimento di Scienze Biomediche per la Salute, 2022 Jul 05. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12377.pdf","fileformat":"Adobe PDF","fileversion":"preprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/932853/2048633/phd_unimi_R12377.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/935475"},"title":"«NELL'INTERESSE DELL'AUGUSTISSIMA CASA». ASBURGO, LOMBARDIA AUSTRIACA E FEUDI IMPERIALI NELL¿ETÀ DELLE RIFORME","internalauthor":"CASATI, MATTEO ENRICO","type":"Tesi di dottorato","year":"2022","abstract":"The aim of this dissertation is to inspect the policies implemented by the Habsburgs   about the imperial fiefs in Lombardy in the age of reforms. Being scattered mainly along   the borders of Austrian Lombardy, and directly subjected to the Holy Roman Empire,  these feudal entities had for centuries enjoyed various immunities, both fiscal and   jurisdictional. Due to their extraterritoriality, they were often useful as shelters for all   kinds of criminals, as well as storages for smuggled goods, and were therefore a source   of many problems for the tax and legal authorities.  Between the sixties and the seventies of the 18th century, in conjunction with the second wave of reforms, in Vienna it was finally decided to act to solve the problem: within a decade many of these fiefs were acquired by Maria Theresa and aggregated to  the Austrian Lombardy, while others, even if remaining in the hands of their feudal lords,   were fiscally homologated the State in the eighties.  Although the imperial fiefs have been object of an increasing historiographic attention in recent years, their fate in the crucial period of the reforms has not been specifically studied until now. We will therefore try to fill this gap by examining the 18th history of the imperial feudalism in Lombardy, which is also an ideal observatory for evaluating some of the directions, limits and results of the policy of rationalisation and fight against particularisms promoted by the Habsburgs in the roaring years of reformism, with particular attention to the themes of territorial control and the fight against smuggling.   The research therefore fits into two historiographic threads that have been characterised by prolific vitality in the last decades: the study of imperial Italy and the relationship between the Empire and the Italian fiefs, and the studies about the police and the control of the territory.  Based mainly on documentation from Milan, Mantua and Vienna, the dissertation  investigates, on the one hand, the peculiarities of the fiefdoms in question and the  assessments made by the House of Austria in their regard, and, on the other, the ways in   which some of them were aggregated or homologated to the Habsburg dominions, the   opportunities and the limits within which the Austrian sovereigns had to act, both in  general and in specific cases, and finally the results and consequences of these processes from the financial, administrative and police point of view.","language":"ita","citation":"«NELL'INTERESSE DELL'AUGUSTISSIMA CASA». ASBURGO, LOMBARDIA AUSTRIACA E FEUDI IMPERIALI NELL¿ETÀ DELLE RIFORME / M.e. Casati ; tutor: S. Levati ; co-tutor: M. Schnettger ; coordinatore: M. Soresina. Dipartimento di Studi Storici, 2022 Sep 19. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12159.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/935475/2058228/phd_unimi_R12159.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1044970"},"title":"THE YIELDING TRANSITION IN SOFT AMORPHOUS SOLIDS UNDER OSCILLATORY SHEAR: FROM MICROSCOPIC REARRANGEMENTS TO MACROSCOPIC FAILURE","internalauthor":"BRIZIOLI, MATTEO","type":"Tesi di dottorato","year":"2024","abstract":"Complex fluids such as polymer solutions, colloidal suspensions, emulsions, or foams are ubiquitous in our daily lives. These soft materials often display a non-trivial response to mechanical perturbations, which depends both on the time scale and the amplitude of the applied perturbation. In particular, yield stress fluids are a wide class of soft materials that respond like solids to small stresses but exhibit fluid-like behavior when the applied stress exceeds a certain threshold value (the yield stress). Beyond its major relevance in various applications from the cosmetic to the food industry, the yielding transition of these soft materials is considered to be a convenient experimental model for the more general phenomenon of mechanical failure in amorphous solids.      By exploiting a custom shear-cell coupled to a standard bright-field microscope, we provide a unique multiscale analysis of the yielding transition under oscillatory shear overcoming the limitation of conventional rheological measurements. Through a novel acquisition protocol and image analysis scheme, we are able to accurately monitor shear-induced structural rearrangements within the material and characterize the mesoscopic deformation field, while simultaneously measuring the rheological response. The investigation of three distinct yield stress materials revealed a complex interplay between brittleness, shear band formation, and features of the shear-induced microscopic dynamics. Specifically, for the most ductile material, we observe Gaussian and non-cooperative particle dynamics, contrasting with the non-Gaussian and cooperative dynamics, and the occurrence of shear bands observed for the most brittle one. These findings offer valuable insights into material behavior under dynamic conditions, paving the way for a deeper understanding of yielding phenomena.","language":"eng","citation":"THE YIELDING TRANSITION IN SOFT AMORPHOUS SOLIDS UNDER OSCILLATORY SHEAR: FROM MICROSCOPIC REARRANGEMENTS TO MACROSCOPIC FAILURE / M. Brizioli ; tutor: F. Giavazzi ; director of the school: R. Vecchi. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2024 Apr 16. 36. ciclo","filename":"phd_unimi_R12811.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1044970/2397887/phd_unimi_R12811.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/826122"},"title":"THE INFLUENCE OF MAOISM AND OF CHINESE COMMUNISM ON THE ITALIAN LEFT, 1949-1976","internalauthor":"GABBAS, MARCO","type":"Tesi di dottorato","year":"2021","abstract":"This work is about the influence of Maoism and of Chinese Communism on the Italian Left since 1949 until 1976.","language":"eng","citation":"THE INFLUENCE OF MAOISM AND OF CHINESE COMMUNISM ON THE ITALIAN LEFT, 1949-1976 / M. Gabbas ; tutor: D. Saresella. Università degli Studi di Milano, 2021 Mar 23. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11954.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/826122/1740884/phd_unimi_R11954.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1048348"},"title":"VIRTUAL ANTHROPOLOGY AND COMMINGLED SKELETAL REMAINS. RESOURCES AND POTENTIAL FOR PERSONAL IDENTIFICATION IN HUMANITARIAN FORENSIC CONTEXTS","internalauthor":"PALAMENGHI, ANDREA","type":"Tesi di dottorato","year":"2024","abstract":"Commingled skeletal remains represent a compelling topic in forensic anthropology, especially in view of the recent mass disasters in the Mediterranean Sea related to the migration crisis. With over 1,000 alleged victims, and thousands of commingled skeletal remains, the shipwreck of April, 8th, 2015 stands among these recurrent tragedies. The advancements of imaging techniques and 3D modelling have brought about innovative tools to forensic anthropology and paved the way to novel research avenues for the analysis of skeletal remains and for personal identification both of the living and the dead, as well. Foremost, research has extensively explored the quantification of similarities and differences between 3D models of anatomical structures as a proxy to infer relationships between AM e PM records and between bones of an individual. The general assumption is that the lowest is the distance between two superimposed models, the most likely is the possibility that the models share a common origin, hence they belong to the same individual.  This dissertation delves into these innovative approaches utilizing the 3D-3D superimposition of virtual bone models to facilitate the sorting of commingled remains, ultimately seeking to comprehend the potential practical application in real case scenarios. The structure of this work follows the two main steps for the re- association of commingled bones, i.e., the joint-matching and the pair-matching, resulting in four research lines. The 3D models were produced with several acquisition techniques (laser scanning, sterephotogrammetry, segmentation and surface scanning) from bones of the CAL (Collezione Antropologica LABANOF) skeletal collection, from CT images of a hospital database and from the skeletal remains of the April, 18th, 2015 shipwreck.  The 3D-3D joint-matching test on atlases and axes provided an exclusionary method and brought into question the validity of this method to re-associate planar joints. The 3D-3D pair-matching of iliac and of pubic bones further demonstrated that the method can be applied to portions of bones, as long as the extent of fragmentation preserves comparable structures. Indeed, the systematic test on the effect of postmortem damage on the pair-matching verified that 3D-3D superimposition is heavily impaired by the incompleteness of the remains. This study therefore confirmed with novel evidence the major setback that postmortem damage creates  for any anthropological analysis. The application of the technique to a set of scapulae from the commingled remains of the shipwreck of April 18th, 2015, showed that 3D- 3D superimposition may represent a beneficial tool for the resolution of the commingling.  This PhD project investigated unaddressed questions about 3D-3D superimposition applied to commingled remains. Indeed, the aim was not to replace visual and osteometric comparisons but to explore the possible application of an additional tool to be used together with traditional methods to strengthen the results within a multidisciplinary approach. Future research would better enlighten the role of up-to- date virtual techniques in the resolution of commingled assemblages from humanitarian contexts.","language":"eng","citation":"VIRTUAL ANTHROPOLOGY AND COMMINGLED SKELETAL REMAINS. RESOURCES AND POTENTIAL FOR PERSONAL IDENTIFICATION IN HUMANITARIAN FORENSIC CONTEXTS / A. Palamenghi ; tutor:  D. M. Gibelli ; co-tutor: D. De Angelis ; coordinator: C. Sforza. Dipartimento di Scienze Biomediche per la Salute, 2024 May 28. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12894.pdf","fileformat":"Adobe PDF","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1048348/2406640/phd_unimi_R12894.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1197648"},"title":"AGRO-HYDROLOGICAL MODELS FOR THE ASSESSMENT OF INNOVATIVE IRRIGATION PRACTICES IN RICE AREAS","internalauthor":"GILARDI, GIULIO LUCA CRISTIAN","type":"Tesi di dottorato","year":"2025","abstract":"This dissertation addresses the outlined research needs through: I) developing and applying a prototype agro‑hydrological framework to assess the effects of alternative rice irrigation strategies on the water resource system at the irrigation district scale (San Giorgio di Lomellina district, about 1,000 hectares); II) using the experience gained with the prototype to develop a more flexible modelling framework integrated with a GIS, QGIS-SWAP-Paddy, suitable for simulating water flows in irrigation systems characterized by rice cultivation, also taking into account other areas (whether cultivated or not, e.g., bare soils, urban areas, etc.); III) defining the most suitable PTFs for describing the hydraulic characteristics of the Lomellina paddy soils, and IV) applying QGIS-SWAP-Paddy to quantify the impacts of AWD and other irrigation strategies on the Lomellina irrigation system water balance.  The dissertation is organized as follows:  -  Chapter 2 presents the development, calibration, and application of a prototype agro‑hydrological framework to a pilot irrigation district to evaluate the effects on the water resource system of different rice irrigation scenarios. This work has been published in the paper: Gilardi, G.L.C.¹, Mayer, A.¹, Rienzner, M.¹, Romani, M.², & Facchi, A.¹ (2023). Effect of Alternate Wetting and Drying (AWD) and Other Irrigation Management Strategies on Water Resources in Rice‑Producing Areas of Northern Italy. Water, 15(12), 2150. https://doi.org/10.3390/w15122150, ¹Department of Agricultural and Environmental Sciences, University of Milan, 20133 Milan, Italy, ²Centro Ricerche sul Riso, Ente Nazionale Risi, 27030 Castello D’Agogna, Italy;  -  Chapter 3 describes the QGIS‑SWAP‑Paddy framework, detailing its workflow, data structure, and showing how the framework can be applied to agricultural areas including agricultural fields and irrigation networks. The framework is presented as an operational modelling tool tailored to low‑land agricultural areas, particularly those dedicated to rice cultivation. This chapter will also serve as the basis for a future comprehensive manual of the developed tool, which will be accompanied by a more concise user guide, in view of its potential publication in the official repository of plugins for the open‑source QGIS software. Moreover, it will be the basis for a scientific paper illustrating the tool;  -  Chapter 4 focuses on the identification of the most suitable PTFs for estimating key hydraulic parameters for the Lomellina paddy soils. This work has formed the basis for the paper just submitted to Soil & Tillage Research: Tkachenko, D.¹, Rienzner, M.¹, Gilardi, G.L.C.¹, Sciaccaluga, M.², Brenna, S.², Gandolfi, C.¹, & Facchi, A.¹. Hydro-pedotransfer functions for the main Italian rice district, ¹Department of Agricultural and Environmental Sciences, University of Milan, 20133 Milan, Italy, ²Ente Regionale per i Servizi all’Agricoltura e alle Foreste (ERSAF), Regione Lombardia;  15  -  Chapter 5 describes the application of the identified PTFs to the Lomellina paddy soils and the use of QGIS‑SWAP‑Paddy framework to assess the effects of AWD and other rice irrigation strategies to the Lomellina irrigation system. This work will serve as the basis for a forthcoming publication on the use of the tool for exploring different irrigation scenarios for the Lomellina district. In the next steps of the PROMEDRICE project (PRIMA-Section 2, 2023 - 2026), the framework will be integrated with the MODFLOW model (https://www.usgs.gov/software/modflow-6-usgs-modular-hydrologic-model/), simulating the water flows in the groundwater system of the Lomellina (under development by researchers from Earth science Department, UNIMI). The objective will be to produce an estimate of the different irrigation strategies, also under climate change conditions, on groundwater aquifer levels and therefore on water reuse in the irrigation system.  -  Chapter 6 summarizes the main findings, discusses implications for irrigation management, and outlines directions for future research.  Annex 1 presents a work that was carried out alongside the main research activities presented in this Thesis, but which is closely connected to them. It illustrates the design and implementation of an extensive monitoring campaign carried out in 2021 in the San Giorgio di Lomellina paddy district to evaluate the occurrence of selected herbicides and nutrient losses in surface and groundwater under the current rice cropping strategies. Although my direct involvement in this work was limited and focused on the analysis of data collected, it provided a meaningful opportunity to contribute specific expertise and to broaden the environmental perspective on rice cultivation in the Lomellina district. This chapter is based on the Author’s Accepted Manuscript of: Tediosi A., Ferrari F., Voccia D. Gharsallah O., Lamastra L., Botteri L., Rossi R., Ferrari T., Ballerini N., Gilardi G.L.C., & Facchi A. (2024) Herbicide and nutrient monitoring in surface waters and groundwater of a paddy district in northern Italy. Environmental Science and Pollution Research, 31:52963–52979. https://doi.org/10.1007/s11356-024-34692-x.","language":"eng","citation":"AGRO-HYDROLOGICAL MODELS FOR THE ASSESSMENT OF INNOVATIVE IRRIGATION PRACTICES IN RICE AREAS / G.l.c. Gilardi ; supervisor: A. Facchi ; co-supervisor: C. Gandolfi ; coordinator: S. R. Pilu. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2025 Dec 17. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13678.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1197648/3188351/phd_unimi_R13678.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1193195"},"title":"DISSECTING THE TRANSCRIPTOMIC IDENTITY OF BRG DURING NEOCORTICAL DEVELOPMENT AND EVOLUTION: FROM MORPHOLOGY TO METABOLISM AND DISEASE","internalauthor":"COKORAC, NIKOLA","type":"Tesi di dottorato","year":"2025","abstract":"Basal radial glia (bRG) play a crucial role in neocortical development by regulating the production and migration of cortical neurons. Interestingly, neurogenic potential and neuronal migration are highly dependent on bRG morphology, with more complex morphotypes exhibiting higher neurogenic and scaffolding potentials. Although the link between proliferative capacity and morphological heterogeneity is becoming increasingly evident, mechanisms underlying this relationship are poorly understood. To investigate the mechanism underlying the proliferative capacity and morphology of bRG in human cortical organoids, we knocked out ADD1, a known morphoregulatory gene. Our results demonstrate that ADD1 regulates cell fate of radial glia, and is required for correct progression of neurogenesis during neocortical development. In parallel, due to its poor characterization, in this PhD thesis, we also investigated the transcriptomic profile of bRG, and identified novel morphoregulatory and metabolic players distinguishing bRG from other cell populations, as well as genes linked to malformations of cortical development, a group of rare but severe disorders of neocortical development. Finally, we placed bRG in the evolutionary context by exploring their transcriptomic signature across the developing human and mouse neocortex, and mouse dentate gyrus. Remarkably, our results suggested that bRG in the mouse dentate gyrus are transcriptionally more resembling those in human neocortex than mouse neocortex. These findings contest the traditional hypothesis supporting the view that highly specialized bRG traits might have existed in the common ancestor of all placental mammals, but were subsequently abandoned in some mammals. Overall, this PhD Thesis brings novel insights into the developmental and evolutionary role of bRG cells, and reports molecular players involved in distinct morphological, metabolic and cytoprotective behavior of bRG.","language":"eng","citation":"DISSECTING THE TRANSCRIPTOMIC IDENTITY OF BRG DURING NEOCORTICAL DEVELOPMENT AND EVOLUTION: FROM MORPHOLOGY TO METABOLISM AND DISEASE / N. Cokorac ; tutor: N. Kalebic ;  co-tutor: G. Testa ;  coordinator: D. Pasini. Dipartimento di Oncologia ed Emato-Oncologia, 2025. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13474.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1193195/3174869/phd_unimi_R13474.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1161761"},"title":"CHARACTERIZATION OF BIOLOGICALLY ACTIVE MOLECULES OFPHARMACOLOGICAL INTEREST EXTRACTED FROM MICROALGAE BYBIOSUSTAINABLE PROCESSES","internalauthor":"LIO, ELIA","type":"Tesi di dottorato","year":"2025","abstract":"Microalgae represent a promising source of high-value secondary metabolites, such as antimicrobial, antioxidant, and immunomodulatory compounds, which are of considerable interest to the pharmaceutical industry. However, conventional extraction technologies—often based on environmentally harmful organic solvents—limit their potential for large-scale industrial exploitation.  In this context, the research carried out during my PhD program aimed to develop integrated strategies for the sustainable extraction of microalgal bioactive molecules, prioritizing the use of green solvents such as dimethyl carbonate (DMC), in line with the principles of green chemistry.  The study focused on the cultivation of the Micractinium pusillum (CELP1) strain, isolated from agricultural water sources in Sicily (Italy), and its comparison with the model species Chlamydomonas reinhardtii cc-1374. Both strains were evaluated in terms of growth kinetics, biomass productivity, extraction yield, and antimicrobial activity, revealing significant differences in their metabolic composition and bioactivity profiles.  In parallel, the industrial strain Chlorella sorokiniana was cultivated under both autotrophic and mixotrophic conditions using agro-industrial by-products as alternative nutrient sources, thereby promoting circular bioeconomy models and reducing cultivation costs. The biomass of Chlorella sorokiniana was then subjected to a controlled alkaline treatment with sodium hydroxide (NaOH) to selectively remove chlorophyll, enhancing the purity and quality of the extracts without compromising the integrity of the bioactive compounds.  Extracts from Chlorella sorokiniana were characterized by gas chromatography–mass spectrometry (GC–MS) and tested for antimicrobial activity against selected bacterial strains. The results confirmed the effectiveness of green solvent-based extraction methods in preserving and enhancing the bioactive content of microalgal biomass, achieving a significant improvement in antimicrobial properties compared to conventional methods based on chlorinated solvents.","language":"eng","citation":"CHARACTERIZATION OF BIOLOGICALLY ACTIVE MOLECULES OFPHARMACOLOGICAL INTEREST EXTRACTED FROM MICROALGAE BYBIOSUSTAINABLE PROCESSES / E. Lio ; supervisore: G. Aldini ; co-supervisore: F. Secundo ; coordinator: G. Vistoli. - Milano. Dipartimento di Scienze Farmaceutiche, 2025 May 09. 37. ciclo","filename":"phd_unimi_R13554.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1161761/2971391/phd_unimi_R13554.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/924352"},"title":"EVALUATION AND CHARACTERIZATION OF DIETARY STRATEGIES ON ENVIRONMENTAL SUSTAINABILITY OF DAIRY COW MILK PRODUCTION","internalauthor":"ROTA GRAZIOSI, ANDREA","type":"Tesi di dottorato","year":"2022","abstract":"The livestock sector is facing different challenges, and the demand for higher sustainability seems to be one of the most urgent. This PhD project debated, in particular, the environmental impacts related to ruminant nutrition, focusing on dairy cows, since nutrition is bound tightly to two of the most important sources of impact: enteric CH4 emission and land use change (LUC). Enteric CH4 emission from ruminants represents 29-38% of the total (anthropic + natural) emission of this powerful (21 CO2 equivalent) greenhouse gas. The production of CH4 is a physiological process used by ruminants to discharge the [H] resulting from rumen fermentation. Different strategies can be implemented to mitigate this impact, and they can be roughly grouped into three main categories: animal and feed management, diet formulation, and rumen manipulation. The second issue investigated in the project is the high reliance of European livestock on soybean meal as a protein source for diet formulation. A total of 30 million tonnes of this feedstuff was imported into Europe in 2020. The main countries of origin are in South America (65% of total import), where 20% of soybean meal production was linked with deforestation (and consequently LUC) in the last decades. Clearing these areas means loss of carbon sink and emission of CO2 in the atmosphere. Other feedstuffs, like grain legumes, oilseed meals alternative to soybean, and high quality forages could be considered to provide protein feed with a lower environmental cost.  In this context, the PhD project was developed as follows:  \uf0b7 To address the problem of CH4 emission, plant essential oils, as modulators of rumen fermentation, were evaluated (Experiment 1). Furthermore, the effect on CH4 emission of different forages in the diet of dairy cows was investigated (Experiment 2). For validation of mitigation strategies and inventory computation of emissions at a national scale, country-specific equations to quantify CH4 emission were evaluated (Experiment 3).  \uf0b7 To address the problem of soybean meal environmental impact, soybean silage and responsible soybean meal (not connected with land use change) were evaluated as protein source alternatives to soybean meal in the diet of lactating cows (Experiments 4 and 5).  Enteric methane direct emission  In the first experiment, Achille moschata essential oil and its main pure components, namely bornyl acetate, camphor, and eucalyptol, were evaluated in an in vitro experiment. The trial comprehended a short-term in vitro incubation (48 h), with 200 mg of compound per L of inoculum, and a long-term one by continuous fermenter (9 d), with 100 mg/L for each compound. In the first incubation, no differences due to the treatments were found for in vitro gas production (on average, 30.4 mL/200 mg DM, P = 0.772 at 24 h and 45.2 mL/200 mg DM, P = 0.545 at 48 h). Camphor and eucalyptol reduced CH4 production when expressed as % of gas production at 48 h (P < 0.05): -7.4% and -7% compared to control. In the second incubation, CH4 was reduced by eucalyptol (-18%, P < 0.05). Regarding volatile fatty acids, the main effects were a decrease of total production for camphor (-19.5%, P < 0.05) and an increase in acetate production at 9 d with bornyl acetate and camphor (+13% and 7.6%, respectively, P < 0.05) compared to control. Total protozoa count was increased compared to the control (on average: +37%, P = 0.006, at 48 h and +48%, P < 0.001, at 9 d) with all the pure compounds tested. In the short-term incubation, all the treatments reduced Bacteroidetes (30.3%, on average, vs. 37.1% of control, P = 0.014) and Firmicutes (26.3%, on average, vs. 30.7% of control, P = 0.031) abundances but increased Proteobacteria (36.0%, on average, vs. 22.5% of control, P = 0.014). In the long-term incubation, eucalyptol increased the genus Ruminococcus abundance (2.60% vs. 1.18% of control, P = 0.011). An adaptation at long time incubation was observed. In particular, considering eucalyptol addition at 9 d incubation, VFA production was reduced (26.8 vs. 33.3 mmol of control, P < 0.05) contrary to the 48 h incubation (P = 0.189). Furthermore, the treatments affected protozoa genera relative abundances at 24 h (increased abundance for Entodinium with all the treatments, P < 0.001, and reduced for Diplodinium, P = 0.001); at 9 d, instead, protozoa genera relative abundances were not affected by the treatment. The additives tested showed potential in reducing CH4 production without compromising the overall fermentation efficiency.  A meta-analysis (Experiment 2) investigated the effects on lactation performance and enteric CH4 of the main forage included in the diet. In the dataset, composed of in vivo experiments, four main forage bases were evaluated: corn silage, alfalfa silage, grass silage, and green forage. Cows fed corn, and alfalfa silages had the highest DMI (21.9 and 22.0 kg/d, P < 0.05) and milk yield (29.7 and 30.4 kg/d, P < 0.05). On the opposite, NDF digestibility was highest for grass silage and green forage (67.6% and 73.1%, P < 0.05) than corn and alfalfa silages (51.8% on average). CH4 production was lower (P < 0.05) for green forage (332 g/d) than the silage diets (on average 438 g/d). Instead, corn silage and alfalfa silage gave the lowest CH4 per kg of milk yield (14.2 g/kg and 14.9 g/kg, P < 0.05). Considering CH4 per kg of DMI, the only difference was between corn silage and grass silage (19.7 g/kg vs. 21.3 g/kg respectively for corn and grass silage, P < 0.05). Finally, prediction models for CH4 production were obtained through a step-wise multi regression. In particular, the models for the prediction of:  CH4 in g/d (CH4 = - 65.3(±63.7) + 11.6(±1.67) × DMI - 4.47(±1.09) × CP - 0.86(±0.33) × Starch + 2.62(±0.78) × OM digestibility + 30.8(±9.45) × Milk fat)  and for  CH4 in g/kg of milk yield (CH4/milk yield = - 55.5(±20.1) - 0.37(±0.13) × DMI + 0.18(±0.05) × Total forage inclusion on diet DM - 0.10(±0.04) × Inclusion of the main forage on diet DM + 0.48(±0.21) × OM + 0.14(±0.06) × NDF + 1.98(±0.86) × Milk fat +4.34(±1.66) × Milk protein)  showed high precision (R2 = 95.4% and 88.6%, respectively), but the best AIC value (320) was found for the model predicting CH4 in g/kg DMI:  CH4/kg DMI = 6.16(±3.89) - 0.36(±0.03) × CP + 0.12(±0.05) ×OM digestibility + 3.77(±0.56) × Milk fat - 3.94(±1.07) × Milk fat yield.  A dataset (66 observations in total) of three in vivo experiments conducted in Italy on lactating cows in respiration chambers was built to evaluate IPCC Tier 2 equations to estimate enteric CH4 production (Experiment 3). In the dataset, the CH4 conversion factor (conversion of gross energy intake into enteric CH4 energy) was lowest for a diet based on grass and alfalfa silages (5.05%, P < 0.05), while the others values ranged between 5.41 and 5.92%. On average, energy digestibility was 69.0% across the dataset, but the diet based on hays had a lower value (64.8%, P < 0.05). The IPCC (2019) Tier 2 (conversion factor = 5.7% or 6.1% for diet with NDF concentration < 35% or >35%, respectively; digestible energy = 70%) gave, on average, a value of CH4 production not statistically different from the ones measured in vivo (382 vs. 388 g/d in vivo, P > 0.05). The IPCC (2006) Tier 2 (conversion factor = 6.5%, digestible energy = 70%) over-predicted CH4 emission (428 vs. 388 g/d in vivo, P < 0.05; μ = -1.05). The most precise models were the two considering digestible energy equal to 70% and average values of conversion factor for IPCC (2006) and IPCC (2019) (R = 0.630); the most accurate models was the one considering a conversion factor equal to 5.7% and energy digestibility measured in vivo (Cb = 0.995). Overall, the best performance among the predicting models tested was for the one based on a conversion factor equal to 5.7% and energy digestibility of 70% (CCC = 0.579 and RMPSE = 9.10%).  Use of alternative protein source to conventional soybean meal  The dietary inclusion of soybean silage in partial replacement of soybean meal for dairy cows was evaluated in vivo in lactating cow diets (Experiment 4). Cows were fed two diets, one with 12.4% of DM from soybean silage in substitution of 35% of the soybean meal of the control diet. The treatment did not affect DMI and milk yield (on average, 23.7 kg/d, P = 0.659, and 33.0 kg/d, P = 0.377, respectively). Cows fed the soybean silage diet had lower milk protein concentration (3.43% vs. 3.55% of the control, P < 0.001) and higher milk urea (30.5 vs. 28.7 mg/dL, P = 0.002). The soybean silage had lower nutrient digestibility than the control: DMD 65.2% vs. 68.6%, OMD 66.4% vs. 69.8%, NDFD 31.5% vs. 38.8% (respectively for soybean silage and control diet; P < 0.001 for all of them). Regarding N balance, cows fed soybean silage excreted more nitrogen in the urines (32.3 % of N intake vs. 28.9%, P = 0.005) and less in the milk (31.3% vs. 32.7%, P =0.003) than the control. When used as a protein source alternative to soybean meal, soybean silage sustained comparable milk production, but NDF digestibility and N use efficiency should be improved.  The environmental impact of the use of soybean silage in comparison to a control diet with soybean meal as the main protein source was evaluated through an LCA approach (Experiment 5). In addition, two scenarios were included in the study, considering the two diets mentioned before, but with soybean meal not connected to LUC (responsible soybean meal). Regarding the single forages, soybean silage had higher global warming potential than alfalfa hay (477 vs. 201 kg CO2eq/ton DM), also when this was expressed per tonnes of protein production (2439 and 1034 kg CO2eq/ton CP, respectively), probably due to the lower contribution of the cultivation phase for alfalfa, being a multi-year crop. The scenario with soybean silage reduced the global warming potential per kg of fat and protein corrected milk (1.17 kg CO2eq) compared to the control (1.38 kg CO2eq). Responsible soybean meal reduced the global warming potential per kg of fat and protein corrected milk (1.13 kg CO2eq/kg vs. 1.38 of the scenario with the control diet). Overall, the best result per kg of fat and protein corrected milk was obtained when responsible soybean meal and soybean silage were used in combination (1.01 kg CO2eq). Also, when global warming potential was evaluated per daily fed TMR, the impact was lowest for the scenario with responsible soybean meal (13.4 kg CO2eq/d) due to the lower contribution of soybean meal to the total impact (11% vs. 43% of the control). Therefore, the two alternative protein sources tested should be preferred when considering environmental impact compared to conventional soybean meals.","language":"eng","citation":"EVALUATION AND CHARACTERIZATION OF DIETARY STRATEGIES ON ENVIRONMENTAL SUSTAINABILITY OF DAIRY COW MILK PRODUCTION / A. Rota Graziosi ; coordinatore: D. Bassi ; supervisore: M. Spanghero, K. Kalscheur ; tutor: S. Colombini. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2022 Apr 27. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12271.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/924352/2024605/phd_unimi_R12271.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/945908"},"title":"IN VITRO GENOTOXIC EVALUATION OF ENVIRONMENTAL POLLUTANTS","internalauthor":"MELZI, GLORIA","type":"Tesi di dottorato","year":"2022","abstract":"Particulate matter (PM) is a complex and heterogeneous mixture of particles and has been recognized as a threat for human health. Hazardousness of PM is not only dependent on its dimensions, but also and in particular on its chemical composition. Initially, PM deposition in human alveoli induces oxidative stress and production of pro-inflammatory mediators. Later, the onset of DNA damages and their possible misrepair can lead to mutations.  This project is part of the PRIN 2017 project RHAPS (Redox-activity and Health-effects of Atmospheric Primary and Secondary aerosol) and of the Horizon2020 project RAPTOR (Research of Aviation PM Technologies, mOdelling and Regulation). The aim of this research is to evaluate the effect of PM coming from different sources on a bronchial epithelial cell line (BEAS-2B) and lung epithelial cell line (Calu-3) considering oxidative stress, genotoxicity, and inflammation as main endpoints.  RHAPS campaign allowed the collection and analysis of different dusts and filters collected in winter and in summer 2021. Winter PM was collected in Bologna (urban site) and San Pietro Capofiume (BO, rural site), while summer only in the site of Bologna. Dusts were diluted in water and used at different concentration to treat the cells, while PM1 was extracted in water with mechanic agitation and cells were treated with the extract diluted 1:10 in complete medium. RAPTOR allowed the collection of the emission of different types of aircraft engines, that were testes in air-liquid interface condition with an innovative method of exposure, the Cloud system, which allow the nebulization of the PM samples and the consequent deposition on the cells.  All the analysis were performed at 24 hours, with the only exception of reactive oxygen species (ROS) detection that was analysed at 30 minutes and 1 hours. Cell viability was assessed with the MTT assay (RHAPS) and LDH assay (RAPTOR) and results were considered in order to avoid the use of cytotoxic concentration of further tests. ROS were detected with DCFH-DA assay. Moreover, comet assay modified with endonucleases ENDOIII and FPG allowed the detection of oxidative damage on the DNA bases. The alkaline version of the comet assay, the immunofluorescence for the phosphorylated histone H2AX (γ-H2AX), and the micronuclei test were used to highlight DNA damage at single and double strands as well as at chromosomal level. Inflammation was evaluated through the analysis of the release of interleukin-8 (IL-8) and CXCL-8 mRNA expression. Gene expression analysis was performed also for other genes involved in the DNA repair pathway (ATM and GADD45α), oxidative stress (HMOX and NQO1), and other mechanisms (ACE-2 and MUC5AC).  Differences were detected in all the assays’ results among the samples analysed. Some samples showed increase level of ROS and oxidised DNA bases. Moreover, BEAS-2B cells resulted to be very sensitive to DNA damage as analysed by the presence of micronuclei and γ-H2AX. IL-8 secretion is stimulated in particular in some of the samples analysed, and its gene expression does not differ much from control level. Also, the other genes analysed showed different pattern of activation, depending on the samples with which they were treated.  Interestingly, these results could be explained at the light of the chemical composition of the PM more than with the only analysis of PM mass concentration parameter; chemical composition seems to really drive the toxicological effect highlighted in this research.","language":"eng","citation":"IN VITRO GENOTOXIC EVALUATION OF ENVIRONMENTAL POLLUTANTS / G. Melzi ; tutor: M. Marinovich ; coordinatore: D. G. Norata. Dipartimento di Scienze Farmacologiche e Biomolecolari, 2022. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12621.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/945908/2098220/phd_unimi_R12621.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1044528"},"title":"TOWARD A BETTER CLEANING AND SELECTIVITY IN ELECTROANALYSIS: TIO2-BASED SENSORS AND ENANTIOSELECTIVE MATERIALS","internalauthor":"COMIS, SILVIA","type":"Tesi di dottorato","year":"2024","abstract":"In the latest years the concern on environmental issues has grown dramatically. One of the major problems of environmental chemistry are emerging contaminants (ECs), which are not commonly monitored in the environment. They can cause undesirable effects on ecosystems and human health. This group of substances includes pharmaceutical and personal care products (PPCPs), endocrine disrupting chemicals, hormones, pesticides, plasticizers, flame retardants and so on. Some of these emerging contaminants have been added to the list of priority substances and corresponding individual environmental quality standards have been set. These substances include pharmaceuticals (macrolide antibiotics, estrogenic hormones, carbamazepine, diclofenac, ibuprofen), industrial chemicals (bisphenol A), metals (silver) and pesticides (triclosan, nicosulfuron, glyphosate, neonicotinoids, pyrethroids).  Modern analytical techniques can easily detect emerging contaminants in the environment, but they are expensive and time consuming. In this context, electrochemical sensors could overcome these problems since they are easy to use, they can be portable, disposable and they can be adapted to every necessity.Thanks to their properties and characteristics, such as high active surface, increased surface/volume ratio, increased selectivity, nanomaterials are broadly used in a wide range of applications, like energy, catalysis and electroanalysis.  One of the most valued characteristics for modern sensors are self-cleaning properties, i.e. the possibility to use the sensor more than once and to detect analytes in complex matrices, remotely without the need to clean and restore them for long time.   Starting from the aforementioned points, the aim of this PhD thesis is the study of different materials to enhance the selectivity and the cleaning properties of electrochemical sensors. In particular, titanium dioxide was studied for its photocatalytic activity to give photo-renewable properties to electrochemical sensors using different supports (fluorine-doped tin oxide glass electrodes and gold disk microelectrodes) in the detection of different emerging contaminants. Its properties were also studied for the photoelectrochemical detection of ciprofloxacin, a fluoroquinolone antibiotic. Titanium dioxide was coupled with gold nanoparticles (AuNPs) to enhance its signal and with mesoporous silica to increase the selectivity of the devices.  At first, the focus was on the study of the aging time of the titanium dioxide sol and how it influences the electrochemical and photoelectrochemical performances on the final structures. The starting device, an FTO glass, was covered with titanium dioxide and it was electrochemically characterised by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), atomic force microscopy (AFM) and transient photocurrent analysis. Once the study of the aging time of the sol was over, AuNPs were added to the device to form a heterojunction. This device was used for the detection of different emerging contaminants and the photocatalytic properties of TiO2 were used to photo-renew the surface of the sensor.  Then this device was used for the photoelectrochemical detection of ciprofloxacin with different light sources. In particular, a low-power light source was used for this purpose, an UV LED. The determination of ciprofloxacin was also possible at low applied potential (+0.1 V vs SCE) and with good detection limits and good sensitivity. The analysis of possible interferences showed that the device was sensible to the presence of humic acids at high concentrations. For this reason, vertically aligned mesoporous silica was added to the device, in order to use its porosity to load gold nanoparticles and to use the charge- and size-exclusion properties of the material. The device was electrochemically characterised with CV, EIS, transmission electron microscopy (TEM) and transient photocurrent analysis. Then ciprofloxacin was detected with this device, obtaining good analytical parameters. Moreover, possible interferents were analysed and, in this case, even high concentrations of humic acids did not interfere with the determination of ciprofloxacin.  The photo-renewable properties of titanium dioxide were also studied using a gold disk microelectrode in the presence of dopamine, a molecule known for its soiling problems. The titanium dioxide layer was deposited onto the microelectrode surface through a pseudo-calcination process and its behaviour was studied after the use of the sensor for the detection of dopamine. It has been seen that it is possible to restore the initial properties of the electrode even after its soiling.   In last part of this PhD thesis, the enantioselective properties of oligo-BT2T4 enantiopure films and the electrocatalytic properties of multi-walled carbon nanotubes (MWCNTs) were studied together on the same device at the same time. At first the electrochemical properties of the materials were studied using a non-chiral probe in CV and EIS. Then the enantioselectivity of the oligo-BT2T4 enantiopure films was tested using a chiral probe in cyclic voltammetry. The surface of the device was also analysed using scanning electron microscopy (SEM). The presence of MWCNTs allows the detection of the chiral probe at lower potentials than would have happened only with the enantiopure film, thus having a catalytic effect.  In conclusion, several materials are here investigated starting from their physico-chemical and electrochemical characterizations. Their application as electroanalytical sensors is explored, evidencing the presence of synergistic effects in the hybrid systems with respect to the single components, assuring enhanced properties and superior performances.","language":"eng","citation":"TOWARD A BETTER CLEANING AND SELECTIVITY IN ELECTROANALYSIS: TIO2-BASED SENSORS AND ENANTIOSELECTIVE MATERIALS / S. Comis ; tutor: L. Falciola ; coordinatore: D. Passarella. Dipartimento di Chimica, 2024 Apr 19. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R13061.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1044528/2396989/phd_unimi_R13061.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1205584"},"title":"THE ROBOTFALCON: A NEW METHODOLOGY TO STUDY PREY-PREDATOR INTERACTION AND AN INNOVATIVE BIRD DETERRENCE TOOL","internalauthor":"VERTUA, IRENE","type":"Tesi di dottorato","year":"2026","abstract":"Predation and predator–prey interactions are among the key processes shaping species traits and the functioning of ecosystems. Predators can influence prey through both lethal and non-lethal effects. The latter are less straightforward and therefore less explored than the former, yet they are expected to be of comparable, if not greater, importance in shaping prey adaptations. Birds, due to their complex anti-predator behaviours, are expected to be strongly influenced by non-lethal effects, such as fear-mediated shifts in distribution in space and time, camouflage, and escape behaviours or group responses. This thesis examines the anti-predatory responses of different bird species, at multiple levels of organisation and across different contexts, to the non-lethal threat posed by the RobotFalcon (RF), and tests its applicability as a deterrence tool. The RF is a predator-like fixed-wing aircraft resembling a peregrine falcon, which allows researchers to manipulate the predator component of predator–prey interactions, thereby overcoming several challenges typically associated with studying this interplay. Chapter I investigates how individual homing pigeons adjust their behaviour when exposed to a threat (i.e. the RF) along their stereotyped homing route. Under predation risk, individuals prioritise altitude adjustments over route changes, challenging predictions from the Landscape of Fear framework. Chapter II explores the interplay between individual- and group-level spatial responses in feral pigeons and greylag geese. The main findings highlight the role that individual personality may play in shaping group performance and behaviour, underscoring the importance of considering personality when studying collective dynamics. Chapter III assesses the effectiveness of the RF as a deterrence tool for two species that frequently come into conflict with human activities: the feral pigeon and the black-headed gull. The results indicate variable applicability of this method, likely linked to differences in resource value exploited by different species at different life-history stages and sites. By employing the RF as an ethological tool, this research introduces a novel experimental framework for studying predator-prey interactions and bird deterrence, contributing to both behavioural and ecological sciences.","language":"eng","citation":"THE ROBOTFALCON: A NEW METHODOLOGY TO STUDY PREY-PREDATOR INTERACTION AND AN INNOVATIVE BIRD DETERRENCE TOOL / I. Vertua ; tutor: D. Rubolini; co-tutor: R. Ambrosini. - Università Statale di Milano. Dipartimento di Scienze e Politiche Ambientali, 2025 Jan 09. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13819_1.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 05-GEN-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1171516"},"title":"DEVELOPMENT OF HIGH-EFFICIENCY POWER DISTRIBUTION ARCHITECTURES BASED ON GAN DEVICES FOR THE LIQUID ARGON CALORIMETER ATLAS EXPERIMENT AT THE LHC","internalauthor":"CARBONE, ANTONIO","type":"Tesi di dottorato","year":"2025","abstract":"Power management becomes more critical as society moves towards sustainability and minimum environmental footprint. High-energy physics experiment, such as the ATLAS detector in the CERN Large Hadron Collider (LHC) at CERN, also require energy sustainability, spatial limitations, and operation reliability requirements. This thesis is focused on the development and application of a new power distribution solution for the front-end electronics of the ATLAS Liquid Argon (LAr) calorimeter.  This development is necessitated by the upgrade that the experiment will receive in the coming years. To meet the more stringent performance demands, Wide Band Gap (WBG) materials like gallium nitride (GaN) are also employed in place of traditional silicon. GaN devices possess inherent benefits of increased efficiency, reduced conduction and switching losses, better thermal management, and better radiation hardness. All these are precious features in the radiation-ensured environment of particle physics experiments.  The main task of the thesis is addresses the complete redesign of the Power Distribution Board (PDB2) of the LAr Trigger Board. PDB2 is the new board that integrates new DC-DC converters, called bPOL, that are GaN-based one which will be capable of withstanding doses greater than 2000 kGy, which will ensure compatibility with the new voltage and the hard radiation environment. The updated PDB had the same mechanical limitations as the original but featured substantial efficiency and reliability improvements.   This thesis also describe the design and prototyping of a new Low Voltage Power Supply (LVPS) system, and it was co-designed with CAEN. The system relocates the power units into more comfortable positions of the detector and provides an output of 48 V as a step towards reducing current and related cable losses.","language":"eng","citation":"DEVELOPMENT OF HIGH-EFFICIENCY POWER DISTRIBUTION ARCHITECTURES BASED ON GAN DEVICES FOR THE LIQUID ARGON CALORIMETER OF THE ATLAS EXPERIMENT AT THE LHC / A. Carbone ; tutor: M.Lazzaroni,  F.Tartarelli ; director of the school: A. Mennella. Dipartimento di Fisica Aldo Pontremoli, 2025. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13570.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1171516/3091840/phd_unimi_R13570.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/823240"},"title":"HDAC8 AND COHESIN: 'OMICS' ANALYSES FOR THE IDENTIFICATION AND FUNCTIONAL VALIDATION OF THEIR TARGETS USING ZEBRAFISH (DANIO RERIO) AND IN VITRO MODEL SYSTEMS","internalauthor":"SPREAFICO, MARCO","type":"Tesi di dottorato","year":"2021","abstract":"The use of pan-HDACi for disease treatment has gained an interest in recent years, albeit exhibiting low specificity, variable efficacy and side effects. Each HDAC with its own activity could be considered as an independent pharmacological target to develop an effective therapy that circumvents the adverse effects of pan-HDACi treatment. HDAC8 belongs to class I HDAC and is known to modulate cohesin complex activity through deacetylation of SMC3. It possesses a unique structure among HDACs, which allowed the development of highly specific inhibitors, such as the PCI-34051. However, HDAC8 function and its involvement in pathological conditions is still largely unknown. To examine in depth HDAC8 physiological and pathological roles and assess whether it can represent a valuable pharmacological target, we analysed its function and the effect of its inhibition by using both in vitro (cell lines) and in vivo (zebrafish) models. In particular, we assessed HDAC8 function in three different tissues and related disorders: i) haematopoietic stem and progenitor cells (HSPC) and acute myeloid leukemia (AML); ii) neural stem cells (NSC) and Cornelia de Lange syndrome (CdLS); iii) skeletal muscle and Duchenne muscular dystrophy (DMD). We found that HDAC8 overexpression increased the proliferation of HSPCs in zebrafish and that its inhibition with PCI treatment restored normal phenotype, favouring cell cycle arrest, and induced apoptosis of AML cells. By contrast, HDAC8 knockdown lead to impairment of both central nervous system development and skeletal muscle differentiation. Furthermore, we found that HDAC8 overexpression is also associated with DMD phenotype and demonstrated that treatment with PCI inhibitor almost restored normal condition. Such positive effects were underlined by multiple mechanisms, which included cell cycle arrest, apoptosis induction and modulation of canonical Wnt pathway. Moreover, by acetylome profiling we identified α-tubulin as HDAC8 target thus revealing HDAC8 involvement in regulation of microtubule structure.  Additionally, to confirm the involvement of HDAC8 in the aforementioned pathologies, we investigated also the role of its partner NIPBL. By RNA-seq analysis we assessed the effect of NIPBL knockdown on gene expression revealing a number of differentially expressed genes linked to pathways altered in CdLS or AML.","language":"eng","citation":"HDAC8 AND COHESIN: 'OMICS' ANALYSES FOR THE IDENTIFICATION AND FUNCTIONAL VALIDATION OF THEIR TARGETS USING ZEBRAFISH (DANIO RERIO) AND IN VITRO MODEL SYSTEMS / M. Spreafico ; tutor: A. Pistocchi ; supervisor: E. Battaglioli ; coordinatore: M. Locati. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2021 Mar 25. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11854.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/823240/1731089/phd_unimi_R11854.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1128524"},"title":"IL CIMENTO DEL LIBRO ELETTRONICO: L'EDITORIA DALLA 'DEMOCRATIZZAZIONE' DEL COMPUTER AL WEB 2.0.","internalauthor":"CREMASCOLI, ANGELICA","type":"Tesi di dottorato","year":"2025","abstract":"\"The subject of this study is the revolution triggered by the absorption of computing logic and tools within the so-called publishing industry, which began in Italy, as well as in the rest of the Western world, during the 1970s. The focus is particularly on the informatization of the \"\"book\"\", meaning its deconstruction and reconstruction within electronic spaces, as well as the reconfiguration of its formats and technologies. This phenomenon is closely linked to issues concerning the redefinition of classical models of writing, reading, and textuality, which have emerged alongside the growing literary function of the computer.  While existing studies tend to confine electronic publishing to an epilogue or appendix of the history of the book, this research proposes a new periodization. Through the identification and detailed analysis of the three main phases of the informatic-editorial revolution—the era of electronic publishing (1978-1990), the era of multimedia publishing (1991-1999), and the era of digital publishing (2000-2020)—this study assigns a deeper and more complex chronological scope and a greater significance to the process compared to conventional reconstructions.  In Italy, as well as in other parts of the world, particularly in Anglo-Saxon contexts, since the late 1970s, there has been a progression: from the discovery of telematics and the computer as a cultural medium capable of producing and manipulating creative content through software, interfaces, and screens (electronic publishing); to the introduction of new formats and media that allow for the integration of text, images, and sounds, radically transforming the reading experience (multimedia publishing); and finally, to the migration of the publishing industry online, along with its reinterpretation and recontextualization in terms of convergence and transmediality, which completes and consolidates the dematerialization and \"\"softwarization\"\" of the book (digital publishing). This outlines a complex path, beginning with the emergence of IT innovations related to the storage, organization, processing, and transportation of information. It passes through a transitional phase dominated by CD-ROMs and reaches the comprehensive digitization of the sector, describing the development of the book, both as an object and as a generator of practices, from the moment in which computing technologies began to consolidate and penetrate the productive and cultural fabric of society, ultimately revolutionizing it.  Therefore, this research aims to achieve a deeper understanding of the historical, technological, and cultural dynamics that have led to the birth, evolution, and affirmation of the electronic book. It embraces a broad and interdisciplinary field of inquiry that spans the history of publishing, the history of communication, cultural media history, and the history of the circulation and transmission of knowledge.\"","language":"ita","citation":"\"IL CIMENTO DEL LIBRO ELETTRONICO: L'EDITORIA DALLA 'DEMOCRATIZZAZIONE' DEL COMPUTER AL WEB 2.0 / A. Cremascoli ; tutor: I. Piazzoni; co-tutor: R. Cesana ; coordinatore: M. Soresina. - Università degli Studi di Milano. Dipartimento di Studi Storici \"\"Federico Chabod\"\", 2025. 37. ciclo, Anno Accademico 2023/2024.\"","filename":"phd_unimi_R13251.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1128524/2618849/phd_unimi_R13251.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1221455"},"title":"REGENERATIVE MEDICINE STRATEGIES FOR ENDOMETRITIS IN REPRODUCTIVE MARES:IN VITRO AND IN VIVO STUDIES","internalauthor":"GASPARI, GIULIA","type":"Tesi di dottorato","year":"2026","abstract":"Endometritis is a fertility-impairing pathology frequent in reproductive mares. Persistent post-breeding induced endometritis (PPBIE) is caused by a uterine inflammatory imbalance, while chronic degenerative endometritis (CDE) involves endometrial fibrotic alterations and has been associated with advanced age. Causing a considerate alteration of uterine environment, endometritis is believed also to impair fetal-maternal communication. Since conventional therapies often fail to achieve a resolutive endometrial regeneration, this project aimed at identifying novel alternative approaches based on the employment of secretome (conditioned medium: CM) and extracellular vesicles (EVs) derived from mesenchymal stromal/stem cells (MSCs) isolated extra-foetal adnexa as sources of regenerative medicine. Platelet rich plasma (PRP) was also examined as further alternative approach.  The initial phase of research involved in vitro studies:  1) Wharton’s jelly-derived conditioned medium (WJ-CM) and PRP were investigated in counteracting in vitro LPS-induced inflammation on equine endometrial cells (ECs). Unexpectedly, PRP did not exert an anti-inflammatory effect on stressed ECs, causing cytotoxicity and increasing ROS levels. Contrarily, WJ-CM showed a significant decrease in PGE-2 release after 24 hours of incubation, confirming its anti-inflammatory activity.   Both these regenerative products contain soluble factors and EVs. Therefore, the attention of this thesis was directed on EVs, but specifically those obtained from amniotic mesenchymal stromal/stem cells (AMCs), which are isolated from another extra-foetal tissue, namely the amniotic membrane.   2) The literature provide evidence for the anti-inflammatory and pro-regenerative properties of amniotic-derived extracellular vesicles (AMC-EVs), even in reproductive disorders. However, the mechanism of interaction between AMC-EVs and recipient ECs and the modality of EV-uptake remain to be fully elucidated. Therefore, in vitro analyses were performed to characterize the glycoprofile of ECs and AMC-EVs using a panel of FITC-conjugated lectins. Results show that ECs and AMC-EVs express fucosylated and sialylated glycans on their surface, which are actively involved in the internalization of AMC-EVs by ECs.   3) Given the potential future application of AMCs and EVs in regenerative medicine, a comparative proteomic analysis was conducted to assess the specific functional features of AMCs and their EVs. The results show that AMCs and EVs are characterized by a distinct proteomic profile, showing the expression of different sets of proteins involved in regenerative processes and thus diversified therapeutic properties. Proteins promoting anti-inflammatory activity, oxidative stress resistance and angiogenesis exhibited increased expression levels in AMCs, while ECM organization and deposition are predominantly upregulated in EVs. This emphasizes their important complementary roles in the fine regulation of the main processes involved in tissue regeneration, proposing AMCs and EVs as a dynamic and effective “couple” rather than separated actors with similar effects. Consequently, to date, we are still unable to definitively elect cells over EVs (or vice versa) as better therapeutic candidate.  4) Extracellular vesicles are internalized by ECs and exerted a functional effect in a mare treated via intrauterine infusion, which resulted in a successful pregnancy. But which bioactive molecules are transferred from EVs to target cells? The miRNA cargo of AMCs and their EVs was previously characterized by the research group under which the present project was conducted. However, most of the intercellular communication is likely mediated also by the proteomic cargo of these vesicles. In this context, the proteins involved in AMC-EV effects were evaluated in vitro assessing the effect of their incorporation into equine ECs challenged with LPS to induce inflammation. Treatment with AMC-EVs resulted in the upregulation of several proteins implicated in the modulation of the inflammatory response, components of the extracellular matrix, antioxidant enzymes and mediators, as well as various transcription factors and regulatory molecules. In contrast, a subset of pro-inflammatory mediators—including specific cytokines, oxidative stress-related factors, and inhibitors of matrix metalloproteinases—were found to be downregulated. These findings indicate that AMC-EVs may exert anti-inflammatory effects on LPS-stimulated endothelial cells through a multifaceted mechanism involving cytokine modulation, enhancement of antioxidant defenses, regulation of gene transcription, remodeling of the extracellular matrix, and modulation of key signaling pathways associated with inflammation, confirming the regenerative properties of AMC-EVs and their possible employment as cell-free therapy.  Alongside the in vitro experiments, also in vivo studies were performed.  5) Previous studies showed that AMC-EVs decrease pro-inflammatory cytokine levels and improve endometrial cell proliferation in vitro. Moreover, also the in vitro studies performed during this PhD reinforce the potential role of AMC-EVs for endometrial regeneration. Therefore, mare reproductive diseases were approached, including two kinds of endometritis.   Among the various forms of endometritis that negatively impact fertility, PPBIE represents a major cause of subfertility in mares. In the present project, stallion semen was supplemented with AMC-EVs at the time of insemination in the attempt of preventing or limiting the development of PPBIE after artificial insemination. Before administration in mares, the effect of AMC-EVs on sperm mobility parameters was assessed to exclude sperm toxicity. Sixteen susceptible mares were enrolled and inseminated with semen (n = 8; control group) or with semen supplemented with AMC-EVs (n = 8; EV group). The supplementation of AMC-EVs to the inseminating dose resulted in a reduction in polymorphonuclear neutrophil infiltration as well as intrauterine fluid accumulation. Intrauterine levels of IL-6 were significantly decreased, while anti-inflammatory IL-10 was up-regulated, suggesting successful modulation of the post-insemination inflammatory response and possible future use of this procedure in mares susceptible to PPBIE.  6) Considering the efficacy of AMC-EVs in preventing the onset of PPBIE, an additional in vivo study evaluated AMC-EV treatment in mares affected by CDE.   The aim of this project was to attempt restoring embryo-maternal communication and improving endometrial histological conditions by intrauterine administrations of AMC-EVs in twelve mares. These animals were divided into Group 1 (n=7), receiving a single treatment cycle (two administrations), and Group 2 (n=5) receiving two treatment cycles (four administrations). Each administration consisted of 2×10¹⁰ AMC-EVs diluted in 50 ml of sterile saline solution. Eleven mares were able to conceive after the treatment with AMC-EVs without significant difference in pregnancy outcomes between one or two treatment cycles. However, no improvement in endometrial histology was observed, suggesting that under the adopted therapeutical protocol AMC-EVs did not induce a complete tissue regeneration, but likely contributed to restoring functional paracrine interaction between embryo and maternal tissues.","language":"eng","citation":"REGENERATIVE MEDICINE STRATEGIES FOR ENDOMETRITIS IN REPRODUCTIVE MARES: IN VITRO AND IN VIVO STUDIES / G. Gaspari ; supervisor: A. Lange Consiglio ; co-supervisor: F. Cremonesi ; PhD coordinator: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2026 Feb 25. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13916_3.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 04-SET-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1135395"},"title":"SEMICLASSICAL MOLECULAR DYNAMICS OF ADIABATIC AND NONADIABATIC PROCESSES","internalauthor":"MOSCATO, DAVIDE","type":"Tesi di dottorato","year":"2025","abstract":"\"Molecular dynamics over the years has been established as a powerful yet sim-  ple technique capable of offering new physical insights into molecular processes.  Some of the most desirable features are that it retains favorable scalability with  the increasing number of degrees of freedom and can also be used to reproduce  processes happening on relatively long time scales. On the other hand, since molec-  ular dynamics is based on classical mechanics, it neglects the quantum nature of  the nuclear motion and will eventually lead to some noticeable deviations from the  real behavior of molecular systems. Instead, when considering a quantum picture  of the nuclear dynamics all of the previously cited desirable features of molecular  dynamics tend to vanish. Making the whole picture usually more complicated and  computationally daunting. Semiclassical methods are in part able to conciliate the  best features of both worlds, allowing for an intuitive description of the underlying  nuclear quantum dynamics based on classical molecular dynamics and at the same  time keeping the scalability in function of the system dimensionality favorable.  Throughout this thesis, semiclassical methods are employed to compute vibrational  and vibronic spectra. More specifically, the first part of the manuscript will be dedi-  cated to a quick review of the theory of the semiclassical initial value representation  and its application to spectroscopy. The objective of the first Chapter is not only  to show the origins of the semiclassical approximation but also to describe some  strategies and further approximations that can pave the way for the simulations of  molecular systems featuring up to 10000 degrees of freedom. Later, in the same part  of the manuscript, it is also explored the idea of including nonadiabatic effects to semiclassical vibrational spectroscopy by employing the Meyer-Miller-Stock-Thoss  mapping.  In Chapter 3 a simple study case regarding the formaldehyde molecule is used to  dig deeper into a tedious question regarding what can be regarded as a classical  anharmonic effect and what can be classified as a \"\"quantum effect\"\" in vibrational  spectroscopy. This Chapter also serves as a point to assess the validity of classical  methods when compared to quantum mechanical ones and validate some of the best  practices to employ regarding the former.  In Chapter 4 both quasiclassical and semiclassical methods are used to reproduce  the experimental spectrum of the solvated G-quadruplex and explain the effects of  solvation on the observed vibrational features. To describe the dynamics of such a  large system, an empirical force field must be employed, a topic that is not central  to the Chapter and will be used as a starting point for the next one, regards the  reliability of this way to describe the potential energy surface. To avoid the loss of  accuracy that comes with employing a classical force field, but at the same time  avoid the computational overheads that can be faced when employing a full ab  initio description of the system, in Chapter 5 semiclassical molecular dynamics is  employed alongside hybrid QM/MM potentials to obtain a new physical picture of  solvation for the case of solvated thymidine. Such system turned out to be a very  intriguing study case where the modeling of solute-solvent interactions is essential  for the correct reproducibility of the experimentally observed spectroscopic behav-  ior.  Finally, in Chapter 6 applications of the novel time-averaged semiclassical approach  to nonadiabatic vibronic spectroscopy are displayed for analytical model systems  of growing difficulty. During this part of the manuscript, some of the features and  limitations of the method will highlighted upon comparison with numerically exact  results. Conclusions of the entire work and future perspectives are drawn in Chapter  7.\"","language":"eng","citation":"SEMICLASSICAL MOLECULAR DYNAMICS OF ADIABATIC AND NONADIABATIC PROCESSES / D. Moscato ; tutor: M. Ceotto ; coordinatore: D. Passarella. - Aula G23, Via Golgi 19, Milano. Dipartimento di Chimica, 2025 Feb 03. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13523.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1135395/2635600/phd_unimi_R13523.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/948468"},"title":"DEMOCRACY AND JUSTICE IN COLLECTIVE ACTION INITIATIVES IN THE ENERGY FIELD","internalauthor":"DUDKA, AURORE JEANNE STANISLAVA","type":"Tesi di dottorato","year":"2022","abstract":"With the deployment of renewable energy technologies, the energy market is going towards a polycentric system characterized by the cohabitation of large- and small-scale installations. This configuration allows for the presence of new actors, fostering the deployment of renewable energy and representing a new tool to fight against climate change. This thesis investigates the role of one of these new players: energy communities. Energy communities represent a form of collective management based on the principle of “one people, one voice”, where citizens are the direct owners of energy, contrasting thus with the previous energetic model based on fossil-fuel energy and big companies and states. Furthermore, energy communities, intensely caring about social issues and inclusivity within their initiatives, imply political and social shifts. In this, they are related to energy democracy and justice, allowing all citizens to participate directly in the energy transition. This research inquiry analyses the reality of these initiatives, investigating whether possible gaps emerge between the citizen and the energy communities’ characteristics for potential inclusiveness at a time when part of the literature tends to raise attention towards the fact that energy communities could still be far from bringing more energy democracy and justice in this field. Another point to underline is that thanks to adopting a comparative perspective, this research also looks to identify how some traditional determinants of collective action initiatives as size but also socio-territorial context, can impact the capacity of these initiatives to bring more energy democracy and justice.","language":"eng","citation":"DEMOCRACY AND JUSTICE IN COLLECTIVE ACTION INITIATIVES IN THE ENERGY FIELD / A.j.s. Dudka ; tutor: L. Dorigatti ; coordinatore: G. Ballarino. Dipartimento di Scienze Sociali e Politiche, 2022 Dec 19. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12254.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/948468/2109441/phd_unimi_R12254.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/988828"},"title":"(RE)IMPARARE DALLA PANDEMIA: HACER COMUNIDAD DI FRONTE AL COVID-19 (OAXACA, MESSICO)","internalauthor":"FUSAR POLI, ELENA","type":"Tesi di dottorato","year":"2023","abstract":"This PhD thesis focuses on the social transformations triggered by the Covid-19 pandemic in the Mexican state of Oaxaca and, particularly, in the village of San Pablo Huitzo. The thesis combines nine months of ethnographic fieldwork with anthropological theoretical reflections. The social transformations examined represent a model of development beyond development. The interpretation of these transformations goes through the processes of learning, re-learning and re-signification of community knowledge and skills. These processes have been required to cope with Covid-19 and the structural limits of the health and public welfare system that the pandemic circumstance has highlighted. Many villages of Oaxaca adopted several strategies to prevent and treat viral contagion, according to their level of political, alimentary, medical, cultural, and organizational autonomy. These strategies were based on encierro (the closure of village’s borders), on a massive return to the earth, with a marked agroecological connotation, and the revitalization of traditional medicine.  These strategies are part of an overall movement of 'turning inwards', characterized by a renewed focus on the community, the territory, and the local dimension. This movement has gone with a widespread reflection on the way of life perceived as the most suitable for the communities of Oaxaca. “Care” as a concept represents the thread of the thesis, which concludes by introducing some questions for possible future developments: which transformations occurred during the pandemic will also affect beyond Covid-19? During and beyond a pandemic, how can anthropology be part of the cure?","language":"ita","citation":"(RE)IMPARARE DALLA PANDEMIA: HACER COMUNIDAD DI FRONTE AL COVID-19 (OAXACA, MESSICO) / E. Fusar Poli ; tutor: S. Allovio ; coordinatore: A. Pinotti. Università degli Studi di Milano, 2023 Jul 17. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12483.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/988828/2256853/phd_unimi_R12483.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1018414"},"title":"A COMPREHENSIVE OVERVIEW OF PSYCHOLOGICAL AND ETHICAL IMPLICATIONS ON THE ROLE OF CAREGIVER IN THE CLINICAL PATHWAY OF PATIENTS NEWLY DIAGNOSED WITH BREAST AND PROSTATE CANCER","internalauthor":"CINCIDDA, CLIZIA","type":"Tesi di dottorato","year":"2023","abstract":"In recent years, research on the caregivers’ involvement in the Shared Decision-Making and cancer care has burgeoned in the psychological field; however, knowledge gaps still exist because most studies have failed to acknowledge the multidimensional nature of agreement/disagreement among dyads in the Shared Decision-Making and cancer trajectory, especially during the early phase of the disease (diagnosis and starting of treatments). My Ph.D. thesis focused on the agreement among patient-caregiver dyads along the cancer care pathway, from the diagnosis onward, and their mutual influence on the psychological adjustment to cancer in breast and prostate cancer patients and their caregivers. Along the cancer trajectory, dyads may experience episodes of conflicts, so it has been evaluated the concept of conflict from an ethical standpoint. The current projects highlighted the importance and need for a multidisciplinary approach to dyads, involving physicians, psycho-oncologists, and clinical ethicists. A holistic approach may help patients and caregivers coping with cancer, being supportive to each other and expressing their preferences, fears, and needs. Specifically, four studies addressed the dyadic agreement in the Decision-Making and the interdependence among dyads from a psychological standpoint through quantitative and qualitative methods. In particular, the first study explored the preferences of breast and prostate cancer patients and their caregivers in the Shared Decision-Making. Given the relevance of caregivers’ involvement in the Decision-Making, two studies demonstrated the importance of a renovated family-centered model of cancer care and the need of structuring psychological interventions tailored on the dyads or on the single member. Specifically, although patients often have at least one caregiver by their side, who provide practical and emotional support, it is unclear whether dyads establish their roles and the level of involvement in the Decision-Making process. Indeed, two studies showed that most dyads disagree on the preferences and actual involvement in the Decision-Making. Moreover, caregivers are not just a supporter, as she experiences the disease almost as much as the patients. Dyadic members experience high distress and influence each other’s adjustment to cancer. Findings from the qualitative assessment support the idea of cancer as a family disease. Dyads described the cancer diagnosis as an expected and shocking event, that needs to be addressed together as soon as possible. However, patients and caregivers experience different concerns: patients’ worries refer to the cancer recurrence and the body image, while caregivers’ worries about their ability to support patients. Then, in order to evaluate the caregivers’ involvement at a multilevel, two studies assess the concept of conflict from an ethical standpoint. The first study proposed a taxonomy of the moral conflict that may emerge along the cancer trajectory. Finally, a case report provides the basis for future investigations about the presence of moral conflicts even in the early stage of cancer (diagnosis). In conclusion, findings of this PhD projects suggest the importance of caregivers’ involvement along the cancer care pathway and the need to promote psychological interventions both for patients, caregivers, and the dyads. Finally, the present thesis gives future directions to increase breast and prostate cancer dyad well-being, reducing the Fear of Cancer Recurrence.","language":"eng","citation":"A COMPREHENSIVE OVERVIEW OF PSYCHOLOGICAL AND ETHICAL IMPLICATIONS ON THE ROLE OF CAREGIVER IN THE CLINICAL PATHWAY OF PATIENTS NEWLY DIAGNOSED WITH BREAST AND PROSTATE CANCER / C. Cincidda ; added supervisor: S. Oliveri ; internal advisor: V. Sanchini ; tutor: G. Pravettoni ; phd coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2023 Dec 12. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12680.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1018414/2327906/phd_unimi_R12680.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1024850"},"title":"DIFFERENT TECHNIQUES FOR DENTAL IMPLANTS SITE PREPARATION: A CONTROLLED CLINICAL TRIAL","internalauthor":"MORANDI, BENEDETTA","type":"Tesi di dottorato","year":"2024","abstract":"Dental implants should be considered a highly predictable long-term and evidence-based treatment option for single, partial, and complete edentulism of the jaws, as indicated by numerous scientific articles. The primary aim of the present study was to determine whether the application of one implant site preparation protocol (“Step drilling sequence”) could lead to a significantly lower marginal bone resorption as compared to another protocol (“Straight drilling sequence”) at 1-year follow-up. The secondary aims were to evaluate if the tested protocol (Step drilling sequence) could modify the clinical and/or patient-centered variables We included and treated 60 subjects, for a total of 86 implants. We found no evidence of a difference in bone resorption, which increased significantly over time, between the two groups. Regarding the secondary outcomes, no statistically significant difference was observed between the test group and the control group, neither for peri-implant probing depth (PD), for bleeding index (BI), plaque index (PI) nor for the quality of life. In conclusion, from a purely biological perspective, there is currently no evidence in favor of using a step drill over a traditional straight drill. However, from a clinical standpoint, the use of step drills is advantageous for operator convenience compared to traditional drills.","language":"eng","citation":"DIFFERENT TECHNIQUES FOR DENTAL IMPLANTS SITE PREPARATION: A CONTROLLED CLINICAL TRIAL / B. Morandi ; tutor: S. Taschieri ; coordinatore: M. Del Fabbro. - Milano. Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, 2024. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12992.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1024850/2348778/phd_unimi_R12992.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/945285"},"title":"SURGICAL TREATMENT OF ORAL LEUKOPLAKIA: A RANDOMIZED CONTROLLED CLINICAL TRIAL COMPARING SURGERY WITH WAIT AND SEE APPROACH","internalauthor":"LOMBARDI, NICCOLO' GIANCESARE","type":"Tesi di dottorato","year":"2022","abstract":"Rationale of the study: Different treatments have been proposed for the management of the most common oral potentially malignant disorders (i.e., leukoplakia and erythroleukoplakia) in order to prevent the risk of oral cancer. However, there is currently no consensus on the most effective approach for the patients affected by such lesions. Surgery is often performed, but in literature there is no randomized clinical trial that demonstrates its real effectiveness in preventing malignant transformation.  Objective: To compare the incidence of oral squamous cell carcinoma (OSCC) in a group of subjects undergoing surgical treatment and a similar group under strict clinical and histological surveillance (“wait and see” approach). To evaluate the long-term recurrence rate in test group after surgical excision of the oral leukoplakia.  Study Design: Multicentric randomized controlled clinical trial (RCT).  Setting: Unit of Oral Medicine - ASST Santi Paolo e Carlo Milano - Head and Neck Department San Paolo Hospital of Milan - Università degli Studi di Milano - Reference Center of the study; Unit of Oral and Medicine and Oncology - CIR Dental School of Turin - Università degli Studi di Torino  Patients and Method: Inclusion criteria: adult patients to whom, after an incisional diagnostic biopsy, have been diagnosed an oral leukoplakia or erythroplakia. Exclusion criteria: patients affected by a previous oral cancer, patients under the age of 18, pregnant patients, patients affected by PVL, lesions located in anatomical risk areas in which the excision may cause post-surgical deficit (salivary ducts, nerves, arteries…) and lesions more extensive than 3cm.  Patients included in the study are divided into two groups: surgery (test group) and wait and see (control group). The randomization has been created using an online tool.  Demographics data, habits, clinical information are collected for both groups. Technique of excision, surgical margins, recurrence and intra and post-surgical complications, are collected in the test group, while clinical and histopathological changes are collected in the control group.  Outcomes Primary: oral cancer incidence Secondary: time to malignant progression from diagnosis, recurrence rate in test group.  Conclusion and clinical relevance: This study will compare surgical treatment with “wait and see” approach in order to evaluate the real effectiveness of surgery in preventing and reducing oral cancer incidence in a group of subjects affected by oral leukoplakia. This study will contribute to determine which is the most appropriate management for such patients and to establish a gold-standard treatment.","language":"eng","citation":"SURGICAL TREATMENT OF ORAL LEUKOPLAKIA: A RANDOMIZED CONTROLLED CLINICAL TRIAL COMPARING SURGERY WITH WAIT AND SEE APPROACH / N.g. Lombardi ; tutor: G. Lodi ; coordinator: M. Del Fabbro. Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, 2022 Dec 14. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12549.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/945285/2095236/phd_unimi_R12549.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/934593"},"title":"IDENTIFICATION AND CHARACTERIZATION OF A NOVEL NFIX PHOSPHORYLATION IN SKELETAL MUSCLE","internalauthor":"MURA, GIADA","type":"Tesi di dottorato","year":"2022","abstract":"Nfix is a transcription factor involved in several biological processes spanning from the development of different tissues (brain, muscle, immune system) to cancer. Mutations in the Nfix gene are also at the basis of rare genetic disorders: the Malan syndrome and the Marshall-Smith syndrome.  In skeletal muscle, Nfix drives the transition from embryonic to fetal myogenesis in developmental myoblasts and the skewing from M1 to M2 macrophages. In the adult, Nfix plays a role in the maintenance of the correct timing of skeletal muscle regeneration upon injury regulating the expression of key genes in muscle stem cells. Silencing Nfix in dystrophic mice leads to a morphological and functional amelioration of the dystrophic phenotype by slowing down the degeneration-regeneration cycles, switching muscle fibers towards a slow-twitching phenotype, and by limiting the deposition of fibrotic tissue.  Despite the key roles of this transcription factor, a thorough understanding of its regulatory mechanisms in skeletal muscle and pathological conditions is lacking. Studies focusing on Nfix post-translational modifications (PTMs) are highly underrepresented in the literature. This works aims to fill this knowledge gap, through the characterization of the post-translational modifications of this protein and their biological role.  With this work, we demonstrate that Nfix is phosphorylated in skeletal myoblasts, both in fetal myoblasts during development and in adult muscle cells, in vitro and in vivo. The presence of at least one phosphorylation site in the C-terminal, transcriptionally active domain of Nfix, phospho-serine 301 (pS301), was confirmed both in vitro and in vivo in skeletal muscle cells and tissue. Our data are backed by several other high-throughput proteomics data, including data from human muscle biopsies. Furthermore, a search for cancer-relevant variants of S301 on cBioPortal Cancer Genomics database revealed a melanoma patient with a phosphorylation-disruptive serine-to-phenylalanine (S301F) mutation, suggesting a possible role of Nfix phosphorylation in cancer mechanisms. Serine 301 is very well-conserved among Nfix vertebrate orthologs, suggesting a functional relevance. This phosphorylation can be recognized as a slower migrating Nfix species in western blot experiments of cultured myoblasts. The phosphorylation-mediated mobility shift is dependent on the phosphate negative charge, as demonstrated by the S301D (serine-to-aspartate substitution) phosphomimetic Nfix variant. Ser 301 phosphorylation is detected already during fetal myogenesis and its levels remain constant during differentiation of postnatal myoblasts in culture. Data from cell lines obtained from murine Nfix-null myoblasts expressing phospho-deficient (S301A) and phospho-mimetic (S301D) Nfix mutants reveal no evident phenotypical abnormalities, both in proliferation and differentiation.  Strikingly, we found that this phosphorylation is induced upon late activation of muscle stem cells (MuSCs), as it is absent in freshly isolated MuSCs but present in cultured ones. RNA-seq experiments performed on S301A-, S301D-, and Nfix2_WT-expressing myoblasts revealed a common role for Nfix in regulating cell cycle, differentiation, cell metabolism, and cell adhesion processes, all pathways differentially regulated between quiescent and activated MuSCs.  We have also shown that this phosphorylation is sensitive to oxidative stress and proteasome inhibition, as it significantly decreases upon hydrogen peroxide (H2O2) and proteasome inhibitors treatment in myoblasts. Intriguingly, the regulation of Nfix phosphorylation by oxidative stress could have interesting impacts in a dystrophic context, where reactive oxygen species such as H2O2 are abundant and dysregulated. However, pS301-Nfix levels are unchanged among wild-type and dystrophic sgca-null muscles, when detected via western blot.  To conclude, we highlight a possible role for pS301-Nfix in the regulation of MuSCs activation, cell cycle progression, and cell adhesion. Furthermore, Nfix phosphorylation levels could be tuned by the cells' metabolic state via reactive oxygen species.  The importance of this study relies on the clarification of Nfix regulatory mechanisms, a knowledge that could be employed in a dystrophic context to manipulate Nfix transcriptional activity and modulate MuSCs biology.  Furthermore, the dysregulation of Nfix phosphorylation could have a role in Marshall-Smith syndrome pathogenesis. Indeed, the Nfix residues interested by phosphorylation are coded by exons 5 to 8, which are the most affected by mutations in Marshall-Smith patients, that are characterized by de novo heterozygous mutations in the Nfix C-terminal domain, generating mutant proteins that seem to acquire dominant-negative/gain-of-function properties. An impaired interpretation of signaling pathways downstream of Nfix phosphorylation could be a relevant pathogenic mechanism of Marshall-Smith syndrome.","language":"eng","citation":"IDENTIFICATION AND CHARACTERIZATION OF A NOVEL NFIX PHOSPHORYLATION IN SKELETAL MUSCLE / G. Mura ; thesis committee member: R. Mantovani ; thesis committee member: S. Molinari ; thesis committee member: M. Murgia ; thesis reviewer: A. Pisconti ; thesis reviewer: S. Tajbakhsh ; scientific supervisor: G. Messina. Dipartimento di Bioscienze, 2022 Jul 19. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12386.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/934593/2054814/phd_unimi_R12386.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1232960"},"title":"DECODING MUSCLE EXCITATION IN RESISTANCE TRAINING: A HIGH-DENSITY SEMG APPROACH","internalauthor":"PADOVAN, RICCARDO","type":"Tesi di dottorato","year":"2026","abstract":"Resistance training (RT) is a primary stimulus for neuromuscular and structural adaptations, yet the characterization of muscle excitation during RT remains limited by methodological constraints. Traditional surface electromyography (sEMG) provides a global estimate of muscle activity but lacks the spatial resolution required to capture detailed excitation patterns within and across muscles.  This doctoral thesis aimed to advance the understanding of muscle excitation in RT by integrating high-density surface electromyography (HD-sEMG), enabling the simultaneous assessment of amplitude and spatial characteristics of neuromuscular activation. The project followed a progressive methodological approach, beginning with studies using classical bipolar sEMG to investigate how variations in exercise execution influence global muscle excitation. These initial investigations were followed by a series of studies employing HD-sEMG to overcome the limitations of traditional methods.  Across six experimental studies conducted in resistance-trained individuals, this thesis examined the effects of biomechanical variables, including grip configuration, lifting aids, and load manipulation, on both the magnitude and spatial distribution of muscle excitation. HD-sEMG allowed for the extraction of spatial features such as root mean square amplitude maps and centroid displacement, providing novel insights into regional activation patterns and their modulation across different exercise conditions and movement phases.  The findings demonstrate that muscle excitation during RT is not uniformly distributed, but instead exhibits condition-specific spatial patterns that are not detectable using conventional sEMG. These results highlight the importance of spatially resolved analyses for interpreting neuromuscular function and refining exercise prescription.  Overall, this thesis establishes HD-sEMG as a valuable non-invasive tool for investigating muscle excitation in RT and contributes to a more comprehensive understanding of neuromuscular strategies underlying resistance exercise.","language":"eng","citation":"DECODING MUSCLE EXCITATION IN RESISTANCE TRAINING: A HIGH-DENSITY SEMG APPROACH / R. Padovan ; supervisor: E. Cè, G. Coratella, E. Helms. Dipartimento di Scienze Biomediche per la Salute, 2026 Apr 21. 38. ciclo, Anno Accademico 2025.","filename":"phd_unimi_R13672.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1232960/3298144/phd_unimi_R13672.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1123180"},"title":"IMPACT OF DRP1 ACTIVATION, UNFOLDED PROTEIN RESPONSE INDUCTION AND FGF21 LEVELS IN DMD PROGRESSION","internalauthor":"CASATI, SILVIA ROSANNA","type":"Tesi di dottorato","year":"2025","abstract":"Duchenne muscular dystrophy (DMD) is a severe genetic progressive muscle-wasting disease. The transmission of this pathology is X-linked recessive with an incidence of at least 1:5000 newborn boys. Patients typically present the first symptoms related to motor impairments very early in childhood and if not adequately treated, they die prematurely because of cardiac or respiratory complications.  Mutations in the DMD gene that lead to the complete loss of dystrophin protein are responsible for this very severe phenotype. Dystrophin is a subsarcolemmal protein that not only provides structural integrity and functional stability to the muscle fiber during contraction but also plays crucial roles in cell signaling pathways. In muscle, dystrophin deficiency triggers a cascade of consequences, extending from myofiber necrosis and chronic inflammation to reduced and aberrant muscle regeneration which culminates in excessive deposition of fibrotic and adipose tissue. In addition, mitochondrial dysfunctions are recognized as a hallmark of DMD since dystrophic muscles have been reported to exhibit several metabolic impairments, reduced mitophagy, defective mitochondrial biogenesis, disrupted Ca2+ homeostasis, and altered mitochondrial dynamics.  To date, there is no definitive cure for DMD, despite remarkable signs of progress have been made in developing new therapeutic strategies. However, therapeutic interventions aimed at targeting secondary pathological mechanisms to preserve muscle function are still urgently needed.  A precise balance between mitochondrial fission and fusion processes is necessary to maintain a functional mitochondrial network, especially in muscle which is a highly metabolically active tissue that requires a continuous energy supply for muscle contraction. However, only a few studies have addressed mitochondrial dynamics in DMD, highlighting a dramatic fragmentation of the mitochondrial network.  In this context, we hypothesize that mitochondrial dynamics may represent a potential therapeutic target for DMD.  For this PhD project, we used an mdx-PhAM mouse model, characterized by intrinsically fluorescent and photoconvertible mitochondria, to precisely analyze mitochondrial network morphology. We demonstrated that mdx muscle fibers display a disorganized and less interconnected mitochondrial network. Drp1, the master regulator of mitochondrial fission, and its receptors located on the mitochondrial membrane, such as Fis1 and Mff, are responsible for mitochondrial network fragmentation. We found that all these pro-fission proteins are upregulated in dystrophic muscles from 12 weeks of age. Further analysis revealed that Drp1 activity was enhanced in mdx muscles compared to WT controls, as evidenced by its increased levels in the mitochondrial fraction of mdx muscles, as well as by its increased interaction with Fis1. This unbalanced fission could promote mitochondrial stress and therefore enhance a specific transcriptional program known as UPR, which could impact dystrophic muscle degeneration. Consistently, we revealed a significant upregulation of proteins associated with the mitochondrial-specific UPR (UPRmt) and a muscle-specific induction of the stress mitokine FGF21. FGF21 detrimental effects have been reported concerning bone loss in mdx mice however it could also impact fibro-adipogenic progenitors differentiation considering that these cells express FGF receptor.  We therefore decided to inhibit Drp1 with daily intraperitoneal injections of Mdivi-1 and we observed beneficial effects at functional and histological levels. Inflammation and fibrosis were also remarkably reduced. In parallel, we observed a reduction in muscle levels of FGF21 after the treatment, suggesting a role of this myokine also in establishing dystrophic damage. Mdivi-1 also improved mitochondrial activity and preserved the myogenic potential of dystrophic muscle satellite cells.  We also focused on another strategy to modulate Drp1-mediated excessive fission in mdx mice injecting an AAV-vector encoding for a validated Drp1 shRNA. We observed that the viral genome was still present after 11 weeks from the injection, suggesting a therapeutic action in preserving muscles. Indeed, AAV-shDrp1 had a positive effect on in situ muscle fragility and hypertrophy, possibly due to the observed reduction of fibrotic markers.  In conclusion, the results of my PhD project reveled that Drp1 is an emerging target in DMD and its modulation is a promising approach to counteract muscular dystrophy progression.","language":"eng","citation":"IMPACT OF DRP1 ACTIVATION, UNFOLDED PROTEIN RESPONSE INDUCTION AND FGF21 LEVELS IN DMD PROGRESSION / S.r. Casati ; tutor: C. De Palma ; coordinatore: N. Landsberger ; external advisor: S. Falcone. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2025 Jan 21. 37. ciclo","filename":"phd_unimi_R13400.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1123180/2604524/phd_unimi_R13400.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/920992"},"title":"VALORIZATION OF SECONDARY METAL RESOURCES THROUGH HYDROMETALLURGICAL PROCESSES","internalauthor":"GRASSI, ANDREA STEFANO","type":"Tesi di dottorato","year":"2022","abstract":"Abstract  This executive doctorate project comes from the collaboration between the company Engitec Technologies S.p.A. and the Università degli Studi di Milano. The student joined the company staff, gaining access to the company laboratories and pilot plants.   The project was focused on the study and optimization of hydrometallurgical processes for the recovery of metals from secondary resources. The two hydrometallurgical processes object of this work are proposed as alternatives to the state-of-the-art technologies applied worldwide for the recovery of zinc and lead. These two processes are capable to produce zinc and lead metals at high purity, avoiding purification and pyrometallurgical steps.   Through a critical analysis of the available literature, research work initially focussed on the comprehension of the mechanisms and reactions at the base of the recovery processes. New alternative ways and optimizations were then put forward. In addition, thanks to a period spent working directly on a pilot plant installed in South Africa, identification of industrial-scale issues was pursued.  As a result of this experimentation, many improvements were proposed and unravelled, resulting in ad-hoc equipment and concepts, conference presentations and a patent. The doctorate work brought to a series of steps forward in the comprehension and development of these processes, and to the permanent employment of the student in the company staff.    Summary  Reserves of natural resources are limited and nowadays it is necessary to pay more and more attention to the opportunities that a circular economy can provide. The technologies objects of this study are proposed as sustainable solutions to the shortage of raw materials from primary sources. The zinc technology is able to extract metal from zinc-bearing materials, as steel mill dusts, electrolysis wastes, mineral ores, and by-products. The Lead technology is able to extract lead metal directly from lead-acid-battery pastes; however, it can be applied in many other fields, as Cu/Au/Ag/Zn refining processes.   These processes are based on hydrometallurgical approaches and avoid completely the high-temperatures treatments typical of pyrometallurgy. At the same time, the peculiar chemistry of Engitec processes (based on ammonium chloride) leads to a simpler series of treatments, as the removal of the chlorine-washing step in the standard Zinc sulphate electrolytic process.    The Zero Liquid Discharge policy (ZLD) is adopted by the company for all hydrometallurgical processes, implying that no liquid effluents are released in the environment. The side-streams of the plants are designed to be solid products or by-products, decreasing the water and CO2 footprint as much as possible.  The two processes for recovering zinc and lead are called EZINEX® and F.A.S.T. respectively and are based on the same concept with minor differences. The research focused primarily on the EZINEX® process due to market-related reasons.    The first step is the leaching of the target metal using concentrated ammonium chloride solutions: the achievement of high extraction yields is one of the essential elements for these processes. The problem related to the presence of zinc-ferrites in steel mill dust was addressed by testing different reducing agents, although a satisfying solution is still to be found.    From the experience gained on the pilot plant installed in South Africa, it was possible to notice that the presence of calcium in solution is harmful for the plant heat exchangers. It was hypothesized and verified with experimental tests the possibility to keep under control the calcium concentration through the controlled precipitation of calcium sulphate without the addition of further reagents and using the ammonium sulphate that is generated in the scrubber.   During the leaching step, chemical species other than zinc are also brought into solution. Final metal at high purity can be obtained only if these species are managed and removed before electrolysis. Examples of these impurities are copper, silver, manganese, lead, and cadmium. Manganese is removed by the addition of permanganate that transforms the dissolved manganese into a filterable manganese dioxide, by a comproportion redox reaction. Other metal species (Cu, Ag, Pb, Cd) are removed exploiting a cementation reaction.  The analysis of demanganization reaction was performed by kinetic studies, together with electrochemical and chimico-physical experiments. A connection between the redox potential and the Mn(II) concentration was pointed out, and a mathematical function correlating the redox set-point and the plant solution pH was derived. This equation is able to control the on-field equipment to optimize the reagent consumption. At the same time, separation of the solid manganese oxide product was improved by exploring techniques alternative to simple filtering, as: i) flocculating agents, and ii) the most promising centrifugal solid-liquid separation.    Cementation of copper, silver, cadmium, and lead by addition of metallic zinc powder has a considerable impact on the cost of refined zinc. Therefore, alternative methods to perform this purification were evaluated.     A first study involved the testing of a rotary reactor loaded with metallic zinc pellets. A refresh of the zinc active surface, covered by the reaction products, is achieved by mixing and friction between the zinc pellets. A consequent increase in reaction yield was proved by investigating the influence of solution flow rate, rotation speed, and Zinc load. In addition, the necessary zinc for the cementation reaction can be self-produced by simple treatments of the electrolyzed zinc metal.    A second alternative to zinc metal powder is the use of an electrodepuration cell. By polarising the cathodes of the cell to a certain potential it is possible to selectively reduce various interfering cations without the use of chemical reagents. Initially the reduction potentials of the interferents were determined and then different lab-scale cell configurations were realized and tested. The potentialities of this technique were confirmed. However, optimization of the cell design is still an open question.    The electrolysis cell is the final step of the process.  Zinc is reduced to its metallic form using electrical current. A fundamental aspect of this process is represented by the choice of the anodic material. The advantage of using activated titanium electrodes is a reduction in power consumption of about 17%, however, the use of activated titanium requires precise considerations, such as the absence of manganese in the electrolysis solution. The effect of manganese on the stability of these catalytic electrodes was studied and it was concluded that manganese is deleterious to their durability.   The metallic zinc deposit of the plant quality was analysed. Several commercial additives were applied to increase the compactness and smoothness of the deposit. The campaign of experiments led to identify as the best additive a mixture of gum arabic, aescine and agar.  The development of the technology involved chemical/engineering/industrial challenges with consequent advantages and disadvantages. This doctorate, starting from Engitec previous experience, explored and solved some problems, partly detectable only in a pre-industrial plant such as the one built in South Africa.","language":"eng","citation":"VALORIZATION OF SECONDARY METAL RESOURCES THROUGH HYDROMETALLURGICAL PROCESSES / A.s. Grassi ; supervisors: M. Maccagni, E. Guerrini, S. Trasatti ; coordinator: G. F. Ficetola. Università degli Studi di Milano, 2022 May 04. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12442.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/920992/2015904/phd_unimi_R12442.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1257715"},"title":"SECURITY ANALYSIS OF CRYPTOGRAPHIC PRIMITIVES AND ITS AUTOMATION","internalauthor":"PELIZZOLA, SIMONE","type":"Tesi di dottorato","year":"2026","abstract":"The security of communication in connected devices heavily relies on cryptographic solutions, both symmetric and asymmetric.    Differential, impossible differential, and linear cryptanalysis have led to some of the most efficient key recovery attacks against symmetric block ciphers since their introduction in the 1990s.    However, such a security analysis of a cryptographic primitive is often a computationally heavy and error-prone process. This work details an automated tool for converting such instances into Combinatorial Optimization Problems (COP), with a deep analysis of the performance of various solvers and techniques, and some improvements in the state of the art of the security analysis of some cryptographic primitives.    Afterwards, the focus is shifted to asymmetric cryptography, and a new traceable, secure homomorphic network coding signature scheme is proposed.","language":"eng","citation":"SECURITY ANALYSIS OF CRYPTOGRAPHIC PRIMITIVES AND ITS AUTOMATION / S. Pelizzola ; tutor: A. Visconti, M. Ceria ; coordinatore: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2026 Jul 23. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13773.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1257715/3362690/phd_unimi_R13773.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1083630"},"title":"EXTRACTION AND DIAGNOSTIC LINES FOR A LINAC-BASED CARBON ION MEDICAL FACILITY","internalauthor":"PASINO, ELEONORA","type":"Tesi di dottorato","year":"2024","abstract":"In the continuous pursuit of combating cancer, the field of medical physics stands at the forefront of innovation, continually seeking novel methodologies to enhance treatment efficacy while minimizing collateral damage to healthy tissues. Carbon ion therapy has emerged as a promising frontier, offering unparalleled precision and biological effectiveness in targeting cancers, deeply penetrating tissues and concentrating energy at the tumor site while sparing surrounding tissues.   Linear accelerators (linacs) represent the latest technology proposed in the field of hadron therapy, capable of producing high quality, pulsed beams at high repetition rates. The application of linacs to carbon ion therapy could improve its reliability, efficiency, and compactness. Although a complete carbon ion linac is still conceptual, a carbon ion pre-injector is under construction at CERN to demonstrate the feasibility of producing a beam suitable for medical applications, in terms of beam quality and current.   The main topic of this thesis work is the design of an innovative source extraction system for the carbon ion pre-injector, which allows to directly match the beam from the source to the adjacent accelerating structure. The transition from the source to the accelerator is therefore as compact as possible to reach a better performance of the accelerator in terms of brilliance and beam quality, but also to improve the aspect ratio of the linac footprint and to facilitate the operation and reproducibility of the system.   The ELISA experiment (Experimental LInac for Surface Analysis) represents an essential test bed of the studies in the thesis. The ELISA source commissioning allows to study the characterization of the source and to optimize the parameters of the extraction system, leading to a knowledge and expertise that can be exploited to improve the performance of the carbon ion pre-injector. The design of a diagnostic test bench for the carbon ion pre-injector is also part of this thesis work, with the aim to validate the performance of the first accelerating cavity with beam measurements and to test the reliability of the first part of the pre-injector.","language":"eng","citation":"EXTRACTION AND DIAGNOSTIC LINES FOR A LINAC-BASED CARBON ION MEDICAL FACILITY / E. Pasino ; supervisor: M. Paris ; co-supervisor: A. Lombardi ; referees: M. Vretenar, T. Pieloni. - Dipartimento di Fisica Aldo Pontremoli. Dipartimento di Fisica Aldo Pontremoli, 2024 Jul 16. 36. ciclo","filename":"phd_unimi_R12802.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1083630/2495156/phd_unimi_R12802.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1219155"},"title":"ZOONOSI, RESISTENZE ANTIMICROBICHE E INNOVAZIONE NELL¿ALLEVAMENTO DEL BOVINO DA LATTE: APPROCCI INTEGRATI SECONDO IL PARADIGMA ONE HEALTH","internalauthor":"ZAGHEN, FRANCESCA","type":"Tesi di dottorato","year":"2026","abstract":"The intensive use of antibiotics in human and veterinary medicine has promoted the global spread of antimicrobial resistance (AMR), with serious implications for public health and the sustainability of livestock farming. In this context, zoonotic pathogens such as S.aureus and S.agalactiae represent a complex threat, capable of crossing species barriers and spreading resistance genes. This thesis adopts an integrated One Health approach to analyse the spread of resistant bacterial strains in milk, assess the milk resistome, and propose innovative solutions for the control of contagious mastitis. To evaluate the risk associated with zoonotic pathogens and antimicrobial resistance genes, epidemiological and genomic analyses of bacterial strains were integrated with metagenomic studies of milking filters, aimed at monitoring the spread of AMR. Furthermore, the effectiveness and applicability of antimicrobial elastomers to produce milking liners were assessed, with the goal of reducing the transmission of contagious pathogens during milking. The introduction of these elastomers for milking significantly reduced the transmission of contagious pathogens, contributing to a decrease in mastitis incidence. Epidemiological analysis of over 36,000 isolates enabled the identification of resistance patterns and their distribution in S.aureus and S.agalactiae. Furthermore, the application of metagenomic techniques to milking filters revealed a widespread presence of AMR genes, confirming the role of the farm environment in the circulation of resistance. Meanwhile, the adoption of advanced diagnostic protocols improved monitoring of the herd’s health status, enabling targeted interventions and a reduction in antibiotic use. These results demonstrate the effectiveness of an integrated and innovative approach in managing bovine infections, preventing the spread of AMR, and promoting public, animal, and environmental health according to the principles of the One Health paradigm. The implications of this study suggest the possibility of implementing replicable models of surveillance and health intervention in dairy farm, contributing concretely to the global fight against AMR.","language":"ita","citation":"ZOONOSI, RESISTENZE ANTIMICROBICHE E INNOVAZIONE NELL¿ALLEVAMENTO DEL BOVINO DA LATTE: APPROCCI INTEGRATI SECONDO IL PARADIGMA ONE HEALTH / F. Zaghen ; tutor: A. Zecconi ; cotutor: P. A. Martino ; coordinatore: E. Damiani. - Milano. Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, 2026 Feb 27. 38. ciclo, Anno Accademico 2025.","filename":"phd_unimi_R14063.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1219155/3259826/phd_unimi_R14063.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1158486"},"title":"AMBIENTE E INIZIATIVA ECONOMICA PRIVATA NEL GOVERNO DELLA TRANSIZIONE VERDE. PRINCIPI E VALORI COSTITUZIONALI IN CHIAVE COMPARATA","internalauthor":"PADRIN, CHIARA","type":"Tesi di dottorato","year":"2025","abstract":"The doctoral thesis explores the constitutional relationship between environmental protection and private economic initiative. The research adopts a comparative perspective, focusing on the Italian and French legal systems, while also taking into account the broader framework of European Union law. The primary aim is to examine how constitutional principles and values can inform the governance of the green transition, ensuring a sustainable balance between economic development and environmental safeguarding.    The dissertation is structured into two main sections. Section I investigates the constitutional foundations of the environment - enterprise nexus in Italy and France. In the Italian context, Constitutional Law No. 1/2022, which amended Articles 9 and 41 of the Constitution, represents a pivotal moment in redefining the legal equilibrium between ecological concerns and economic freedoms. This reform provides an opportunity to reflect more deeply on the implications of the newly enshrined constitutional protection of the environment, particularly in relation to Article 41. The analysis includes an in-depth examination of the Italian Constitutional Court’s case law - both before and after the reform - with a focus on the balancing techniques employed in key decisions that highlight the normative tensions between environmental protection, health, labor, and enterprise.    In the French system, the analysis centers on the constitutional principle of liberté d’entreprendre and the 2005 Environmental Charter (Charte de l’Environnement), assessing how these principles interact, also through the lens of the Conseil Constitutionnel’s jurisprudence. Further attention is given to the 2021 proposal for constitutional reform aimed at strengthening environmental protection. Although ultimately unsuccessful, this initiative reflects an increasing constitutional awareness of the need to reconcile ecological imperatives with economic development - an evolution mirrored in positive law through the growing integration of corporate social responsibility within the legal framework.    Section II shifts focus to the governance of the green transition, offering a dual perspective: on one hand, the interaction between national and European sources of law within the paradigm of the “responsible enterprise”; on the other, the evolving balance of powers in response to judicial involvement in environmental and climate-related decision-making.    On the legislative front, the European Green Deal and Next Generation EU mark a transformative moment for EU law. These far-reaching regulatory frameworks extend beyond environmental concerns, demanding structural renewal of the European legal order. Italy’s and France’s Recovery and Resilience Plans illustrate how “green conditionality” has shaped national policy choices at the intersection of enterprise and environmental sustainability. In the same vein, the Corporate Sustainability Reporting Directive (CSRD) and the Corporate Sustainability Due Diligence Directive (CSDDD) underscore a shift toward binding obligations for corporate actors.    The final part of the thesis addresses the role of institutional powers in governing the green transition. Particular attention is given to the increasingly proactive role of national and supranational courts in the field of climate law, which has become a testing ground for reconfiguring the boundaries between political discretion and judicial review. Through an analysis of public and private enforcement models emerging in climate change litigation - targeting both States and corporations - this section aims to assess how judicial intervention is reshaping the constitutional order and to identify viable pathways for steering the ecological transition in line with democratic principles and constitutional governance.","language":"ita","citation":"AMBIENTE E INIZIATIVA ECONOMICA PRIVATA NEL GOVERNO DELLA TRANSIZIONE VERDE. PRINCIPI E VALORI COSTITUZIONALI IN CHIAVE COMPARATA / C. Padrin ; tutor: B. Vimercati;  co-tutor: C. Sanna; coordinatore: F. Biondi. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2025 May 14. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13582.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 08-OTT-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1138355"},"title":"NEW ORGANIC AND HYBRID INORGANIC/ORGANIC LUMINESCENT MATERIALS","internalauthor":"MAVER, DANIELE","type":"Tesi di dottorato","year":"2025","abstract":"Triimidazo[1,2-a:1’,2’-c:1”,2”-e][1,3,5]triazine, is a molecule which has been studied by Cariati et. al. since 2017. This system possesses both Aggregation Induced Emission (AIE) and Room Temperature Ultralong Phosphorescence (RTUP) properties, whose discovery fueled further derivatization of the core: in fact, bio-active products, metal complexes and coordination polymers (CP), and phosphorescent organic emitters were synthesized and characterized. My work focused on a further derivatization of the TT scaffold with selected pendants, aiming at obtaining RTP materials and suitable ligands to be employed in luminescent metal complexes and coordination polymers.","language":"eng","citation":"NEW ORGANIC AND HYBRID INORGANIC/ORGANIC LUMINESCENT MATERIALS / D. Maver ; tutor: E. Cariati ; co-tutor: A. Colombo ; coordinatore: D. Roberto. - Via Golgi 19, Milano. Università degli Studi di Milano, 2025 Feb 04. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13524.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1138355/2644529/phd_unimi_R13524.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1104268"},"title":"GOVERNING FORESTS AS COMMONS, BEYOND EFFICIENCY: CAPABILITIES, CONFLICTS, AND COMPLIANCE WITH SOCIO-ENVIRONMENTAL JUSTICE AGREEMENTS","internalauthor":"LORENZINI, SARA","type":"Tesi di dottorato","year":"2024","abstract":"What we are facing today is a situation of ecological and democratic crisis, necessitating deep and multilayered transformations, which should go into the direction of tackling both inefficiencies and inequalities. The aim should be to develop a new way of co-existing that does not eliminate differences but exploits their creative potential in a democratic way. The sustainability transformations we need must be radical, and that is why they raise concerns. They are neither win-win nor zero-sum processes: they can bring to mutual advantage, but distributional conflicts are inevitable and, as such, they must be acknowledged and made visible. Within this scenario and looking at its possible developments, the literature on the commons can offer a potential ground to analyse and direct sustainability efforts. This paper-based dissertation zooms into the notion of commons to understand whether collaborative outcomes are feasible, which transform social, political, and economic relations while addressing the environmental and democratic crisis. Specifically, it focuses on forest governance and forests-related conflicts as emblematic of the current multiple and entwined crisis, as addressing forest deterioration and depletion is also an issue of recognizing people’s opportunities (capabilities) to look for and pursue aspirations, social identities, and flourishing lives attached to forests (Ballet et al., 2018). The main overarching question is about whether governing forests as commons can counteract reductionism and enhance democratic coexistence also with a view to promote socio-environmental justice.  To answer this, the dissertation takes an interdisciplinary approach, mostly drawing from political economy and institutional economics, but also from political science, political philosophy, and political ecology. The first paper is the result of a systematic review of literature on carrying out balancing exercises in the governance of complex socio-ecological systems from the commons and capability approach scholarships. This work develops an integrative framework that connects the two and can serve as an informational and evaluative tool for institutions and policies aimed at governing co-existence in multiple-use forests. The second article instead digs into the ex-ante processes that can bring to well-designed polycentric governance, which translates values and claims’ heterogeneity into institutional heterogeneity. In particular, the paper highlights the role of conflict in these processes and sheds light on how corollary theories can improve the understanding of these dynamics, which the polycentricity literature has mostly overlooked. Finally, the third paper deals with ex-post compliance with multi-stakeholder agreements for new forest governance arrangements that promote environmental protection together with socio-environmental justice. Specifically, the article analyses the case in which a business company with strong economic power is involved, which can defect and abuse the most marginalized stakeholders, i.e., indigenous communities. Thus, this article also deals with the possible divide between environmental protection and social justice.  Overall, the dissertation defines the commons as institutional and social mediators between the ecological and the wellbeing dimensions and, as such, it proposes to analyze and evaluate their normative implications through the capability approach to justice. The reasoning adds to previous contributions on the issue of ecosystem services as socio-ecological services, i.e., services that do not automatically come from nature but are co-produced by human interactions. Importantly, this thesis finds that such co-production most often involves conflictual processes that can be read as two-level collective action problems where different collectivities bring different and competing claims over the same resource, and struggle for recognition of their stake on it. Thus, for democratic co-existence to emerge, conflicting parties must recognise their interdependence as a positive one, which sets the basis for integrative negotiation and deliberation. Then, choosing a new arrangement for forest governance is a matter of equilibrium selection, where different equilibria imply different distributional effects and a possible divorce between environmental and social objectives. This dissertation suggests that an impartial agreement can be of help in directing such equilibrium selection towards the fairest solution, by eliciting preferences and reciprocal expectations such that conformity with it can emerge endogenously. Thus, efficiency and equity can potentially be kept together.  Certainly, this dissertation opens avenues for further research, including investigating an operationalization of the integrative framework, exploring mixed-methodologies to map and measure heterogeneity of claims over complex socio-ecological systems, and carrying out empirical investigations on why certain beliefs and expectations on a socio-environmental equilibrium should emerge, with a focus on the role of culture in this.","language":"eng","citation":"GOVERNING FORESTS AS COMMONS, BEYOND EFFICIENCY: CAPABILITIES, CONFLICTS, AND COMPLIANCE WITH SOCIO-ENVIRONMENTAL JUSTICE AGREEMENTS / S. Lorenzini ; supervisor: L. Sacconi, N. Von Jacobi ; co-supervisor: N. von Jacobi ; phd program coordinator: L. Sacconi. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2024 Oct 11. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13114.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1104268/2547213/phd_unimi_R13114.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1203427"},"title":"EXPLORING THE ANTI-INFLAMMATORY POTENTIAL OF ANTHOCYANIN-RICH CROPS","internalauthor":"TOCCACELI, MARTA","type":"Tesi di dottorato","year":"2025","abstract":"Anthocyanins (ACNs) are a class of purple-red pigments belonging to the flavonoid family largely present in the human diet. Their consumption is correlated to a lower risk of developing chronic diseases thanks to their ability to modulate several pathways, first and foremost inflammation. Being unhealthy diet one of the major, but most preventable, risk factors of inflammatory-related chronic diseases, there is a growing interest in developing and studying plant-based foods enriched in health-promoting phytonutrients, with a focus on climate change resilience and sustainability.  We previously demonstrated that the consumption of an ACN-rich diet from purple corn protected mice from doxorubicin (DOX)-induced cardiotoxicity compared to mice consuming an ACN-free yellow diet. ACNs improved the short-/mid-term survival, but not the long-term one, probably due to their low bioavailability limiting the dose reaching the heart. Thus, besides investigating the molecular mechanisms involved, we aimed at finding a strategy to improve ACN bioavailability and bioactivity through nano-encapsulation of purple corn cob extract. In terms of circular economy, we developed nanoparticles of starch or zein (ZnNPs), both extractable from maize, and recently described in a paper (Massironi et al., 2025). Interestingly, ACNs loaded in ZnNPs were able to protect DOX-insulted HL-1 cardiomyocytes as a 12.5-fold higher dose of free ACNs. However, in an in vitro model of intestinal absorption based on Caco-2 cells, the main ACN of purple corn, cyanidin 3-glucoside (C3G), was maintained in the apical compartment at 80% when provided encapsulated, suggesting a possible increase in ACN stability and/or a delay in their release. Nonetheless, encapsulated ACNs showed a stronger anti-inflammatory effect against intestinal inflammation compared to free ACNs, thus suggesting a potential use of ACN loaded ZnNPs against inflammatory bowel diseases (IBDs).  In parallel, we investigated the anti-inflammatory potential of extracts from three potato varieties from upland cultivation, which may represent a resilient source of beneficial phytonutrients. When provided at plasma-relevant doses, only the carotenoid-rich Desirée and the ACN-rich Bleuet varieties where able to counteract LPS-induced inflammation in THP-1 macrophages, whereas chlorogenic acid (CGA)-rich Kennebec showed an anti-inflammatory activity only at supraphysiological doses. We also observed that the high CGA in Bleuet extract interfered with ACN anti-inflammatory activity, since the isolated ACN fraction from Bleuet exhibited stronger anti-inflammatory effects than the whole Bleuet extract and the addition of CGA to the ACN fraction significantly reduced its anti-inflammatory effect, probably competing for the same membrane transporters. This could indicate a new starting point to develop/select ACN-rich varieties with a lower content of CGA, eventually representing a novel functional food. This work resulted in a recently published paper (Toccaceli et al., 2025).","language":"eng","citation":"EXPLORING THE ANTI-INFLAMMATORY POTENTIAL OF ANTHOCYANIN-RICH CROPS / M. Toccaceli ; tutor: K. Petroni ; coordinatore: S. Ricagno. Dipartimento di Bioscienze, 2025 Dec 17. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13880.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 17-GIU-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/821416"},"title":"LIPIDOMICS UNVEILS THE ROLE OF BIOACTIVE LIPIDS IN CELLULAR MODELS OF CYSTIC FIBROSIS","internalauthor":"DEI CAS, MICHELE VITTORIO","type":"Tesi di dottorato","year":"2021","abstract":"Cystic fibrosis is a genetic disease affecting mainly the lungs, causing chronic inflammation and recurrent infections. The lipid accrual directly contributes to the persistent damage in the cystic fibrosis airways; thus, the deregulated lipid metabolism can be targeted with pharmacological treatment. Here, we aim at demonstrating, in an in vitro model of cystic fibrosis, the role of inflammatory and bioactive lipids in the disease pathophysiology and its modulation by myriocin, which inhibits sphingolipids synthesis. The blended use of both targeted and untargeted mass spectrometry techniques unveiled an atypical lipid composition in broncho-epithelial cystic fibrosis cells and the derived extracellular vesicles. The airways cells in cystic fibrosis accumulate lipids, exacerbating inflammation that can be partly reversed by myriocin therapy, which acts directly on sphingolipid synthesis and indirectly on the accrual of other lipid classes. The CFTR dysfunction leads to an increased metabolism of sphingolipids, which in turn is connected to the release of ceramide-enriched extracellular vesicles that export a pro-inflammatory signal to the recipient cells. The accumulation of lipids may be the result of dysfunctional lipid traffic in the cell and may be responsible for blocking the ER-Golgi network, overproduction of reactive oxygen species and uncontrolled inflammatory stimuli. We proposed new insights on the role of lipid metabolism in the development of cystic fibrosis pathogenesis by using a validated mass spectrometry lipidomics approach. To conclude, we hypothesize that the metabolism of sphingolipids may be an effective pharmacological target to help the reduction of the intrinsic inflammatory state in the airways.","language":"eng","citation":"LIPIDOMICS UNVEILS THE ROLE OF BIOACTIVE LIPIDS IN CELLULAR MODELS OF CYSTIC FIBROSIS / M.v. Dei Cas ; coordinatore: M. SAMAJA ; tutor: M. SAMAJA ; cotutore: R. GHIDONI. Dipartimento di Scienze della Salute, 2021 Mar 17. 33. ciclo, Anno Accademico 2020. [10.13130/dei-cas-michele-vittorio_phd2021-03-17].","filename":"phd_unimi_R11946.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/821416/1725323/phd_unimi_R11946.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/931057"},"title":"L¿INFLUENZA DELLE SENTENZE DELLA CORTE DI GIUSTIZIA PRIMA, DURANTE E DOPO IL PROCESSO AMMINISTRATIVO","internalauthor":"SORDI, VERONICA","type":"Tesi di dottorato","year":"2022","abstract":"Due to the significant resonance assumed in recent years by the increasing integration of European law into national legal systems and, above all, in light of the contribution that Luxembourg judges are more and more frequently asked to give in order to (re) define (or confirm) internal rules of procedure, the present study aimed to investigate the influence of the European Court of Justice’s judgements in the administrative trial. After outlining the historical and legal reasons that led Member States to cede a portion of their sovereignty to establish a sui generis legal system - the study focused on the major role played by the Court of Justice before the preliminary ruling procedure referred by the national court. Indeed, it was showed how this procedure is critical in the relationship between the EU system and national legal systems, being not only a means of control in the implementation of EU law, but also a guarantee of the subjective legal positions of individuals. The study then addressed the effects that EU jurisprudence has produced on the different stages of administrative judgment to focus on some of its fundamental institutions: after observing the influence of the Court of Justice’s judgements on the definition of European sources effects’ extent and in the resulting improved delimitation of any conflicts between national administrative measures and European law, the paper focused on legitimacy and appeal, also with reference to challengeable acts before the administrative judge. Moreover, the work examined the influence that the EU jurisprudence has had on precautionary and compensatory measures, as well as the consequences it has led to with respect to the internal procedural rules relating to the inviolability of the national res judicata. This influence was finally explored in its different aspects in terms of the actionable remedies to avoid the issuing of a judgment in conflict with European law and the configurability of an action of State responsibility, as a remedy to protect the injured party by a ruling of the administrative court of last instance issued in violation of the European Union law as interpreted by the Court of Justice.","language":"ita","citation":"L¿INFLUENZA DELLE SENTENZE DELLA CORTE DI GIUSTIZIA PRIMA, DURANTE E DOPO IL PROCESSO AMMINISTRATIVO / V. Sordi ; coordinatore: F. Biondi ; tutor: M. Sica. Università degli Studi di Milano, 2022 Jun 06. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12228.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/931057/2047777/phd_unimi_R12228.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1123906"},"title":"INFERRING TUMOR PROPERTIES FROM GENE EXPRESSION DATA","internalauthor":"CAGNINA, DANILO","type":"Tesi di dottorato","year":"2025","abstract":"The wide availability of transcriptomics data, along with the advancement of experimental technologies, computational tools, and statistical methods like machine learning (ML), has significantly improved the use of transcriptome data in cancer research, benefiting both diagnostic and prognostic clinical applications.    Gene expression is used to predict the tissue of origin (TOO) of tumor samples, which is relevant in several scenarios such as the diagnosis of cancer of unknown primary (CUP), early cancer detection by means of circulating tumor cells (CTCs) or cell-free RNA (cfRNA) and the identification of mislabelled cell lines. So far those problems have been addressed separately but we ask if one classifier is sufficient to solve them all and investigate what are the determinants of cancer origin prediction performance. To this end, we develop TOPOS (Tissue of Origin Predictor of Onco-Samples), a ML classifier that can distinguish 15 different tissues and we test it on more than 36,000 samples spanning primary tumors, metastases, CTCs, patient-derived xenografts (PDXs), cancer cell lines and organoids. We demonstrate that by adopting a specific training composition and data processing approach, we can achieve high performance across different onco-types, including CTCs, suggesting the applicability of gene expression data in liquid biopsy.    From cancer transcriptomic profiles we can extract features that hold information about tumors’ prognosis. To identify prognostic biomarkers, statistical methods like Cox regression have been adapted from survival analysis techniques. However, these methods rely on assumptions that may not always hold and restrict charting of feature-survival interaction, like for instance non-monotonic relationships, which have been shown to exist for mutation load and chromosomal instability (CIN). We wonder whether a similarly non-monotonic relationship occurs also at gene expression level and demonstrate that for some genes a poor or favorable outcome is found at a medium transcription level and that the shape of gene expression distribution plays a role in determining which expression range is more likely to be associated with good or bad patient prognosis.    In this study, we have examined a diagnostic and prognostic application of gene expression data and explored how computational techniques can enhance its use in cancer research.","language":"eng","citation":"INFERRING TUMOR PROPERTIES FROM GENE EXPRESSION DATA / D. Cagnina ; tutor: M.  Schaefer   co-tutor:  S. Santaguida. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Jan 21. 36. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13134.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1123906/2606582/phd_unimi_R13134.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/899611"},"title":"LIRE DES ROMANS CHEZ EINAUDI: LES CAS DE NATALIA GINZBURG (1944-1964). LE RAPPORTS DE LECTURE AU PRISME DES HUMANITES NUMERIQUES","internalauthor":"ANTONIETTI, LAURA","type":"Tesi di dottorato","year":"2022","abstract":"The objective of this thesis is to study the editorial activity of Natalia Ginzburg at Einaudi publishing house, in particular as an editorial reader of contemporary narrative works, from her arrival to the temporary interruption of the collaboration (1944-1964). We analyse her contribution to decision-making processes, to the construction of the identity and of the catalogue of the publishing house and, more generally, to the definition of the literary culture of her time. Our objective is, moreover, to define the literary models proposed by Natalia Ginzburg to Einaudi’s readers, the way in which her work was part of the intellectual laboratory of Einaudi and in which her idea of literature harmonized with market issues, the relationship that existed between her opinions on the economic and literary viability of a work and the historical-political context, the method and criteria she used to evaluate a book, the relationship that existed between her choices as a publisher and her poetics as an author.  More specifically, our thesis aims to analyse the reading reports concerning contemporary narrative works, which represent a fundamental step in the decision-making process that leads to the publication of a work and therefore to the construction of the catalogue of a publishing house. Through these documents, the books to be printed were selected. Reading reports therefore embodied cultural models that need to be interpreted according to a specific historical and cultural context. Concerning the processing of these documents, a database for the inventory of sources has been designed with IT support. This database makes it possible to efficiently account for sources by gathering the fundamental information for the description of the corpus in a structured way. The documents were indeed transcribed and encoded according to a model developed in XML TEI, able to highlight the different types of documents (letters, structured reading reports, minutes, etc.), their structure and the existing relationships between them.  The modelling activity had an important methodological and heuristic impact to our work. The tool that was created shows the complexity of the corpus of sources, by highlighting paths that are not immediately evident in a linear analysis of documents, by allowing query and by enhancing their intertextuality and their multiautoriality.  The examination of her reading reports, mostly unpublished, provides the basis for a critical reflection on Ginzburg’s editorial activity, a reflection which is rooted in the belief that editorial writing represents a complex critical genre that deserves to be investigated by specific methods.","language":"ita","citation":"LIRE DES ROMANS CHEZ EINAUDI: LES CAS DE NATALIA GINZBURG (1944-1964). LE RAPPORTS DE LECTURE AU PRISME DES HUMANITES NUMERIQUES / L. Antonietti ; tutor: E.  PIERAZZO ; cotutor: A. CADIOLI. Università degli Studi di Milano, 2022 Mar 25. 32. ciclo, Anno Accademico 2019.","filename":"phd_unimi_R11824.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/899611/2045561/phd_unimi_R11824.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1156183"},"title":"CANCER-DERIVED EXTRACELLULAR VESICLES FOR TARGETED DELIVERY OF EGFRVIII SIRNA TO NEOPLASTIC TISSUE, EVALUATION OF THE HOMING MECHANISM AND POTENTIAL THERAPEUTIC APPLICATIONS IN GLIOBLASTOMA.","internalauthor":"SHOJAEIGHAHRIZJANI, FERESHTEH","type":"Tesi di dottorato","year":"2025","abstract":"Extracellular vesicles (EVs), lipid-bound particles (50–150 nm in diameter), serve as natural delivery systems. Our previous data indicated a heterologous and cross-species tumour tropism for cancer-derived EVs such as colorectal cancer patient-derived EVs (PDEVs) and cancer cell-derived EVs compared to healthy donor EVs and non-transformed cell-derived EVs. For the first part of my PhD project, we evaluated some hypotheses to uncover the tumour tropism mechanism. These hypotheses centered around the half-life of EVs in circulation, EV interaction with cancer cells and extracellular matrix (ECM) and EV cargo release into the recipient cells.  We first showed the eliminated tumour tropism feature upon filtering EVs. We also showed that trypsin treatment reduces EV-uptake rate by the cells. These experiments intensified the importance of EV corona since both trypsinization and filtration could affect the EV corona.  Then we compared the EV uptake rate by cancer cells, transformed macrophages (RAW246.7) and primary macrophages (BDMSCs). Although, the results did not show superior uptake of cancer-derived EVs by cancer cells and RAW264.7, we observed unique interactions with BDMSCs, including large aggregate formation and phagocytosis deficits. This might lead to a higher half-life of cancer-derived EVs in circulation leading to their tumour site accumulation.   We also showed a significant higher affinity of colorectal cancer-derived EVs to laminin as one of the major ECM components. Our mass spectrometry analysis (Proteomics) revealed differential protein expression for colorectal cancer patient-derived EVs (PDEVs) vs healthy donor EVs. Among these proteins, aminopeptidase N (CD13) showed a higher expression in cancer-derived EVs, confirmed by immunoblot analysis. Since CD13 is a potential protein involved in higher binding affinity of cancer-derived EVs to ECM component such as laminin and fibronectin through binding to NGR motif (Aspargine-Glycine-Arginine), we introduced CD13 as a potential candidate for the tumour tropism of cancer-derived EVs.  For the second part of my PhD thesis, we harnessed the tumour tropism of glioblastoma (GBM)-derived EVs for targeted delivery of EGFRvIII siRNA, addressing this oncogenic driver in GBM. Among different approaches for loading siRNA into EVs such as endogenous loading, passive loading, membrane permeabilization, sonication, electroporation and transfection methods; transfection with a cell-penetrating peptide showed effective knock-down of EGFRvIII expression in the U373vIII cells.   In conclusion, while EGFRvIII-targeting siRNA-loaded EVs demonstrated functional activity in vitro and partial efficacy in vivo, overcoming barriers such as correct dosing of siRNA loaded EVs, tumour microenvironment resistance, heterogeneous signaling pathways, and delivery inefficiencies will be critical for future therapeutic success. Combination approaches incorporating the EGFRvIII targeting with existing treatments like temozolomide (TMZ) or radiation could enhance overall survival outcomes. Further studies are necessary to refine EV-based delivery strategies and optimize therapeutic potential.","language":"eng","citation":"CANCER-DERIVED EXTRACELLULAR VESICLES FOR TARGETED DELIVERY OF EGFRVIII SIRNA TO NEOPLASTIC TISSUE, EVALUATION OF THE HOMING MECHANISM AND POTENTIAL THERAPEUTIC APPLICATIONS IN GLIOBLASTOMA / F. Shojaeighahrizjani ; tutor: P. Ciana ; co-tutor: J. Rak ; coordinator: G. D. Norata. - Milan. Università degli Studi di Milano, 2025 Apr 11. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13264.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1156183/2730802/phd_unimi_R13264.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1054528"},"title":"IN VIVO AND IN VITRO EVALUATION OF THE COMBINATION OF RNA INTERFERING AND GENE THERAPY FOR TREATING MITOFUSIN2-RELATED DISEASES","internalauthor":"ABATI, ELENA","type":"Tesi di dottorato","year":"2024","abstract":"Background: Mitofusin-2 (MFN2) is an outer mitochondrial membrane protein essential for mitochondrial networking in most cells. Autosomal dominant mutations in the MFN2 gene cause Charcot-Marie-Tooth type 2A disease (CMT2A), a severe and disabling sensory-motor neuropathy. Here, we propose a novel therapeutic strategy tailored to the correction of the root genetic defect of CMT2A, based on the combination of RNA- interference (RNAi) and gene therapy.  Methods: We devised a strategy whereby both the mutant and wild-type MFN2 mRNA are inhibited by a short hairpin RNA (shRNA), while the wild-type protein is restored by overexpressing a cDNA encoding functional MFN2 modified to be resistant to RNAi. We tested this strategy in vitro, in CMT2A patient-specific human induced pluripotent stem cell (iPSC)-differentiated motor neurons (MNs), transfecting them with two constructs, one encoding a shRNA directed against endogenous MFN2 sequence, the gene responsible for CMT2A, and one encoding an exogenous MFN2 sequence designed to be resistant to silencing. We also delivered the constructs in vivo in newborn MitoCharc1 CMT2A and Thy1.2-MFN2R94Q transgenic mice via cerebrospinal fluid (CSF) delivery using adeno-associated virus 9 (AAV9).  Results: We demonstrated the correct silencing of endogenous MFN2 and replacement with an exogenous copy of the functional wild-type gene in cells. This approach significantly rescues the CMT2A MN phenotype in vitro, stabilizing the altered axonal mitochondrial distribution and correcting abnormal mitophagic processes. After delivery of an AAV9 encoding either the shRNA alone or the combination of shRNA/MFN2 cDNA, we observed a correct MFN2 molecular correction in the MitoCharc1 and Thy1.2-MFN2R94Q mice, but the treatment proved toxic after one month for Thy1.2- MFN2R94Q animals treated with AAV9-encoded shRNA and after two months of life for mice treated with AAV9-encoded shRNA/MFN2 cDNA.  Conclusions: Overall, the combined RNAi and gene therapy strategy proved able to effectively silence mutant MFN2 and restore wild-type protein levels. In addition, it was able to correct alterations in mitochondrial distribution and mitophagic processes in CMT2A MNs. In vivo, this therapeutic strategy achieved molecular efficacy but proved toxic for treated animals. It will therefore be necessary to investigate further the reasons for this toxicity in order to find a safe and effective treatment for CMT2A patients.","language":"eng","citation":"IN VIVO AND IN VITRO EVALUATION OF THE COMBINATION OF RNA INTERFERING AND GENE THERAPY FOR TREATING MITOFUSIN2-RELATED DISEASES / E. Abati ; tutor: S. Corti ; coordinatrice: C. Sforza. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2024 May 21. 37. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13231.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1054528/2421453/phd_unimi_R13231.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1258916"},"title":"AUTONOMIA UNIVERSITARIA E SISTEMA DI VALUTAZIONE: TRA VINCOLI E RESPONSABILITÀ","internalauthor":"IEMMA, MARTINA","type":"Tesi di dottorato","year":"2026","abstract":"More than seventy years after its constitutional recognition and sixteen years after the reform introduced by Law no. 240/2010, university autonomy is in a state of marked tension. External rules and constraints significantly affect universities, compressing their right to self-governance and the academic freedom of professors and researchers, to the point of eroding the original conception of university autonomy set out in Article 33 of the Constitution.  This paper examines the extent to which such autonomy is currently constrained or limited by legislative provisions, evaluation mechanisms, and the principle of accountability. The analysis is structured around four main thematic axes: the constitutional, legislative, and theoretical meaning of university autonomy within the Italian legal system; the balance between autonomy and accountability of universities, with particular attention to legislative constraints and evaluation tools; the dependence of ANVUR on the Ministry; and a comparison with the Flemish model.  Adopting a multidisciplinary approach that integrates legal, historical, and comparative analysis, this study examines Italian constitutional and legislative provisions, with particular reference to Law no. 240/2010 and the role of the National Agency for the Evaluation of the University and Research System (ANVUR), in order to highlight their impact on university autonomy. The paper shows how the triad autonomy, responsibility, evaluation, although originally intended to promote the quality and transparency of the university system, has progressively turned into an instrument of centralised control, thereby limiting the effective autonomy of universities and researchers. Finally, the comparison with the Belgian university system, and in particular the Flemish one, provides useful insights for a possible reconsideration on university autonomy in Italy.","language":"ita","citation":"AUTONOMIA UNIVERSITARIA E SISTEMA DI VALUTAZIONE: TRA VINCOLI E RESPONSABILITÀ / M. Iemma ; tutor: L. Violini ; co-tutor: R. Ruffini ; coordinatore: E. Damiani. Università degli Studi di Milano, 2026 Jul 13. 38. ciclo, Anno Accademico 2025.","filename":"phd_unimi_R14091.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1258916/3365662/phd_unimi_R14091.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1197775"},"title":"ASSESSMENT OF CELL AND METABOLIC IMPACT OF MICROTUBULE TARGETING AGENTS (MTA) IN NEURODEGENERATION AND NEURON MODELS.","internalauthor":"BASELLINI, MILO JARNO","type":"Tesi di dottorato","year":"2025","abstract":"Parkinson’s disease (PD) is primarily characterized by its sporadic onset, with 80–85%  of cases occurring without a clear genetic cause, classified as idiopathic. The complexity of  PD’s pathogenesis makes it challenging to identify a single molecular mechanism responsible  for the disease. Rather, PD progression is associated with a range of pathological processes,  including mitochondrial dysfunction, oxidative stress, disturbances in cytoskeletal dynamics,  abnormal protein aggregation, and neuroinflammation. Current treatment options for PD focus  mainly on alleviating motor symptoms through dopamine replacement therapies, such as  levodopa and dopamine agonists.While these treatments can provide temporary relief, they do  not address the underlying neurodegeneration and typically lose effectiveness over time.  Additionally, long-term use can lead to complications such as motor fluctuations and  dyskinesias. To date, no disease-modifying therapies have been proven to be effective in  ameliorating the progression of PD, underscoring the need for new therapeutic strategies. In  this context, in this work we investigated some of the pathological mechanisms involved in PD,  including its onset, progression, and potential treatment strategies, in order to unveil the  pathophysiological pathways shaping the disease and to provide possible new insights for  therapeutic intervention.  Based on the metabolic characterization and transcriptomic data, and applying specific  metabolic reconstructions after data integration using Genome-Scale Metabolic Models  (GSMM) we report that, in PC12 cell model, neuronal differentiation is accompanied by  switching towards a more glycolytic metabolism, with the glucose catabolism that tends  towards lactate production, rather than the aerobic oxidative pathway, with a general reduction  of TCA and OXPHOS subsystems. Despite surprising, this may depend on the signaling  properties of lactate in promoting neuronal differentiation. In addition, we observe an overall  reduction in amino acids consumption upon differentiation, probably due to the increased  mitochondrial fission, which may fit the assumption that energy requirements for differentiated  cells are reduced compared to growing cells, being mostly post-mitotic and blocked in G0  phase.  This cellular model was then used to test new Maytansinol-derivatives, synthesized  within the TubInTrain consortium, as novel tubulin binders. Despite been proven as weak  inhibitors of microtubules polymerization, one compound resulted effective in microtubules  homeostasis modifiers, promoting microtubules dynamic properties. In addition, downstream  7  metabolomic analysis suggested that the compound could result in changes on cell metabolism.  The results point towards impaired mitochondrial metabolism and neurotransmitter  homeostasis, probably due to the alteration of the microtubule-mediated mitochondria  trafficking and synaptic vesicles axonal transport.  PC12 cells were transfected to overexpress either wild type or disease-associated A53T  α-synuclein, and both microtubular compartment and cell metabolism were studied. We  observed that wild type α-synuclein overexpression, but not disease-related A53T mutated α-  synuclein, resulted in the decrease of acetylated-tubulin, suggesting more dynamic  microtubules, enforcing the hypothesis of a putative interplay between tubulin acetylation and  α-synuclein. In addition, our results show that modulating tubulin acetylation influences α-  synuclein aggregation, supporting the idea that an impaired homeostasis of microtubules PTMs  may be involved in the early stages of neurodegenerative processes. Regarding cell metabolism,  wt α-synuclein overexpression seems not to significantly affect metabolic processes, while  A53T-transfected cells were characterized by an imbalance of some amino acids, mostly related  to oxidative stress response, pro-inflammatory environment and mitochondrial damage. These  results indicate that the disease-associated A53T mutation of α-synuclein may exert its  pathological properties directly binding to mitochondrial membranes and impairing their  physiological functions.  Finally, as the aggregation of α-synuclein is critically involved in the onset and  progression of PD and related synucleinopathies, we employed a cell model that naturally  showed increased oligomeric pathology due to α-synuclein overexpression, namely SK-N-SH  cells, to study the protective impact of Oleuropein aglycone on α-synuclein aggregation and  toxicity. For the detection of synuclein oligomers we took advantage of Proximity Ligation  Assay technique, and according to our results, OA showed great potential in reducing the  oligomeric burden in a neuronal cell model in a dose dependent manner. In addition, OA were  proved capable of reducing the toxicity exerted by in vitro pre-formed α-synuclein fibrils. Our  results were integrated with in vivo investigations in a C. elegans models of PD, suggesting that  OA may effectively reduce the extent of different types of α-synuclein aggregates in both  cellular and animal models of PD.  This study offers a comprehensive view of Parkinson’s disease by examining the  interactions between α-synuclein, mitochondrial function, microtubules, and metabolism in  both cellular and in vivo models. It confirms the usefulness of PC12-based models and suggests  potential therapeutic strategies, includingmicrotubule-targeting drugs and oleanolic acid. These  findings enhance our understanding of PD and point toward new directions for future treatments.","language":"eng","citation":"ASSESSMENT OF CELL AND METABOLIC IMPACT OF MICROTUBULE TARGETING AGENTS (MTA) IN NEURODEGENERATION AND NEURON MODELS / M.j. Basellini ; coordinatore: M. Cascante ; tutor: S. Marin, G. Cappelletti. Dipartimento di Bioscienze, 2025 Sep 22. 35. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13187.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 24-NOV-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1204477"},"title":"EXPLORING BITCOIN WITH COMPUTATIONAL SOCIAL SCIENCE METHODS","internalauthor":"VENTURINI, MARCO","type":"Tesi di dottorato","year":"2026","abstract":"This dissertation investigates the emergence, evolution, and internal dynamics of Bitcoin as a socio-technical and economic system. Conceived as a radical alternative to traditional finance, Bitcoin was designed to decentralise the economic system, eliminate intermediaries, and foster autonomy. Yet, rather than establishing a new financial order, it has quickly developed patterns and structures similar to those of traditional markets. This increasing similarity raises fundamental questions about the mechanisms driving Bitcoin’s trajectory, its sustainability and its implications for global finance.  Drawing on a unique dataset of fifteen years of transaction-level records, this thesis combines network analysis, temporal network modelling, and agent-based modelling to capture Bitcoin’s complexity. The analysis shows that, despite its ideological roots in decentralisation, Bitcoin has evolved into a highly centralised and concentrated network. Wealth, activity, and influence are increasingly accumulated within a small set of actors, producing choke points and stabilisation dynamics that resemble traditional financial structures.  The research further explores Bitcoin’s responses to uncertainty and exogenous shocks, including the Mt. Gox collapse in 2014 and the COVID-19 pandemic in 2020. Results indicate that while the system does adapt through network reconfiguration, its responses are asymmetric: the Mt. Gox crisis produced lasting structural change, whereas the pandemic triggered rapid but temporary adjustments. The latter resembles the reconfiguration patterns observed in traditional markets and reveals the growing influence of institutional participation, which amplifies short-term volatility while reinforcing long-term stability.  Finally, an empirically informed agent-based model of Bitcoin trading demonstrates how micro-level behaviours, by combining price and network preferences, reproduce macro-level concentration and centralisation trends. This highlights how networked interactions and behavioural dynamics influence the system’s structural asymmetries.  Overall, the thesis reveals strong similarities between Bitcoin and traditional financial markets, challenging narratives of radical decentralisation and autonomy. Far from nurturing a libertarian utopia, Bitcoin has converged with familiar market logics, raising questions about its long-term viability, systemic risks and regulatory integration.","language":"eng","citation":"EXPLORING BITCOIN WITH COMPUTATIONAL SOCIAL SCIENCE METHODS / M. Venturini ; supervisor: F. Squazzoni (Unimi), G. Manzo (Sorbonne Université) ;  coordinatore: M. Guerci (Unimi),  A. Wrona (Sorbonne Université). Dipartimento di Scienze Sociali e Politiche, 2026 Jan 09. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13884.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 21-GIU-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1227575"},"title":"SAFETY AND EFFICACY OF INFLATABLE PENILE PROSTHESES IN PEOPLE WITH SPINAL CORD INJURY/DYSFUNCTION: A HOLISTIC TERTIARY REFERRAL CENTER WORKFLOW","internalauthor":"SAMPOGNA, GIANLUCA","type":"Tesi di dottorato","year":"2026","abstract":"1. Introduction  ED is common after SCI/D and often coexists with NLUTD, NBD, spasticity, AD risk and high vulnerability to pressure injuries. PP implantation in SCI/D has historically been regarded as “high risk,” mainly because of increased infection, erosion/extrusion, revision and explant rates reported in older series. This study approaches IPP surgery in SCI/D as a workflow-dependent intervention, where outcomes are influenced by all steps in a Spinal Unit: pre-operative optimization, surgical technique and post-operative management.    2. Aim of the study  The primary objective of the study was to assess the safety of contemporary IPP implantation in selected men with SCI/D managed within a structured multidisciplinary workflow by a tertiary referral Spinal Unit. Secondary objectives included: to assess functional efficacy of IPPs; to quantify patient satisfaction and likelihood of recommending the procedure; to evaluate impact on bladder and bowel management, and IC; to evaluate referral appropriateness in a large screened cohort and develop a referral appropriateness PP score (SCI/D-RAPPS) to use in routine clinical practice; to collect and summarize all the precautions adopted in a practical risk mitigation plan for other surgeons who are approaching IPP surgery in SCI/D.    3. Materials and methods  After the approval by the Institutional Review Board, a prospective, longitudinal, single-center study was initiated in an Italian tertiary referral Spinal Unit setting. The initial enrollment period was from Feb 2023 to Jan 2024 with a 12-month-long follow-up period ending in Jan 2025. Due to reduced enrollment for strict selection process, the study was extended with a new enrollment period from Jun 2024 to May 2025, with follow-up period prolonged up to May 2026. Two linked samples were analyzed: (1) a consecutive cohort of 263 men with SCI/D evaluated for IPP during the enrollment period by our center, considered to develop the SCI/D-RAPPS; (2) the subgroup that underwent three-piece IPP implantation (n = 12) with standardized pre, peri and post-operative data collection within a follow-up of 12 months. To reduce the risk of complications, all factors that may influence surgical outcomes were evaluated and optimized in people addressed to IPP surgery, including bladder and bowel management, IC technique, spasticity management, skin integrity and UTI risk. In the first cohort, multivariate logistic regression with internal bootstrap was used to develop a model to predict appropriateness for IPP evaluation according to different patient characteristics. In the second sample, PROMs were collected for bladder evaluation (e.g., SF-Qualiveen, ICIQ-UI SF, ease of IC insertion), bowel function (e.g., NBD score, MENTOR tool) and patient experience (QoLSPP and 10-point Likert scales for evaluating satisfaction and recommendation).    4. Results  Among 263 evaluated men with SCI/D, 61/263 (23.2%) referrals were classified as appropriate and 202/263 (76.8%) as inappropriate.  In multivariate analysis, referral appropriateness was associated with younger age (OR 0.97 per year), lower comorbidity burden (CCI ≥ 3: OR 0.26), lower UTI burden (OR 0.26), stable partner status (OR 2.52) and an appropriate psychological profile (OR 10.71). Model performance showed Nagelkerke’s R² = 0.298, apparent AUC = 0.801 and corrected AUC = 0.751 after bootstrap validation (B = 1, 000). Using p ≥ 0.30, sensitivity and specificity were 0.705 and 0.738, respectively. A SCI/D-RAPPS software application probability calculator was developed to use this score in routine clinical practice.  Twelve out of 61 (19.7%) patients underwent three-piece IPP implantation, while the others refused after adequate counselling and/or presented clinical issues to solve before IPP. The median admission-to-discharge LOS was 4 days (IQR 4-8), with one markedly prolonged admission (23 days) due to a sacral pressure injury after a prolonged waiting time before entering the operating room because of organizational issues.  After a median follow-up of 16 months (IQR 14-20), explantation was performed in 1 out of 12 cases (8.3%) at 6 months because the scrotal surgical wound persistently failed to heal.  Across 12-month follow-up, bladder-related PROMs (SF-Qualiveen and ICIQ-UI SF) and bowel function (NBD score) remained stable overall. IC management showed an improvement in perceived ease of catheterization, significantly advancing (p = 0.006) from median 7 (pre) to 9 (post). Satisfaction and recommendation scores remained high and stable (p > 0.05) over time; at 12 months, medians for satisfaction and recommendation were 9 and 10, respectively. The QoLSPP total and domains scores remained high and stable throughout 12 months (p > 0.05) with a median total score of 67/80 at 12 months.  The study collected all the precautions adopted and summarized the adopted pathway into a replicable plan to reduce the risks that other surgeons may need to manage in this population.    5. Discussion  In people with SCI/D, IPP implantation should be regarded as the result of a complex selection and optimization pathway. Our referral analysis showed that most patients assessed did not meet appropriateness criteria, indicating that early triage tools such as SCI/D-RAPPS could help limit unnecessary evaluations and focus specialists on those most likely to benefit.  Among implanted patients, satisfaction was high and remained stable over time, while bladder and bowel PROMs did not worsen. This suggests that, in carefully selected patients managed within a specific setting, three-piece IPP can provide effective sexual rehabilitation without compromising other pelvic functions. The improvement observed in IC ease is particularly relevant in SCI/D, where the catheterization technique often has a major impact on independence.  As for complications, a patient with a high comorbidity burden required explantation because of persistent scrotal wound dehiscence. Although the patient remained afebrile and repeated swabs were negative, the clinical course raised suspicion of an underlying chronic infection. Other possible contributing factors were also considered, including an altered inflammatory or immune response in the setting of chronic idiopathic urticaria, mechanical factors related to obesity in paraplegia with pump prominence and scrotal friction possibly altering wound healing.  Overall, these observations support the need for a precise strategy to reduce the risks that covers pre-operative optimization, intra-operative measures and structured post-operative follow-up.    6. Conclusions  In a specialized Spinal Unit, the use of a structured pre-, intra- and post-operative pathway was associated with low complication rate, high patient satisfaction, stable bladder and bowel PROMs and easier IC insertion after IPP implantation in carefully selected men with SCI/D. These findings underscore the value of a multidisciplinary approach. The high rate of inappropriate referrals among screened patients also suggests that SCI/D-RAPPS may be a useful referral-support tool to improve patient selection. In addition, the proposed risk-mitigation plan may help surgeons address the specific technical and clinical challenges of IPP surgery in people with SCI.","language":"eng","citation":"SAFETY AND EFFICACY OF INFLATABLE PENILE PROSTHESES IN PEOPLE WITH SPINAL CORD INJURY/DYSFUNCTION: A HOLISTIC TERTIARY REFERRAL CENTER WORKFLOW / G. Sampogna ; tutor: E. Montanari ; co-tutor: M. Spinelli ; coordinatore: M. Del Fabbro. Dipartimento di Scienze Cliniche e di Comunità, 2026 Mar 20. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13475.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1227575/3281930/phd_unimi_R13475.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/821735"},"title":"DISEASE RISK ASSESSMENT OF INVASIVE ALIEN SPECIES","internalauthor":"CHINCHIO, ELEONORA","type":"Tesi di dottorato","year":"2021","abstract":"Increased global trade and travel have led to a rise in the number of invasive alien species (IAS), i.e. species introduced by humans in geographic areas where are not naturally found, worldwide. Despite the recognized role of wildlife, as well as of wildlife translocations, in the emergence and re-emergence of infections of public health significance, IAS remain mainly studied for their environmental impacts, and their disease risk towards humans and animals is still largely neglected by health professionals.    The main aim of this thesis is therefore to cover this gap by setting the ground for a new “invasion epidemiology” field, and this has been done through two main steps: the review and analysis of both the mechanisms underlying IAS disease risk and the information available in literature on IAS pathogens, and the development of a standardized qualitative disease risk assessment method, applicable to different geographic contexts, to assess the risk of mammal IAS to impact on human and animal health.  First, I reviewed the existing biological and ecological literature on IAS to identify the main mechanisms by which animal IAS may affect disease risk in their area of release. IAS resulted to potentially affect disease risk both directly, by acting as hosts of infectious agents, thus possibly leading to the introduction of new pathogens, and/or the amplification of endemic ones, or indirectly, by altering the ecosystem equilibrium, through competitive and trophic interactions with native host species or the modification of local habitats. This literature review highlighted how IAS may have important health implications, which should be better acknowledged by people working in the human and animal health field, and how the mechanisms underlying the sanitary outcome of a biological invasion, and in particular indirect ones, are extremely complex, being the product of multiple factors. Acknowledging the important limitations of our current ability to predict possible health impacts driven by indirect mechanisms, I decided to address the issue of IAS disease risk by focusing specifically on IAS possible role as infectious agents’ host.   As information on IAS pathogens is not systematized, preventing from knowing the amount and quality of available data to inform possible disease risk assessment procedures, I systematically reviewed the literature on the infectious agents of the main mammal species of European Union concern. Current knowledge on the pathogens harbored by mammal IAS was evaluated through different statistical approaches: the identification of the main factors associated with research intensity and the observed pathogen species richness, the estimation of the true helminth species richness, and a meta-analysis of prevalence of the pathogens of public and animal health significance. Results highlighted the existence of strong information gaps and biases in the way research on mammal IAS pathogens is carried out, the current underestimation of the amount of pathogens harbored by these species and high levels of uncertainty in the pooled prevalence of pathogens of public and animal health significance. However, the review confirmed that mammal IAS harbor pathogens of human and animal health significance, and therefore, the need to identify high-risk species.   Considering that the existing knowledge gaps would have resulted in strong limitations in informing a risk assessment procedure, I developed a qualitative disease risk assessment methodology informed by expert opinion. This tool is specifically aimed at assessing IAS disease risk towards humans, domestic animal populations, and/or wildlife populations and allows to obtain a list of the pathogens of animal and human health significance that mammal IAS could transmit to a population of interest (directly or through the communities of local hosts), each with the related level of risk and uncertainty. Key features of the tool are its flexibility, being applicable to different contexts and for different purposes, and the high resolution of the mechanisms under assessment, which make possible for risk managers identifying the most critical pathogens and mechanisms involved in disease risk, allowing them to direct targeted actions and surveillance plans.  Finally, the need to combine multiple likelihood estimates deriving from several pathways in an overall risk estimate led me to tackle a methodological aspect of qualitative risk assessment procedures, and I proposed a standardized method applicable in such cases, to reduce the subjectivity that relies in the different ways multiple estimates are currently combined.","language":"eng","citation":"DISEASE RISK ASSESSMENT OF INVASIVE ALIEN SPECIES / E. Chinchio ; tutor: N. Ferrari ; co-tutor: M. Crotta ; coordinatore: C. La Vecchia. Dipartimento di Medicina Veterinaria, 2021 Mar 10. 33. ciclo, Anno Accademico 2020. [10.13130/chinchio-eleonora_phd2021-03-10].","filename":"phd_unimi_R12066.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/821735/1726085/phd_unimi_R12066.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/881847"},"title":"SULFUR NUTRITION AND PARTITIONING IN RICE UNDER DIFFERENT STRESS CONDITIONS","internalauthor":"CAVALLARO, VIVIANA","type":"Tesi di dottorato","year":"2021","abstract":"Sulfur (S) is an essential macronutrient required by plants for their correct development. This element is fundamental for the biosynthesis of different compounds, such as the two amino acids, cysteine (Cys) and methionine (Met), vitamins (biotin and thiamine), peptides involved in the response to abiotic stresses (glutathione - GSH, and phytochelatines - PCs), lipids and co-factors. Sulfate (SO42-) is the main S form taken up from soil by root system and then assimilated inside the cells during the sulfur reductive pathway. The uptake and the systemic movements of this anion are accomplished by the SULfate TRansporter (SULTR) gene family, which encode for H+/SO42- membrane co-transporters with different localization, amino acidic sequences, and affinity to sulfate. Since has been demonstrated that S has a key role in the response to different abiotic stresses (such as sulfur deficiency, heavy metal exposure or salt stress), the expression of these genes must be finely regulated, according to the different environmental conditions and requests for S reduced compounds.   The general aim of the present thesis is the description of S systemic fluxes in rice in different stress conditions, to obtain more information about the contribution of S in determining plant tolerance to abiotic stresses. To achieve the goal, we also took advantage of analysis performed with an elemental analyzer coupled with an isotope ratio mass spectrometer (EA-IRMS), a powerful instrument which utilizes stable isotopes of elements as tracers.   The entire research has been divided in three different parts.  In the first work, potential 32S/34S isotope effects occurring during SO42- uptake were investigated in a closed hydroponic system in which a limited amount of substrate (SO42- in the nutrient solution) was continuously removed from the solution by the activity of the sulfate transporters of the root and converted in a final product (total S of the plant). An isotope discrimination against 34S occurred during SO42- uptake: plants had a lighter S isotope composition, and the residual SO42- in the hydroponic solution was enriched in heavy stable isotope. Fractionation during uptake showed two phases characterized by different fractionation factors, reflecting changes in the expression of the OsSULTR deputed to the root uptake which may explain the different isotope phenotypes observed during plant sulfate acquisition. Moreover, the possible 32S/34S isotope effects associated to both S partitioning and metabolism were investigated by comparing plants pre-grown in complete nutrient solutions and then continuously maintained on media containing SO42- (steady-state) or deprived of SO42- for 72h. The SO42- pool of the steady-state shoot was significantly 32S depleted with respect to the SO42- pools of root, while the organic S (Sorg) pools were significantly depleted in 34S compared to both the SO42- pool of both the organs and the S source. These results suggested a higher S assimilation in the aerial part of plants which favor the lighter isotope. Under S starvation, S assimilation progressively enriched the Sorg pools in the lighter 32S isotope and the residual SO42- in both the organs in the heavier 34S isotope. Most pronounced isotope separations were again observed in the shoot, confirming the prominent role of this organ in SO42- assimilation and S allocation. No fractionation due to translocation activity was observed.  In the second part of the work, to validate the results previously obtained, we performed a mass balance study in rice plants exposed for 72h to different Cd concentrations, to investigate possible changes in S stable isotope fractionation due to this stress: in fact, adaptation of S metabolism has a pivotal role in responses to heavy metal exposure. As expected, Cd treatment strongly enhanced SO42- uptake and assimilation, as indicated by the analyses of the S pools (Stot, SO42-, and Sorg).  S isotope analyses performed on the whole plants revealed changes in the S metabolism associated to variations in the discrimination against 34S, which was less evident as Cd concentration in the external medium increased. Transcriptional analysis suggested again that change of the ratio between relative transcripts of OsSULTR1;1 and OsSULTR1;2, as observed for S starvation, may be responsible for the progressive decreased in 34S isotope discrimination. The important role of shoot in S assimilation was confirmed: isotope fractionation associated to sulfate assimilation was higher in shoot than in root, and progressively increased as Cd concentration did.  The last part of work was focused on fully characterize, under hydroponics-controlled conditions in the absence or in the presence of salt stress (80 mM NaCl), the phenotypic behavior in the already available salt tolerant introgression line (IL) Onice 11 (O11), obtained by Marker-Assisted Back-Cross (MABC) selection starting from the cross between the Italian japonica elite cultivars Onice (sensitive recurrent parent) and the indica variety IR64-SalTol (tolerant), donor of the major QTL SalTol. Moreover, S acquisition and metabolism of O11 and both the parental lines were evaluated to investigate their possible implication in determining the different tolerance to salt stress. Results showed the beneficial effect of the introgression of the SalTol QTL from the indica variety into selected japonica rice line, based on different characteristics of selected phenotypic-biochemical-physiological parameters. However, salt stress strongly affected S uptake and assimilation, and we can reasonably suppose that these features do not justify the different salt tolerance in the considered IL O11.   In conclusions, rice plants can discriminate against 34S during SO42- uptake and assimilation. Between plants organs, shoot represents the predominant one involved in S assimilation. Abiotic stresses, such as S starvation or Cd exposure, lead to changes in the ratio of relative transcripts between the OsSULTRs involved in the uptake of sulfate, and this may be the cause of the different isotope phenotypes observed. Finally, salt tolerance in the IL O11 appears to not be dependent on different S metabolism.","language":"eng","citation":"SULFUR NUTRITION AND PARTITIONING IN RICE UNDER DIFFERENT STRESS CONDITIONS / V. Cavallaro ; tutor: G. A. Sacchi ; co-tutor: F. F. Nocito ; coordinatore: P. A. B.; revisori estreni: G. Vigani, S. Astolfi. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2021 Dec 16. 34. ciclo, Anno Accademico 2021. [10.13130/cavallaro-viviana_phd2021-12-16].","filename":"phd_unimi_R12165.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/881847/1908944/phd_unimi_R12165.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/889159"},"title":"UNSUPERVISED GENERATIVE MODELS FOR DATA ANALYSIS AND EXPLAINABLE ARTIFICIAL INTELLIGENCE","internalauthor":"ABUKMEIL, MOHANAD","type":"Tesi di dottorato","year":"2022","abstract":"For more than a century, the methods of learning representation and the exploration of the intrinsic structures of data have developed remarkably and currently include supervised, semi-supervised, and unsupervised methods. However, recent years have witnessed the flourishing of big data, where typical dataset dimensions are high, and the data can come in messy, missing, incomplete, unlabeled, or corrupted forms. Consequently, discovering and learning the hidden structure buried inside such data becomes highly challenging.  From this perspective, latent data analysis and dimensionality reduction play a substantial role in decomposing the exploratory factors and learning the hidden structures of data, which encompasses the significant features that characterize the categories and trends among data samples in an ordered manner. That is by extracting patterns, differentiating trends, and testing hypotheses to identify anomalies, learning compact knowledge, and performing many different machine learning (ML) tasks such as classification, detection, and prediction.  Unsupervised generative learning (UGL) methods are a class of ML characterized by their possibility of analyzing and decomposing latent data, reducing dimensionality, visualizing the manifold of data, and learning representations with limited levels of predefined labels and prior assumptions. Furthermore, explainable artificial intelligence (XAI) is an emerging field of ML that deals with explaining the decisions and behaviors of learned models. XAI is also associated with UGL models to explain the hidden structure of data, and to explain the learned representations of ML models. However, the current UGL models lack large-scale generalizability and explainability in the testing stage, which leads to restricting their potential in ML and XAI applications.  To overcome the aforementioned limitations, this thesis proposes innovative methods that integrate UGL and XAI to enable data factorization and dimensionality reduction to improve the generalizability of the learned ML models.  Moreover, the proposed methods enable visual explainability in modern applications as anomaly detection and autonomous driving systems. The main research contributions are listed as follows:    • A novel overview of UGL models including blind source separation (BSS), manifold learning (MfL), and neural networks (NNs). Also, the overview considers open issues and challenges among each UGL method.  • An innovative method to identify the dimensions of the compact feature space via a generalized rank in the application of image dimensionality reduction.  • An innovative method to hierarchically reduce and visualize the manifold of data to improve the generalizability in limited data learning scenarios, and computational complexity reduction applications.  • An original method to visually explain autoencoders by reconstructing an attention map in the application of anomaly detection and explainable autonomous driving systems.    The novel methods introduced in this thesis are benchmarked on publicly available datasets, and they outperformed the state-of-the-art methods considering different evaluation metrics. Furthermore, superior results were obtained with respect to the state-of-the-art to confirm the feasibility of the proposed methodologies concerning the computational complexity, availability of learning data, model explainability, and high data reconstruction accuracy.","language":"eng","citation":"UNSUPERVISED GENERATIVE MODELS FOR DATA ANALYSIS AND EXPLAINABLE ARTIFICIAL INTELLIGENCE / M. Abukmeil ; relatore: V. Piuri ; correlatore: F. Scotti, A. Genovese ; direttore della scuola di dottorato: P. Boldi. Dipartimento di Informatica Giovanni Degli Antoni, 2022 Jan 24. 34. ciclo, Anno Accademico 2021. [10.13130/abukmeil-mohanad_phd2022-01-24].","filename":"phd_unimi_R12249.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/889159/1929456/phd_unimi_R12249.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/918424"},"title":"THE USE OF FORMER FOOD IN POST-WEANING PIG DIETS: EFFECTS ON GROWTH PERFORMANCE, APPARENT TOTAL TRAC DIGESTIBILITY, GUT HEALTH, FEED SAFETY AND ENVIRONMENTAL IMPACT.","internalauthor":"LUCIANO, ALICE","type":"Tesi di dottorato","year":"2022","abstract":"The demand for livestock products is expected to increase as much as 50  percent by 2050. This increase in the consumption will demand enormous resources. Animal feed is the most challenging, because of the limited availability of natural resources, climatic changes and food-feed-fuel competition. The costs of conventional feed resources, such soymeal, fishmeal and standard cereals like corn, are very high and moreover their availability in the future will be limited. For this reason, scientific research is focusing on the study of alternative sources (e.g., by/co-products from cereals process, former food products, seaweeds, insects) to standard feed ingredients. The focus of this dissertation will be on the use of former food as an alternative ingredient in animal nutrition, especially for pigs. Various subjects will be addressed concerning effects of these materials on pig growth, health and performance as well as their safety and sustainability.","language":"eng","citation":"THE USE OF FORMER FOOD IN POST-WEANING PIG DIETS: EFFECTS ON GROWTH PERFORMANCE, APPARENT TOTAL TRAC DIGESTIBILITY, GUT HEALTH, FEED SAFETY AND ENVIRONMENTAL IMPACT / A. Luciano ; tutor: L. Pinotti ; coordinator: L. Pinotti. Dipartimento di Medicina Veterinaria e Scienze Animali, 2022 Apr 08. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12156.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/918424/2008123/phd_unimi_R12156.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1178995"},"title":"L'EPISTOLARIO DI UGO FOSCOLO: CATALOGO","internalauthor":"STEFANI, MICHELE","type":"Tesi di dottorato","year":"2025","abstract":"This thesis is undertaken within the framework of the research project Ugo Foscolo, Epistolario 1825-1827, which  is funded by the Swiss National Science Foundation (FNS ID 197859). The project is directed by Paolo Borsa  at the University of Fribourg.  Originally, the project aimed at describing the epistolary documents contained in volumes 36-47 of the  Fondo Foscolo held by Biblioteca Labronica “Francesco Domenico Guerrazzi” in Leghorn. However, the  project has expanded its scope beyond this initial goal. This expansion was prompted by factors such as the  criteria used in the existing catalogue, identified gaps, and the discovery of over four hundred Foscolo  autographs not included in the Edizione Nazionale. Consequently, the project evolved to encompass an  updated catalogue of all known letters by Ugo Foscolo, necessitating missions to various institutions holding  Foscolo's papers.  The thesis is structured in two main parts. The first part consists of the catalogue of Foscolo's  correspondence, which has been created and is hosted on DaSCH (Swiss National Data and Service Center for the  Humanities) and Epistulae (Université de Lausanne). The second part presents the research work and is divided  into three chapters.  The first chapter, titled Le carte foscoliane: storia e fondi (Foscolo's Papers: History and Collections), examines  the fate of Foscolo's manuscripts in the period immediately following his death. It focuses on the processes of  dispersal and attempts at reorganisation, with particular attention paid to the English papers.  The second chapter explores the project of the Edizione Nazionale, presenting the history of the EN, its  aims, and the contributions of key figures involved in its development, such as Plinio Carli.  The third chapter, Gli epistolari e l’Epistolario (Epistolaries and the Epistolary), focuses on the realization of  the catalogue. It examines the characteristics of Foscolo's correspondence in relation to other epistolary corpora,  reviews various epistolary description projects, and presents the data model developed and used for describing  Foscolo's letters.  In conclusion, the present work has the objective to offer an organic reconstruction of the history of  Foscolo's epistolary papers and to present their catalogue, which aims to describing the papers and the  relationships between them in a form (that of structured data) that facilitates research. Furthermore, this work  also aims to establish for those who study Foscolo's epistolary documents a single point of access for all data,  information on the witnesses, links to resources in the catalogues of the holdings, and historical publications","language":"ita","citation":"\"L'EPISTOLARIO DI UGO FOSCOLO: CATALOGO / M. Stefani ; tutor: P. Borsa (Université de Fribourg) ; tutor: F. Venuda (Università degli Studi di Milano). - Fribourg (Switzerland). Dipartimento di Studi Storici \"\"Federico Chabod\"\", 2025 Jun 24. 37. ciclo, Anno Accademico 2024/2025.\"","filename":"phd_unimi_R13655.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 18-FEB-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1234158"},"title":"INTEGRATED AND SUSTAINABLE STRATEGY FOR THE INVESTIGATION OF NOVEL FOOD SAFETY,FOCUSING ON BIOACTIVE PEPTIDES AND PHYTOCOMPLEXES","internalauthor":"FANZAGA, MELISSA","type":"Tesi di dottorato","year":"2026","abstract":"\"In recent years, there has been increasing attention within the European food sector toward foods that are expected to provide health benefits in addition to basic nutrition. This shift is actually reflected in the growing interest in functional foods and in the search for new ingredients that may contribute to health maintenance or disease prevention. In this context, bioactive compounds have received particular attention, especially concerning food-derived bioactive peptides (BAPs) and natural extracts obtained from different food sources. Notably, BAPs can be released from both animal and plant proteins, and, over the years, a plethora of studies have reported and demonstrated their multifunctional bioactivities, although their effectiveness could actually depend on several factors that need to be thoroughly analyzed. Many researchers have explored alternative protein sources as a sustainable reservoir of potentially bioactive peptides, while, at the same time, sustainability concerns increasingly influence food science research, since a large amount of by-products is generated during food processing, although many of these materials could be valorized, being still rich in proteins and other compounds with potential biological activity. Despite the promising properties of BAPs, their development as nutraceutical ingredients faces significant challenges, including potential degradation during gastrointestinal digestion, variable intestinal absorption, and uncertain biological activity in systemic circulation. A comprehensive evaluation requires, therefore, integrated approaches, alongside careful consideration of production methods, green technologies, and regulatory compliance to ensure the safety and efficacy of the final product.  Within this scenario, my PhD project was conducted as part of Spoke 3 of the PNRR - funded PE10 project on Sustainable Food Systems, entitled “ON Foods - Research and Innovation Network on Food and Nutrition Sustainability, Safety and Security (Working ON Foods)\"\", addressing the safety evaluation of novel ingredients and traditional food products. Specifically, this thesis aims to develop an integrated methodological framework for the production and characterization of bioactive peptides  obtained from sustainable and novel sources, built around the need to evaluate bioactive food-derived compounds in a realistic and biologically meaningful way, taking into account not only their bioactive potential but also their safety, metabolic stability, and actual relevance after digestion and intestinal absorption. For this reason, the work followed a stepwise experimental strategy in which food processing, in vitro and cellular models, and in vivo studies were closely interconnected. Different  protein-rich matrices were selected, including both animal and plant sources, as well as by-products from the food production chain. Proteins were extracted and hydrolyzed using food-grade enzymes in both standard and immobilized conditions for some peculiar matrices to target applicability within the food and nutraceutical context. In detail, enzymatic hydrolysis was carried out either through conventional enzymatic protocols or in combination with simulated gastrointestinal digestion of the resulting peptides, depending on the specific objective of each case study. For selected raw matrices, specifically soybean okara and herring side streams, ultrasound-assisted processing was explored as a green pretreatment strategy, with the aim of altering the structural organization of the starting materials and improving the release of bioactive compounds and protein accessibility prior to extraction and enzymatic hydrolysis. High-resolution mass spectrometry (HRMS) approaches, namely untargeted peptidomic and metabolomic techniques, were exploited to define the specific composition of peptides or secondary metabolites present in the final products, providing a molecular-level understanding of the functional potential of these matrices, besides evaluating the composition of their bioaccessible and bioavailable fractions, respectively.  Overall, this methodological strategy reflects an integrated approach, combining complementary models and international expertise to address the complexity of developing safe and biologically relevant food-derived ingredients for nutraceutical applications.\"","language":"eng","citation":"INTEGRATED AND SUSTAINABLE STRATEGY FOR THE INVESTIGATION OF NOVEL FOOD SAFETY,FOCUSING ON BIOACTIVE PEPTIDES AND PHYTOCOMPLEXES / M. Fanzaga ; tutor:  C. Lammi ;  coordinator:  G. Vistoli. Dipartimento di Scienze Farmaceutiche, 2026 Apr 17. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14159.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 14-APR-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/932991"},"title":"ATRIAL COMPLEX NETWORKS IN ENDOCAVITARY RECORDINGS DURING ATRIAL FIBRILLATION","internalauthor":"VILA, MUHAMED","type":"Tesi di dottorato","year":"2022","abstract":"The incidence and prevalence of atrial diseases, particularly atrial fibrillation (AF), are today reaching pandemic proportions. Despite the considerable research efforts and progress regarding the understanding of mechanisms driving AF, the ability to treat it remains to be problematic. This thesis aims to contribute to reducing the burden of atrial arrhythmia from the technical point of view by processing the electrical signals coming from the heart. Specifically, the main objective of this thesis is to investigate signal processing techniques of invasive atrial signals that provide useful tools for helping electrophysiologists and technicians in the decision process during ablation treatment procedures or arrhythmia studies.    First, we proposed a new algorithm, for ventricular activity cancellation in atrial signals during AF. The methodology combines two common techniques, average beat subtraction (ABS) and interpolation, in a unified framework. Such framework was able to refine and improve the ventricular activity estimate, under the stationary assumption of the atrial activity in very short time windows. Briefly, the local atrial activity is first modeled with an autoregressive (AR) process, then the estimate is refined by maximizing the log maximum a posteriori of the atrial residual activity according to the fitted AR model. The new algorithm was tested on both synthetic and real atrial signals, and the performance was compared with the other five algorithms. The proposed algorithm outperformed all the others in terms of average root mean square error (0.038 vs 0.045 for interpolation; p<0.05) on synthetic data. On real data, it outperformed two variants of ABS (p<0.05) and performed similarly to interpolation when considering the high-power residues left (both <3%), and the log-likelihood with the fitted AR model.    Second, we investigated a novel approach to atrial propagation pattern analysis based on directed networks (graphs). The networks are generated by processing signals collected during electrophysiologic studies. Network vertices represent the locations of the recordings and edges are determined by computing measures between recorded signals. The algorithm automatically identifies potential targets for treatment, such as rotational activity, spreading from electrode to electrode creating a closed loop, or focal activity, manifesting as a divergence of excitation from a given region. The method was tested on two subjects in sinus rhythm, seven in an experimental model of in-silico simulations, and ten subjects diagnosed with complex atrial tachycardia who underwent catheter ablation. The algorithm correctly detected the electrical propagation of both sinus rhythm cases and all in-silico simulations. Regarding the clinical cases, arrhythmia mechanisms were identified in most of the cases (9 out of 10), i.e., cycles around the mitral valve, tricuspid valve, and figure-of-eight macroreentries.    Third, we proposed a recommender system, built as a solution to an optimization problem, able to suggest the optimal ablation strategy for the treatment of complex atrial tachycardia. The problem was designed on top of directed network mapping. The optimization problem modeled the optimal ablation strategy as that one interrupting all reentrant mechanisms while minimizing the ablated atrial surface. Considering the exponential complexity of finding the optimal solution to the problem, we introduced a heuristic algorithm with polynomial complexity. The proposed algorithm was applied to the data of i) 6 simulated scenarios including both left and right atrial flutter; and ii) 10 subjects that underwent a clinical routine. The recommender system suggested the optimal strategy in 4 out of 6 simulated scenarios. On clinical data, the recommended ablation lines were found satisfactory on 67% of the cases according to the clinician's opinion comparing to the actual treatment performed, while they were correctly located in 89% considering the mechanism in place. The algorithm made use of only data collected during mapping and was able to process them nearly real-time.","language":"eng","citation":"ATRIAL COMPLEX NETWORKS IN ENDOCAVITARY RECORDINGS DURING ATRIAL FIBRILLATION / M. Vila ; tutor: S. Roberto, M. W. Rivolta ; coordinatore: P. Boldi. Dipartimento di Informatica Giovanni Degli Antoni, 2022 Jul 18. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12143.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/932991/2048907/phd_unimi_R12143.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1021808"},"title":"MINING AND LEARNING WEB3 PLATFORMS: A TEMPORAL NETWORK PERSPECTIVE","internalauthor":"BA, CHEICK TIDIANE","type":"Tesi di dottorato","year":"2024","abstract":"\"In the past decade, there has been a notable shift in Internet services, challenging the traditional structure of Web 2.0 dominated by a few centralized platforms. This transformation has given rise to the concept of Web3, i.e. the design of platforms and software systems built on blockchain technologies to promote a decentralized Web. Indeed, blockchain technology offers many design options for decentralized systems, such as decentralized storage, consensus-based validation of stored data, and the vital option to implement economic systems. Various sectors have witnessed the application of Web3 principles, leading to Decentralized online social media and Decentralized Finance (DeFi), to cite a few well-known examples. Despite the growing influence of Web3, comprehensive studies on its applications, especially beyond decentralized finance, are limited. The vast and timestamped data stored on Web3 platforms offers a unique opportunity for researchers to perform detailed and in-depth analysis of users' traits, potential for the extraction of detailed insights into innovative techno-social systems, characterized by multi-faceted interactions - social, economic, and financial - among people and between people and platform.    However, blockchain-based systems are often highly interconnected and exhibit intricate interdependencies that span different interaction layers within the same blockchain and multiple blockchain networks simultaneously. This interconnected yet intricate nature of blockchain-based systems presents substantial challenges, necessitating novel solutions in data collection, modeling, analysis, and prediction tasks. There are many open questions where the key points are the interplay between the temporal and the heterogeneous dimensions characterizing blockchain-based systems. These aspects, still marginal in the current literature, are the main subject of this thesis.     This thesis explores the interconnected nature of the Web3 paradigm, utilizing models, algorithms and methods from the field of network science. Network science is a multidisciplinary field, that examines dynamic interactions and complex structures within various system through networks ( also called graphs). In a network, we represent the entities involved as nodes, connected by links (or edges) that represent interactions or dependencies. Modeling through networks has yielded significant insights across domains such as communication networks, urban mobility, scientific collaborations, brain networks, genomics, financial transactions, and social media. Throughout this work, we showcase how network science is a suitable analytics framework to model the complexity of Web3 by tackling different aspects and open questions on Web3 through a network science approach.    The thesis is structured as follows: the introduction provides a comprehensive overview of the main research questions, emphasizing the novelty and key contributions. In Part I, \"\"Modeling Web3 as a network\"\", the focus is on introducing essential concepts for employing network-based methodologies to model Web3 data, including a background of Web3 platforms and detailing the datasets used. Then, Part II, \"\"Network evolution dynamics\"\", delves into the temporal patterns of users' activity and link formation within Web3 systems. After that, Part III, \"\"The interplay of currency and user behavior\"\", explores the relationship between user activity and economic dimensions, particularly cryptocurrency and reward systems unique to Web3. And then, Part IV, \"\"Modeling and prediction of user migration\"\", investigates cross-chain behaviors like user migration, leveraging heterogeneous temporal data and dynamic socio-economic environments. In addition, Part V, \"\"Machine learning on multilayer graphs\"\", introduces a framework enhancing graph neural network performance on the multilayered structure of Web3 platforms. Finally, the Conclusions summarize the key findings, highlighting open problems and suggesting future research directions.\"","language":"eng","citation":"MINING AND LEARNING WEB3 PLATFORMS: A TEMPORAL NETWORK PERSPECTIVE / C.t. Ba ; tutor: S. Gaito ; co-relatore: M.  Zignani ; coordinatore: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2023. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12835.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1021808/2338529/phd_unimi_R12835.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1042808"},"title":"NON-STATIONARY MULTIARMED BANDITS FOR SATIATION AND SEASONALITY PHENOMENA IN MUSIC RECOMMENDER SYSTEMS","internalauthor":"CLERICI, GIULIA","type":"Tesi di dottorato","year":"2024","abstract":"This thesis delves into theoretical aspects of non-stationary multiarmed bandits, motivated by their application to music recommender systems. An intrinsic challenge of such systems lies in evolving user preferences. Rather than finding a single optimal item, the objective is to craft an ordered sequence of items aligning with the user's behaviour. Indeed, these systems need to address dynamic user preferences, characterized by phenomena like satiation. Our goal is to study these phenomena in a sequential learning setting characterized by partial feedback, adopting multiarmed bandits as the approach to tackle this problem. We first introduce a novel model with finitely many arms, which handles contrasting phenomena like satiation and seasonality in a unified framework. We formalize this model, called \\textit{Last Switch Dependent Bandit}, as a non-stationary multiarmed bandit where the expected reward of an arm is determined by its state, which indicates the time elapsed since the arm last took part in a switch of actions. This model can generalize to different types of non-stationarity as we relaxed many typical assumptions. Furthermore, it can recover state-dependent bandits in the literature. In this thesis, we will discuss this bandit problem and the solution proposed to solve it, which is based on upper confidence bounds and techniques derived from combinatorial semi-bandits. We conclude this work by providing an upper bound of the regret, to assess the performance of the proposed solution.     Aware of the limitations of finite action sets, which are not always representative of real-world applications, a new linear bandit model is proposed to handle non-stationary phenomena within an infinite set of actions, posing complex challenges for cross-arm dependencies. We formalize a model called \\textit{Linear Bandit with Memory}, where the expected reward of an action is influenced by the learner's past actions in a fixed-size window, called \\textit{memory matrix}. Specifically, the two parameters $m$ and $\\gamma$, the size of the window and the exponent respectively, characterizing this memory matrix can produce two types of behaviours: rotting and rising. In our discussion, we show how our model generalizes stationary linear bandits, as well as partially recovering rested rotting and rising bandits in the limit $m \\rightarrow +\\infty$. %we show how our model can recover the rested variants of rotting and rising bandits, as well as stationary linear bandits.   We study the complex problem of modelling the interactions among arms in a linear non-stationary setting and propose a solution to solve it. Furthermore, we study the setting where $m$ and $\\gamma$ are unknown and propose a meta-bandit algorithm for model selection to jointly learn the parameters and solve the bandit problem. For both models, our contributions consist in defining novel multiarmed bandit problems, proving sound theoretical guarantees, and discussing our contributions with respect to the literature.    Additionally, within the context of music streaming services, we present an additional line of research exploring the Spotify\\texttrademark music credits network. We represent this music credits network as a directed graph and study the relationship between music genres and graph-related metrics. After observing interesting patterns on several centrality measures conditioned on music genre, we introduce a novel node-wise index of reciprocity as a potential index for informed recommendations.","language":"eng","citation":"NON-STATIONARY MULTIARMED BANDITS FOR SATIATION AND SEASONALITY PHENOMENA IN MUSIC RECOMMENDER SYSTEMS / G. Clerici ; supervisore: N. Cesa-Bianchi ; co-supervisore: P. Laforgue ; coordinatore di dottorato: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2024. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R12909.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1042808/2393114/phd_unimi_R12909.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/981728"},"title":"CHARACTERIZATION OF BIOACTIVE PEPTIDES IDENTIFIED FROM GENETICALLY ENCODED LIBRARIES.","internalauthor":"ROSA, STEFANO","type":"Tesi di dottorato","year":"2023","abstract":"Modern agriculture relies on the application of huge amounts of pesticides to protect crops from pathogens and pests and prevent yield losses. Unfortunately, the continuous application of these active ingredients is causing the fast development of resistance, toxicity on non-target organisms and environmental accumulation. New solutions must be designed to increase sustainability of agricultural practices and dramatically reduce resistance insurgence. In this scenario, antimicrobial peptides (AMPs) can represent a solution as they show specificity, efficacy and rapid degradation, thus avoiding the long-term effects observed for chemical pesticides. During the last years, some AMPs have been successfully commercialized as plant protection products (PPPs) and some screening pipelines have been developed to provide a fast identification of new antimicrobial peptides.   Genetically encoded peptide libraries (GEPLs) allow to screen millions of different amino acid combinations, to identify peptides that can bind a target protein or inhibit a protein-protein interaction (PPI) of choice. This technology has been mainly exploited to identify peptides to be used as human therapeutics, while its potential for PPPs development is poorly explored. In the frame of the “Novel PESTicides for a sustainable agriculture” (NoPEST) project, GEPLs have been constructed to identify peptides to protect crops from disruptive diseases caused by oomycetes. With this aim, a yeast two-hybrid suitable library was constructed to identify cyclic peptides (CPs), which provide enhanced levels of in vivo stability and affinity for the target protein respect to linear counterparts. The produced combinatorial library of cyclic peptides (CYCLIC) was firstly validated identifying G4CP2, a peptide capable to interfere with GAL4 activity and, consequently, with galactose metabolism in yeast cells, thus demonstrating that the library can be used to isolate bioactive molecules. After validation, 14 cell wall biosynthetic enzymes have been selected and screened with CYCLIC to identify CPs having the ability to interfere with the activity of these target proteins and, consequently, with the cell wall biosynthesis and/or integrity in target oomycetes. Different CPs with an antimicrobial activity have been identified, among those, CP32 has been identified based on its binding to the Phytophthora infestans cellulose synthase A2 (PiCesA2), having very good performances in inhibiting the related disease symptoms (late blight). Microscopy, chemical and biochemical analysis are now used to elucidate the precise mechanism of action of CP32 and to confirm its interaction with the target enzyme. By shading light on these aspects, together with a good toxicological profile, the developed pipeline can be finally validated. These data might also suggest CP32 suitability for future improvements and commercialisation.","language":"eng","citation":"CHARACTERIZATION OF BIOACTIVE PEPTIDES IDENTIFIED FROM GENETICALLY ENCODED LIBRARIES / S. Rosa ; tutor: S. Masiero; coordinatore: S. Masiero, P. Pesaresi, M. P. M. Guarino. Dipartimento di Bioscienze, 2023 Jul 11. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12633.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/981728/2237789/phd_unimi_R12633.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1131635"},"title":"GUT ABSTRACTIONS. A PHILOSOPHICAL STUDY FOR THE PRESENT OF FOOD.","internalauthor":"SERINI, BEATRICE MARIA","type":"Tesi di dottorato","year":"2025","abstract":"This dissertation investigates the role of the microbial turn within the domain of nutrition, focusing on the emergence of microbiome science and its centrality to envisioning food futures. By adopting a philosophical approach that conceptualizes philosophy as a form of negotiation, the research explores how diverse ontologies structure the categories and concepts shaping our engagement with food, including knowledge, values, norms, and practices. Specifically, the study examines two distinct probiotic food futures: one aligned with precision medicine and the other with the resurgence of food fermentation practices. These approaches reflect contrasting interpretations of the interplay between food, microbes, and health. The dissertation highlights a persistent tension within these probiotic futures between their aspirational promises and their tangible realizations, which creates a fragmented discursive space, where stakeholders operate from often incompatible worldviews. To face these challenges, the dissertation offers a philosophical framework grounded in ontology and conceptual analysis, aimed at systematically analyzing and comparing probiotic futures. These tools seek to move beyond the rhetoric of promissory hopes and scientific hype, offering conceptual clarifications that pave the way for more grounded and realistic accounts of probiotic approaches to food.","language":"eng","citation":"GUT ABSTRACTIONS. A PHILOSOPHICAL STUDY FOR THE PRESENT OF FOOD / B.m. Serini ; tutor: A. Borghini ; director: F. Guala. - Università degli Studi di Milano. Dipartimento di Filosofia Piero Martinetti, 2025 Jan 09. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13050.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1131635/2625870/phd_unimi_R13050.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/828287"},"title":"COMPLIANCE AND CLIMATE CHANGE. THE MOTIVATING POWER OF DELIBERATION","internalauthor":"BACCHETTA, SILVIA","type":"Tesi di dottorato","year":"2021","abstract":"This dissertation addresses the problem of individuals’ noncompliance with climate change-related norms and behaviours. Starting from the consideration that noncompliance regarding environmental matters is too widespread to dismiss and that individuals’ compliance ought to be stable in order to effectively address climate change, this work asks how individuals should be motivated to comply with climate change norms over time. I will argue that it is possible to distinguish between individuals’ pertinent and non-pertinent reasons for compliance. This distinction plays on the correlation established between an individual’s motivation and the policy’s rationale. When the individual’s motivation and the policy’s rationale converge, then there are pertinent reasons for compliance. If instead, they diverge, there are non-pertinent reasons for compliance. Therefore, pertinent reasons derive from the coexistence of (a) aptly devised policies and (b) individuals’ environmental concern motivating them to act. The hypothesis advanced is that only pertinent reasons can ensure stable compliance.  To prompt stable compliance, I propose an argument which develops into two phases. The first phase focuses on proving that pertinent reasons are more likely to sustain stable compliance than non-pertinent ones. Assuming that individuals are either equipped with an environmental concern or not, I will split them into two groups, concerned and unconcerned individuals. I will play on the possible political means that can be used to elicit reasons for compliance in both concerned and unconcerned people. For concerned individuals, I will argue that efficacy-driven policies would have a twofold role in bridging a cognitive gap (by showing individuals how to act upon their concern practically) and motivating them to comply with climate-related policies. Considering that there would be a convergence between the policy rationale and individuals’ environmental concern, I will conclude that concerned individuals would likely have pertinent reasons for compliance. By contrast, for unconcerned individuals, I will argue that to motivate them to comply, the political authority should play on their self-interest, by using incentives and sanctions as leverage to prompt unconcerned individuals’ compliance. I will conclude that unconcerned individuals would likely have non-pertinent reasons for compliance, as the policy rationale and the individuals’ motivation diverge.  Once established that concerned individuals would have pertinent reasons and that unconcerned people would instead have non-pertinent reasons to comply, I will focus on stable compliance. I will assess if pertinent and/or non-pertinent reasons could sustain compliance over time. To do so, I develop a counter-reasoning envisaging what might happen if the political authority would withdraw the policies addressing climate change. From this argument, it will emerge that individuals motivated by non-pertinent reasons, would likely stop to comply once that the incentives are removed. By contrast, individuals motivated by pertinent reasons would likely maintain their compliance because of their environmental concern, even if the effective policies are no longer at work, thus proving my initial hypothesis that pertinent reason can fulfil the stability requirement.  However, this conclusion will highlight that the crucial element for having stable compliance does not lie specifically into having pertinent reasons. Instead, it derives from the fact that pertinent reasons can exist only under the condition of having an environmental concern. Therefore, in the second phase of my argument, I will investigate if it is possible to raise in unconcerned individuals an environmental concern, so as to make it more likely for them to develop pertinent reasons. To do this, I will drop the assumption that considered having an environmental concern in one’s motivational set as a given fact, and I will argue that it is possible to raise such a concern in unconcerned individuals. Through deliberation, it is indeed possible to induce reflection on unconcerned individuals' interests, values, and opinions to raise in them a concern about environmental matters. I will further discern unconcerned individuals into more specific ‘ideal-types’ representing the main contrarian stances regarding climate change – tackling both epistemic and normative disagreements. I will argue that for most contrarian stances, it is indeed possible to raise an environmental concern.","language":"eng","citation":"COMPLIANCE AND CLIMATE CHANGE. THE MOTIVATING POWER OF DELIBERATION / S. Bacchetta ; supervisore: F. Pasquali ; coordinatore: M. Jessoula. Dipartimento di Scienze Sociali e Politiche, 2021 Mar 26. 32. ciclo, Anno Accademico 2019. [10.13130/bacchetta-silvia_phd2021-03-26].","filename":"phd_unimi_R11631.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/828287/1746830/phd_unimi_R11631.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/932786"},"title":"RESPONSABILITÀ DA REATO DEGLI ENTI E RIPARAZIONE AMBIENTALE","internalauthor":"MOSSA VERRE, MARCO","type":"Tesi di dottorato","year":"2022","abstract":"Reparative measures and sanctions for legal entities are two key policy options for an effective response against environmental crimes. Italian environmental criminal law includes several reparative obligations or mitigations/exclusions of the penalty due to reparation activities. These legal provisions address just the criminal sanction for natural persons. However, a closer look at the remedial activities involved demonstrates that, commonly, the individual can comply with reparative obligations only by using the means of the corporation. Analyzing the interplays between the individual and corporate dimension of remedial activities for environmental crimes is the aim of this doctoral thesis, in order to identify flaws in the current legislation and to advocate the needing for rationally reforming the environmental reparation measures, involving primarily the corporation and fitting with rules and policy goals of the legislative decree 231/2001.","language":"ita","citation":"RESPONSABILITÀ DA REATO DEGLI ENTI E RIPARAZIONE AMBIENTALE / M. Mossa Verre ; tutor: C. Paliero ; coordinatore: C.R. Luzzati. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2022 Jul 07. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12289.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/932786/2048577/phd_unimi_R12289.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/889668"},"title":"RESUMMATION AND MACHINE LEARNING TECHNIQUES TOWARDS PRECISION PHENOMENOLOGY AT THE LHC","internalauthor":"RABEMANANJARA, TANJONA RADONIRINA","type":"Tesi di dottorato","year":"2021","abstract":"The present thesis focuses on three distinct yet complementary areas in QCD. The first area concerns the resummation of large logarithmic contributions appearing in transverse momentum distributions. In particular, we focus on the hadroproduction of colour singlet final states such as Higgs boson produced via gluon fusion and the production of a lepton-pair via Drell--Yan mechanism. We present phenomenological studies of a combined resummation formalism in which standard resummation of logarithms of Q/pT is supplemented with the resummation of logarithmic contributions at large x. In such a formalism, small-pT and threshold logarithms are resummed up to NNLL and NNLL* respectively. The second area concerns the construction of an approximate NNLO expression for the transverse momentum spectra of the Higgs boson production by exploiting the analytical structure of various resummed formulae in Mellin space. The approximation we construct relies on the combination of two types of resummations, namely threshold and high-energy (or small-x). Detailed phenomenological studies, both at the partonic and hadronic level, are presented. And finally, the third area concerns the a posteriori treatment of Parton Distribution Functions (PDFs), specifically the compression of Monte Carlo PDF replicas using techniques from deep generative models such as generative adversarial models (or GANs in short). We show that such a GAN-based methodology results in a compression methodology that is able to provide a compressed set with smaller number of replicas and a more adequate representation of the original probability distribution. The possibility of using this methodology to address the problem of finite size effects in PDF determination is also investigated.","language":"eng","citation":"RESUMMATION AND MACHINE LEARNING TECHNIQUES TOWARDS PRECISION PHENOMENOLOGY AT THE LHC / T.r. Rabemananjara ; supervisor: S. Forte ; coordinatore: M. Paris. Dipartimento di Fisica Aldo Pontremoli, 2021 Dec 20. 34. ciclo, Anno Accademico 2021. [10.13130/rabemananjara-tanjona-radonirina_phd2021-12-20].","filename":"phd_unimi_R12206.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/889668/1931071/phd_unimi_R12206.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1195942"},"title":"INVESTIGATING EPIGENETIC MECHANISMS OF CHEMORESISTANCE IN OVARIAN CANCER: THE ROLE OF H3K27ME3","internalauthor":"CARMINATI, MICHELE","type":"Tesi di dottorato","year":"2025","abstract":"Histone Post-Translational Modifications (PTMs) are key epigenetic players in physiology and disease, generating a complex combinatorial code that regulates gene expression, nuclear functions and chromatin organization. Aberrant levels of histone PTMs are recognized as general hallmarks of cancer and their profiling in tumour can both allow the identification of epigenetic markers for patient stratification and suggest novel epigenetic pathways to be targeted for therapy.  With the aim to investigate epigenetic aberrations occurring in Epithelial Ovarian Cancer (EOC), we performed a Mass Spectrometry (MS)-based epi-proteomic profiling of histone PTMs in a cohort of 35 EOC patients stratified based on their survival outcomes. This analysis revealed reduced H3K27me3 level in patients displaying short-term survival (< 2 years after diagnosis) and associated with an increased tumour resistance to chemotherapy, compared to Long-Term Survivors (LTS) (> 10 years after diagnosis), with an improved sensitivity to the platinum-based treatment. By epi-proteomic profiling, we also confirmed a similar loss of this histone mark in an independent clinical cohort of chemoresistant tumours, compared to chemosensitive ones.  To explore the molecular mechanisms linking H3K27me3 loss to the onset of chemoresistance in EOC, we generated in vitro platinum-resistant cell line models by exposing the platinum-sensitive A2780 cells to increasing concentrations of Carboplatin (CBP). The induction of platinum-resistance correlates with a decrease of H3K27me3, consistent with the findings from the clinical cohorts.   Using a multi-omics approach, we investigated the downstream effects of H3K27me3 decrease in chemoresistant patients by integrating H3K27me3 ChIP-sequencing and RNA-sequencing data from A2780 cells before and after the induction of platinum-resistance. Functional enrichment analysis of genes whose transcriptional upregulation was concurrent with a loss of H3K27me3 in chemoresistant cells highlighted a significant association with the presence of H3K27me3-H3K4me3 chromatin bivalent domains and the maintenance of an undifferentiated state, suggesting a link between the onset of chemoresistance and the emergence in the cells of stem-like features.   With the goal to test if an H3K27me3 increase could counteract the onset of chemoresistance, we pharmacologically elevated H3K27me3 signal, through treatment of platinum-resistant cells with the KDM6 demethylases inhibitor GSK-J4; this resulted in downregulated transcriptional pathways associated with stemness and invasive tumour features and decreased colony and sphere formation, two processed associated with the emergence of stem-like cell populations. As a next step, we plan to evaluate the in vivo efficacy of GSK-J4 in mouse models implanted with patient-derived tumours exhibiting different responses to the chemotherapy.  Collectively, our findings suggest that H3K27me3 is lost during the acquisition of chemoresistance, and such loss is associated with the upregulation of a set of genes promoting the maintenance of a stem-like state of the cells, potentially contributing to EOC recurrence and to poor patient survival. Moreover, the inhibitory effect of the epi-drug GSK-J4 on more undifferentiated cancer cells could represent a novel therapeutic avenue to target chemoresistant EOC cells with enhanced stem-like features.","language":"eng","citation":"INVESTIGATING EPIGENETIC MECHANISMS OF CHEMORESISTANCE IN OVARIAN CANCER: THE ROLE OF H3K27ME3 / M. Carminati ; tutor: T. Bonaldi ; internal advisor: U. Cavallaro coordinator: D. Pasini. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Dec 17. 37. ciclo, Anno Accademico 2025.","filename":"phd_unimi_R13466.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1195942/3183637/phd_unimi_R13466.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1195475"},"title":"NEUROINFLAMMATION ACROSS BOUNDARIES: INSIGHTS FROM HUMAN ISCHEMIC STROKE AND BIOMATERIAL CRANIOPLASTY","internalauthor":"MANNELLA, FRANCESCA CAROLINA","type":"Tesi di dottorato","year":"2025","abstract":"Neuroinflammation is a complex process, involving cellular and molecular events, which is activated in the central nervous system by acute and chronic insults such as ischemic stroke and traumatic brain injury (TBI). While this response can initially protect against tissue damage and promote repair, its chronic or dysregulated activation often exacerbates neural injury and impairs functional recovery. Glial cells—microglia, astrocytes, and oligodendrocytes—are key players in these mechanisms, influencing both tissue repair and degeneration. In clinical practice, interventions such as cranioplasty (CP) add further complexity, as the introduction of biomaterials and the risk of post-surgical infection can directly and indirectly modulate the inflammatory environment and patient outcomes. On these bases, the overarching aim of this thesis is to elucidate the role of neuroinflammation in two major clinical contexts: (1) human ischemic stroke, with a focus on glial cell responses and fluid biomarker analysis, and (2) CP with biomaterials, particularly in relation to infection risk and strategies for clinical management. To this end, the work is organized in two sections. The first part combines advanced histopathological and molecular analyses to dissect the spatial and temporal dynamics of glial activation and tissue repair in human post-mortem stroke specimens. A particular focus is given to microglial and astrocytic responses in the peri-infarct region, the accumulation and fate of oligodendrocyte precursor cells, and sex-specific differences in glial reactivity. Bulk transcriptomics analysis provides molecular context, revealing robust upregulation of TREM2-driven phagocytic pathways, providing mechanistic context to histological findings. In parallel, fluid biomarker analysis demonstrates that glia-associated markers (sTNFR2 and sTREM2) are increased in the cerebrospinal fluid (CSF) of female stroke patients, while these changes are less pronounced in plasma, indicating a compartment-specific immune response. Ongoing spatial transcriptomics analyses will further refine the understanding of region-specific gene expression and glial dynamics in stroke lesions. Post-mortem human stroke brain specimens, plasma and CSF were made available through a collaboration with prof. Kate Lykke Lambertsen from the University of Southern Denmark (Odense, DK).   The second part addresses the management of patients undergoing CP with porous hydroxyapatite implants (CustomBone Service, FinCeramica Faenza Spa, Faenza, Italy), using data from a multicenter cohort and experimental in vitro assays. This work identifies key clinical and surgical predictors of post-CP infection and demonstrates that tailored infection control strategies—including antibiotic regimens and surgical debridement—can increase implant retention and facilitate patient recovery. In vitro, hydroxyapatite exhibits antibacterial properties, supporting its role as a bioactive material that may contribute to a tissue environment more permissive to brain repair, likely indirectly modulating neuroinflammation by reducing infectious complications.  In summary, this thesis advances understanding of neuroinflammatory mechanisms and their clinical implications in both spontaneous (ischemic) and post-surgical brain injury. The findings highlight the value of integrating post-mortem human tissue and fluid biomarkers with clinical data to refine patient monitoring and personalized management and support the pursuit of targeted therapies aimed at optimizing neural recovery and outcomes after stroke and neurosurgical intervention.","language":"eng","citation":"NEUROINFLAMMATION ACROSS BOUNDARIES: INSIGHTS FROM HUMAN ISCHEMIC STROKE AND BIOMATERIAL CRANIOPLASTY / F.c. Mannella ; tutor: G. D. Norata ; co-tutor: M. Fumagalli ; coordinatore: G. D. Norata. Dipartimento di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti, 2025. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13992.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1195475/3181176/phd_unimi_R13992.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1240481"},"title":"EVOLUTION OF THE EASTERN ALPS FROM THE PALEOZOIC ONWARD: CONSTRAINTS AND INSIGHTS FROM THE (ULTRA)BASIC ECLOGITIC COMPLEX OF MILCHENKAR ÖTZTAL-STUBAI COMPLEX (EASTERN ALPS, TYROL, AUSTRIA)","internalauthor":"PICCIN, STEFANO","type":"Tesi di dottorato","year":"2026","abstract":"The Ötztal-Stubai Complex (OSC) is one of the widest tectonic units of the Alps, belonging to the Eastern Austroalpine domain and extending between the Engadine and Tauern windows, the Northern Calcareous Alps and the Vinschgau/Venosta valley. Together with other polycyclic crystalline basements of the Alps, the OSC preserves various evidences of Late Ediacaran to Ordovician events attributed to the peri-Gondwanan Cadomian orogeny (e.g., Neubauer et al., 2022), particulary in the form of metaigneous bodies ranging from (ultra)basic intrusions to acidic, peraluminous granitoids. The Northern Eclogite Zone (NEZ) of the Central Metabasite Zone comprises abundant garnet amphibolites hosting variably retrogressed eclogites and subordinate occurrences of their gabbroic protoliths, often showing igneous cumulitic textures, with crystallization ages around 530 Ma (Miller & Thöni, 1995).  In the Milchenkar area, petrological and geochemical analyses on preserved olivine gabbro,  anorthosite and pegmatoid gabbro samples allowed to infer the main crystallization processes, conditions of intrusion and main geochemical features of the parental melt. Olivine gabbros are the most primitive products and are characterized by the predominant fractionation of cumulus olivine and by the appearance of clinopyroxene before plagioclase; in all the samples analysed, orthopyroxene is a minor constituent and does not impact differentiation trends. Thermobarometric estimates on the igneous protoliths yield a temperature of 1200 ◦C for the initial crystallization of clinopyroxene at a minimum pressure of 5 kbar. Trace element compositions of the main igneous minerals and modeled equilibrium melts suggest the generation of a tholeiitic parental melt from a depleted mantle source possibly at conditions of garnet stability, and the intrusion in continental crust in an extensional context, with some similiarities to the Oligocenic Red Sea rift. Additionally, the relatively alkalic nature of the melt suggested by mineral chemistry and whole rock compositions is consistent with the inferred source. These results point to the propagation of a continental rifting context, already postulated for the Central European Cadomian domain (Linnemann et al., 2008a) in Cambrian times, to the Proto-Alpine terranes located further east along the peri-Gondwana margin.  The subsequent metamorphic evolution of the NEZ is characterized by a pervasive, although  partially retrogressed, high pressure event resulting in the eclogitization of the (ultra)basic complex completely affecting the more evolved gabbroic rocks and involving the aforementioned protoliths in part. Textural and mineralogical variations of the mafic eclogites suggest the occurrence of at least two high pressure stages, the first of which is characterized by the previously unreported occurrence of corundum and Mg-staurolite. In contrast with Variscan age estimates for the high pressure metamorphism (Miller & Thöni, 1995), the newly discovered occurrence of eclogite-hosted leucosomes preliminary dated to 484 Ma (in situ U-Pb on zircon magmatic rims, Milchenkar area) suggests the possible existence of an eclogitic event in the OSC pre-dating the widespread anatectic plutonism of Ordovician age. This would be consistent with a protracted active margin scenario for the Proto-Alpine Cadomian terranes (e.g., von Raumer et al., 2013) in those times, also supported by subduction-related magmatism and further, although scattered, evidences of high pressure metamorphism.  Moreover, U-Pb radiometric dating performed on zircon separates of the S-type Suztal Granite, neighbouring the NEZ, yields a crystallization age of 463.94 ± 0.65 Ma, confirming previous estimates, while in the Vallelunga/Langtaufers area, preliminary petrological analyses of calc-silicate nodules hosted in metasedimentary rocks suggest the occurrence of a high temperature metasomatic event pre-dating the Variscan metamorphism.","language":"eng","citation":"EVOLUTION OF THE EASTERN ALPS FROM THE PALEOZOIC ONWARD: CONSTRAINTS AND INSIGHTS FROM THE (ULTRA)BASIC ECLOGITIC COMPLEX OF MILCHENKAR ÖTZTAL-STUBAI COMPLEX (EASTERN ALPS, TYROL, AUSTRIA) / S. Piccin ; tutor: S. Tumiati ; co-tutor: S. Zanchetta ; coordinatore: G. Muttoni ;  reviewer: R. Tribuzio, N. Malaspina defense committee: P. Fumagalli, R. Tribuzio, R. Esposito. - Milano. Dipartimento di Scienze della Terra Ardito Desio, 2026 Apr 30. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13720.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 30-APR-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1119921"},"title":"FOREGROUND CONTROL AND CHARACTERIZATION IN COSMIC MICROWAVE BACKGROUND EXPERIMENTS","internalauthor":"MANZAN, ELENIA","type":"Tesi di dottorato","year":"2024","abstract":"The CMB is a relic radiation from the early stage of the Universe, when radiation was initially coupled with the primordial plasma, currently detected as a blackbody spectrum in the microwave range. Measuring its intensity anisotropies and the so-called E-modes polarization pattern have proven to be powerful tools to constrain the cosmological parameters to sub-percent precision.  The present and future challenges in CMB observations are represented by two scenarios: polarization measurements to detect a specific pattern, called B-modes, which, according to the Inflation theory, should have been caused by the presence of gravitational waves in the primordial plasma, and tiny spectral distortions to the CMB blackbody emission, predicted both within and beyond the ΛCDM theory. Both signals are faint (below µK) and their detection thus requires instruments with ultra-low noise, excellent control over instrumental systematic effects, and accurate foreground removal, which is the contamination from spurious sky signals, such as the Galactic microwave emission, dominated by the synchrotron and thermal dust contributions, or our atmosphere.  My research activity has focused on the foreground control and characterization for two ground-based CMB experiments: QUBIC (Q & U Bolometric Interferometer for Cosmology), which is the first-ever experiment for CMB polarization measurements that combines bolometric detectors with interferometry, instead of relying on traditional direct-imaging methods, and COSMO (COSmic Monopole Observer), a ground-based experiment for CMB spectral distortion measurements.  My contribution to QUBIC is divided into three studies: simulations of foreground removal, characterization of the atmospheric contribution at the observing site, in Argentina, and a preliminary performance forecast for the QUBIC-TD, which is a reduced version of the final instrument constructed to demonstrate bolometric interferometry, currently installed in Argentina. For COSMO, instead, I performed laboratory measurements to characterize its multi-mode antenna system, which I designed before my PhD.","language":"eng","citation":"FOREGROUND CONTROL AND CHARACTERIZATION IN COSMIC MICROWAVE BACKGROUND EXPERIMENTS / E. Manzan ; supervisore: A. Mennella ; coordinatore: A. Mennella. - Aula Caldirola, Dipartimento di Fisica Aldo Pontremoli. Dipartimento di Fisica Aldo Pontremoli, 2024 Dec 13. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13225.pdf","fileformat":"Adobe PDF","fileversion":"preprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1119921/2595918/phd_unimi_R13225.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1260041"},"title":"ENTERPRISES-DRIVEN ITS ACADEMY AS A DRIVER FOR LABOUR MARKET DEVELOPMENT AND MIGRANTS INTEGRATION IN LOMBARDIA:A CASE FOR SOCIAL INNOVATION AND SOCIAL ENTREPRENEURSHIP","internalauthor":"ORBAN, AHMED ADHAM AHMED EID","type":"Tesi di dottorato","year":"2026","abstract":"This doctoral dissertation explores the potential for Italy's Istituti Tecnologici Superiori (ITS)— which are the equivalent of the Technical and Vocational Education and Training (TVET)—to be redefined and implemented as a framework for social innovation aimed at tackling two interrelated societal issues: ongoing shortage in labour market skilled-labour and the systematic marginalisation of migrants and refugees from access to quality vocational training opportunities. The research illustrates that TVET, when purposefully designed to promote inclusion and integrated within collective skill development systems, serves as a robust mechanism for both labour market enhancement and the integration of migrants. By conducting a comparative analysis of Germany, alongside original qualitative research involving nine semi-structured interviews with leaders of Italian ITS and their corporate partners in Lombardy, the thesis uncovers a significant paradox: while ITS programs boast employment rates exceeding 80 percent, persistent shortages of students hinder the ability to scale their impact. This imbalance between supply and demand is not attributed to the quality of training but rather to a lack of sustainable financial resources, visibility, cultural obstacles, and inadequate outreach to marginalised communities.  The thesis introduces Juvinate (JVN8), an initiative for a social enterprise grounded in research that applies social innovation principles to close recruitment gaps and promote the integration of migrants. JVN8 encompasses pre-vocational training, cultural and lingual orientation, employment through entrepreneurship, employer engagement, and focused job placement support across three levels of innovation—incremental, institutional, and disruptive—showcasing how entrepreneurial initiatives can create social value while addressing entrenched barriers. The research concludes that while social entrepreneurship is essential, it is not sufficient unless social initiatives are integrated within existing institutional governance frameworks and the complementary strengths of public, private, and civil society sectors are harnessed.  This thesis contributes to the comprehension of how social innovation and social entrepreneurship can be utilised as effective instruments for fostering more inclusive and efficient labour market systems and societies.","language":"eng","citation":"ENTERPRISES-DRIVEN ITS ACADEMY AS A DRIVER FOR LABOUR MARKET DEVELOPMENT AND MIGRANTS INTEGRATION IN LOMBARDIA:A CASE FOR SOCIAL INNOVATION AND SOCIAL ENTREPRENEURSHIP / A.a.a.e. Orban ; tutor: G. Ballarino ; co-tutor: M. Turri ; coordinatore: E. Damiani. - UNIMI. Dipartimento di Economia, Management e Metodi Quantitativi, 2026 Jul 13. 38. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R14163.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1260041/3368058/phd_unimi_R14163.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1215615"},"title":"LO SFRUTTAMENTO DEL LAVORO IN AGRICOLTURA E LE INFILTRAZIONI DELLA CRIMINALITÀ ORGANIZZATA DI TIPO MAFIOSO. UN¿ANALISI SUL TERRITORIO LOMBARDO.","internalauthor":"LOCARNI, MARTINA","type":"Tesi di dottorato","year":"2026","abstract":"This research investigates labour exploitation and the infiltration of organised crime of a mafia type in the agricultural sector in Lombardy. Through a multidisciplinary approach that integrates sociological, socio-economic and legal perspectives, the research mainly uses qualitative methods, supported by quantitative data. It analyses the organisation of the labour market and the forms of labour exploitation, as well as the role of ordinary and mafia-type organised crime within the agri-food supply chain and the agricultural labour market. The study highlights the consequences of labour exploitation on the community and market dynamics, offering reflections on prevention, enforcement and social responsibility tools. The results provide a framework for measures aimed at protecting workers' rights and promoting a more ethical and sustainable economic system.","language":"ita","citation":"LO SFRUTTAMENTO DEL LAVORO IN AGRICOLTURA E LE INFILTRAZIONI DELLA CRIMINALITÀ ORGANIZZATA DI TIPO MAFIOSO. UN' ANALISI SUL TERRITORIO LOMBARDO / M. Locarni ; tutor: F. Basile ;  co-tutor: M. Massari ;  coordinatore: E. Damiani. - Università degli Studi di Milano. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2026 Feb 27. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14087.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 17-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/932178"},"title":"GLI EPIGRAMMI 'DI PLATONE'. EDIZIONE, COMMENTO, FORTUNA","internalauthor":"PELUCCHI, MARCO","type":"Tesi di dottorato","year":"2022","abstract":"This thesis provides a new critical edition and full commentary of the epigrams transmitted under Plato's name. The edition includes for the first time all the epigrams assigned to 'Plato' by the ancient tradition and offers a critical text based on a review of the manuscript tradition and philological work. The commentary provides an in-depth analysis of the epigrams, from both the philological and the literary and exegetical points of view. An introductory study addresses the problem of the epigrams' authenticity by reviewing the scholarly debate on the topic. It also traces the history of Plato's epigrams in antiquity, proposing a reconstruction of relevant context and possible reasons why the epigrams were composed and assigned to Plato.","language":"ita","citation":"GLI EPIGRAMMI 'DI PLATONE'. EDIZIONE, COMMENTO, FORTUNA / M. Pelucchi ; tutor: G. Benedetto ; coordinatore: F. Slavazzi. Dipartimento di Studi Letterari, Filologici e Linguistici, 2022 Jul 08. 34. ciclo","filename":"phd_unimi_R12171.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/932178/2046196/phd_unimi_R12171.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1056588"},"title":"INVESTIGATING GENOME PROTECTION AT G-QUADRUPLEXES: STRUCTURAL-FUNCTIONAL ANALYSIS OF S. CEREVISIAE DOMESTICATED TRANSPOSASE VID22","internalauthor":"BERNINI, GIULIA MARIA","type":"Tesi di dottorato","year":"2024","abstract":"Genome instability is a characteristic feature of ageing and several human pathologies, including cancer. Genome instability is elicited by exogenous DNA damaging agents and by multiple endogenous factors, among which G-quadruplex non-canonical DNA secondary structures. These structurally heterogeneous nucleic acid folds have been implicated in the modulation of multiple biological processes, including transcription and replication. Consequently, perturbation of G-quadruplex homeostasis is linked to alterations in gene expression, replication stress, DNA breakage, and, ultimately, enhanced genome instability. We recently found that Saccharomyces cerevisiae Vid22, a putative member of the hAT family of DNA transposases by prediction of a BED-type zinc finger domain and an RNase H fold, binds at G-quadruplex forming sites and counteracts their detrimental effects on genome stability. In this work, I mutated various residues of Vid22 protein or the DNA sequence of one of its binding loci in the genome to investigate the intrinsic and extrinsic requirements for its recruitment to chromatin. Vid22 enrichment at certain loci depends on the presence of a G-quadruplex and contributes to the binding of Tbf1, a multifunctional general regulatory factor, to DNA. Moreover, Vid22 role in genome protection correlates with its physical interaction with Tbf1. Disruption of the putative DNA-binding BED domain only partially affects Vid22 interaction with DNA and Tbf1, whereas mutation of C-terminal residues abolishes both processes and correlates with cell hypersensitivity to genotoxic stress. Moreover, Vid22 forms homodimers in vivo. The computational model and low-resolution structure of Vid22 dimer display striking similarities to that formed by the active hAT Hermes transposase dimer despite their evolutionary distance and sequence divergence. Similarly to Hermes, Vid22 C-terminus seems to be crucial in maintaining the proper protein tertiary structure. Mutation of the C-terminus also abolishes Vid22 self-interaction due to its spatial proximity to a second putative DNA-binding region directly involved in dimerisation (residues 170-210) inferred by homology to Hermes, which existence is corroborated by the impairment of self-interaction in the vid22 F195A mutant. Thus, Vid22 has evolved from the domestication of a hAT DNA transposase to support genome stability and G-quadruplex regulation in budding yeast. Because the human genome also encodes uncharacterised proteins predicted to possess similar domain organisation and evolutionary origin, research on Vid22 may pave the way for their study, besides providing novel insights into G-quadruplex recognition and biology.","language":"eng","citation":"INVESTIGATING GENOME PROTECTION AT G-QUADRUPLEXES: STRUCTURAL-FUNCTIONAL ANALYSIS OF S. CEREVISIAE DOMESTICATED TRANSPOSASE VID22 / G.m. Bernini ; supervisor: M. Muzi Falconi ; tutor: F. Lazzaro ; coordinator: R. Mantovani. - Dipartimento di Bioscienze. Università degli Studi di Milano, 2024 Jun 25. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12993.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1056588/2426372/phd_unimi_R12993.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/910101"},"title":"REE-BEARING CARBONATE SYSTEMS AT HIGH PRESSURE:AN EXPERIMENTAL STUDY","internalauthor":"SPARTA', DEBORAH","type":"Tesi di dottorato","year":"2022","abstract":"Abstract  REE bearing carbonate systems at high pressure: an experimental study  Carbonatites are important sources of Rare Earth Elements (REE). REE mainly reside in Ca-bearing phases carbonates, apatites, Ca-Nb oxides, Ca-silicates and in accessory phases such as monazite, burbankite, bastnäsite. At liquid phases, carbonate melts display remarkable physical properties. In particular, carbon-rich and silica-poor melts, i.e. transitional melts, are efficient metasomatizing agents of carbon between the mantle and the crust.  This study focuses on two main issues: I) the effect of REE such as La and Y on the structure and melting behavior of transitional carbonate-silicate melts, which has been investigated in simple model with variable CaCO3:SiO2 ratio at 1 GPa; and II) the stability and mineral physics of REE-bearing carbonates at high pressure, in particular of La-burbankite.  Few experimental works have explored phase relations, structure and the role of REE in carbonate-rich melts. The typical unquenchable nature of carbon-rich melts makes for a difficult, determination of the structure of carbon-rich glasses. Wyllie and Jones (1986) synthesized a REE-bearing carbonatite glass in a series of experiments performed in the system CaO–CaF2–BaSO4–CO2–H2O–La(OH)3 using a composition similar to carbonatites ore deposits in Mountain Pass (California). At 0.1 GPa the investigated carbonatite composition starts to melt at temperatures as low as 550°C. As today, there are no data available regarding melting behavior, structural properties of melts, and the stability of REE-bearing phases in model system of hydrous carbon-rich low silica. Furthermore, although in alkali free systems a complete miscibility between silicate and carbonate liquids is expected, the compositional threshold at which carbonate-silicate liquids might form a glass, i.e. are quenchable, is still scarcely explored in simple model systems. In this study, I investigated i) how viable is the quenching of a carbon-rich melt as a function of the bulk SiO2:CaCO3 ratio, ii) the structure of these glasses, iii) and the role of REE in the molecular structure(La, Y). I also determined the CO2 solubility in transitional melts by micro-Raman spectroscopy. Single stage and end-loaded piston cylinder experiments have been performed at 1 GPa in two model systems: CaO–SiO2–La2O3–H2O–CO2 in the range 700–1250°C, and CaO–SiO2–Y2O3–H2O–CO2 in the range 1200–1250°C. The starting materials were prepared as a powder mixture of La2(CO3)3 or La2O3 or Y2O3 and amorphous SiO2 and CaCO3 with approximately 5-10 wt.% of H2O. Different bulk compositions with different SiO2:CaCO3 ratio have been considered. Run products were characterized by backscattered electrons images (BSE), X-ray diffractometry, micro-Raman spectroscopy, nuclear magnetic resonance (NMR) of selected experiments, and chemically analyzed by electron microprobe. At subsolidus conditions (T < 1000°C), all bulk compositions in CaO–SiO2–La2O3–H2O–CO2 system contain calcite and quartz coexisting with a Ca-La silicate phase with an apatite-type structure of general formula between La3Ca2(Si3O12)OH and La4Ca(Si3O12)O. Liquidus conditions have been observed in runs on bulk compositions with SiO2:CaCO3 = 0.28 1.4 at T >1150°C for both investigated systems. Homogeneous quenched glasses have been retrieved for composition with up to SiO2:CaCO3=0.28 ratio, whereas at lower ratio (0.12) dendritic textures are visible. Deconvolution of Raman spectra of glasses reveal a CO2 content up to 20.40% in the CaO–SiO2–La2O3–CO2–H2O system and up to 10.80% in the CaO–SiO2–Y2O3–CO2–H2O system classifying the melts as carbonate-silicate transitional melt.  While studiyng the behavior of Ca-rich carbonatitic hydrous glasses with REE, we also investigated the influence on the REE distribution of an alkaline carbonate, burbankite [(Na,Ca)3(Sr,Ba,Ce,REE)3(CO3)5], at upper mantle conditions. Recently, the alkaline-carbonate system has been observed at High Pressure and High Temperature (HP-HT) by Shatzky et al., (2016); they found a new class of Ca-rich alkaline-alkaline earth carbonates and burbankite with the latter being abundantely presents in carbonatites that constitutes important ore concentrations of strategic metals, including Nb and REE elements on Earth’s surface. A La rich burbankite [Na3Ca2La(CO3)5] was synthesized at 5 GPa and 1000°C, to scope out the possibility that REE can enter the structure of this carbonate also at upper mantle conditions. Furthermore, the elastic properties of the synthesized La-burbankite have been determined by in-situ HP and HT single crystal X-ray diffraction measurements at synchrotron facilities using a diamond-anvil cell for HP experiments and a quartz-glass capillary for the HT experiments. The determination of these thermoelastic parameters allowed to calculate the possible density of this phase at upper mantle conditions, that is ca. 3.2 g/cm3 at 5.5–6.0 GPa and 900–1000°C. Results suggest that potentially the La-burbankite could fractionate at HP and HT from a carbonatitic melt, because the latter has a lower density (ca. 2.1-3.1 g/cm3) and may constitute a REEs reservoir at upper mantle conditions.","language":"eng","citation":"REE-BEARING CARBONATE SYSTEMS AT HIGH PRESSURE:AN EXPERIMENTAL STUDY / D. Sparta' ; tutor: P. Fumagalli ;  co-tutor: G.Borghini ; coordinatore: F. Camara Artigas. Università degli Studi di Milano, 2022 Feb 17. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12158.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/910101/1986276/phd_unimi_R12158.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1054088"},"title":"PLANT-ARTHROPOD INTERACTIONS IN MOUNTAIN ECOSYSTEMS","internalauthor":"EUSTACCHIO, ELENA","type":"Tesi di dottorato","year":"2024","abstract":"The present Ph.D. thesis is organized as a collection of research papers published, submitted, and in preparation.  Chapter 1. Here is introduced the knowledge about plant and arthropod interactions in mountain ecosystems and the aims of the Ph.D. project followed by an introduction to the two different study cases of my research. A brief overview of the two Ph.D. side projects is also reported in this chapter.  Chapter 2, “Plant-arthropod interactions: the case study of Androsace brevis (Hegetschweiler) Cesati (Primulaceae)”. This chapter focuses on the characterization of flower-visiting arthropod community linked to the alpine plant species Androsace brevis, a narrow-endemic plant of Southern-Central Alps (Italy) characterized by a short (about two weeks) and early (May-June) flowering period. This species is particularly threatened by climate warming. The first study (paragraph 2.1) describes the floral and pollen morphology of A. brevis, which were useful in investigating the pollination biology of this species as well as its possible pollination strategies and vectors. The study reported in paragraph 2.2 focuses on the development and subsequent evaluation of two methodological approaches employed for the study of the flower-visiting arthropod communities of A. brevis: manual sampling and video-observations. Subsequently, a detailed characterization of the A. brevis flower-visiting arthropod community in relation with weather conditions, was carried out selecting two A. brevis populations (Cugn Peak, Como, Lepontine Alps, Italy; Benigni Hut, Bergamo, Orobic Alps, Italy) (paragraph 2.3). In paragraph 2.4, the pollen grains retrieved from A. brevis flower-visiting arthropod collected at Benigni Hut for three consecutive years have been analysed from both qualitative and quantitative point of view by light microscopy. Palynological analysis allowed to identify the pollination network that characterize the high-altitude ecosystem during a particular period of the year as the early season (May-June) in alpine environment, when the snow cover still present on the ground and few plants are flowering (work in preparation). Finally, in paragraph 2.5, a specific investigation on the high-altitude communities of Braconidae (Hymenoptera) was carried out for the same two sites previously reported, resulting in the discovery of four new species of Braconidae for the Italian fauna. Additionally, this study reports the first record of the alien species Lysiphlebus testaceipes (Cresson, 1880) in an Alpine context.  Chapter 3, “Plant and flower-visiting arthropod communities within the Stelvio National Park”. This study applied the two methodological approaches developed with the previous project to a broader context. The study was conducted in the Martello Valley (Bolzano province, South Tyrol, Italy) within the Stelvio National Park. The effects of the altitudinal gradient (from 900 to 2700 m asl) and the different type of land management (from the natural grasslands to the apple orchards) were investigated on the flower-visiting arthropod abundance and community composition (paragraph 3.1, in preparation). Moreover, a molecular approach (ITS2 metabarcoding) has been developed as an alternative to the traditional palynological analysis conducted by light microscopy (paragraph 3.2, submitted).  Chapter 4, “Ph.D. Side projects”. In this chapter, a new plant species (Campanula bergomensis, Campanulaceae) and a new insect species (Oreonebria tresignore, Carabidae) for Orobic Alps (Bergamo, Northen Italy) are characterized both morphologically and genetically (paragraphs 4.1, 4.2).  Chapter 5, “Conclusions and future prospects” of the research.  Chapter 6, “Ph.D. Activities”. Here is presented the activities carried out during my Ph.D., comprehensive of all the papers published, submitted, in preparation, and future papers on data collected for the Ph.D. project; all the congresses and seminaries; teaching activities and participation in projects.","language":"eng","citation":"PLANT-ARTHROPOD INTERACTIONS IN MOUNTAIN ECOSYSTEMS / E. Eustacchio ; tutor: M. S. Caccianiga ; co-tutor: M. Casartelli ; coordinatore: M. Guarino. - Aula C21, Città Studi. Dipartimento di Bioscienze, 2024 Jun 03. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R12882.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1054088/2420232/phd_unimi_R12882.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1219280"},"title":"SEMICLASSICAL VIBRATIONAL SPECTROSCOPY BEYOND POWER SPECTRA","internalauthor":"LANZI, CECILIA","type":"Tesi di dottorato","year":"2026","abstract":"Infrared (IR) spectroscopy is a fundamental technique for probing molecular structure, dynamics, and intermolecular interactions. However, the increasing spectral complexity of medium- and large-sized systems makes theoretical support essential for reliable spectral assignment. Semiclassical (SC) molecular dynamics offers an effective compromise between accuracy and computational cost, incorporating key quantum effects through the propagation of classical trajectories. Traditionally, SC vibrational spectroscopy has focused on the calculation of power spectra, which provide vibrational energy levels but do not directly reproduce experimental IR intensities.    This Ph.D. thesis presents the development of a new semiclassical approach for the direct calculation of IR absorption spectra (SC IR) within the semiclassical initial value representation framework. The method enables the simultaneous prediction of vibrational frequencies and physically meaningful transition intensities, producing signals exclusively for IR-active modes and allowing direct comparison with experimental spectra. After validation on model systems and small molecules, an extended formulation (e-SC IR) based on mode-by-mode simulations is introduced to treat larger molecular systems with improved efficiency. These developments extend semiclassical vibrational spectroscopy beyond power spectra toward a more realistic and experimentally oriented description of IR absorption spectra.","language":"eng","citation":"SEMICLASSICAL VIBRATIONAL SPECTROSCOPY BEYOND POWER SPECTRA / C. Lanzi ; tutor: R. Conte ;  co-tutor: M. Ceotto ;  coordinatore: D. Passarella. Dipartimento di Chimica, 2026 Feb 18. 38. ciclo, Anno Accademico 2025.","filename":"phd_unimi_R13922.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1219280/3260093/phd_unimi_R13922.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1238405"},"title":"BIOACTIVE-RICH MUSHROOMS FOR FOOD REFORMULATION","internalauthor":"BEARZI, GIULIA","type":"Tesi di dottorato","year":"2026","abstract":"Rising global concerns about animal product consumption and environmental sustainability have fueled the rapid expansion of plant-based protein sources, with bioactive-rich mushrooms (BRMs) emerging as a frontrunner. Extracts and powders of BRMs are widely used as dietary supplements and functional foods, particularly in Eastern countries, due to their high nutritional value: abundant dietary fiber, proteins, vitamins, trace minerals, and bioactive compounds like lectins, phenolics, and volatile organics, all while being low in calories and fat. Cultivation of BRMs through solid-state fermentation (SSF) on agri-food by-products is inherently sustainable, reducing waste and carbon footprints. However, it is important to optimize growing conditions and to have fast and reliable methods to monitor mushroom development. Moreover, the use in food applications of BRM mycelium or whole fermented biomass, obtained through SSF, is still poorly investigated.  Within this context, this PhD project investigated the potential application of BRM mycelium or fermented biomass for food reformulation, aiming to introduce innovative protein ingredients and sources of health-promoting bioactive compounds. Specifically, SSF of Pleurotus ostreatus and Ganoderma annularis was studied, using substrates such as fresh-cut mixed salad by-products, brewer’s spent grain, and apple pomace. This study was conducted within the ONFoods project, contributing to the objectives of Spoke 04 “Food Quality and Nutrition,” funded by the National Recovery and Resilience Plan (NRRP). Part of this work was conducted at IRTA Fruitcentre (Lleida, Spain) during a five-month research stay abroad.  At first a literature survey comprehensively reviewed BRMs, emphasizing nutritional composition (proteins, fibers, micronutrients), as well as cultivation techniques (i.e., SSF and submerged fermentation) and parameters (e.g., substrate humidity, nutrients, fermentation temperature). The survey pinpointed knowledge gaps and enabled the selection of BRM strains to investigate.  Then, SSF of P. ostreatus and G. annularis on agri-food by-products (i.e., fresh-cut mixed salad by-product, brewer's spent grain) were performed and advanced methods for monitoring were developed, based on digital imaging, active thermography, and Fourier-transform near infrared (FT-NIR) spectroscopy. Moreover, the mycelial biomasses were analyzed for protein, lipids, polyphenols, and β-glucan content to evaluate the quality obtained. Another SSF trial was set up to optimize growing conditions of P. ostreatus on apple pomace, considering the type of inoculum (I.e., liquid and solid), the container (i.e., trays with lid, trays in bags, and bags), and the type of wetting solutions (i.e., no solution, water, nutrient-enriched solution, and aquafaba – cooking water of chickpeas) as experimental factors. The results demonstrated that the best combination consisted in the use of the solid inoculum, trays closed in bags and aquafaba as wetting solution. Both the mycelium and the whole fermented biomass were evaluated and the products obtained under the optimized conditions were dried for the following food applications.  The final part of the work focused on food reformulation incorporating the BRM biomasses previously produced. High-consumption staple products were considered, like cookies and gluten-free (GF) bread, but also innovative prototypes were developed, including miso-like paste and 3D-printed products, demonstrating BRM versatility. GF bread was reformulated by partially substituting (at 5, 7.5, and 10%) rice flour and corn starch with P. ostreatus mycelium powder obtained from fresh-cut mixed salad by-product, resulting in an improved nutritional profile but reduced specific volume and crumb softness compared to the reference product. Cookies were reformulated by replacing wheat flour (at 5 and 10%) with P. ostreatus mycelium or whole fermented biomass powders obtained from apple pomace. No notable differences were observed in dough properties, whereas clear differences emerged in the final product, which maintained compositional characteristics comparable to reference samples while potentially exhibiting higher levels of bioactive compounds due to fermentation-derived products.  A sweet miso-like product was developed by substituting (at 50 and 100% level) soybeans with fresh whole fermented biomass of P. ostreatus and apple pomace. After maturation, products with good microbial quality as well as physical and chemical properties closely aligned with traditional miso were obtained. At last, 3D-printed prototypes suitable for dysphagic patients were developed using the powders of P. ostreatus mycelium and whole fermented biomass produced through SSF on apple pomace. For comparison, a powder of commercial P. ostreatus fruiting bodies was also used. The effect of methylcellulose addition (1%) was evaluated as well. The results obtained indicated that the prototypes showed satisfactory technological properties (i.e., printability and texture of the final product), thereby supporting the potential for innovative applications of fungi biomasses in this context.  To maximize the potential of BRMs in food and health-related industries, future research should prioritize the development of biomass scalable production methods and the investigation of sensory properties and acceptability of the innovative food products, as well as the bioavailability of key nutritional compounds.","language":"eng","citation":"BIOACTIVE-RICH MUSHROOMS FOR FOOD REFORMULATION / G. Bearzi ; tutor: C. Alamprese co-tutor: M. Rollini coordinatore: D. Mora. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2026 May 05. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14165.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 24-OTT-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1124265"},"title":"ADVANCED AAV-MEDIATED LIVER-DIRECTED GENE THERAPIES FOR HAEMOPHILIA A AND MUCOPOLYSACCHARIDOSIS TYPE VI","internalauthor":"ESPOSITO, FEDERICA","type":"Tesi di dottorato","year":"2024","abstract":"Liver-directed gene therapy using adeno-associated viral (AAV) vectors holds  significant promise for providing long-term transgene expression following a  single systhemic administration. However, both the limited cargo capacity (~4.7  kb) and the non-integrative nature of AAV vectors prevent their application to  conditions caused by either mutations in large genes (i.e. F8 whose coding  sequence exceeds ~ 4.7 kb) or to those that require early stage of intervention,  such as early-onset inborn errors of metabolism. My PhD project aims to  overcome these shortcomings and broaden the therapeutic applications of AAVs.  To overcome the issue of limited cargo capacity, I explored an AAV-mediated  protein trans-splicing (PTS) strategy utilizing split inteins. PTS is a natural  mechanism employed by organisms across all domains of life to reconstitute large  proteins from shorter precursors. Split inteins facilitate this process by selfexcising  from the host protein in an energy-independent manner. I used this  approach for haemophilia A (HemA), the most common X-linked bleeding  disorder (affecting 1 in 5,000 males), caused by a deficiency of clotting factor 8  (F8, ~7 kb). I first demonstrated the successful full-length reconstitution of the  large (~5 kb) and highly active B-domain deleted (B-DD) N6-F8 variant in vitro.  Subsequently, I designed two separate AAV vectors, with regular size genomes,  each encoding for half of the N6-F8, flanked by split inteins. The AAV-N6 intein  system led to successful reconstitution of functional full-length N6-F8 in the  mouse liver, achieving therapeutic F8 activity in haemophilic mice without  eliciting anti-F8 immune responses.  In parallel, I developed an AAV-mediated CRISPR/Cas9 homology-independent  targeted integration (AAV-HITI) platform to achieve stable transgene integration  at the 3’ end of the mouse Albumin locus, which is highly expressed in  hepatocytes. This approach mitigates the loss of episomal AAV genomes in  proliferative tissues, thereby preserving therapeutic efficacy over time.  14  I demonstrated AAV-HITI efficacy, in mouse models of HemA and  Mucopolysaccharidosis type VI (MPS VI), a lysosomal storage disorder,  achieving stable therapeutic levels of systemic proteins even at low AAV doses.  Importantly, I performed comprehensive molecular analyses to characterize the  AAV-HITI outcomes within the target site confirming successful targeted  integration. Moreover, in AAV-HITI treated livers nor gross chromosomal  rearrangements or significant off-target insertions/deletions were observed 1-year  post neonatal delivery. Furthermore, I demonstrated the effectiveness of this  platorm in adult MPS VI and HemA mice, using vector doses that are within the  safe range for human translation.  Overall, my findings support two distinct AAV-mediated liver-directed platforms  to address major limitations of current AAV-based therapies. The AAV-intein  N6-F8 system holds promise as a potential therapeutic option for HemA, while  the AAV-HITI platform could serve as a durable therapeutic option for livertargeted  diseases, particularly those requiring early intervention.  These innovations represent significant advancements in overcoming challenges  related to cargo capacity, stable transgene expression, and long-term efficacy in  gene therapy.","language":"eng","citation":"ADVANCED AAV-MEDIATED LIVER-DIRECTED GENE THERAPIES FOR HAEMOPHILIA A AND MUCOPOLYSACCHARIDOSIS TYPE VI / F. Esposito ; tutor:  A. Auricchio ; internal supervisor: N. Brunetti-Pierri ; external supervisor: A. Follenzi ; coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2024 Dec. 36. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13154_3.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1124265/2607879/phd_unimi_R13154_3.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/950439"},"title":"OPTIMIZATION OF AAV9 GENE THERAPY FOR SPINAL MUSCULAR ATROPHY WITH RESPIRATORY DISTRESS TYPE 1 USING IN VIVO DISEASE MODELS","internalauthor":"PAGLIARI, ELISA","type":"Tesi di dottorato","year":"2023","abstract":"Spinal Muscular Atrophy with Respiratory Distress type 1 (SMARD1) is a rare autosomal recessive motoneuron disease with infantile onset, with an estimated incidence of 1/100’000. It is caused by mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene, which lead to a deficient amount of the encoded protein. The main clinical symptoms are distal muscular atrophy associated with diaphragmatic palsy. Nowadays no therapies are approved.  In this work, we compared the efficiency of two adeno‐associated virus serotype 9 (AAV9)-IGHMBP2 vectors, carrying different promoters, by administering them intracerebroventricularly in SMARD1 mice model (nmd), during the presymptomatic phase of the disease at postnatal day 1. This comparison allowed us to determine which is the best construct to be translated to the clinic. Then, with the aim to precisely define the therapeutic window, we evaluated AAV9-based treatment in already symptomatic mice at P7 by systemic subcutaneous injection.  Expression analysis at P20 on mice treated at the presymptomatic stage demonstrated a significant increase in the IGHMBP2 protein expression level compared to the control. Treatments also resulted in an extended survival time, higher body weight, and improvement in motor behaviors. Histopathological analysis showed in muscles increased innervation of the neuromuscular junctions and enlargement of fibers diameter and, in spinal cords, increased motoneurons number with reduced gliosis and astrogliosis. We also found a restoration of the IGF1 axis, altered in nmd mice. To support the translatability of the therapy, we confirmed the lack of a significant alteration of the major toxicity biomarkers after the treatment and the rescue of the one pathologically altered. Long-term effects were also evaluated at P200 demonstrating differences between the two constructs in maintaining the motoneurons number and mediating cardiac fibrosis amelioration.   Results of similar analysis performed on delayed treated mice cohort showed equivalent results, demonstrating that also a treatment in the symptomatic phase could partially rescue the SMARD1 phenotype.  Our presymptomatic treatment results lay the foundation for the launch of the ongoing gene therapy-mediated phase I/IIa clinical trial for IGHMBP2-related disease, a crucial step forward in the authorization of the first therapy for SMARD1 pathology, which is up to now treated only with palliative and supportive care. Good results were obtained also delaying the treatment in the early symptomatic phase, but further studies are needed to assess the therapeutic window of this extremely promising approach.","language":"eng","citation":"OPTIMIZATION OF AAV9 GENE THERAPY FOR SPINAL MUSCULAR ATROPHY WITH RESPIRATORY DISTRESS TYPE 1 USING IN VIVO DISEASE MODELS / E. Pagliari ; tutor: S.P. Corti ; supervisore: M. Nizzardo ; degree course coordinator: C. Sforza. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2023 Jan 23. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12659.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/950439/2117885/phd_unimi_R12659.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1258796"},"title":"ENDURING SOLIDARITIES. SPACES, PRACTICES, AND RELATIONS OF MIGRANT SUPPORT ALONG THE BALKAN ROUTES.","internalauthor":"MARTINI, CHIARA","type":"Tesi di dottorato","year":"2026","abstract":"This thesis examines grassroots solidarity practices along the Balkan migration routes in the context of increasingly restrictive European border regimes. Focusing on Greece, Bulgaria, and Bosnia and Herzegovina, the study investigates how bordering processes shape migrants’ trajectories and lived experiences, and how diverse forms of solidarity emerge in response to border violence, institutional abandonment, and everyday precarity. Since the so-called “long summer of migration” of 2015, the Balkan region has become a key site for the experimentation and consolidation of European migration control policies. Borders in this context extend far beyond official checkpoints, permeating forests, urban spaces, detention facilities, and informal camps, and operating through a combination of physical violence, bureaucratic obstruction, legal uncertainty, and temporal exhaustion. At the same time, these borders are continuously negotiated and contested through everyday practices of care, support, and collective action enacted by migrants, activists, volunteers, and local communities. The thesis is grounded in a multi-sited ethnography conducted between October 2023 and November 2024 across the three research sites. The empirical material is based on prolonged participant observation and 56 semi-structured interviews with a heterogeneous range of actors engaged in grassroots solidarity initiatives, including activists, volunteers, local residents, and people on the move. The research is also informed by the author’s direct involvement in solidarity practices, which enables a reflexive engagement with the field while maintaining analytical distance. Methodologically, the study emphasizes ethnography as a key tool for capturing the relational, affective, and situational dimensions of both migration experiences and solidaristic practices.     Analytically, the thesis explores grassroots solidarity through three interrelated dimensions: spaces, practices, and relations. First, it examines the creation and transformation of collective and community spaces in both border zones and urban settings. In contexts characterized by organized institutional abandonment, grassroots actors respond by building informal and semi-formal infrastructures of reception, care, and exchange. These spaces - including community centers, informal shelters, kitchens, and meeting points - function not only as sites of material support, but also as social infrastructures where alternative forms of belonging, recognition, and political imagination are tentatively enacted. Second, the thesis analyzes the practices that unfold within these spaces, ranging from the distribution of food and basic necessities to legal and medical support, educational activities, and mutual aid networks. While many of these practices are not explicitly framed as political by those who enact them, the analysis highlights their political and transformative potential. By addressing immediate needs neglected or actively produced by border regimes, such practices challenge criminalizing and dehumanizing logics and disrupt dominant narratives that portray migrants solely as victims or threats. At the same time, the study critically examines the ambivalences of these practices, showing how they may reproduce hierarchies, dependencies, or assistentialist dynamics even as they contest structural violence. Third, the thesis foregrounds the relational dynamics that constitute and sustain solidarity over time. It investigates how relationships among migrants, volunteers, activists, and local actors are formed, negotiated, and sometimes fractured within the constraints imposed by border regimes. Particular attention is paid to power asymmetries, internal conflicts, emotional labour, and the tensions between humanitarian and political orientations. These relations are conceptualized as forms of “odd kinship”: provisional, fragile, and often asymmetrical alliances that nonetheless create openings for alternative ways of caring, belonging, and acting together. Rather than romanticizing solidarity, the thesis emphasizes its precarious and contested nature, highlighting how solidaristic relations are continuously reshaped by exhaustion, legal risks, institutional pressures, and changing migration policies.     By examining solidarity as a fluid and adaptive process, the thesis contributes to ongoing debates on the criminalization of solidarity, the limits and strengths of practical help, and the political significance of everyday practices of care. It shows how grassroots initiatives operate within, against, and beyond institutional frameworks, navigating legal ambiguity and surveillance while sustaining networks of support across local, national, and transnational scales. In doing so, the study challenges rigid distinctions between humanitarian aid and political action, legality and illegality, and between those who provide support and those who receive it. Overall, the thesis argues that grassroots solidarity along the Balkan routes constitutes a crucial site for understanding contemporary border regimes and their contestation. While solidaristic practices cannot undo the structural violence of borders, they expose its everyday workings and generate fragile yet meaningful spaces of resistance, recognition, and collective survival. By centering relationality, situated practices, and lived experience, the study offers a nuanced account of solidarity as an imperfect, negotiated, and deeply human response to the bordering processes that shape mobility in contemporary Europe.","language":"eng","citation":"ENDURING SOLIDARITIES. SPACES, PRACTICES, AND RELATIONS OF MIGRANT SUPPORT ALONG THE BALKAN ROUTES / C. Martini ; PhD supervisor: M. Ambrosini ;  PhD co-supervisor: P. Bonizzoni ; PhD coordinator: P. Rebughini. Dipartimento di Scienze Sociali e Politiche, 2026 Jul 07. 38. ciclo","filename":"phd_unimi_R13915.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1258796/3365494/phd_unimi_R13915.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1121001"},"title":"LUMINESCENT COMPOUNDS FOR APPLICATIONS IN PHOTONICS","internalauthor":"MAURI, LUCA","type":"Tesi di dottorato","year":"2024","abstract":"Luminescent compounds have seen a growing interest for the possibility to employ them for several applications, from energy conversion to the biomedical field, but also sensors, light-emitting devices, and many others. The variety of luminescent compounds is huge, and this offers a wide flexibility in terms of chemical and photophysical properties, that enables the possibility to use them for all these applications.  This Ph.D. thesis deals with the synthesis and characterization of luminescent compounds for potential applications in photonics, which can be defined as a branch of optics related with generation, modulation, detection, and processing of photons. It is divided in three parts, each concerning an independent project.  In the first part, made in collaboration with Prof. Gianmarco Griffini (Politecnico di Milano), the synthesis and characterization of two luminescent diol dyes, D-BT and A-PDI, have been described, and both dyes were characterized by intense absorption bands and high luminescence quantum yields. These dyes have been accurately chosen to realize luminescent solar concentrators (LSCs), considering two main aspects. Firstly, the extension of the device absorption spectrum when used together, second, an efficient energy transfer between them to improve the overall device performance. Furthermore, the presence of two hydroxyl groups was chosen for the subsequent incorporation of the dyes in polymeric structures. This was aimed to minimize the mobility of the dye in the polymeric matrix, therefore reducing the tendency to form aggregates, and to improve the dye dispersion.  A series of nine luminescent polyurethanes containing one dye or both, plus three blends of polymers containing different dyes has been synthesized and characterized in thin-film configuration. Except for the shift of the emission bands, that was associated with the different chemical environment than in solution. Polymers containing two dyes were characterized by broader absorption spectra than those functionalized with only one luminophore, and energy transfer processes took place very effectively, with measured efficiencies up to 90 %.  Device characterization displayed very interesting results, starting from the elevate internal photon efficiencies, up to 48 %. The LSC device based on polymer PU-DA15, containing both dyes, in particular, was characterized by an excellent external photon efficiency of 3.97 % and by a moderate device efficiency of 0.64 %. However, what characterizes this type of device is its remarkable transparency, in fact, its average visible-light transmittance was approximately 90 %. Also a high light utilization efficiency of 58 was calculated for the same polymer.  The second part, made in collaboration with Dr. Henri Doucet during a stay of three months at Université de Rennes (France), reports the synthesis of fourteen new phenyl-functionalized, difluorinated NˆCˆN ligands through direct arylation via C-H activation reactions, never attempted on this kind of substrate. The synthesized ligands were then coordinated with Pt(II) cations to obtain the corresponding Pt(II) complexes.  Photophysical characterization showed intense absorption bands in the near UV region, with a tail in the visible, responsible for the pale-yellow colour of the derivatives. However, a strong absorption in the visible was measured when the ligands were functionalized with triphenylamines. Luminescent quantum yields were usually high (up to 90 %) and emission lifetimes long, in the range of µs. Pyridine functionalization had a strong effect on the photophysical properties, depending on the electron-donating character of the substituents and on their steric hindrance.  The third, and last, part of this doctoral thesis, was made during a stay in Ikeda (Japan) in collaboration with Dr. Kenji Kamada (National Institute of Advanced Industrial Science and Technology, AIST). The two-photon absorption properties of three samples were determined and the experimental data were compared with simulated ones.  Compound T1, in spite of being an octupolar structure, was characterized by a moderate cross-section of 190 GM at 587 nm. However, this is only a preliminary result, and T1 was prepared to set and optimize the synthetic procedures to obtain a class of molecules characterized by more appropriate functional groups suited to increase the TPA cross-section and to red-shift the spectrum.  Also Pt(II) complexes having NˆCˆN ligands, compounds Pt1-2, were investigated: despite the modest TPA cross-section of Pt1, a very good result was obtained for Pt2, with a cross-section of 251 GM at 805 nm. Theoretical calculations confirmed that the presence of triphenylamines on the side pyridine rings is associated with an intense charge transfer from them to the molecular core that, together with the efficient conjugation, allowed a reasonably intense TPA.","language":"eng","citation":"LUMINESCENT COMPOUNDS FOR APPLICATIONS IN PHOTONICS / L. Mauri ; tutor: C. Dragonetti ; co-tutor: A. Colombo ; coordinatore: D. Passarella. - Aula 110, Settore didattico, via Celoria 20. Dipartimento di Chimica, 2024 Dec 20. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13351.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1121001/2596561/phd_unimi_R13351.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/947449"},"title":"STUDY OF PHYSIO-PATHOLOGICAL MECHANISMS AT THE BASE OF SCHWANNOMA DEVELOPMENT","internalauthor":"MELFI, VALENTINA","type":"Tesi di dottorato","year":"2022","abstract":"Schwannomas are the most common type of peripheral nerve tumor. Usually, schwannomas are benign, well‐circumscribed tumors clinging to peripheral nerves, consisting of a clonal population of Schwann cells (SCs), which often undergo cystic and degenerative changes. Most cases are sporadic, however, some are associated with neurofibromatosis type 2 (NF2), schwannomatosis (SCH) or the pathology called Carney's complex. The schwannoma affecting the auditory nerve, called vestibular schwannoma (VS), is the most common benign tumor of the cerebellopontine angle. The occurrence of VSs is frequent among patients with NF2, the autosomal dominant multiple syndromes resulting from mutations in the NF2 gene, coding for the protein merlin. The tumor suppressor merlin is a cytoskeleton-associated protein, which loss of function is the main cause for transformation of SCs into schwannomas. However, a large amount of VSs is sporadic and unilateral suggesting the presence of unknown pathogenic mechanisms beside NF2 gene mutation. Also, SCH is due to changes in NF2 gene, although recently other mutations in SMARCB1 and LZTR1 genes were found. Considerable overlap has been found between SCH and NF2, in terms of the occurrence of associated types of tumors, whereas both diseases are considered as separated clinical entities. Therefore, it is not excluded that mutations in other genes, may be responsible for the appearance of schwannomas presenting a characteristic clinical phenotype. The identification of such genes and/or cellular mechanisms has found limitations in the lack of in vitro cell models of human origin that may be useful to this purpose.   In this thesis, human SCs were isolated, purified and characterized, for the first time, from the schwannomas, by using a positive immunomagnetic cell labelling technique, allowing the specific and high-purity enrichment of SCs in culture. The SCs from peripheral schwannoma were then immortalized using the LtAg-SV40, in order to obtain a continuous cell line for future studies addressed to better understand the schwannoma pathogenesis.  Notably, the onset of schwannoma may be influenced by the exposure to environmental challenges, likely the electromagnetic fields (EMF), such as those generated by mobile phones or electronic devices. In fact, it was suggested that EMFs can induce cellular changes towards non-physiological behavior, that may be pathologically relevant to the development of schwannoma. Overall, in this work of thesis we focused our attention on the investigation of putative genes, pathways, and molecular targets responsible for the oncotrasformation of SCs, studying the possible factors, also environmental, that could induce the development of schwannomas. The data are promising but further confirmatory studies will be needed for a more direct cause–effect correlation between EMF and SCs oncotransformation and finally to arrive at definitive conclusions widely accepted by the international scientific community.","language":"eng","citation":"STUDY OF PHYSIO-PATHOLOGICAL MECHANISMS AT THE BASE OF SCHWANNOMA DEVELOPMENT / V. Melfi ; tutor: V. Magnaghi; coordinatore: G.D. Norata. Dipartimento di Scienze Farmacologiche e Biomolecolari, 2022 Dec 12. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12567.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/947449/2106267/phd_unimi_R12567.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1167078"},"title":"VALORIZZAZIONE DELL¿HERITAGE, CIRCOLARITÀ, VINTAGE E UPCYCLING.OPPORTUNITÀ PER LE AZIENDE PER UNA MODA PIÙ SOSTENIBILE","internalauthor":"AUTORINO, SERENA","type":"Tesi di dottorato","year":"2025","abstract":"The contemporary fashion system, dominated by fast fashion and the characteristics of speed and obsolescence, seems to contrast with the concept of sustainability, today crucial for companies, institutions and consumers, all responsible actors for a more ethical and respectful future, from an environmental and social point of view. Although the challenges are complex, many companies are committed to developing sustainable products and to positively influence the system through innovation and dissemination.  The research analyzes fashion as a complex system, which goes beyond production, and includes communication, consumer choices and alternative and circular options.  The work examines the main critical issues of the sector to outline possible solutions. It studies cases of virtuous companies, with a focus on the Made in Italy that stand out for its ability to combine artisan tradition and innovation, enhancing the short supply chain and local skills. Significant examples include Ermenegildo Zegna, Rifò Lab and emerging brands that adopt innovative or upcycling strategies, proposing models in line with the needs of new generations. What emerges is the importance of a circular system that starts from design and ends with the management of end-of- life garments, for which companies and consumers are both responsible. Other relevant aspects that have emerged are: textile recovery, a historical Italian practice with great potential for the future; company archives, which through the conservation and reinterpretation of the past, offer inspiration for capsule collections, projects and a more conscious design, promoting quality and durability; the affirmation of second hand and vintage as increasingly popular options for consumers; the use of heritage in the strategies of some Italian luxury names, which demonstrates the central role of tradition for change; the importance of dissemination and training both towards the future generation of designers and towards consumers.  A specific and in-depth study was conducted in collaboration with the OTB Group, focusing in particular on the Diesel brand, to analyze a brilliant example of a well-structured and diversified corporate sustainability strategy, which demonstrates how innovation and responsibility can guide the sector towards a more aware and responsible future.","language":"ita","citation":"\"Valorizzazione dell’Heritage, Circolarità, Vintage e Upcycling. Opportunità per le aziende per una Moda più Sostenibile / S. Autorino ; tutor: E. Scarpellini ; coordinatrice: P. Grillo. - via santa sofia, milano. Dipartimento di Studi Storici \"\"Federico Chabod\"\", 2025 Jun 04. 37. ciclo, Anno Accademico 2023/2024.\"","filename":"phd_unimi_R13579.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1167078/3078727/phd_unimi_R13579.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1258079"},"title":"THE POLITICS OF BELONGING AND YOUTH WORK IN MILAN","internalauthor":"ALBERTINALE, GIOVANNI ANTONIO","type":"Tesi di dottorato","year":"2026","abstract":"The thesis examines the role of youth work—understood as a form of non-formal socio-educational practice—in the everyday lives of young people with a migration background in the city of Milan. It investigates the role of this actor in the construction, suspension, or renegotiation of the criteria of national belonging within the socio-educational spaces in which it operates (Youth Centres). Starting from an urban and media context marked by the growing stigmatization of young people with a migration background—frequently represented as “illegitimate” subjects or as individuals to be “sent back”—the research mobilizes Bourdieusian concepts to position itself at the intersection of youth work studies and analyses of the politics of belonging. By conceptualizing the nation as a field traversed built on dominant criteria of belonging, the thesis employs the concept of the politics of belonging to investigate how such criteria are reproduced, delegitimized, or reformulated within non-formal educational spaces. Drawing on a Bourdieusian-inspired analytical framework and a qualitative methodology, youth work is examined as a specific position within the educational field, characterized by an unequal distribution of educational and symbolic capital and by a historically constituted professional habitus.  At the empirical level, the research first explores the dispositions and expectations structuring the habitus of youth workers—particularly the asymmetry of recognition, the relational disposition, and the aspiration to social justice—showing how these elements shape a solidaristic posture towards young people. Second, the analysis of everyday interactions within Youth Centres makes it possible to identify practices of belonging-work, through which youth workers tend to suspend the use of national criteria of judgement, promoting instead a normative horizon of singularity centred on individual life projects. However, this delegitimization of national categories appears as ambiguous and situated, as such categories re-emerge in more indirect or subtle forms in specific interactional contexts. Finally, by giving voice to the lived experiences of young people with a migration background, the research analyses the plural forms of belonging experienced within Youth Centres, relating them to experiences of exclusion and stigmatization encountered in the wider urban and social space. Taken as a whole, the research contributes to an understanding of youth work as a space for the negotiation of national belonging, highlighting both its critical potential vis-à-vis dominant criteria and its structural tensions and contradictions.","language":"eng","citation":"THE POLITICS OF BELONGING AND YOUTH WORK IN MILAN / G.a. Albertinale ; tutor: M. Ambrosini ; cotutor: P. Rebughini ; supervisori: L. Domaneschi, N. De Luigi ; coordinatore: E. Damiani. Dipartimento di Scienze Sociali e Politiche, 2026 Jun 30. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14083.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 30-DIC-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1205256"},"title":"ARABIDOPSIS BSISTER AND SEEDSTICK MADS-BOX TRANSCRIPTION FACTORS MATERNALLY CONTROL THE OVULE AND SEED DEVELOPMENT IN ARABIDOPSIS THALIANA","internalauthor":"BABOLIN, NICOLA","type":"Tesi di dottorato","year":"2025","abstract":"Seeds derive from the fertilization of ovules and represent the next generation of the plant. Two  key genes, ARABIDOPSIS Bsister (ABS) and SEEDSTICK (STK), encode MADS-domain  transcription factors (TFs) that are expressed in the sporophytic tissues and are essential for  proper ovule di\udbc0\uddaferentiation and seed development. In the abs stk double mutant, ovule  development and seed set are signi\udbc0\uddb1cantly impaired, leading to the production of very few  viable seeds. Furthermore, the ovules in the double mutant exhibit defects in integument  di\udbc0\uddaferentiation and show an excessive accumulation of starch within the embryo sac. Although  most abs stk ovules are successfully fertilized, the development of the embryo is arrested a few  days after fertilization in most of the seeds. To better understand the roles of ABS and STK  during ovule and early seed development, the phenotypes of the abs stk double mutant have  been investigated using morphological, omics, and genetic approaches. This comprehensive  analysis revealed that sugar metabolism is signi\udbc0\uddb1cantly impacted in the abs stk double mutant.  6      Additionally, two di\udbc0\uddaferent strategies have been employed to modulate starch accumulation in  the abs stk double mutant, which resulted in a partial rescue of the embryo and seed  developmental defects. By examining callose deposition and nutrient \udbc0\uddb2ow into developing  seeds, a model has been proposed in which these two transcription factors modulate nutrient  transfer during the transition from ovule to seed. In conclusion, these \udbc0\uddb1ndings highlight the  signi\udbc0\uddb1cance of maternal tissues in regulating genetic factors related to nutrient availability, as  well as the delicate interaction between metabolic and developmental processes during seed  development.","language":"eng","citation":"ARABIDOPSIS BSISTER AND SEEDSTICK MADS-BOX TRANSCRIPTION FACTORS MATERNALLY CONTROL THE OVULE AND SEED DEVELOPMENT IN ARABIDOPSIS THALIANA / N. Babolin ; tutor: L. Colombo ;  coordinatore scuola dottorato: S. Ricagno. Dipartimento di Bioscienze, 2025 Dec 19. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13868.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 29-GIU-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1026878"},"title":"Γ-HYDROXY LACTONE AS A VERSATILE SCAFFOLD FOR THE DEVELOPMENT OF NOVEL BIOACTIVE COMPOUNDS","internalauthor":"CAZZANIGA, GIULIA","type":"Tesi di dottorato","year":"2024","abstract":"Drug resistance in mycobacteria is a rapidly increasing phenomenon requiring the identification of new drugs. The inhibition of Protein Tyrosine Phosphatase B (MptpB), which interferes with host immune responses, may provide a new strategy to fight tuberculosis (TB), while preventing cross-resistance issues. On this basis, starting from a virtual screening (VS) campaign and subsequent structure elucidation studies guided by X-ray analysis, an unexpected γ-hydroxy lactone derivative (compound VS1) with significant enzymatic activity against MptpB was identified. Structure-activity relationship (SAR) studies led to several simplified derivatives that maintained the inhibitory activity of VS1 against MptpB, albeit without significantly improving it.   Interestingly, VS1 shares its characteristic core lactone moiety with a natural product (BLI) isolated from the marine sponge-derived fungus Aspergillus terreus SCSIO 4100. Given that BLI was recently reported as an innovative inhibitor of the phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ), we applied a repurposing strategy to find a new pharmacological application of our in-house library of γ-hydroxy lactone compounds in the field of insulin resistance. Indeed, PPARγ represents a key target for the treatment of type 2 diabetes and metabolic syndrome. To avoid the serious adverse effects related to the PPARγ agonism profile of traditional antidiabetic drugs, a new opportunity is represented by the development of molecules acting as inhibitors of PPARγ phosphorylation by the cyclin-dependent kinase 5 (Cdk5). Their mechanism of action is mediated by the stabilization of the PPARγ β-sheet containing Ser245. We approached this study by performing a biological screening, through Surface Plasmon Resonance (SPR) technology-based experiments, of the in-house library of synthetic γ-hydroxy-lactone derivatives. These studies, together with transactivation assay, and phosphorylation inhibition assay led to the identification of compound 8 as a promising PPARγ non-agonist (PPARγ KD = 3.75 μM). Crystallographic experiments allowed us to deeply investigate the interaction of 8 with the enzyme, and the co-crystal data were used as starting point for computational studies, leading to optimized derivatives of 8, endowed with higher affinity for PPARγ. These new γ-hydroxy lactone-based PPARγ non-agonists represent promising anti-diabetic candidates, effective for the treatment of insulin resistance, but without adverse effects.  Furthermore, during my period abroad, at the Institute for Bioengineering of Catalonia in Spain, I focused my attention on the field of nanomedicine to improve the selectivity and efficacy of anti-TB candidates. Two pro-drugs of the first-in-class Salicylate Synthase I (MbtI) inhibitor (MIC = 32 μM), previously developed in our laboratory, were successfully encapsulated in poly(2-(methacryloyloxy) ethyl-phosphorylcholine)-co-poly(2-(diisopropylamino)ethyl methacrylate) (PMPC-PDPA) polymersomes (POs). Such a carrier allows us to (i) solubilize the hydrophobic drugs, (ii) target infected phagocytes via phenotypic association to scavenger receptors class B, (iii) efficiently deliver the cargo within the cell cytosol where most bacilli harbour, and (iv) effectively kill intracellular pathogens selectively. The POs were fully characterized by DLS, HPLC, and TEM; their cytotoxicity was assessed against macrophage cell line (THP-1) and Primary Human Lung Fibroblasts (HLF). Future work includes evaluating the antimycobacterial activity of the drug-containing POs in Mtb-infected primary cells.  These multidisciplinary projects were developed thanks to the cooperation of scientists from the University of Milan (Italy), the University of Pavia (Italy), the University of Pisa (Italy), the University of Bari (Italy), the CNR of Rome (Italy), and the Institute for Bioengineering of Catalonia (Barcelona, Spain).","language":"eng","citation":"Γ-HYDROXY LACTONE AS A VERSATILE SCAFFOLD FOR THE DEVELOPMENT OF NOVEL BIOACTIVE COMPOUNDS / G. Cazzaniga ; tutor: S. Villa ; coordinatore: G. Vistoli ; revisori: I. L. Batalha, J. Zitko. Università degli Studi di Milano, 2024 Feb 13. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12857.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1026878/2354539/phd_unimi_R12857.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/820693"},"title":"TARGETING EGFR/ERK/FOS SIGNALING AS A NOVEL APPROACH FOR HPV-POSITIVE HEAD AND NECK CANCER TREATMENT","internalauthor":"MEDDA, ALESSANDRO","type":"Tesi di dottorato","year":"2021","abstract":"Squamous cell carcinoma of the head and neck (HNSCC) is the 6th most common cancer worldwide. It accounts for 600.000 new cases and 350.000 deaths every year. HNSCC can be subdivided into two distinct subgroups: HPV-positive and HPV-negative. They present very different features including etiological agent, age, socioeconomic status, prognosis, genetic landscape, and tissue differentiation. Nevertheless, all HNSCC patients are treated with the same therapies, comprising chemo- and radiotherapy, and/or surgery. Specific therapies for HPV-positive HNSCC are needed. HPV oncoproteins E6/E7 are the drivers of oncogenesis in HPV-related cancers and they can be used as targets for therapy. To this end, we studied the effects of the knock down of E6/E7 in HNSCC-positive cell lines and we looked for pharmacological treatments to downregulate E6/E7 levels. We found that targeting the EGFR/ERK/FOS signaling pathway induced a transcriptional reduction of E6/E7 and that the ERK inhibitor Ravoxertinib was effective in killing HPV-positive HNSCC cell lines. Thus, this is a potential novel approach to address HPV+ HNSCC cancer.","language":"eng","citation":"TARGETING EGFR/ERK/FOS SIGNALING AS A NOVEL APPROACH FOR HPV-POSITIVE HEAD AND NECK CANCER TREATMENT / A. Medda ; tutor: S. Chiocca ; phd coordinator: G. Viale. Dipartimento di Oncologia ed Emato-Oncologia, 2021 Mar 30. 32. ciclo, Anno Accademico 2020. [10.13130/medda-alessandro_phd2021-03-30].","filename":"phd_unimi_R11753.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/820693/1722734/phd_unimi_R11753.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1156533"},"title":"ANTIREALISM AND TIME: AN ESSAY IN METHOD AND METAPHYSICS","internalauthor":"FREIJ, YAZAN AYMAN MOHAMMAD","type":"Tesi di dottorato","year":"2025","abstract":"The first chapter of this thesis is preoccupied with the question of the metaphysical method. In particular, I argue for a broad antirealist approach to metaphysics that rejects the ‘unique true theory’ claim of metaphysical realism. I show that only this broad metaphysical antirealism can avoid the problems of progress and underdetermination that plague the realist project. As a result, I show that we should reject the notion of truth and falsity in metaphysics, and instead opt for metaphysical theories that capture the understanding of each philosopher provided that such theories have explanatory power and are internally consistent. Then, the way to choose between several candidate theories would be by appealing to theoretical virtues that ground aesthetic beauty which of course vary according to taste. Accordingly, in the second chapter, I provide arguments that appeal to two such virtues (simplicity and utility) to argue for holistic antirealism, the thesis that a property exists mind-independently but cannot be conceptualized without reference to experience. Holistic antirealism is then used to show how we can use our perceptual experience of local presentness to derive global presentness and therefore overcome the argument from special relativity against the global present. In the third chapter, I show that we must rely on perceptual experience to infer the dynamicity of time. Afterwards, I argue that to account for this dynamicity in terms of the world as we perceive it we need an ontology of the world that includes objects and events and where time is the attraction and repulsion between events and objects that participate in them. Finally, in the fourth chapter, I argue that perceptual experience is the source of our belief in the asymmetry between the openness of the future and the fixity of the past. As a final synthesis, I combine the holistic antirealism from Chapter Two and the object-event ontology from Chapter Three to give an account that characterizes the indeterminacy of the future and the determinacy of the past.","language":"eng","citation":"ANTIREALISM AND TIME: AN ESSAY IN METHOD AND METAPHYSICS / Y.a.m. Freij ; tutor: G. Torrengo, J. Tallant ; coordinatore: F. Guala. Dipartimento di Filosofia Piero Martinetti, 2025 Feb 10. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13238.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1156533/2711685/phd_unimi_R13238.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/958996"},"title":"INTRA-TUMORAL INFILTRATION OF GZMKHIGH CD8+ T EFFECTOR MEMORY CELLS IS ASSOCIATED WITH POOR CLINICAL OUTCOME IN NON-METASTATIC COLORECTAL CANCER.","internalauthor":"TIBERTI, SILVIA","type":"Tesi di dottorato","year":"2023","abstract":"As with most solid tumor malignancies, CRC possess more than one major histological subtype that likely generate disparate immune responses. The heterogeneity in the immune cell response to CRC highlights the need to develop novel immune diagnostics that could predict the risk of disease relapse and devise a secondary strategy to address that risk. The purpose of this study was to prospectively provide a clear description of the patient-specific immune landscape present in CRC to target the dominant immune suppressive factors within a given tumor that may improve response rates while ushering in the age of personalized therapies for cancer patients. We described a functional interplay between neutrophils and CD8+ T cells that impacts on tumor immune escape and relapse. Specifically, we showed that tumor infiltrating neutrophils expressing high levels of CD15 interact with CD8+ T effector memory cells skewing them to produce GZMK, associated with tumor progression in CRC patients. Our fundings identify a unique immune signature, which might inform therapeutic decision making, possibly leading to new immunotherapeutic targets.","language":"eng","citation":"INTRA-TUMORAL INFILTRATION OF GZMKHIGH CD8+ T EFFECTOR MEMORY CELLS IS ASSOCIATED WITH POOR CLINICAL OUTCOME IN NON-METASTATIC COLORECTAL CANCER / S. Tiberti ; internal advisor: S. Casola ; external advisor: S. Sdelci ; tutor: T. Manzo ; co-tutor: S. Santaguida ; phd coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2023 Apr 13. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12401.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/958996/2161108/phd_unimi_R12401.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1210721"},"title":"DUAL TARGETING OF RFAP AND FIMH IMPAIRS AIEC INTRACELLULAR SURVIVAL AND LIMITS OMV-DEPENDENT IL-23/PTH17 AXIS ACTIVATION, OFFERING A NOVEL THERAPEUTIC STRATEGY FOR CROHN¿S DISEASE","internalauthor":"DUSETTI, IRENE","type":"Tesi di dottorato","year":"2026","abstract":"Crohn’s disease (CD) is a chronic inflammatory disorder characterized by an aberrant inflammatory response against a dysbiotic gut microbiota. Especially, intestinal enrichment of the adherent-invasive Escherichia coli strain (AIEC), together with a dysregulated activation of the IL-23/pTh17 axis, is a distinctive feature of CD. In this context, current therapies primarily suppress the exaggerated inflammation without directly targeting AIEC, and the only AIEC-based approach under investigation is the inhibition of FimH, which mediates adhesion to intestinal epithelial cells. However, whether FimH inhibitors also affect other key steps of AIEC-host interaction, such as intramacrophagic replication, the associated excessive TNF-α secretion, and especially the marked activation of the IL-23/pTh17 axis, remains unknown. Therefore, here we aimed to characterize the pleiotropic activity of specific AIEC virulence determinants to assess whether their simultaneous targeting can prevent the cascade of pathogenic events leading to chronic inflammation. To this aim, we generated and functionally characterized single and double mutants in the LF82 strain, focusing on ΔfimH, ΔrfaP, and ΔybaT for their specific inhibitory effect on distinct host-AIEC pathogenic interactions.  Our functional analysis revealed that the ΔrfaPΔfimH double mutant strongly impairs intracellular persistence within macrophages and dendritic cells and, most notably, completely abolished intracellular survival within intestinal epithelial cells. Consistently, the associated pro-inflammatory response — including IL-8, CCL20, TNF-α, and the pTh17-polarizing cytokine IL-23/IL-1β, was markedly reduced in response to ΔrfaPΔfimH double mutant strain. Remarkably, we demonstrated for the first time that OMVs released by LF82 are sufficient to drive the pathogenic skewing of protective cTh17 cells into pathogenic IFN-γ-producing Th17 cells, thereby revealing a previously unrecognized mechanism through which AIEC promotes mucosal immune dysregulation. Strikingly, OMVs derived from the ΔrfaPΔfimH double mutant displayed a reduced ability to induce pTh17 generation.  In conclusion, our study strongly proves that dual targeting of RfaP and FimH represents a novel and highly promising therapeutic strategy to simultaneously impair key mechanisms of AIEC virulence and to attenuate the exaggerated inflammatory response that characterizes CD patients.","language":"eng","citation":"DUAL TARGETING OF RFAP AND FIMH IMPAIRS AIEC INTRACELLULAR SURVIVAL AND LIMITS OMV-DEPENDENT IL-23/PTH17 AXIS ACTIVATION, OFFERING A NOVEL THERAPEUTIC STRATEGY FOR CROHN'S DISEASE / I. Dusetti ; tutor: P. Landini ;  co-tutor: M. Paroni ;  coordinatore: S. Ricagno. - Dipartimento di Bioscienze, Università degli studi di Milano. Dipartimento di Bioscienze, 2026 Jan 26. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13912.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 26-LUG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1196636"},"title":"HUMAN RIGHTS-BASED CLIMATE LITIGATION AND THE ROLE OF UNGA RESOLUTION 76/300: TOWARDS A RIGHT TO A HEALTHY ENVIRONMENT UNDER INTERNATIONAL LAW?","internalauthor":"MINGOZZI, PIERRE CLEMENT","type":"Tesi di dottorato","year":"2025","abstract":"This dissertation explores the potential and challenges of employing international  human rights law to address the impacts of climate change, with a specific focus on the emerging right to a healthy environment under international law. It begins by tracing the gradual ‘greening’ of established human rights, such as the rights to life, health, and private and family life, through environmental litigation. Indeed, over time these rights have been increasingly interpreted to encompass environmental dimensions, enabling individuals and communities to seek redress for harms caused by environmental degradation, including those linked to climate change. This development reflects a broader ‘rights turn’ in climate litigation. This shift is expected to gain renewed momentum following the recognition of the right to a healthy environment by the United Nations General Assembly in Resolution 76/300 (2022). Therefore, the research critically examines whether this right has acquired meaningful legal status under international law, whether as a customary norm, a general principle, or an interpretative standard, and assesses its practical relevance in ongoing and emerging climate-related litigation before international courts and judicial or quasi-judicial bodies. Drawing on a wide range of  sources, including treaty law, jurisprudence, state practice, and soft law instruments, the thesis investigates how (and whether) this right is being invoked, interpreted, and operationalized across legal systems. While the strategic use of human rights frameworks, particularly the right to a healthy environment, offers new avenues for climate accountability, the research also identifies significant conceptual and procedural limitations. These include issues of justiciability, causation, legal standing, and the relationship between environmental and human rights obligations. The findings suggest that although international adjudicatory bodies have become increasingly receptive to environmental claims, the normative clarity and enforceability of the right to a healthy environment remain contested.","language":"eng","citation":"HUMAN RIGHTS-BASED CLIMATE LITIGATION AND THE ROLE OF UNGA RESOLUTION 76/300: TOWARDS A RIGHT TO A HEALTHY ENVIRONMENT UNDER INTERNATIONAL LAW? / P.c. Mingozzi ; Tutor. G. Adinolfi & E. Truilhé. Dipartimento di Studi Internazionali, Giuridici e Storico - Politici, 2025 Dec 12. 37. ciclo","filename":"phd_unimi_R13227.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 19-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/838700"},"title":"MOLECULAR CHARACTERIZATION OF GENES INVOLVED IN THE PRESENCE OF ANTHOCYANINS IN EGGPLANT (S. MELONGENA L.)","internalauthor":"FLORIO, FRANCESCO ELIA","type":"Tesi di dottorato","year":"2021","abstract":"Eggplant (Solanum melongena L.) is a berry-producing vegetable belonging to the large Solanaceae family. Eggplant berries are rich in important secondary metabolites like phenolic compounds (chlorogenic acid in the flesh and anthocyanins in the peel) and flavonols, two classes of antioxidant molecules with suggested health-promoting effects in humans. Anthocyanins pathway is one of most investigated and well characterized pathway among the higher plants. However, the information available for eggplant anthocyanins pathway are rather limited whit the respect to other Solanaceous crop like tomato (S. lycopersicum ) and potato (S. tuberosum). As part of this Ph.D. project, focusing on the highly conserved MYB-bHLH-WD (MBW) transcriptional complex model, which is pivotal in the transcriptional regulation of many anthocyanins related genes, the eggplant MBW were identified and functional characterized. Moreover, a regulatory R3 MYB type repressor (Smel- MYBL1), never reported before, was identified and characterized as well. Fruit peel pigmentation of different varieties of eggplant can vary widely from white to green to purple and violet; in particular, the black/dark purple and dark/light violet peel pigmentations reflect the alternative presence of two different anthocyanins: delfinidine-3-rutinoside (D3R) and delphinidin-3-[p-coumaroylrutinoside]-5- glucoside (nasunin), respectively. The conversion of D3R into nasunin is still an unelucidated part of the anthocyanin pathway in eggplant. The genes responsible of this metabolic step, the SmAAT was identified and functionally characterized through complementation in genotypes carrying the recessive mutant aat allele. Moreover, another genes, Sm5GT1, putatively involved in this step were identified, but more efforts are needed to characterize it. Furthermore, the ripening process is a pivotal aspect which affects the anthocyanins content. The eggplant ripening is commonly divided into three stages: unripe (stage A), commercially ripen (stage B) and physiologically ripen (stage C). Anthocyanin pigments are accumulated to the highest levels at the unripe fruit stage and their levels dramatically decreased as ripening progresses (Mennella et al., 2012), although the total phenolic content remained quite stable (Esteban et al., 1992) leading to the hypothesis that some other still undetermined phenolics are produced during this stage instead of anthocyanins. Focusing on these evidences a list of phenols never reported before in the eggplant peel were identified by HPLC-DAD- UV-VIS analysis. The identification of those new compounds and the recent availability of eggplant genetic resources have allowed the identification of the genes putatively involved in the ripening metabolism of the eggplant berries. The characterization by RT-qPCR three genes were carried out: SmFLS and a couple of SmGT. This genes are now the best candidate for future experiments aimed at irrefutably proving this function.","language":"eng","citation":"MOLECULAR CHARACTERIZATION OF GENES INVOLVED IN THE PRESENCE OF ANTHOCYANINS IN EGGPLANT (S. MELONGENA L.) / F.e. Florio ; supervisor: A. Ferrante ; co-supervisor: G. Rotino ; coordinator: D. Bassi. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2021 Apr 20. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12119.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/838700/1785569/phd_unimi_R12119.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/899650"},"title":"DO CLUSTER BASED INDUSTRIAL PARK CATALYSE DEVELOPMENTAL SPILLOVERS? EVIDENCES FROM ETHIOPIA'S EXPERIENCE","internalauthor":"MAMADE, GAMACHU FUFA","type":"Tesi di dottorato","year":"2022","abstract":"Cluster based industrialization programme where specialized resident firms share specific location known for its contribution increasing productivity through integrated services address organizational red tape. This programme is well known in most industrial economies of which industrial district is of the successful modalities in Europe including (Italy, Germany, Britain) and other  OECD countries. Based on such successful experiences of industrial economies in the nineteenth century, with specialized adjustments including ad hoc policies; cluster-based industrialization programme or special economic zones implemented in most South-east Asian countries starting from 21st century. This thesis aims to investigate developmental impact of industrial park programme, barriers coexisting and how it affects outcomes of the initiative in low-income country, using Ethiopia as a case study. The study offers empirical findings based on mixed methods employed (comparative case study & survey), utilized both primary and secondary data sources including; interviews, questionnaire, observation and secondary sources (document analysis). Over  the past five or six decades there is an increasing importance of industrial park development as strategic instrument for local economic development especially in the context of many developing countries and massive proliferation experienced across the world. Industrial park is considered as a policy instrument alleviate structural constraints pertaining to institutional deficiencies, social barriers, political problems, poor economic and technological environment and other binding constraints of industrialization sector. Being a development strategy to foster local economic development it often implemented by low income countries or those with low comparative advantage with the presumption they are precursors of technology and innovation center. In the condition of well management and effective implementation, economic zones in general and industrial park in particular would serve as instrument spur local industrialization agenda, catalyse developmental spillovers on the local economy. Yet virtually little is known about development trajectory of Ethiopia’s industrial park development and its practical impact in the context of latecomer to the initiative. This paper aims to address this gap in the literature based on compelling data from different dimensions including IP program issues, IP characteristics, contextual or mediating factors at both national and regional/local level. Ethiopia aspires to be manufacturing hub of  Africa and desires to attract large number of FDI. Although it is daunting to put clear picture of industrial park impact in the long run because the initiative is more of process. The present study stipulated that the program created significant number of direct employments in the local labour market which is amongst the major of its many connections with local economic development, it  falls short of meeting desired goals. The paper finds that the program has shown positive take-off contributed more in creating significant number of jobs and nothing more could be said about their impact on the country’s industrialization agenda provided that the program is in nascent stage of development. Apparently, as in the case of other Sub-Saharan African countries (SSA)  engagement of resident firms in country’s industrial parks delimited their main tasks to simple assembly/processing operations given the economic zones tend to adopt more of traditional export processing zones. In such modality of operation, the likelihood of skill and technology transfer seldom happen but mostly non-existent. The initiative failed to form integration with local economy as it has been pronounced in the policy framework. Along with enclave model Ethiopia’s industrial park program mainly inspired by preferential trade regimes like AGOA and EBA, which makes the initiative myopic and hard to ensure sustainability. This makes the initiative less reliable due to the fact that success factors of industrial park subjected to capacity to invest and capitalize comparative advantage of local economy in time as well as in space than fancy policy or mere physical presence of parks. The finding revealed that similar to other zones in most developing countries, Ethiopia perhaps presents a serious practical challenge to both public IPs and private zone alike.  This warranty strategic intervention in order to resolve binding constraints for local manufacturing sectors. Indicative of loss of focus in the private industrial park should be well incorporated in the body of documents designed for supervision and regulatory system in the upcoming private zones in Ethiopia. The results regarding labour conditions including; wage, standards, rights of workers, health & safety, unionization, hours worked showed that there is variation across industrial park as well as sectors of production. In Ethiopia, unlike most zone developing countries, the same labour law proclamation elsewhere in the national economy apply to industrial parks. Although the laws to control non-conducive working conditions and legal breaches maintained, authorities turn blind eyes mainly in fear of losing investors by improving labour standards. The labour composition is dominated by young, less educated, unskilled female workers at low pay of up to 650 ETB/month which is less than 1US$ per day. This situation exacerbated by non-existing trade unions, lack of resources and staff for the inspectorate department and government’s lack of will in reinforcing the labour law. To put further on this, poor working conditions in the industrial parks attributed to incapable and failures in domestic labour institutions. However, major limitation of this study is it lacks detail synthesis on industrial parks labour conditions and same economic activities in  the outside environment in comparative perspective without which it is difficult to make generalization. The study concludes that although there exist progressions along identified performance indicators in Ethiopia’s industrial parks, the prospect largely depend on improvement of; policy environment, shortfalls in the areas of implementation, shift from myopic to long term objectives and strong political commitment as experienced by most successful countries in programme operation.","language":"eng","citation":"DO CLUSTER BASED INDUSTRIAL PARK CATALYSE DEVELOPMENTAL SPILLOVERS? EVIDENCES FROM ETHIOPIA'S EXPERIENCE / G.f. Mamade ; supervisors: S. Bertolini, E. Dansero ; program director: G.Ballarino. Università degli Studi di Milano, 2022 Jan 17. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12100.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/899650/1959377/phd_unimi_R12100.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/956861"},"title":"SHELF-LIFE EFFECTS AS A STRATEGIC TOOL FOR THE SUSTAINABLE ECO-DESIGN OF FOOD PACKAGING SOLUTIONS: A MATTER OF LIFE CYCLE THINKING","internalauthor":"FRIGERIO, VALERIA","type":"Tesi di dottorato","year":"2023","abstract":"Food packaging is a key player in defining the overall sustainability of a food-packaging system. Long seen as an additional environmental burden, food packaging has recently been redeemed as reducing potential food losses and waste. Eco-designed packaging solutions could significantly reduce the overall environmental impacts of food systems while guaranteeing food protection.  This work aimed at investigating the role of primary shelf-life, depending on the technical characteristics of packaging solutions, on the sustainability definition of food-packaging systems. The development and testing of a generalised framework allow to perform simplified packaging eco-design choices based on accessible information (e.g., technical sheet information) while considering shelf-life environmental effect. As being one of the most popular technologies for extending shelf-life, Modified Atmosphere Packaging (MAP) was the focus of this research. The case of hard ripened cheese packed in MAP conditions was used to exemplify and demonstrate the key findings of this work. To this purpose, existing mathematical models for gas transfer prediction, thus for primary shelf-life prediction, will be coupled with Life Cycle Assessment (LCA) methodology.   Great attention will be given to shelf-life estimation and its inclusion into LCA studies from a methodological point of view. Shelf-life effects on food systems’ sustainability will be first investigated. Gas transfer model for shelf-life prediction will be implemented and validated thanks to simulation approach results. This, to provide a simplified way of predicting shelf-life with accessible information by exploiting known physical laws of gases’ mass transfer (i.e., Henry and Fick’s laws). In this context, a simplified testing approach for CO2 solubility into solid food matrices (not respiring) was developed and validated. Shelf-life inclusion into LCA methodology was studied from a methodological point of view. Two different approaches, and relative Functional Units, were compared and described to help harmonisation in the field. Existing approaches for coupling shelf-life to probability of food waste were implemented in this work. Eventually, shelf-life prediction tool and studied LCA methodologies will be coupled, offering an innovative eco-design framework all based on simple and accessible information.  This work increased the knowledge of shelf-life environmental effect on the overall sustainability of food-packaging systems. It offered an innovative framework for food packaging eco-design based on accessible technical information. This approach, based on modelling, could pave the way to a new definition of packaging sustainability and offer an innovative tool for sustainable strategic choices within the food packaging field.","language":"eng","citation":"SHELF-LIFE EFFECTS AS A STRATEGIC TOOL FOR THE SUSTAINABLE ECO-DESIGN OF FOOD PACKAGING SOLUTIONS: A MATTER OF LIFE CYCLE THINKING / V. Frigerio ; advisor: S. Limbo ; coadvisor: R. Guidetti ; phd dean: D. Mora. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2023. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12729.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/956861/2152387/phd_unimi_R12729.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1021190"},"title":"USE OF MULTIPLE ANALYTIC APPROACHES TO IDENTIFY NEW MARKERS/RISK FACTORS FOR CARDIOVASCULAR DISEASES AND EVALUATE THEIR ROLE AS POSSIBLE PHARMACOLOGICAL TARGETS","internalauthor":"XIE, SINING","type":"Tesi di dottorato","year":"2024","abstract":"Atherosclerotic cardiovascular disease (ASCVD) is one of the leading causes of morbidity and mortality worldwide. Elevated levels of low-density lipoprotein cholesterol (LDL-C), one of the most closely related markers of ASCVD, have persisted as a major modifiable risk factor. Although several therapeutic options are available to properly address higher LDL-C levels, many patients are still at risk probably due to the presence of other risk factors impacting on cardiovascular disease even when LDL-C is well controlled. Large epidemiological studies, Mendelian randomized studies, and genome-wide association studies confirmed that elevated lipoprotein(a) [Lp(a)] concentration is an independent risk factor for cardiovascular diseases. However, no approved therapies for patients with elevated Lp(a) levels are available yet. In addition, ASCVD is an inflammation-based disease. Although Mendelian randomization study did not show a causal relationship between C-reactive protein (CRP) and ASCVD, several randomized controlled trials (RCTs) illustrated that patients achieved both lower LDL-C levels and CRP levels could get better clinical outcomes.   The main objectives of the present thesis are: 1) assessing the risk of major coronary events (MCEs) among individuals with different Lp(a) or CRP levels, and the joint risk related to both, and to investigate if these results could be influenced by current lipid-lowering therapies (LLTs) and LDL-C levels; 2) evaluating the effect of several LLTs on Lp(a) levels and whether there were differences among patients with various baseline Lp(a) levels; 3) evaluating the effect of LLTs on CRP levels, and whether this effect is associated with the change of LDL-C or triglyceride (TG) concentration.  In this thesis, we first summarized the traditional cardiovascular risk factors, current lipid-lowering strategies, and potential residual risk factors. Then, to address the first aim several cross-sectional analyses were conducted based on the data from the UK Biobank, a prospective cohort study with deep genetic, physical, and health data, collected on about 500,000 volunteer participants recruited throughout the UK. The access to this largescale biomedical database has been fundamental to carried out the analyses presented in the first part of this thesis, which have provided key evidence to improve our knowledge about cardiovascular disease. We found a stepwise increased risk of MCEs related to elevated Lp(a) and CRP levels, regardless of LDL-C levels at baseline. Additionally, patients with both high Lp(a) and high CRP (median 123.82 nmol/L and 3.84 mg/L, respectively) levels experienced more than doubled risk compared to patients with low Lp(a) and low CRP (median 5.1 nmol/L and 0.49 mg/L, respectively) concentration. Finally, PubMed, Web of Science, EMBASE, Cochrane Library, and ClinicalTrial.gov were searched to collect the data for two comprehensive meta-analyses useful to address the second and the third aim, respectively. Pooled estimates were assessed by fixed-effect or random-effects model. Between-study heterogeneity was tested and measured by Cochrane’s Q test and I2 statistics. Overall, 69,859 subjects from 98 RCTs and 171,668 subjects from 53 RCTs were included in our meta-analyses on Lp(a) and CRP concentration, respectively. We discovered that among LLTs, PCSK9i (-6.41 mg/dL, 95%CI [-7.57 to -5.24]) and CETPi (-6.60 mg/dL, 95%CI [-9.26 to -3.95]) decreased Lp(a) levels. On the other hand, statins (-0.65 mg/L, 95%CI [-0.87 to -0.43]), bempedoic acid (-0.43 mg/L, 95%CI [-0.67 to -0.20]), ezetimibe (-0.28 mg/L, 95%CI [-0.48 to -0.08]), and omega3FAs (-0.27 mg/L, 95%CI [-0.52 to -0.01]) reduced serum CRP concentration, independently of LDL-C or TG changes. These reductions seem to be greater in some specific groups of patients, mainly those with high Lp(a) or CRP levels at baseline.  Our findings confirmed that Lp(a) and CRP are both associated with the risk of ASCVD. Although we found some drugs had a significant lowering effect on these two markers, current LLTs can only provide little benefits. Thus, optimal therapeutic strategies for cardiovascular prevention should: 1) minimize LDL-C, according to the individual goal, based on CV risk class; 2) take into account residual risk (controlling Lp(a) and CRP concentration, if necessary); 3) consider the opportunity of a personalized LLT, e.g. prioritizing PCSK9i for patients with slightly higher Lp(a) levels and statins or bempedoic acid for individuals with slightly elevated CRP levels, and pursuing a more aggressive LDL-C reduction, while waiting for specific targeted therapies, in the attempt of reducing residual cardiovascular risk.","language":"eng","citation":"USE OF MULTIPLE ANALYTIC APPROACHES TO IDENTIFY NEW MARKERS/RISK FACTORS FOR CARDIOVASCULAR DISEASES AND EVALUATE THEIR ROLE AS POSSIBLE PHARMACOLOGICAL TARGETS / S. Xie ; tutor: M. Casula ; co-tutor: S. Carugo ; PhD coordinator: G. D. Norata. Università degli Studi di Milano, 2024 Jan 18. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12843.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1021190/2336508/phd_unimi_R12843.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/924482"},"title":"EVALUATION OF DIFFERENT ABATEMENT SYSTEMS FOR EMISSIONS OF AMMONIA, PM AND ODOUR IN INTENSIVE LIVESTOCK FARMS","internalauthor":"CONTI, CECILIA","type":"Tesi di dottorato","year":"2022","abstract":"Agriculture in the 21st century faces multiple challenges: it has to produce more food to feed a growing population with a smaller rural labour force, adopt and learn new technologies, satisfy consumers’ changing tastes and expectations, and at the same time adopt more efficient and sustainable production methods to cope with climate change, soil erosion and biodiversity loss. Livestock contribution to greenhouse gases (GHG), ammonia (NH3), and odor emissions is relevant. Thus, the identification and adoption of mitigation strategies for intensive livestock farming is necessary, not only to reduce the environmental impact related to livestock production, but also to help solving the issue related to air pollution. Indeed, GHG, NH3 and odor emission other having a negative effect on the environment, represent a risk for human and animals’ health. Air treatment technologies have the double benefit of abating pollutants emissions and improving air quality inside the barns. Alternatively, considering several aspects i) that animal proteins place a heavy burden on our natural resources, ii) the world population and demanding consumers are rapidly increasing, iii) the amount of agricultural land is limited, there is an urgent need to find alternatives to conventional meat products. Terrestrial invertebrates farming represents an environmentally sustainable solution. Earthworms require less land and water, present lower GHG emissions and higher feed conversion efficiency, moreover they are rich in proteins and essential amino acids. The aim of this thesis was to evaluate different mitigation strategies to reduce GHG, NH3 and odor emissions deriving from intensive livestock farming, also taking in consideration their environmental impact. The Life Cycle Assessment (LCA) methodology was applied to quantify the environmental impact of the strategies proposed. In the first step, livestock contribution to air pollutants emissions was quantified. Agricultural NH3 emissions did not even reduce during lockdown periods imposed by Covid-19 pandemic. Thereafter, odor annoyance issue was deeply analysed. Finally, environmental benefits achievable by applying different solutions (i.e. air treatment technologies, manure additive, earthworms rearing) were assessed. The results in this thesis outlined that the adoption of mitigation strategies is fundamental and promising, but each one presents different abatement efficiency on air emissions. Thus, a combination of measures is often the best solution to control emissions, at the same time also an integrated approach combining different methods and techniques could represent the best solution to depict exhaustively the problem and define a good strategy for its management. In this regard, LCA helps to identify the most important contributors to the environmental impact.","language":"eng","citation":"EVALUATION OF DIFFERENT ABATEMENT SYSTEMS FOR EMISSIONS OF AMMONIA, PM AND ODOUR IN INTENSIVE LIVESTOCK FARMS / C. Conti ; tutor: J. Bacenetti ; co-tutor: M. Guarino. Dipartimento di Scienze e Politiche Ambientali, 2022 May 19. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12216.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/924482/2024939/phd_unimi_R12216.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1028875"},"title":"FROM BATCH TO FLOW: RETHINK THE WAY OF DOING CHEMISTRY","internalauthor":"BRUCOLI, JACOPO","type":"Tesi di dottorato","year":"2024","abstract":"In this thesis, the application of flow chemistry to overcome batch limitations in the process development of organic reactions was explored. Specifically, novel and challenging protocols for the synthesis of APIs were investigated, with the aim to develop alternative synthetic methodologies, and a special focus on improving   the efficiency, sustainability and industrial applicability of the new synthetic strategy.   The thesis is organized into four main chapters, a first introductive section to give a brief background on Flow chemistry basics, and three chapters on the research projects, organolithium chemistry, photochemistry, alkyl nitrite in α-keto nitrosation reaction.   The last section of every chapter is dedicated to the discussion of the result where on water organolithium addition to imines, Pd mediated cross coupling reactions, synthesis of benzoxaboroles, photochemical synthesis of tryptamines and a scale-up and tech transfer of a continuous production and use of an alkyl nitrite are presented.   In the first chapter, it is provided a general introduction to the concept of flow chemistry, explaining the main instruments and parameters, emphasizing the beneficial effects deriving from its use in organic synthesis in particular for safety aspects. A special attention is paid also to reactor modelling and design and the differences between PFR and CSTR.   In the second part, organolithium chemistry is briefly introduced and explored for the synthesis of useful API or intermediates like benzoxaboroles, amines and cross-coupling products. It is provided an overview of the current state of art for the appropriate class of chemistry methodologies that were developed both from the batch and in continuo point of view.   In the third chapter, it is described a deoxygenative strategy for the Csp3-Csp2 cross-coupling reaction for the preparation of novel interesting tryptamine derivatives, by the use of photochemistry.  First, we examine the use of metallaphotoredox chemistry to perform cross coupling reaction, then the importance of tryptamine is discussed, pointing out current synthetic challenges and the absence of photochemical methodologies for this transformation.   In the fourth chapter, the use of alkyl nitrites as useful nitrosation agents in industry is described, pointing out the current limitation on the scale up and demonstrating the successful development of an in continuo process to sustain the pilot plant production batch of an α-keto nitrosation reaction.   Finally, after the Conclusion and the References, in the fifth chapter the experimental section, with all analytical data, is reported.   In this thesis, new flow chemistry protocols were developed to provide scalability and applicability at industrial level and to realize more efficient and sustainable synthetic strategies for the preparation of challenging organic molecules, with broad implications in the fields of chemistry and pharmaceuticals.","language":"eng","citation":"FROM BATCH TO FLOW: RETHINK THE WAY OF DOING CHEMISTRY / J. Brucoli ; tutor: M. Benaglia ; coordinator: R. M. Dominique. - Università degli Studi di Milano. Dipartimento di Chimica, 2024 Feb 26. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R13124.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1028875/2359925/phd_unimi_R13124.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/923651"},"title":"WHEN AESTHETICS MEETS ETHICS: THE SOUTH AFRICAN SHORT STORY IN ENGLISH, 1920-2010","internalauthor":"FOSSATI, MARTA","type":"Tesi di dottorato","year":"2022","abstract":"This thesis explores the development of the short-story genre in English in South Africa from the late 1920s to the present day. I intend to close read a corpus of short stories by eight South African writers (Rolfes and Herbert Dhlomo, Peter Abrahams, Can Themba, Alex La Guma, Mtutuzeli Matshoba, Ahmed Essop, and Zoë Wicomb) with particular focus on the dialogue between ethics and aesthetics performed by these texts vis-à-vis the evolution of South Africa’s socio-political situation (before, during, and after apartheid). Often considered a minor genre, the short story actually thrives in post-colonial contexts, like South Africa, where the writing and publishing conditions available to writers can be under a set of material constraints; the brevity of the short story, however, allows for swifter conditions of production and circulation than the ones required by the novel. Consequently, my analysis also focuses on the various publishing venues of these short stories, in particular local newspapers and little magazines, considered as pivotal spaces for the intersection between ethics and aesthetics, which often results in a cross-fertilization between journalism and the short story. Negotiating the different tensions of literature, politics, journalism, and commercial interests, the shifting contexts and editorial policies of newspapers and magazines represent particularly interesting case studies from which the unstable nature of the definition of the ‘literary’ emerges, which is never detached from a political dimension.  This study also seeks to expose the fictional and ideological nature of the ‘poetics of authenticity’ that frequently characterises the selected short stories, which display (and often play with) the conventions of realism to achieve a certain patina of authenticity. The poetics (and politics) of authenticity is, I believe, the most significant feature of the interdependence of ethics and aesthetics in the South African short stories in English analysed in this thesis. Between the late 1920s and the early 1980s – that is, before and during apartheid – claims to authenticity mark, albeit in different ways and through different fictional strategies, the selected short stories. This reflectionist trend, which is always a literary construct, responds to the ethical imperative of documenting the lives of the Black population under a segregationist regime, but it is also influenced by the available publishing venues (newspapers and magazines). As the South African short story in English progresses in its post-apartheid phase, essentialist, fixed notions such as ‘authenticity’ are exposed as a fictional construct by authors such as Zoë Wicomb. Ultimately, this study aims to foreground the impossibility of separating the literary (both the text and its materiality) from the political.","language":"eng","citation":"WHEN AESTHETICS MEETS ETHICS: THE SOUTH AFRICAN SHORT STORY IN ENGLISH, 1920-2010 / M. Fossati ; tutor: G. Iannaccaro ; co-tutor: A. Van Der Vlies ; coordinatore: M. Calvi. Dipartimento di Lingue, Letterature, Culture e Mediazioni, 2022 May 05. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12327.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/923651/2022661/phd_unimi_R12327.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1040037"},"title":"DECIPHERING AND EXPLOITING ANEUPLOIDY IN CANCER","internalauthor":"IPPOLITO, MARICA ROSARIA","type":"Tesi di dottorato","year":"2024","abstract":"Aneuploidy - a state of karyotype imbalance – arises from errors in the process of chromosome segregation and induces a multitude of cellular stresses that are mostly detrimental in untransformed cells. Importantly, aneuploidy is a pervasive feature of tumors, being present in the vast majority of both solid and blood cancers. In the first part of my PhD, I have been focusing on understanding how cancer cells can exploit aneuploidy-associated stresses for their survival and proliferation. My work sheds light on how cancer cells capitalize on aneuploidy-induced genome instability and associated gene copy-number changes caused by aneuploidy to withstand selective pressures, such as chemotherapy. The development of resistance to chemotherapeutic drugs appears to be influenced by the emergence of recurrent karyotypes, suggesting that gene dosage could contribute to chemoresistance. This establishes a direct correlation between aneuploidy-induced gene copy number alterations and chemoresistance, potentially explaining the failure of some chemotherapy treatments.  While aneuploidy is recognized as a characteristic of human cancer, the cellular processes that cells employ to manage the resulting stresses are not well understood. These processes may reveal vulnerabilities that could be exploited to target cancer cells. In the second part of my PhD, I generated and characterized several stable clones with varying degrees of chromosome imbalances. Through comprehensive genomic profiling of six isogenic clones via whole-exome and RNA sequencing, along with extensive CRISPR/Cas9 and drug screening, I explored their cellular dependency landscapes. In line with earlier findings, I observed increased DNA damage and p53 pathway activation in aneuploid cells. These cells also showed an increased DNA damage response (DDR), leading to greater resistance against further DNA damage. Notably, aneuploid cells had increased RAF/MEK/ERK pathway activity and were particularly sensitive to drugs targeting this pathway, especially those inhibiting CRAF. CRAF activity was also identified as a key factor in the resistance to DNA damage induction, with its inhibition increasing the sensitivity of aneuploid cells to DNA-damaging drugs.  Additionally, I observed that aneuploid cells had ramped up RNA synthesis and degradation, with a consequent increase in the activity of the nonsense-mediated decay (NMD) and microRNA-mediated mRNA silencing pathways, making them more vulnerable to disruptions in RNA degradation pathway. Importantly, the elevated dependency of aneuploid cells on the RAF/MEK/ERK pathway and intact RNA degradation pathways was not only confirmed in another isogenic aneuploid model but also a study of numerous human cancer cell lines, reinforcing their significance in cancer. In conclusion, my study serves as a comprehensive resource of genetically-matched, karyotypically stable cells in different states of aneuploidy and uncovers new, therapeutically relevant cellular dependencies in aneuploid cells.","language":"eng","citation":"DECIPHERING AND EXPLOITING ANEUPLOIDY IN CANCER / M.r. Ippolito ; tutor: S. Santaguida ; supervisori: S. Taylor, S. Minucci ; coordinatore: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2024 Apr 11. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12697_01.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1040037/2385259/phd_unimi_R12697_01.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1072869"},"title":"BIVALENT SOCIAL FREEDOM: A DEFENCE","internalauthor":"HUSEYNLI, ILKIN","type":"Tesi di dottorato","year":"2024","abstract":"When I am unable to drive due to a road blockade, there seems to be a morally relevant difference between a case in which the road is blocked by some workers (involved, say, in road works or a strike) and a case in which the road is blocked by a naturally occuring landslide. Many social and political philosophers have tried to capture this pre-theoretical judgment at a more abstract level through the formulation of a concept of freedom that refers specifically to the social or interpersonal relation of prevention, a concept they have attempted to refine in a way that will prove plausible, logically consistent, and fruitful as a building block in the construction of explicative and normative theories. To this end, they make a distinction between unfreedoms and mere inabilities: one is unfree when one’s inability is brought about by others (in the above example, the workers) but merely unable when one’s inability is brought about by oneself or nature (in the above example, the landslide). The nature of this distinction is open to interpretation, because saying that others brought about an inability might mean that the inability is causally or morally attributable to their conduct. The ‘causality view’ holds that I am unfree to drive because the workers are causally responsible for the blockade, whereas the ‘responsibility view’ holds that to determine whether I am unfree, we should ask whether the workers are morally responsible for the blockade. Each view has some strengths and some weaknesses. I aim to capture their strengths and avoid their weaknesses by suggesting a novel interpretation of moral responsibility as answerability, according to which we are answerable for all of our actions in virtue of the fact that our actions reflect our evaluative judgments. This interpretation allows for a plausible resolution of the disagreement between the causality and responsibility views.","language":"eng","citation":"BIVALENT SOCIAL FREEDOM: A DEFENCE / I. Huseynli ; co-supervisor: Ian Carter (University of Pavia), Nicola Riva (University of Milan) ; coordinator: Matteo Jessoula. - University of Milan, Milan, Italy. Università degli Studi di Milano, 2024 Jun 24. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12931.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1072869/2468675/phd_unimi_R12931.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/963059"},"title":"SUSTAINABLE PRODUCTION AND PHYSICO-CHEMICAL CHARACTERIZATION OF BIOSURFACTANTS FROM RENEWABLE RESOURCES","internalauthor":"SANGIORGIO, SARA","type":"Tesi di dottorato","year":"2023","abstract":"Cheese whey permeate (CWP) represents the main waste stream of the dairy industry. To produce 10 kg of cheese, around 100 kg of milk are used and roughly 90 kg of cheese whey (CW) are generated as a by-product. CW is still considered a valuable source of milk proteins, which are recovered by ultrafiltration, thus resulting in around 89 kg of CWP, but it contains a high concentration of lactose (up to 45-50 g/L). In the frame of applying a bio-based circular economy approach, this study aims at exploring the use of lactose and its hydrolysis products, glucose and galactose, as cheap and abundant substrates to produce value-added products, like sugar fatty acid esters (SFAEs). SFAEs are non-ionic surfactants that are characterized by excellent surface and interfacial tension reduction capability, low toxicity, and biodegradability. Moreover, the components of SFAEs can derive from natural resources, thus allowing the final product to be labeled as natural and bio-based as well. These features make them extremely promising for industrial applications as emulsifiers in the cosmetic and food sectors. Some SFAEs are currently produced at industrial level and they are available on the market (i.e. sorbitan and ethoxylated sorbitan esters, Span® and Tween®, as well as sucrose esters and alkyl polyglycosides). However, their current synthesis still rely on acid homogeneous catalysis and harsh reaction conditions, which result, in most cases, in complex mixtures of products with different degrees of esterification and different acylation positions, as well as mixtures of undesired by-products, deriving from side reactions, such as sugar dehydration/caramelization. In this thesis, alternative and more sustainable approaches have been described. In particular, enzymatic esterification, acetalization or Fischer glycosylation followed by solvent-free esterification, were investigated as sustainable alternatives to the currently established chemical schemes for the preparation of a small library of performant SFAEs, by exploring the use of challenging substrates, i.e., lactose and CWP. Moreover, the physico-chemical properties, such as interfacial tension features, W/O emulsification capability and the relative stability over time, of the prepared biosurfactants were evaluated to assess their potential application as bio-emulsifiers in the food, pharmaceutical and cosmetic industries.","language":"eng","citation":"SUSTAINABLE PRODUCTION AND PHYSICO-CHEMICAL CHARACTERIZATION OF BIOSURFACTANTS FROM RENEWABLE RESOURCES / S. Sangiorgio ; tutor: G. Speranza ; co-tutors: G. Cappelletti, D. Ubiali. Dipartimento di Chimica, 2023 Apr 17. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12512.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/963059/2173549/phd_unimi_R12512.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1206041"},"title":"MULTIPARAMETRIC SCORE FOR PREDICTION OF MYOCARDIAL FIBROSIS IN PATIENTS WITH MITRAL VALVE PROLAPSE: THE SCIMITAR TRIAL","internalauthor":"MANTEGAZZA, VALENTINA","type":"Tesi di dottorato","year":"2026","abstract":"Background. A subset of patients with mitral valve prolapse (MVP) —particularly those with Barlow’s  disease —may develop ventricular arrhythmias (VAs) and sudden cardiac death. Several imaging and clinical features have been proposed as arrhythmic risk factors, yet no validated stratification models exist.  Methods. The SCIMITAR study is an ongoing multicentre observational study enrolling adult patients  with MVP at transthoracic echocardiography (TTE), independent of mitral regurgitation grade. Both prospective and retrospective cohorts are included. Patients undergo clinical, electrocardiographic, 24hour Holter, TTE, and cardiac magnetic resonance (CMR). The primary aims are to develop a scoring model predictive of fibrosis on CMR, and to identify features associated with significant (≥mild) VAs on 24-hour Holter, namely ≥5% total premature ventricular complexes burden and/or ventricular tachycardias (VTs).  Results. To date, 162 patients have been enrolled. Late gadolinium enhancement (LGE) was  detected in 39.5% of patients, and significant VAs in 30.2%, while severe VAs (non-sustained VTs  with a heart rate >180 bpm or sustained VT) occurred in 3.7%. LGE-positive patients demonstrated  a higher prevalence of prior VAs ablation, true mitral annular disjunction (MAD) at TTE (31.3% vs.  15.5%, p=0.017), and more than moderate (non-sustained VTs with a heart rate of 120-179 bpm)  VAs (21.9% vs. 10.2%, p=0.041) compared with LGE-negative individuals. Demographic and clinical features showed limited predictive value. No clinically significant difference was documented between patients showing significant VAs compared to those without significant VAs. Conversely, associations were detected between ≥moderate VAs and leaflet thickening, true-MAD at TTE, left ventricular (LV) curling by CMR and LGE, consistently with previously described arrhythmogenic mechanisms.  Conclusions. Preliminary findings highlight the possible interplay of MAD, LV mechanics, and myocardial fibrosis in the arrhythmogenic profile of MVP. Although severe VAs are infrequent, multimodality imaging and multiparametric clinical approach appear essential for individualized risk stratification.","language":"eng","citation":"MULTIPARAMETRIC SCORE FOR PREDICTION OF MYOCARDIAL FIBROSIS IN PATIENTS WITH MITRAL VALVE PROLAPSE: THE SCIMITAR TRIAL / V. Mantegazza ; tutor: C. Sforza ; co-tutor:  G. Pontone ; coordinatore: M. S.Clerici. Dipartimento di Scienze Biomediche per la Salute, 2026 Jan 15. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13735.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1206041/3217335/phd_unimi_R13735.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1246256"},"title":"BEES, HONEY AND TERRITORY: A COMPLEX NETWORK OF INTERACTIONS BETWEEN LANDSCAPE, BEEKEEPING AND HONEY QUALITY","internalauthor":"HOLZER, ERICA","type":"Tesi di dottorato","year":"2026","abstract":"From ecological, economic and cultural perspectives, bees are among the most important groups of insects. This is due to their central role in pollination pro-cesses and the production of numerous hive products. The genus Apis and the tribe Meliponini, which includes stingless bees, are fundamental components of natural and agricultural systems. Through pollination, they contribute to main-taining plant biodiversity and ensuring stable food production worldwide.   However, bee populations have become increasingly exposed to multiple stressors in recent decades, including climate change, agricultural intensifica-tion, habitat loss, pollution, and the spread of pathogens. Many of these stress-ors are closely associated with human activities and beekeeping practices.  Against this backdrop, the thesis entitled “Bees, Honey and Territory: A Complex Network of Interactions between Landscape, Beekeeping and Honey Quality”, aims to analyse the relationships between bees, floral resources, land-scape structure, and honey quality. The research takes an integrated approach, combining ecological, sanitary, productive and territorial considerations.   The main objective is to understand how interactions between pollinating in-sects, environmental conditions and beekeeping management influence the composition of honey and the health of bee communities. Particular attention is given to the interactions between domesticated and wild pollinators, and to the role of territory in shaping the characteristics of apicultural products.  Bees of the genus Apis are among the most extensively studied pollinators worldwide, playing a crucial role in plant reproduction and agricultural produc-tivity. Apis mellifera in particular has undergone a long process of domestication and is now distributed across almost all continents, providing valuable ecologi-cal and economic pollination services. However, the growing number of man-aged colonies, particularly in urban and semi-natural environments, has given rise to new ecological concerns. These include the competition with wild polli-nators for floral resources and the transmission pathogens between managed and wild species, which could alter pollination networks and affect the stability of native communities.  Meanwhile, stingless bees (Meliponini) are among the most important polli-nator groups in tropical and subtropical regions. They play a vital role in the functioning of natural ecosystems and the pollination of numerous tropical crops. Despite their ecological and cultural importance, they face similar threats to honeybees, including habitat degradation, exposure to agrochemicals and transmission of pathogens. Furthermore, despite the long-standing tradition of meliponiculture in many tropical countries, scientific knowledge of the charac-teristics of stingless bee honeys is limited, particularly in highly biodiverse re-gions such as Bolivia. This highlights the need for integrated studies linking honey composition to ecological and territorial factors.  Within this framework, the thesis explores the intricate connections between pollinators, plant resources, landscape structure, and the characteristics of hon-ey.  Not only is honey a food product resulting from the biological activity of bees, it is also a reflection of the ecological context in which it is produced. By collecting nectar and pollen from various plant species across diverse land-scapes, bees combine floral resources on a territorial scale. This results in honeys with specific chemical, physical, and sensory characteristics that are closely linked to their botanical and geographical origin. Consequently, honey can be interpreted as a territorial product reflecting environmental conditions and bee-keeping practices.  A central theme of the thesis is the interaction between domesticated honey-bees and wild pollinators. The intensification of beekeeping and the global spread of Apis mellifera have altered pollination networks and the availability of floral resources. In certain contexts, high densities of managed colonies can re-duce the availability of resources for wild species and increase the likelihood of pathogens being transmitted across different taxa. These processes, often re-ferred to as competition and pathogen spillover, pose significant challenges to pollinator conservation. Therefore, understanding these dynamics is essential for developing sustainable management strategies that balance apicultural pro-duction with biodiversity protection.  Another key aspect of the research relates to the connection between honey and territory. Bees forage over spatially variable areas, collecting nectar and pol-len from a variety of plant species. The resulting honeys have distinctive chemi-cal compositions and sensory properties that reflect the botanical and geograph-ical characteristics of the area in which the bees foraged. By analysing pollen content and physicochemical parameters, foraging patterns can be reconstructed and honey can be interpreted as an ecological indicator of the landscape ex-plored by bees. In this sense, honey acts as a biological archive, capable of re-cording information about plant communities, environmental conditions, and land use.  The thesis also addresses the broader issues of pollinator conservation and the sustainability of beekeeping practices. Anthropogenic pressures, including climate change, habitat fragmentation, pesticide exposure and pathogen spread, are increasingly endangering bee populations worldwide. These stressors often act synergistically, compromising both managed colonies and wild pollinator communities.   Overall, the thesis takes a systemic approach to examining the relationships between bees, the landscape and honey production. It emphasises that the quali-ty and characteristics of honey are influenced by the intricate interplay of eco-logical processes, geographical features and management practices. By linking pollinator ecology, pathogen dynamics and honey characterisation, the research improves our understanding of the connections between biodiversity, apiculture and food quality.  By emphasising the role of territory in shaping honey characteristics and pol-linator health, the thesis supports the development of sustainable management practices that consider interactions between environmental conditions, beekeep-ing strategies, and product quality.","language":"eng","citation":"BEES, HONEY AND TERRITORY: A COMPLEX NETWORK OF INTERACTIONS BETWEEN LANDSCAPE, BEEKEEPING AND HONEY QUALITY / E. Holzer ; tutor: D. Lupi ; co-tutor: S. Savoldelli ; coordinatore: D. Mora. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2026 May 22. 38. ciclo","filename":"phd_unimi_R13859_2.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 18-NOV-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1047008"},"title":"AGGREGATION MECHANISMS OF TDP-43 PROTEIN IN RESPONSE TO STRESS IN AMYOTROPHIC LATERAL SCLEROSIS AND THERAPEUTIC APPROACHES","internalauthor":"CASIRAGHI, VALERIA","type":"Tesi di dottorato","year":"2024","abstract":"Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disorder affecting upper  and/or lower motor neurons for which no effective cure is available to date. The neuropathological hallmark of the disease, present in 97% of ALS cases, consists in TDP-  43 proteinopathy characterized by the accumulation of ubiquitinated and phosphorylated TAR DNA-binding protein 43 (TDP-43) in the cytoplasm, accompanied by the concomitant loss of TDP-43 splicing activity in the nucleus of affected neurons. The scarcity of experimental models of TDP-43 proteinopathy capable of recapitulating both gain and loss of TDP-43 function has hindered the discovery of novel therapeutic approaches for the treatment of ALS.  Aim of this work was therefore to generate human 2D and 3D in vitro models of TDP-43  proteinopathy, recapitulating TDP-43 cytoplasmic mislocalization and loss of nuclear  function, to be used for drug screening approaches.  We induced a chronic and mild oxidative insult by sodium arsenite (ARS) in human  neuroblastoma SK-N-BE cells and ALS patient-derived primary fibroblasts, induced  pluripotent stem cells (iPSCs)-motor neurons and brain organoids. As a readout of TDP-43 functionality, we tested its subcellular localization and its splicing activity towards the target genes UNC13A and POLDIP3. We demonstrated that chronic oxidative stress in these cellular models induced TDP-43 cytoplasmic mislocalization and defective TDP-43 splicing activity, thus recapitulating both TDP-43 proteinopathy features. Since we observed dysregulated gene expression of autophagy and senescence markers in ARS-treated human neuroblastoma cells, we preliminarily tested in this experimental model three drugs involved in promoting autophagy, namely rapamycin, lithium carbonate and metformin. Only rapamycin was capable of significantly rescuing ARS-induced loss of TDP-43 splicing activity on UNC13A. We therefore tested rapamycin in primary fibroblasts obtained from ALS patients with mutations in the C9orf72 gene, where we demonstrated that it reduced ARS-induced formation of phosphorylated TDP-43 (P-TDP-43) aggregates and stress granules (SGs). We also tested rapamycin in iPSCs-motor neurons from C9orf72-mutated patients, where we confirmed its efficacy in attenuating P-TDP-43 aggregates, SGs and loss of TDP-43 splicing activity on UNC13A induced by ARS treatment. We then employed a more complex 3D neuroglial model, namely iPSC-brain organoids, obtained from C9orf72 ALS patients and exposed to chronic ARS, where we observed that rapamycin rescued loss of TDP-43 splicing activity on UNC13A gene.  In conclusion, we generated and characterized different human cell models of TDP-43  proteinopathy in which rapamycin was able to rescue chronic oxidative stress-induced TDP-43 cytoplasmic mislocalization and defects in its splicing activity. We therefore propose that human SK-N-BE cells and ALS patient-derived 2D and 3D iPSC models chronically treated with ARS can be exploited as in vitro models to be used for future drug screening approaches.","language":"eng","citation":"AGGREGATION MECHANISMS OF TDP-43 PROTEIN IN RESPONSE TO STRESS IN AMYOTROPHIC LATERAL SCLEROSIS AND THERAPEUTIC APPROACHES / V. Casiraghi ; tutor: A. Ratti ; director: N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2024 May 09. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13108_2.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1047008/2402769/phd_unimi_R13108_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1022713"},"title":"IDENTITÀ RELIGIOSA E DIRITTI DI GENERE. L'IMPATTO DEGLI STATUTI PERSONALI SU BASE RELIGIOSA SULLE DONNE CRISTIANE IN CISGIORDANIA","internalauthor":"BULGAR, LARISA ANASTASIA","type":"Tesi di dottorato","year":"2024","abstract":"This doctoral thesis investigates the elements of discrimination that exist within the normative sources of Christian communities in the West Bank. The research analyses the impact of religiously based personal statutes on women in the local communities - in particular the Catholic, Orthodox and Protestant communities. The analysis of the complex legal context of the West Bank aims to highlight both the criticalities present in the positive law itself and the opportunities for change promoted 'from within' the Palestinian Christian communities, in particular the ambitious reform project that has affected the Palestinian Lutheran community in 2014.","language":"ita","citation":"IDENTITÀ RELIGIOSA E DIRITTI DI GENERE. L'IMPATTO DEGLI STATUTI PERSONALI SU BASE RELIGIOSA SULLE DONNE CRISTIANE IN CISGIORDANIA / L.a. Bulgar ; tutor: D. Milani, F. Poggi. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2023. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12851.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1022713/2341041/phd_unimi_R12851.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/913775"},"title":"PUBERTAL INDUCTION IN GIRLS WITH HYPOGONADISM: ESTROGEN REPLACEMENT THERAPY OUTCOMES AND OPTIMIZATION OF PROGESTERONE INTRODUCTION","internalauthor":"RODARI, GIULIA","type":"Tesi di dottorato","year":"2022","abstract":"Background: Pubertal induction in girls with hypogonadism through estrogen replacement therapy (ERT) aims at mimicking physiological puberty. To date, the best induction regimen, being physiological and effective at the same time, is still to be established. Moreover, available data in the literature show a poor uterine development at the end of the induction in more than a half hypogonadal patients: this probably represents one of the most important contributing factors for negative pregnancy outcomes of this specific population.  Aims: We analysed longitudinal data on pubertal induction in girls with hypogonadotropic hypogonadism or primary ovarian insufficiency (congenital, acquired, isolated or associated with multiple pituitary hormone deficiencies, either associated with Turner Syndrome or secondary to late effects of cancer treatment) in order to insight into auxological and uterine outcomes in the light of different underlying diagnosis and regimens used.  Methods: Due to the lack of licensed specific hormone preparations for pubertal induction, randomized-controlled trials are not feasible; thus, a multicentre clinical registry was created. Out of 106 hypogonadal girls (chronological age>10.9 years, Tanner stage≤2) who received ERT for pubertal induction, we considered 95 girls (median age 13.5 years) treated with transdermal (TD) 17β-estradiol patches for at least one year (median 3.3 years). Induction was started at a median dose of 0.14 mcg/kg/day TD 17β-estradiol, with a six-monthly increase.  Auxological, biochemical (estradiol levels) and radiological (pelvic US) data were collected at baseline and during follow-up. In 61/95 girls, progesterone was introduced after a median of 2.2 years. Induction was considered completed for the 49/95 patients who were started on combined oral contraceptive (COC) or progesterone plus at least 50 mcg/day or 1 mcg/kg/day of TD 17β-estradiol.  Results: At the end of induction, 90.0% patients had achieved Tanner stage IV and 41.0% Tanner stage V, the latter being associated with 17β-estradiol dose at progesterone introduction (P=0.034). Uterine longitudinal diameter (ULD) showed a gradual increase during ERT and a significant correlation with 17β-estradiol dosage (P<0.0001) at any point of induction. Nonetheless, the final ULD was>65 mm in only 17/45 (38%). At multiple regression analysis, a history of pelvic irradiation represented the major determinant of reduced final ULD (P=0.034). After correction for uterine irradiation, ULD was associated with 17β-estradiol dose at progesterone introduction (P=0.043). Final ULD was not significantly different from the one assed after COC introduction.  Conclusions: Our results show that therapeutic goals should be individualized and tailored to the underlying different diagnostic categories. Moreover, adolescence represents a critical window for uterine and breast development: indeed, given the evidence that progestins may hamper the subsequent changes in uterus volume or the achievement of the last Tanner stage, such therapy should be started only in the presence of a concomitant adequate ERT dose and an appropriate clinical response (uterus and breast development). At present, data collection is ongoing to confirm these assumptions on a larger scale and to identify the best induction regimen for each diagnostic category, with particular focus on the specific needs of childhood cancer survivors.","language":"eng","citation":"PUBERTAL INDUCTION IN GIRLS WITH HYPOGONADISM: ESTROGEN REPLACEMENT THERAPY OUTCOMES AND OPTIMIZATION OF PROGESTERONE INTRODUCTION / G. Rodari ; tutor: M. Arosio ; coordinator: M. Del Fabbro. Dipartimento di Scienze Cliniche e di Comunità, 2022 Mar 16. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12414.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/913775/1995333/phd_unimi_R12414.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1165855"},"title":"POLITICAL BELIEF SYSTEMS AS NETWORKS OF ATTITUDES: CONCEPTUALIZATIONS AND IMPLICATIONS","internalauthor":"BERTERO, ARTURO","type":"Tesi di dottorato","year":"2025","abstract":"This thesis advances the study of political belief systems by integrating network-based approaches from political science, sociology, and psychometrics. The research is grounded in Philip Converse’s seminal work, which conceptualized political belief systems as interconnected networks of attitudes. Despite the foundational importance of this framework, the field has been slow to empirically embrace this networked perspective. This thesis seeks to fill this gap by employing innovative methods to study belief systems. The research is centered around two core questions: First, how can political attitudes be conceptualized as a belief system? This involves refining the construct of a belief system and investigating the implications deriving from considering attitudes as parts of a broader cognitive structure. Second, how can existing network methodologies be integrated to study belief systems? By combining Belief Network Analysis (BNA), Correlational Class Analysis (CCA), and Pairwise Markov Random Fields (PMRFs)—previously isolated within distinct research domains—the thesis promotes cross-fertilization between disciplines. Chapter 2 presents the theoretical and methodological foundations of the belief system literature. Following Converse, I define political belief systems as networks of causally interacting political attitudes. I then discuss why the dominant view on measurement in social   sciences — the latent variable model— is limited in studying these constructs. Next, I motivate why network approaches can provide new insights in this field. Finally, I conduct a scoping review of all papers adopting these approaches to study socio-political attitudes. Chapters 3, 4, and 5 present three empirical analyses. Chapter 3 contributes to the growing literature on subjective inequality by applying CCA and Exploratory Graph Analysis (EGA) to survey data from the U.S. and the Netherlands (n = 2,501 and 1,618). These methods uncover distinct cognitive structures in both countries, with CCA identifying groups sharing similar   construals and EGA modeling these as belief systems. The analysis shows that the two belief systems of each country have distinct sociodemographic correlates and that attitudes toward inequality are more socially patterned in the U.S. Moreover, we show that belief systems might represent independent factors in determining different levels of support for redistribution. These findings highlight that ignoring the structural organization of attitudes limits our understanding of public opinions on inequality and redistributive policies. Chapter 4 extends the inquiry by examining how multiple political attitudes coalesce to form a political belief system. Using original data from the 2022 Italian general election, this chapter applies three network models to explore variations in belief system structures across different social groups. The results show that political interest increases the interdependence of attitudes, leading to tighter belief systems, while education levels do not have a similar effect. Interestingly, despite ideological differences, voters from Italy’s two main coalitions (left and right) organize their attitudes similarly, whereas Movimento 5 Stelle voters display   significantly different belief structures. This chapter addresses a significant gap by showing how distinct political groups organize their support for parties and issues. Chapter 5 introduces a novel approach to Propensity to Vote (PTV) data, conceptualizing PTV as behavioral intentions embedded in a belief system regarding vote choice. Rather than using traditional data reduction techniques, this chapter models PTV data as networks, where items are connected by weighted edges representing their unique shared variance. Using data from   the European Election Studies (1989–2019; 28 countries, n = 121,959), this chapter shows that national political contexts influence the structure of PTV networks. Higher levels of party institutionalization are linked to higher network connectivity, while higher affective polarization correlates with the negativity of PTV belief systems (i.e., the higher ratio of negative to positive edges). Furthermore, increased negativity in these networks is associated with higher voter turnout in both EU and national elections, suggesting that PTV belief systems might have important downstream effects on political behavior.   In conclusion, this thesis offers both conceptual and methodological dvancements in the study of political belief systems. By integrating network-based approaches, it provides new tools to understand how political attitudes are organized and how they vary across different sociopolitical contexts and sociodemographic segments. The findings underscore the importance of accounting for the structural features of belief systems and highlight the need for further research into their causal dynamics.","language":"eng","citation":"POLITICAL BELIEF SYSTEMS AS NETWORKS OF ATTITUDES: CONCEPTUALIZATIONS AND IMPLICATIONS / A. Bertero ; supervisor: C. Vezzoni, co-supervisor: R. Vacca ; co-authors (Chapter 3): G. Franetovic, J. J. B. Mijs  Co-Authors (Chapter 5): M. J. Brandt ; coordinator: M. Jessoula. Dipartimento di Scienze Sociali e Politiche, 2025 May 23. 37. ciclo","filename":"phd_unimi_R13221_04.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1165855/3075279/phd_unimi_R13221_04.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/946015"},"title":"MECHANOPROPERTIES, HETEROGENEITY AND CELL MIGRATION IN GLIOBLASTOMA","internalauthor":"CRESTANI, MICHELE","type":"Tesi di dottorato","year":"2022","abstract":"Glioblastomas (GBMs) are primary brain tumors endowed with inter- and intra-patient  heterogeneity and extreme di↵usivity. As heterogeneity is studied with genomic and  transcriptomic analysis, little is known on how it is reflected on cell migration, mechanoproperties  and motility modes. Generally, the tumor cells invade the brain moving on  brain vasculature or white matter tracks: Patient-Derived Xenograft (PDX) has been a  standard to reproduce them in order to study GBM invasion. However, PDX presents  many disadvantages, including time consumption, hard standardization, high cost and  ethical concerns.  The present PhD thesis report aims at summarizing the existing literature through  an historical journey that gradually walks the reader towards the state of the art in  the biological knowledge, therapeutic treatments, and bioengineering of GBM. It also  reports the results of this PhD work. They include novel bioengineering tools for  studying the mechanoproperties in GBM and the development of methods to dissect  their migration and motility modes. Finally, a stand-alone assay aims at fostering a  discussion on how the scientific mindset and science have evolved and are evolving to  drive technological innovation in nowadays’ world.  The main goal of this PhD work was to develop bioengineering tools to crack  mechanoproperties and GBM motility. Initially, by utilizing clones of patient-derived  GBM cells that were either highly proliferative or highly invasive, I co-studied their cellular  architecture, migratory, and biophysical properties. One of the milestones of this  PhD work consists in the link between that invasiveness and cellular fitness. The most  invasive cells were sti↵er, developed higher mechanical forces on the substrate, and  moved stochastically. The mechano-chemical-induced expression of the formin FMN1  supports the mechanical cohesion of the cytoskeleton and enhances cell’s mechanoproperties,  leading to a higher motility and invasive phenotype.  In order to scale up the motility screen to several GBM clones, I co-developed SP2G  (SPheroid SPreading on Grids), the live imaging of GBM spheroids spreading on grid  micropatterns mimicking the brain vasculature. To counteract the issues in PDX and  rapidly identify the most invasive sub-populations hidden in heterogeneous GBMs, we  developed an in vivo mimicry platform named SP2G (SPheroid SPreading on Grids).  Live imaging of tumor-derived spheroids spreading on gridded micro patterns imitating  the brain vasculature mimicked 3D motility features observed in brain or 3D matrices.  Using patient-derived samples coupled with a semi-automated ImageJ/Fiji macro suite,  SP2G easily characterized and sorted di↵erences in cell migration and motility modes  through a set of 6 parameters (area expansion, di↵usivity, boundary speed, collective  migration, directional persistence, hurdling). Moreover, SP2G exposed the hidden  intra-patient heterogeneity in cell motility that correlated molecularly to specific integrins.  Thus, SP2G is intended as a versatile and potentially pan-cancer workflow to  identify the invasive tumor sub-populations in patient-derived specimens. SP2G represents  an integrative tool, available as open-source Fiji macro suite, for therapeutic  evaluations at single patient level.","language":"eng","citation":"MECHANOPROPERTIES, HETEROGENEITY AND CELL MIGRATION IN GLIOBLASTOMA / M. Crestani ; tutor: N. Gauthier, P. Monzo. Dipartimento di Oncologia ed Emato-Oncologia, 2022 Dec 16. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12422.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/946015/2098782/phd_unimi_R12422.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/908406"},"title":"A ZEBRAFISH XENOGRAFT PLATFORM FOR SEMI-QUANTITATIVE ANALYSIS OF INDIVIDUAL STEPS OF THE METASTATIC CASCADE","internalauthor":"RUSCITTO, FEDERICA","type":"Tesi di dottorato","year":"2022","abstract":"Metastatic disease represents the main cause of most cancer-related deaths, yet this process remains one of the most enigmatic aspects of cancer biology. Metastatic progression includes multiple distinct phases, such as invasion, intra- and extravasation, seeding at distant sites, micro-metastasis formation and metastatic outgrowth. Only a deep understanding of each of these steps may offer novel targets to be exploited in a clinical setting. Emerging evidence suggests that metastatization is not a genetically selected trait, but the result of phenotypic adaptation to the unfavorable microenvironmental conditions which cancer cells are exposed to (e.g. hypoxia or low nutrients in the primary site or bloodstream). Functional genomic and differential expression screenings allowed to identify numerous potential metastasis genes, that need to be prioritized and validated with appropriate pre-clinical in vivo systems, ideally able to recapitulate and explore the entire metastatic cascade. Mouse models present several critical limitations, including the difficulty to visualize and quantify the metastatic phases, except in sophisticated experimental contexts. Therefore, I propose xenotransplantation of human cancer cells in zebrafish larvae as a system to evaluate primary tumor implantation and growth and to quantitatively dissect metastatic progression, with the purpose of mapping gene functions in the multistep cascade. First, I set up a robust protocol for subcutaneous and intravenous transplantation of fluorescently labeled cells in zebrafish larvae, using the metastatic breast cancer (BC) cell line MDA-MB-231 and non-tumorigenic MCF10A mammary cells as a control. MDA-MB-231 cells survive, proliferate and disseminate in the zebrafish host, developing tumors with conserved histological features and originating extravascular metastases in just 4 days. Using a zebrafish strain with fluorescent vasculature and visually following each fish by live microscopy, I optimized a set of analytical tools to quantitatively investigate incidence, numerosity, size and proliferative index of metastases, as well as measuring frequency of metastasis initiating cells and the severity of metastatic progression. Secondly, I challenged the zebrafish platform by transplanting MDA-MB-231 cells separately interfered for 6 genetic targets, previously identified in our laboratory, as potential novel mediators of BC metastasis. I successfully validated the contribution of 5 out of 6 of these genes in BC metastatization, attributing a specific role in the metastatic cascade for each of them. The identification and in vivo validation of this stage-specific determinants of metastasis offers potential new targets to halt metastatic disease, to be further explored in future pre-clinical and clinical studies, paving the way to novel and effective anti-metastatic therapeutic approaches.","language":"eng","citation":"A ZEBRAFISH XENOGRAFT PLATFORM FOR SEMI-QUANTITATIVE ANALYSIS OF INDIVIDUAL STEPS OF THE METASTATIC CASCADE / F. Ruscitto ; tutors: E. Migliaccio, G. Pelicci ; phd coordinator: S. Minucci. Università degli Studi di Milano, 2022 Mar 14. 33. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12085.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/908406/1982252/phd_unimi_R12085.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1123678"},"title":"THE ROLE OF MOLECULAR SIGNATURES IN COMPLICATED CELIAC DISEASE","internalauthor":"NANDI, NICOLETTA","type":"Tesi di dottorato","year":"2024","abstract":"Introduction: Refractory celiac disease (RCD) is defined as the persistence of symptoms and villous atrophy despite adherence to a gluten-free diet (GFD). Based on their molecular signatures, aberrant intraepithelial lymphocytes (aIELs) and monoclonal TCRγ rearrangement, RCD patients are differentiated into RCD type 1 (RCD1) and RCD type 2 (RCD2). This distinction is challenging but essential, as RCD2 is associated with enteropathy-associated lymphoma (EATL) and a poor prognosis, with no effective treatment currently available. Flow cytometry (f-cyt) is the diagnostic modality of choice in RCD to characterize IELs phenotypes, however limited data are available on the role of f-cyt in differentiating RCD from other chronic enteropathies. Moreover, altered molecular signatures at diagnosis have a prognostic significance, but there is limited evidence on their role in monitoring RCD patients during follow-up.  Aims: This study aimed at evaluating: 1. the presence of aIELs in a cohort of non-celiac, celiac and RCD patients by means of f-cyt of intestinal lymphocytes isolated from duodenal biopsies; 2. the association between clinical, endoscopic and biochemical characteristics of RCD patients and the presence of aIELs; 3. if f-cyt analysis of aIELs can accurately identify high-risk RCD patients in our cohort, either used alone or in combination with TCRγ rearrangement and duodenal atrophy; 4. the performance of γδ IELs in adult patients as a supporting tool and possible biomarker of celiac disease; 5. the treatment regimens for RCD and their clinical efficacy and effect on histopathologic and immunologic parameters.  Methods: This single-center retrospective study included all adult patients who underwent f-cyt analysis between 2015 and 2023 at Fondazione Ca’ Granda IRCCS Policlinico di Milano (Milan, Italy). Patients were categorized based on the presence of aIELs and clinical diagnoses: RCD, non-complicated CD, non-celiac enteropathies (NCE).  Clinical, endoscopic, histological data were analyzed to assess outcomes based on IELs phenotype at diagnosis and at follow-up. Treatment regimens for RCD and related outcomes were described and analyzed.  Results: A total of 119 patients (38 RCD, 59 non-complicated CD, 22 NCE; 77 females; mean age 53.6 ± 14.7 years) underwent 168 f-cyt. Follow-up f-cyt data were available for 32 RCD patients (19 RCD1, 13 RCD2). Aberrant phenotype (aIELS>20%) was significantly associated with malabsorption, higher mortality (HR 3.78, 95% CI 1.30-11.01, p 0.02), and increased EATL occurrence (HR 9.00, 95% CI 2.10-38.61, p < 0.01) in RCD2. When patients were stratified based on the combination of TCR clonality and aberrant phenotype, there was no significant difference in outcomes among those with one or both markers altered. The presence of aIELs>20% demonstrated good diagnostic performance for RCD2 (AUC 0.95, 95% CI 0.8791-1.000; p < 0.01); however, there were six false positive cases in our cohort. During follow-up, there was no significant difference in outcomes between patients who achieved normalization of aIELs or TCR clonality and those who did not. In RCD patients, the correlation between molecular response and both histological response (κ = 0.12) and clinical response (κ = 0.27) was poor.  Conclusion: Our study confirms the accuracy and prognostic role of aIELs in RCD, in line with previous research. Of note, an aberrant phenotype was observed in six NCEs (false positives RCD2), suggesting to further investigate f-cyt use in NCEs. Another novel finding from our study is that neither normalization of aIELs nor TCR clonality correlated well with histological or clinical outcomes, suggesting limited utility for these markers in assessing treatment response. Further studies are needed to confirm these findings, and to identify other possible biomarkers for monitoring disease progression.","language":"eng","citation":"THE ROLE OF MOLECULAR SIGNATURES IN COMPLICATED CELIAC DISEASE / N. Nandi ; relatore M. Vecchi ; correlatore: L. Elli. Università degli Studi di Milano, 2024 Dec 19. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13407.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1123678/2605844/phd_unimi_R13407.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1154236"},"title":"MARKER-BASED CRISPR SCREENINGS TO CHARACTERIZE KINASES CONTROLLING MACROPHAGE ACTIVATION","internalauthor":"PILERI, FRANCESCO","type":"Tesi di dottorato","year":"2025","abstract":"Identifying the complete set of components in cellular circuitries is a critical yet remarkably complex task in mammalian cells. Pathways involved in innate immune cell activation in response to various stimuli have been extensively characterized, but it remains unclear whether the full complement of regulators involved in signal transduction and the functional interplay among them have been identified.    Kinases form the backbone of most signal transduction cascades, and their pharmacological inhibition is a validated therapeutic strategy in cancer and autoimmune disorders. However, clinically approved kinase inhibitors target only a small fraction of the human kinome, and roughly one-third of kinases remain functionally uncharacterized (so-called dark kinases).    To systematically map kinase involvement in macrophage activation, in this project I employed a kinase-targeted CRISPR screen using stimulus-inducible molecules as functional readouts. Two independent screens were performed in bone marrow-derived macrophages (BMDMs) activated with either lipopolysaccharide (LPS) or interleukin 4 (IL-4), inducing distinct transcriptional and functional phenotypes.    The screens successfully identified known positive and negative regulators of the LPS and IL-4 pathways. In addition, both subunits of the TGFb receptor emerged as top-ranked negative regulators of RETNLA, the IL-4-inducible marker used in the screen. This unexpected finding prompted a deeper investigation into the role of TGFb signaling in modulating the IL-4-driven transcriptional program.    Transcriptomic and proteomic analyses revealed extensive cross-talk between IL-4 and TGFb signaling. While distinct subsets of IL-4- or TGFb-induced genes were reciprocally antagonized, others—including the canonical IL-4 target gene Arginase 1—were synergistically upregulated when both cytokines were present. Further mechanistic analyses, including acetylation profiling, chromatin accessibility assays, and ChIP-seq, pointed to a role for SMAD proteins in mediating these diverging effects. Additionally, metabolic profiling demonstrated a profound rewiring of arginine metabolism upon co-stimulation with IL-4 and TGFb.    These findings provide both a modular framework for dissecting kinase-driven signaling networks in immune cells and novel insights into the intricate interplay between IL-4 and TGFb signaling, with potential implications for immunological and metabolic regulation.","language":"eng","citation":"MARKER-BASED CRISPR SCREENINGS TO CHARACTERIZE KINASES CONTROLLING MACROPHAGE ACTIVATION / F. Pileri ; supervisor: G. Natoli ; added supervisors: F. Gualdrini, S. Polletti; internal advisor: B. Amati ; phd coordinator: D. Pasini. Dipartimento di Scienze della Salute, 2025 Apr 03. 36. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13148_1.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1154236/2713973/phd_unimi_R13148_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/950436"},"title":"CHARACTERIZATION AND ENGINEERING OF QUANTUM SYSTEMS","internalauthor":"CANDELORO, ALESSANDRO","type":"Tesi di dottorato","year":"2022","abstract":"Characterization and engineering are the basis for any technological development that aspires to exploit scientific breakthroughs and novel physical phenomena. Nowadays, it is impossible to ignore the exceptional results and developments that quantum mechanics, in combination with information theory, has developed in recent decades. This thesis is part of this line of research, with the scope of providing new results regarding quantum sensing and quantum control. Firstly, the need for quantum systems to work in well-established temperature regimes has brought much attention to quantum thermometry. Establishing new methods to probe temperatures of fragile systems is critical for the development of trustworthy quantum devices.  Decoherence is detrimental for many tasks, but the paradigm of quantum probing offers a new perspective on it. Instead of considering it as an undesirable phenomenon, we exploit this inherent fragility to probe features of the environment. Secondly, the ability to jointly estimate parameters is of pivotal importance in several fields, from imaging to gravitational wave detectors. The measurement of quantum systems has several limitations: these might come from an external noisy environment, or they might be quantum in nature, such as the impossibility of simultaneously measuring non-commutative observables. The fundamental understanding of quantum incompatibility in metrology can be impactful both at the foundational and applicative levels. We provide results regarding the quantification of measurement incompatibility, while also studying probe incompatibility, optimizing the initial preparation for the characterization of non-linearities in quantum optical devices. Finally, the last contribution of this PhD thesis consists of a new proposal for quantum search with continuous-time quantum walks. The proposed protocol combines three different fields of research, i.e. continuous measurement, feedback and quantum walks, to provide a novel method to perform quantum search protocols on graphs.","language":"eng","citation":"CHARACTERIZATION AND ENGINEERING OF QUANTUM SYSTEMS / A. Candeloro ; tutor: M. PARIS ; coordinatore: M. PARIS. Dipartimento di Fisica Aldo Pontremoli, 2022 Dec 22. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12750.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/950436/2117863/phd_unimi_R12750.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/829899"},"title":"L'ESECUZIONE DELLE SENTENZE DELLA CORTE EDU NEL SISTEMA PROCESSUALE AMMINISTRATIVO E LA CERTEZZA DEL DIRITTO.","internalauthor":"ROMANI, ELISABETTA","type":"Tesi di dottorato","year":"2021","abstract":"The phenomenon of multilevel jurisdictions has been progressively caused a decreasing of the effectiveness of the res judicata, thus overcoming the traditional view anchored to the principle of intangibility and, therefore, affecting the value of legal certainty.  From the dynamism of the protection of human rights, administrative procedural law could not be excluded, which had to deal with the problem concerning the enforcement of judgments of the European Court of Human Rights (hereinafter “ECtHR”), which modify, totally or partially, the statement declared on a national level by an Administrative Court or by the State Council. Therefore, a conflict between administrative national rulings and rulings of the ECtHR is reasonably possible, thanks to the subsidiarity principle and to the rule provided by Article no. 35 of the European Convention of Human Rights (hereinafter “ECHR”).   With particular reference to an administrative res judicata in violation of ECHR, the full enforcement of a ruling by the ECtHR is an issue characterized by absolute relevance, as also demonstrated by the recent rulings of the Italian Constitutional Court no. 123/2017 and no. 19/2018. Such constitutional question regards the execution of the decisum stated by the ECtHR in Mottola and others v. Italy, Staibano and others v. Italy and Guadagno v. Italy.   The administrative judges raised the issue of constitutionality, by means of which they suggested to introduce the reopening of domestic judicial proceeding, which cases in administrative procedural law are strictly defined and do not include the violation of ECHR and of ECtHR’s case-law.  The Constitutional Court ruled that the question concerning the constitutionality of Article no. 106 of Code of Administrative Procedure, raised with reference to Articles no. 117, § 1 of the Constitution and no. 46 of the ECHR, was unfounded. These decisions show that in the Italian legal system there is nowadays no legal remedy for the implementation of supranational law if there is a domestic res judicata, bringing out a gap in the enforcement.  In particular, the question that we have to answer is as follows: Which value should prevail? On the one hand, there is the protection of human rights and the tendency to enhance substantial justice, even overcoming legal instruments as the res judicata, and on the other there is the principle of legal certainty, which hide the will to defend the national sovereignty.   With particular reference to the administrative proceedings, such balancing is made even more complex by the need to ensure respect for the right of defense (Article no. 24 of the Italian Constitution) of third parties and for their legitimate expectations and reliance on legal certainty. In the ECtHR system, third parties do not have a right to participate in the judgment before ECtHR, despite the fact they have taken part in the domestic proceeding and, thus, they are influenced by the res judicata.  The main purpose of the paper is to demonstrate that all arguments of the Constitutional Court can be overcome and to propose possible solutions, which allow the domestic legal system to carry out what has been stated by the ECtHR and to protect its effectiveness. This will avoid that the intangibility of the res judicata could result in a violation of the fundamental rights and values protected by the ECHR system.","language":"ita","citation":"L'ESECUZIONE DELLE SENTENZE DELLA CORTE EDU NEL SISTEMA PROCESSUALE AMMINISTRATIVO E LA CERTEZZA DEL DIRITTO / E. Romani ; tutor: F. Goisis ; coordinator: U. D. Galetta. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2021 Apr 01. 33. ciclo, Anno Accademico 2020. [10.13130/romani-elisabetta_phd2021-04-01].","filename":"phd_unimi_R11967.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/829899/1753564/phd_unimi_R11967.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1163657"},"title":"MODELLING AND NUMERICAL STUDY OF MARBLE SULPHATION IN CULTURALE HERITAGE: A RANDOM PDE-ODE SYSTEM","internalauthor":"ARCECI, FRANCESCA","type":"Tesi di dottorato","year":"2025","abstract":"The final scope of this thesis is to investigate from a numerical point of view a new approach to the mathematical modelling of the degradation process in the context of Cultural Heritage,  focusing on the description of the marble sulphation chemical reaction.     Our contribution is a numerical analysis of a novel random model of the sulphation reaction on the half-line. Given a system of non-linear reaction-diffusion partial and ordinary differential equations (PDE-ODE) system,   already present in the literature and describing the penetration of sulphur dioxide through the pores of a calcium carbonate-based surface which reacts with a consequent formation of gypsum, a source of randomness has been introduced as a Dirichlet dynamical boundary condition, with the aim to better model the sulphur dioxide evolution in the air.     A direct observation of some recent sulphur dioxide time series recorded in Milan suggests that an appropriate model needs to incorporate a significant stochastic fluctuation component, boundedness and a mean-reverting behaviour. The novelty relies on the choice of a class of stochastic processes with such properties, known as Pearson diffusions, and which can be introduced as solutions of an It\\^o's stochastic differential equations (SDE). For completeness, positiveness, boundedness, and stability for the Pearson SDE, as well as its numerical scheme, known as Lamperti Sloping Smooth Truncation, based on the well-known Euler-Maruyama method, are discussed and implemented, respectively.     The entirely original results are presented in the second part of the thesis.   The numerical approximation of the overall system, combination of a non-linear reaction-diffusion PDE-ODE system with a stochastic boundary condition given by a specific Pearson process is investigated. Following recent theoretical results about the existence and uniqueness of a mild solution of this random system, a new numerical splitting scheme is proposed: an autonomous heat equation which inherits the stochastic boundary condition, and a non-linear and non local random system, coupled with the first, but with deterministic boundary conditions. We present an FTCS approximation and we provide the stability conditions for the discrete scheme. Furthermore, the order of spatial accuracy is numerically estimated to be one.   Numerical quantitative and qualitative analyses of the impact of the randomness at the boundary are illustrated, both in the framework of single realizations of the process, i.e. in a pathwise sense, and also by considering distribution, first and second moments of large samples. We analyse both slow and accelerated regimes, by considering increasing values of the reaction rates. In the fast reaction case, a formation of a moving stochastic front can be observed.    The final part of the thesis presents a theoretical convergence result. We consider a semi-discrete approximation of the system and prove the convergence of the discrete solution to the unique mild solution of the original random system, through a space-discrete approach. The same splitting strategy is adopted to derive some a priori estimates for the splitted discrete variables. Relevant results on compact embedding for time-space Besov spaces on the lattice as well some recent estimate results for the discrete heat kernel are exploited to prove a useful estimate for the solution to the discrete random heat equation. Furthermore, an $L^2$ a priori estimate for the second splitted variable together with its discrete derivative is provided. The final convergence result is obtained by a compactness argument, by first introducing piecewise constant interpolation and discretization operators on the lattice and by exploiting the uniform a priori estimate for the total system variable.","language":"eng","citation":"MODELLING AND NUMERICAL STUDY OF MARBLE SULPHATION IN CULTURALE HERITAGE: A RANDOM PDE-ODE SYSTEM / F. Arceci ; tutor: S. Ugolini ;  cotutor: D. Morale. Dipartimento di Matematica Federigo Enriques, 2025 May 19. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13642.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1163657/3065845/phd_unimi_R13642.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1198278"},"title":"EXPLORING THE GUT MICROBIOME IN HEALTHY AGING: FROM METABOLIC ASSOCIATIONS TO AN EXPERIMENTAL FRAMEWORK FOR NOVEL HEALTH-ASSOCIATED MICROBIAL SPECIES ISOLATION","internalauthor":"NABINEJAD, AMIR","type":"Tesi di dottorato","year":"2025","abstract":"Chronological aging is coupled with a progressive decline in health and a perturbation of physiological homeostasis. The gut microbiome, a key modulator of host metabolism and immunity, can be altered by this process and, in turn, influence its progression. While extensive evidence links microbial features to cardiometabolic health, a comprehensive strategy for assessing the gut microbiome's holistic association with an individual's health status remains a key need.  Here, we developed a novel, quantitative framework to address this gap. First, we computed a Metabolic Risk Index (MRI) for prevalent species-level genome bins (SGBs) by leveraging a key set of validated and emerging metabolic biomarkers in 1,043 middle-aged to elderly participants from the PLIC cohort. Our analysis revealed that SGBs with the strongest and most consistent association with a healthy metabolic profile were largely uncharacterized species, lacking cultured representatives in public repositories. Building on the MRI, we created a Metabolic Deviation (MetaDev) score for each individual's gut microbiota profile. The MetaDev score showed strong correlations with systemic cardiometabolic markers and lifestyle factors, and was also highly predictive of a wide range of diseases. Its most pronounced effects were observed at the extremes of the score’s distribution, including conditions such as heart failure, cerebral stroke, lung cancer, and type 2 diabetes. These associations were robustly validated in an independent cohort.  To move from statistical associations to mechanistic understanding, we established a metagenomic-guided culture-based workflow called MetaCulture to isolate these health-associated uncharacterized microbial species. By developing rapid, cost-effective, high-throughput molecular tools for targeted detection, our workflow overcomes the significant challenges of low species abundance and complex culture requirements, enabling the efficient isolation of pure colonies. As a proof-of-concept, we successfully applied MetaCulture to isolate strains of two uncharacterized clades. First, we isolated and assembled the draft genome of a representative strain of SGB4706, a species with a low MRI value and promising anti-inflammatory potential. Second, we isolated two strains of Catenibacterium mitsuokai subsp. tridentinum subsp. nov., a clade associated with non-urbanized populations, and investigated its engraftment and function in a mouse model.   Altogether, this study provides a new framework for identifying key health-associated microbes and a powerful workflow for their isolation, thereby enabling their experimental validation. This work offers a clear path to identify individuals with unfavorable gut microbiome profiles, and can thus guide targeted lifestyle interventions and the development of next-generation biotherapeutics, including novel health-associated microbial strains and strategies to enhance their presence or function.","language":"eng","citation":"EXPLORING THE GUT MICROBIOME IN HEALTHY AGING: FROM METABOLIC ASSOCIATIONS TO AN EXPERIMENTAL FRAMEWORK FOR NOVEL HEALTH-ASSOCIATED MICROBIAL SPECIES ISOLATION / A. Nabinejad ; tutor: N. Segata ; co-tutor: S. Tamburini ; external advisor: M. Rescigno ; internal advisor: D. Pasini. Dipartimento di Scienze della Salute, 2025 Dec 17. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13513.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 25-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1039311"},"title":"INVESTIGATING ALTERNATIVE SPLICING REPROGRAMMING REGULATED BY THE E-CADHERIN/B-CATENIN AXIS","internalauthor":"MAESTRINI, GIORGIA","type":"Tesi di dottorato","year":"2024","abstract":"Alternative splicing (AS) is vital for proteome flexibility and its aberrations are key drivers of cancer progression. We identified an alternatively spliced exon cassette in myosin VI, an actin motor protein. In healthy epithelial tissues like the ovary and intestine, this exon cassette is carefully regulated, producing the myosin VIlong isoform involved in endocytic functions. However, in epithelial tumors like colorectal adenocarcinoma (COAD), aberrant splicing leads to the expression of the myosin VIshort isoform, promoting tumor-cell migration. Using the Caco-2 cell line, capable of modulating isoform expression under different conditions, we uncovered the molecular mechanism behind this dysregulation, pinpointing E-cadherin and β-catenin as central players in myosin VI AS regulation. β-catenin's nuclear translocation induces myosin VIshort expression, while its depletion rescues myosin VIlong. Furthermore, we uncovered β-catenin's broader involvement in AS oncogenic reprogramming, impacting nearly 500 AS events. Among them, we characterized the α6A isoform of the integrin receptor as upregulated by β-catenin hyperactivation, potentially contributing to CRC invasiveness.   To uncover the molecular mechanism that leads to β-catenin-mediated AS reprogramming we specifically blocked the transcriptional activity of β-catenin by overexpressing a dominant negative form of its transcriptional partner and we found it contributes to regulate AS. Among the different deregulated genes, only the splicing factor RBM47 well fit as a downstream β-catenin target as its depletion causes the concordant modulation of the AS events tested, while a concomitant β-catenin depletion restores the control phenotype. This study elucidates β-catenin's novel role in AS reprogramming during epithelial maturation and intestinal tumor development.","language":"eng","citation":"INVESTIGATING ALTERNATIVE SPLICING REPROGRAMMING REGULATED BY THE E-CADHERIN/B-CATENIN AXIS / G. Maestrini ; tutor: S. Polo ; co-tutor: C. Niño ; coordinatore: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2024 Apr 11. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12731.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1039311/2412027/phd_unimi_R12731.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1143955"},"title":"DESIGN, SYNTHESIS AND BIOLOGICAL PROFILING OF NEW COMPOUNDS: INFECTIOUS AND NEURODEGENERATIVE DISEASES AS TARGETS","internalauthor":"PEDRINI, MARTINA","type":"Tesi di dottorato","year":"2024","abstract":"The convergence of the COVID-19 pandemic and the rapidly expanding aging population represents a critical intersection fraught with multifaceted social and economic implications. On one front, the emergence of the SARS-CoV-2 virus has precipitated a global health crisis of unprecedented proportions, amplifying preexisting economic vulnerabilities and catalyzing a frenetic pursuit of antiviral therapeutics guided by molecular insights. This dual crisis has underscored the imperative for robust intervention strategies to mitigate the spread of the virus and alleviate its profound socio-economic repercussions.  Simultaneously, the demographic landscape is undergoing a profound transformation, as evidenced by a United Nations report revealing a marked escalation in the proportion of elderly individuals within global populations, surging to 15% in 2019 and forecasted to double by 2050. This demographic shift carries profound implications for healthcare systems, social welfare structures, and economic sustainability, particularly given the escalating incidence of neurodegenerative diseases prevalent among the elderly demographic cohort. The escalating prevalence of conditions such as Alzheimer's disease and Parkinson's disease accentuates the pressing need for concerted research efforts aimed at elucidating the underlying mechanisms and advancing therapeutic interventions.  Against this backdrop of intersecting crises, my doctoral research endeavors over the past three years have been meticulously focused on the realm of organic chemistry. My primary objective has been the design, synthesis, and characterization of bioactive molecules specifically tailored to target key pathological pathways associated with both COVID-19 infection and neurodegenerative disorders. Through a multidisciplinary approach encompassing molecular modeling, synthetic chemistry, and pharmacological evaluation, my research seeks to unravel the intricate molecular interactions underpinning disease pathogenesis and to pioneer novel therapeutic avenues capable of addressing these formidable challenges at their roots. In doing so, I aspire to contribute meaningfully to the advancement of medical science and the amelioration of human suffering in the face of these converging global crises.  During the part of my Ph.D. research thesis, I immersed myself in the captivating realm of proteinopathies, dedicating my efforts to the synthesis and characterization of innovative neuroprotective compounds aimed at combatting the devastating neuropathologies stemming from misfolded proteins. This ambitious endeavor commenced with a meticulous exploration of Proteolysis Targeting Chimera (PROTAC) technology as a promising therapeutic avenue. Within the confines of Chapter 1 of my dissertation, I delved into the intricate design and synthesis of dual-action modulators meticulously engineered to facilitate the degradation of α-Synuclein (αSyn)via the ubiquitin proteasome system, thus holding promise for mitigating αSyn-driven neurodegenerative processes.  Subsequently, I embarked on a compelling project detailed in Chapter 2, wherein I endeavored to optimize guanylhydrazone (GH) lead compounds. This endeavor was driven by the aspiration to preserve the binding affinity of these compounds for the retromer complex at the critical Vps35-Vps29 interface, thereby bolstering their potential therapeutic efficacy. Concurrently, I rigorously pursued strategies to minimize off-target effects, particularly concerning interactions with the 5-HT receptor class, thus striving to enhance the safety profile and clinical viability of these neuroprotective agents.  In a captivating collaboration spanning continents and academic institutions, the culmination of my doctoral odyssey unfolded in Chapter 3, where I delved into the realm of RNA-targeted small molecules. This fascinating venture materialized through collaborative efforts with esteemed researchers, including Prof. Disney at the Scripps Research Institute of Florida (USA) during an enriching six-month visiting Ph.D. stage. Together, we embarked on a rigorous exploration of the biophysical and in vitro characteristics of a select cohort of GH compounds, previously synthesized within our UniMi research group. Our focus centered on unraveling their potential as binders for G4C2 expanded RNA within the c9orf72 gene, shedding light on novel avenues for therapeutic intervention in debilitating neurodegenerative disorders.  Within the dynamic landscape of COVID-19 research, my Ph.D. investigations were dedicated to the meticulous design and development of small molecules meticulously engineered to target two pivotal components crucial to the progression of SARS-CoV-2 infection.  In Chapter 4 of my Ph.D. research endeavors, I directed my attention towards indispensable component of the SARS-CoV-2 virion—the outward Spike (S) glycoprotein. This integral protein orchestrates the initial stages of viral infection by mediating the fusion of viral and host cell membranes, thereby facilitating viral entry into host cells. Fully cognizant of the pivotal role played by the S glycoprotein in viral pathogenesis, I endeavored to leverage the principles of medicinal chemistry to synthesize a repertoire of potential therapeutic agents meticulously tailored to disrupt crucial molecular interactions essential for viral entry and subsequent infection.  Simultaneously, the focal point of Chapter 5 of my dissertation centered on the SARS-CoV-2 main protease (Mpro), a catalytic enzyme indispensable for the maturation of viral proteins essential for viral replication within host cells. Recognizing the critical role of Mpro in the viral life cycle, I endeavored to harness the power of medicinal chemistry to synthesize a diverse array of putative hits tailored to inhibit this key enzymatic target, thus impeding viral replication and curtailing the spread of infection.","language":"eng","citation":"DESIGN, SYNTHESIS AND BIOLOGICAL PROFILING OF NEW COMPOUNDS: INFECTIOUS AND NEURODEGENERATIVE DISEASES AS TARGETS / M. Pedrini ; coordinatore: D. Passarella ;  tutor: D. Passarella ;  co-tutor: P. Seneci. Dipartimento di Chimica, 2024 Jun 27. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12858.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1143955/2666691/phd_unimi_R12858.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1019211"},"title":"EFFECT OF MICROTUBULE-TARGETING AGENTS ON STRUCTURAL SIGNALING AND CHEMICAL TRANSPORT IN CELLS","internalauthor":"BONATO, FRANCESCA","type":"Tesi di dottorato","year":"2023","abstract":"Microtubules, along with actin and intermediate filaments, are key components of the cellular cytoskeleton and play pivotal roles in several biological functions, including intracellular trafficking, positioning of cellular components in interphase, mitotic spindle formation during cell division, maintaining of cell morphology and cell motility. Structurally, microtubules are formed by αβ-tubulin heterodimers that polymerize in a head-to-tail fashion to create protofilaments, which subsequently assemble into hollow cylindrical polar filaments. Microtubules’ behavior and function depend on their polymerization dynamics, with the first layer of regulation being the GTPase cycle of tubulin and its addition to the growing microtubule end. This process causes tubulin to transition from a curved conformation in solution to a straight conformation in the microtubule lattice. In cells, secondary layers of regulation (associated proteins, post-translational modifications, and tubulin isotypes levels) allow for a more precise modulation and differentiation of microtubule activities.    Due to their involvement in key cellular activities, compounds that interfere with the microtubule cytoskeleton have been developed as cytotoxic agents, demonstrating remarkable efficacy against a wide spectrum of cancer types. Paclitaxel, a natural product extracted from yew tree bark, was the first microtubule-targeting agent (MTA) to be approved for clinical use in 1992, followed by two synthetic derivatives, docetaxel and cabazitaxel. These molecules bind to the taxane binding site in the microtubule, inducing its structural stabilization and preventing depolymerization events. Although the ability of taxanes to disrupt microtubule dynamics is closely linked to their chemotherapeutic effects, the exact cellular mechanism behind their anticancer activity remains under debate. At present, taxanes remain among the first-line treatments for several solid tumors, including breast cancer, ovarian carcinoma, pancreatic adenocarcinoma, non-small lung cancer, and prostate cancer. However, the clinical use of these molecules is limited by taxane-induced peripheral neurotoxicity, which severely affects up to 30% of patients and frequently leads to therapy discontinuation.  To protect neurons from damage during taxane chemotherapy, it is essential to gain an improved mechanistic understanding of these drugs’ pathological effects on neurons. Due to their complex and elongated structures, neurons rely on intracellular active transport for cargo movement along the axon, making them especially susceptible to deficits in this process caused by taxane treatment. A recent hypothesis links axonal transport impairment to lattice expansion, a structural alteration induced by taxanes that appears to be unrelated to the stabilization effect. Locally expanded dimers may act as lattice point defects and cause premature detachment or stalling of the microtubule-associated motor proteins. Moreover, since current models of the microtubule structure describe the expanded lattice as a distinct structural feature localized near the tip, the spread of this structural signal along the whole lattice could impact the recognition patterns of motor proteins. Interestingly, unpublished results from our laboratory show that flutax-2, a C7-modified fluorescent taxane, does not induce microtubule lattice expansion.   The present work, titled “Effects of microtubule-targeting agents on structural signaling and chemical transport in cells” focuses on two primary objectives. First, it aims to investigate the influence of C7-modifications of the taxane core on the cellular, biochemical, and structural properties of microtubules, in particular on lattice axial expansion. Second, it seeks to describe the relationship between the microtubule structural modifications induced by taxanes and the impairment of intracellular transport. These objectives were pursued through a multidisciplinary approach that included the in-silico design and chemical synthesis of new C7-decorated taxanes engineered to emulate the binding mode of flutax-2. Subsequently, the in vitro biochemical and structural characterization of these compounds was carried out, and their effect on cellular systems was extensively investigated.   The findings presented in this thesis highlight the potential of C7-modification for generating taxanes able to override common cellular resistance mechanisms and/or to exert reduced impact on microtubule structure, thereby mitigating their interference over intracellular transport. Furthermore, the results obtained suggest that microtubule lattice expansion alone cannot account for the altered transport within taxanes-treated cells.","language":"eng","citation":"EFFECT OF MICROTUBULE-TARGETING AGENTS ON STRUCTURAL SIGNALING AND CHEMICAL TRANSPORT IN CELLS / F. Bonato ; tutor: J. F. Díaz Pereira ; tutor: M. Á. O. Blanco ; tutor: D. Passarella. Università degli Studi di Milano, 2023 Dec 19. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R13188.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1019211/2330221/phd_unimi_R13188.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1153996"},"title":"ELUCIDATING THE IMPACT OF ASCITES ON HIGH GRADE SEROUS OVARIAN CANCER THROUGH MULTIPLE IN VITRO PATIENT-SPECIFIC MODELS","internalauthor":"BARZAGHI, BIANCA","type":"Tesi di dottorato","year":"2025","abstract":"High-grade serous ovarian cancer (HGSOC) is a highly heterogeneous and aggressive malignancy characterized by marked inter-/intra-tumor variability and a dynamic tumor microenvironment (TME). The TME, and particularly ascitic fluid (AF), plays a critical role in OC progression by influencing tumor and stromal cell behavior, promoting metastasis and driving therapy resistance. Current in vitro models often fail to replicate the complexity of the TME, being limited in their ability to fully capture HGSOC biology. Here, we explored the impact of AF supplementation on multiple patient-derived in vitro models, specifically 2D cells, 3D stem-enriched spheroids and polyclonal organoids, to develop preclinical models able to capture and faithfully reproduce the heterogeneity and complexity of this tumor and its TME.    We could show that AF supplementation improves culturing conditions by increasing cell proliferation, sphere formation and propagation, while also preserving the original metabolic profiles of patient-derived samples. In parallel, 2D cells and 3D spheroids revealed a model-specific effect of ascites, with a downregulation of genes involved in the biosynthesis of cholesterol and in inflammatory response in 2D cells, and an upregulation of proliferation and glycolysis in 3D spheres. Additionally, we identified a common effect of AF on both models, showing AF-dependent genes and pathways related to cell cycle regulation and cellular proliferation. Among them, CDKN2B was notably downregulated in the presence of AF, highlighting a novel regulatory mechanism directly driven by the ascitic TME in HGSOC.    Integrative analyses revealed that the in vitro models were mostly enriched for tumor stroma cellular subpopulations, warranting a perspective shift from a tumor epithelial-centric view to a systematic, and now finally experimentally tractable, appraisal of the TME, particularly cancer-associated fibroblasts (CAFs), paving the way to a refined understanding of tumor progression in light of tumor-TME cross-interaction.   In this context, the study underscores the critical role of AF in shaping the interactions between tumor and non-tumor cells and the surrounding microenvironment, highlighting the importance of TME for a comprehensive understanding of HGSOC biology. The integration of AF into in vitro systems represents a significant step forward in creating more defined models for studying stroma and/or tumor interactions, allowing in the future to position these models within the broader landscape of HGSOC biology and potentially guide more refined therapeutic strategies.","language":"eng","citation":"ELUCIDATING THE IMPACT OF ASCITES ON HIGH GRADE SEROUS OVARIAN CANCER THROUGH MULTIPLE IN VITRO PATIENT-SPECIFIC MODELS / B. Barzaghi ; tutor: G. Testa; co-supervisor: P. Lo Riso ; coordinator: D. Pasini. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Apr 03. 36. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13130.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1153996/2713570/phd_unimi_R13130.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/807452"},"title":"LE COMUNICAZIONI SELETTIVE AGLI AZIONISTI NELLE SOCIETÀ QUOTATE: PROFILI SOCIETARI E DI CORPORATE GOVERNANCE","internalauthor":"FAZZINI, PIETRO","type":"Tesi di dottorato","year":"2021","abstract":"This work deals with the issue of board-shareholders dialogues in Italian listed companies and the problem arising from the selective disclosure of corporate information that may occur in such context. In particular, it looks at the phenomenon from the yet quite uncharted perspective of corporate law, and tries to understand the extent of its admissibility under the rules and prin-ciples that govern the structure of corporate organization and corporate governance in Italy.   The rules regulating selective disclosure both in the EU and in the Anglo-American legal systems mainly focus on preventing market abuses and enhancing transparency and therefore aim to curb to the maximum extent possible any selective disclosure, on the premise that it pro-duces information asymmetries and disparity of treatment among investors. However, such per-spective substantially fails to take into consideration that, from a corporate perspective, selective disclosure may find several causes of justification. The main purpose of this work is, on one side, to investigate such profiles and, on the other side, to build a theoretical framework where the ef-fects of selective disclosure are considered both from a market/investor and corporate perspec-tive and the boundaries of its legitimacy are construed accordingly. In doing so a significant ef-fort is devoted to the analysis of recent evolutionary trends in global and local equity markets and particularly to the phenomenon of equity reintermediation and the uncertain development of shareholder activism, in the view of understanding the impact of such phenomena on the dis-cipline of shareholder-targeted selective disclosure.   The work is divided in three main parts. In the first one, I analyze how different types of investors can make use of selective disclosure and for which purposes. I then try to show if and how particular interests of each type of shareholder can be reconciled with the concept of issu-er’s corporate purpose (interesse sociale), on one side, and with the notion of legitimate interest underlying the disclosure rules set forth in the Market Abuse Regulation and the principle of equality of treatment, on the other side. In the second part, I attempt to reconstruct a compre-hensive discipline of selective disclosure, which take into account the main structural differences among shareholders, in terms of interest, investment purpose and strategy. In this part, profiles pertaining to the controlling shareholders and minority (professional) investors are dealt with separately. In the third and last part, I analyze the implications of selective disclosure from the perspective of directors’ fiduciary duties (namely, the duty of loyalty) and related liability regime. In particular, I focus on the hypothesis where information is selectively exchanged between a single investor-appointed director and its appointing sponsor, especially but not only in the con-text of activist campaigns.","language":"ita","citation":"LE COMUNICAZIONI SELETTIVE AGLI AZIONISTI NELLE SOCIETÀ QUOTATE: PROFILI SOCIETARI E DI CORPORATE GOVERNANCE / P. Fazzini ; tutor: prof. Roberto Sacchi ; coordinatore: prof. ssa M. T. Carinci ; referente del curriculum: prof. R. Sacchi. Università degli Studi di Milano, 2021 Jan 12. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11947.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/807452/1679262/phd_unimi_R11947.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1142173"},"title":"DONT' BE FOOLED BY FAKE NEWS? MAPPING THE SOCIAL, COGNITIVE, AND POLITICAL MECHANISMS OF MISINFORMATION BELIEF.","internalauthor":"TORREGGIANI, FABIO","type":"Tesi di dottorato","year":"2025","abstract":"Why do people believe in fake news? I explore this question using five studies on more than 4200 participants. While there is extensive research on this question, most studies have primarily tried to identify specific individual mechanisms, e.g. cognitive styles, without considering the possible interplay of various mechanisms. Instead, this dissertation has jointly considered five drivers of misinformation beliefs: cognitive styles, motivated reasoning, anti-elitism, institutional trust, and social norms. The second contribution of this doctoral thesis is the inclusion of these latter three explanations (one of which - social norms - is also experimentally manipulated), as the literature often focused on cognitive drivers while only rarely exploring social ones. This dissertation also aimed to make relevant methodological contributions. First, instead of using artificial or semiartificial stimuli to test participants’ truth discernment, it collected and validated a new dataset of 80 existing social media posts. Second, it also tested its hypotheses in Italy, outside the widely explored context of English-speaking countries. The results of these studies indicate that cognitive styles, such as the tendency to rely on intuition or analytical thinking, significantly influence participants’ ability to discern truth, even when using real social media posts as stimuli. However, the effects of other drivers were less pronounced. Motivated reasoning, for instance, had only marginal effects, possibly due to the low perceived partisanship of the collected posts. Similarly, I found no consistently significant effects of anti-elitism and institutional trust, except for trust in universities. Regarding social norms, I observed that individual motivations for information accuracy were associated with higher truth discernment, while social expectations had no discernible impact. The social norm treatment message yielded mixed results but was largely inconclusive. My findings have two main insights: for methodological issues, my thesis testifies to the importance of using more realistic stimuli selection in experimental research on misinformation; for substantive issues, my study shows that cognitive drivers, although crucial, cannot be considered the sole determinants for misinformation beliefs.","language":"eng","citation":"Dont' Be Fooled By Fake News? Mapping The Social, Cognitive, And Political Mechanisms Of Misinformation Belief / F. Torreggiani ; tutor: G. Ballarino, A. Szekely ; coordinatore: M. Guerci. - Milano. Dipartimento di Scienze Sociali e Politiche, 2025 Feb 10. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R12974.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1142173/2659210/phd_unimi_R12974.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/957828"},"title":"STUDY OF THE MUTUAL INTERACTION BETWEEN EXTRACELLULAR MATRIX AND CELLS IN PERITONEAL METASTASIS","internalauthor":"LORENC, EWELINA JULIA","type":"Tesi di dottorato","year":"2023","abstract":"This thesis project is related to the field of mechanobiology, a novel and emerging area of biology. The work is mainly focused on the biomechanical interaction of cancer cells with extracellular matrix extracted from human patients during peritoneal metastasis. AFM microscopy with large colloidal probes was used as the main experimental tool.   Presented results of mechanical characterization of ECM, together with additional biotechnological studies, revealed that signs of forming pre-metastatic niche are already present in normal derived tissue, which gives a chance to use the nano- and microscale characterization of the mechanical properties of tissues as a cancer diagnosis tool.   It was also demonstrated that the decellularized peritoneal ECM can be adapted as a scaffold for culture of organoids to create ex vivo model of human peritoneal metastasis lesion. AFM nanoindentation measurements revealed significant stiffening over time of both normal and neoplastic ECM repopulated with neoplastic organoids. It revealed that tumour derived organoids introduced to microenvironment of different elastic modulus and biological characteristics are expressing different behaviour.   Part of the work presented in this thesis was focused in investigating the mechanical properties of biological tissue after applying different freezing protocols. Additionally, steps for tissue sample preparation were optimized to allow for AFM measurements.   Spheroids were investigated as 3D models with the main target to characterize their mechanical properties and understand possible applications in cancer research. First, protocol for AFM measurements was optimized. The versality of AFM and its probes allowed to study elasticity of spheroids in different terms. Finally, measurements of spheroids were carried out also with microfluidic cytometry showing a parallel method to measure their viscoelasticity.","language":"eng","citation":"STUDY OF THE MUTUAL INTERACTION BETWEEN EXTRACELLULAR MATRIX AND CELLS IN PERITONEAL METASTASIS / E.j. Lorenc ; supervisor: A. Podesta' ; co-supervisor: M. Chighizola ; tutor: M. Gariboldi; Dr. L. Varinelli ;. Università degli Studi di Milano, 2023 Mar 13. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12472.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/957828/2157613/phd_unimi_R12472.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/945230"},"title":"EPIGENETIC AND FUNCTIONAL ASSESSMENT OF ENHANCEROPATHIES ACROSS HUMAN MODELS: FOCUS ON GABRIELE-DE VRIES SYNDROME","internalauthor":"FARIA PEREIRA, MARLENE CRISTINA","type":"Tesi di dottorato","year":"2022","abstract":"Yin Yang 1 (YY1) is a ubiquitous zinc finger transcription factor (TF) that occupies active enhancers and promoters contributing to physical interactions between these regions via DNA looping. Increasing evidence shows that disruption of non-coding regions such as enhancers is prevalent across different neurodevelopmental disorders (NDDs) with intellectual disability (ID) features. Indeed, YY1 haploinsufficiency causes a NDD with ID, named Gabriele-de Vries syndrome (GADEVS). Although it is known that YY1 controls the expression of a dazzling list of genes and influences various cellular processes in numerous cell types, the impact of this TF in the neurodevelopment of the human cortex is yet to be unraveled. By taking advantage of disease-modeling as a tool to investigate the pathogenesis of GADEVS across different time points and tissues we gathered new insights about how YY1 haploinsufficiency exerts such a dramatic phenotype in individuals carrying mutations. We reprogrammed patient-derived and healthy somatic cells into induced-pluripotent stem cells (iPSCs) and observed, already at the pluripotent stage, a major transcriptional dysregulation. Moreover, since YY1-mutated patients exhibit ID features, we differentiated our cohort of iPSCs into cortical neurons as well organoids and were able to capture stage-specific striking features, not only at the transcriptomic level, but also structural and compartmentalization impairments. Of note, YY1-mutated neurons displayed synaptic disparities, sufficient to induce astrogliosis-like features in surrounding astrocytes, both shown to be critical for proper brain function and plasticity forms in the CNS. Instead, in cortical organoids we recapitulated features of abnormal ventricle formation, pathological hallmarks observed in GADEVS patients and mice models followed by ID and developmental delay. This study showed, for the first time, the molecular signatures that possibly lead to cognitive defects in human patients and provide the first solid foundation for the development of therapeutic strategies and drug screening in the future.","language":"eng","citation":"EPIGENETIC AND FUNCTIONAL ASSESSMENT OF ENHANCEROPATHIES ACROSS HUMAN MODELS: FOCUS ON GABRIELE-DE VRIES SYNDROME / M.c. Faria Pereira ; tutor: G. Testa : coordinatore: S. Minucci. Università degli Studi di Milano, 2022 Dec 16. 33. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12142.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/945230/2094722/phd_unimi_R12142.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/945096"},"title":"AM I RADICAL, RIGHT? THE RADICAL RIGHT FAMILY IDEOLOGICAL OUTLOOK AND RADICAL RIGHT ATTITUDE AMONG THE PUBLIC","internalauthor":"PIACENTINI, FRANCESCO","type":"Tesi di dottorato","year":"2022","abstract":"The emergence of Radical Right Parties (RRPs) has been one of the most studied European political phenomena in the last thirty years, producing a prolific flow of research on both the ideological outlook of the radical right party family and the characteristics of its voters. Nonetheless, the academic debate on these issues is far from being appeased. The following work contributes to the debate by looking at the rise of RRPs in Europe through the perspective of their ideological outlook and by investigating both the supply side and the demand side by means of a data-driven machine learning approach. The literature on RRPs ideological outlook has been prolific and discordant, yet most scholars tend to agree on two main core ideological features that appropriately characterize the radical right family and set it apart from others: nativism and authoritarianism. These core features are complemented by other ancillary elements, on which the debate is more open. The most discussed example is represented by the evolution of RRPs’ positions on economic issues. On this concern, some scholars claim that we are facing a real differentiation within the radical right that needs to be included in the ideological definition of the family, while others argue we are witnessing a series of blurrying processes that intervene on secondary issues holding limited definitory power. As far as radical right voters are concerned, their behavior has been analyzed under many different lenses, still the only condition on which all scholars agree is the centrality of individual attitudes towards immigration in shaping radical right voting. In a few words, we describe the awkward situation where ideologically complex parties, which are not considered single-issue parties, seem to mobilize voters on the basis of a single issue. The aim of the study is to put theoretical studies on the radical right ideology to an empirical test, starting from party-level data and by checking whether those who have been defined as the core features of the radical right family have a crucial role in defining the ideological borders of the radical right or not. Then, we define the potential voting base by following the ideological characterization that emerged empirically. Results confirm the centrality of both nativism and authoritarianism (and Euroscepticism, in addition) in shaping the radical right ideological outlook, while economic positions are the main division line that shapes heterogeneity within the family. The empirical clusters based on the criteria defined previously produce a classification which is coherent with the ones provided by the literature. Results also give empirical evidence of a process of radicalization that characterizes a group of center-right parties, which progressively get close to nativist and authoritarian positions, in continuity with the findings of studies on center-right radicalization. We also confirm that the emergence of a nativist, authoritarian and Eurosceptic set of attitudes among the public, which significantly shapes the probability to vote for a RRP.","language":"eng","citation":"AM I RADICAL, RIGHT? THE RADICAL RIGHT FAMILY IDEOLOGICAL OUTLOOK AND RADICAL RIGHT ATTITUDE AMONG THE PUBLIC / F. Piacentini ; tutor: C. Vezzoni ; phd director: M. Jessoula. Dipartimento di Scienze Sociali e Politiche, 2022 Dec 06. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12193.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/945096/2094161/phd_unimi_R12193.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1090328"},"title":"IL RIUTILIZZO SOCIALE DEI BENI CONFISCATI AL CRIMINE ORGANIZZATO E LA RIQUALIFICATORE DEI TERRITORI. UNO STUDIO COMPARATO TRA LECCO E BARI.","internalauthor":"PALERMO, CLAUDIA","type":"Tesi di dottorato","year":"2024","abstract":"This thesis aims to explore the differences in the re-use of assets confiscated from mafias between northern and southern Italy, with a particular focus on Lecco and Bari. It begins by drawing a distinction between the terms ‘mafia’ and ‘mafias’, highlighting the variety and complexity of Italian criminal organisations. The terms ‘mafia’, ‘mafias’ and ‘organised crime’ are often confused, but it is important to distinguish between them in order to fully understand the complexity of the criminal phenomenon in Italy. While the term ‘mafia’ often refers to the criminal organisation originating in Sicily, with national and international ramifications, the term ‘mafia’ collectively refers to the various mafia-type criminal organisations present in different regions of Italy. These organisations are involved in a wide range of illicit activities such as drug and arms trafficking, money laundering, extortion and corruption, and exercise significant control over political and economic activities.  Among the various factors identified as contributing to the expansion of the mafia in Italy, corruption, the limited availability of economic opportunities, the fragility of institutions and the lack of transparency in the management of property all feature prominently. Although Italy's anti-Mafia legislation is among the most incisive in the world, its implementation is often slowed down by bureaucratic and procedural challenges.  Confiscating the assets of mafia clans is a crucial measure in the fight against organised crime. However, the process of confiscating and socially re-using these assets can be lengthy and complex. Despite these challenges, the social reuse of confiscated assets helps to reclassify and add value to territories, transforming criminal areas into economic and cultural resources. In this way, spaces that were once illicit become licit places, contributing to social and economic well-being.  The research focuses on the social reuse of confiscated properties in Lecco and Bari, analysing the disparities in procedures and projects between northern and southern Italy. It examines the complex relationship between illegally occupied spaces, requalification policies, institutions and social dynamics.  The research explores the ways in which confiscated property is distributed, participation in tenders to obtain it for social purposes, the accessibility of procedures and the challenges faced by cooperatives and associations, linked to issues of timing and cohabitation between mafia power and legal power. The research highlights the importance of collaboration between associations and cooperatives in social reuse, promoting an appropriate transformation of territories.  The comparative analysis between Lecco and Bari highlights the similarities and differences in the incidence and impact of organised crime: the infiltration of the ‘ndrangheta in Lecco and the presence of criminal groups in Bari highlight the need for a coordinated response from the authorities. Despite geographical and socio-cultural differences, the two cities face similar challenges in relation to organised crime. Understanding criminal dynamics and cooperation between authorities are essential to counter the infiltration of criminal organisations and promote the social re-use of confiscated assets.  It is interesting to note that social reuse not only counters the presence of the mafia, but also intervenes in areas that are often neglected, facilitating the link between citizens and institutions. We would like to stress the importance of cooperation between institutional authorities, associations and citizens to ensure effective management of confiscated property and promote the social and economic well-being of the communities concerned.","language":"ita","citation":"IL RIUTILIZZO SOCIALE DEI BENI CONFISCATI AL CRIMINE ORGANIZZATO E LA RIQUALIFICATORE DEI TERRITORI. UNO STUDIO COMPARATO TRA LECCO E BARI / C. Palermo ; tutor: N. Dalla Chiesa (Università Statale degli Studi di Milano),  P. Froment  (Université Paris 8 – Vincennes Saint Denis). - Université Paris 8 – Vincennes Saint Denis. Università degli Studi di Milano, 2024 Dec 06. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12469.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1090328/2556853/phd_unimi_R12469.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1015289"},"title":"DIGITAL LABOUR RELATIONS IN THE GIG ECONOMY: PLATFORM-TO-CONSUMER FOOD DELIVERY SERVICES IN GLOBAL NORTH AND GLOBAL SOUTH","internalauthor":"SHARMA, PADMINI","type":"Tesi di dottorato","year":"2023","abstract":"The platform business model has been expanding exponentially over time reshaping capitalism as well as work and labour relations within it. In less than a decade, digital platforms have grown from a niche market to engulf different industries and services across the globe, in developed and developing nations alike. These models connect service providers with service seekers over a digital platform where real-time data is processed through intricate algorithmic programming under diverse market conditions to allocate tasks, determine income, and assess the performance of the service providers. These digital platforms being automated, and data-rich digitised institutional environments seek to mediate economic transactions by hiring workers on a piece-rate basis to perform marginal or casual working activities (Kalleberg and Dunn, 2016; De Stefano, 2016; Atmore, 2017; Duggan et al. 2019). Nonetheless, over the advantages received across digital platforms, many scholars argue that there is nothing novel in these platform models and indeed, it holds the potential to undo what the labour unions have been working to do over the past hundred years (Healy et al. 2017; Nilsen et al. 2020). This even encompasses precipitating a ‘race to the bottom’ where workers undercut each other for advantage over wages and other performance expectations.    These digital platforms, contrary to what is claimed, do not lend support towards (re)configuring hierarchies, rigidities, and biases in labour relations rather they reinforce them under novel mechanisms. Hence, over time, significant research has been done to examine the changing structural and legal dimensionalities encountered in these digital platforms that highlight how traditional labour relations have undergone sea changes in post-industrialised societies. Nonetheless, no literature has adopted a multi-level analysis that seeks to connect the meso-level workings within these platforms with the broader political-economic context and the micro-level socio-political interactions among the workers. This often ignores analysing the workings within these platforms in context to the broader political, economic, or social arrangements, and secondly, it also ignores that the macro context can influence the workers’ experiences and actions. Hence, this research seeks to explore how are the variations in the individual firm-level configurations and the agential practices among workers related to the broader macro-structural conditions.     This research uses labour process theorisation through a critical realist perspective that seeks to create an integrative approach in reflecting on the linkages between the micro-level relations within the broader macro contexts. Hence, a comparative case study approach has been used to explore cross-national variations and similarities in examining how platform-based technologies influence labour relations across distinct tech hubs in Global North and Global South. In this, one hundred and twenty platform-to-consumer food delivery workers have been selected across cities of India [Mumbai and Guwahati] and Italy [Milan and Bologna] using stratified purposive sampling. Observations and unstructured interviews were used to collect the data, which was designed to involve respondents in critical thinking and explore their experiences from both a reflective and experiential perspective. Each interview has been transcribed verbatim and analysed within, and across the cases using the statistical software MAXQDA to store, code and thematically analyse the data.","language":"eng","citation":"DIGITAL LABOUR RELATIONS IN THE GIG ECONOMY: PLATFORM-TO-CONSUMER FOOD DELIVERY SERVICES IN GLOBAL NORTH AND GLOBAL SOUTH / P. Sharma ; tutor: R. Pedersini ; coordinator: M. Guerci. Dipartimento di Scienze Sociali e Politiche, 2023 Nov 09. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12653.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1015289/2319113/phd_unimi_R12653.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/965436"},"title":"I DIRITTI DI VOICE DEI SOCI NEL CONCORDATO PREVENTIVO DELLA SOCIETÀ","internalauthor":"VIOLA, FILIPPO","type":"Tesi di dottorato","year":"2023","abstract":"The dissertation addresses the issue of the position of shareholders in companies under composition with creditors, with regard to their voice rights and powers, both in the initial stage of access to the procedure and in the stage of approval and execution of the plan.  In relation to the first phase, the question arises in terms of whether or not shareholders shall participate in the decision on access to the procedure and in the definition of the contents of the plan, as well as the manner in which such participation shall be articulated. These issues, which can be traced back to the perspective of the analysis of shareholders ex latere debitoris, are corporate governance-related and are linked with those of information rights in favor of shareholders at the stage of entry into the procedure.   The second phase focuses on the position of shareholders (ex latere creditoris) with respect to the approval of the plan, also in those specific cases in which the plan itself contemplates transactions that, by rule of corporate law, require their consent. In this regard, the thesis examines the implications of the recent Italian choice (made also by way of transposition of Directive (EU) 2019/1032) to provide for the placement of shareholders – on a mandatory or optional basis as the case may be – in special voting classes, as well as creditors. Such analysis is carried out in order to understand, in general terms, the reasons behind the classification of voters and to examine the level of protection thus offered to shareholders, as well as the impact of the mentioned choice on the issue of countering shareholders’ obstructive behaviors.  The dissertation pays particular attention to the differences between restructuring procedures and liquidation procedures and offers differentiated interpretative solutions, despite the current Italian law sometimes does not provide for any distinction in this regard.   Moreover, an approach aimed at enhancing the relevance of company’s size (and, in particular, the special features of “smaller” companies) is adopted, as the mentioned Directive allowed for. In particular, the role that shareholders play depending on the structural and socio-economic features of the company is adequately taken into account.  This leads, on the one hand, to reject hypotheses that ignore the differences related to the type and dimension of companies, and, on the other hand, to propose interpretative solutions that are consistent with the real protection needs that arise in each individual case.","language":"ita","citation":"I DIRITTI DI VOICE DEI SOCI NEL CONCORDATO PREVENTIVO DELLA SOCIETÀ / F. Viola ; coordinatore del corso di dottorato: G. Ludovico ; tutor: M. Rescigno. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2023 May 05. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12635.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/965436/2181728/phd_unimi_R12635.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1018289"},"title":"UNRAVELING TAZ REGULATION IN BREAST CANCER BY CRISPR SCREENING","internalauthor":"CHIESA, ARIANNA","type":"Tesi di dottorato","year":"2023","abstract":"YAP and TAZ are transcriptional coactivators belonging to the Hippo signaling pathway. Their activity is regulated by a complex network of upstream signals. As consequence, they orchestrate a wide spectrum of downstream cellular responses. In physiological conditions, a precisely balanced equilibrium governs activation and inhibition of YAP/TAZ. Disruption of this equilibrium unleashes YAP/TAZ oncogenic potential, promoting the development and progression of several human malignancies. In particular, TAZ overexpression has been associated with increasing aggressiveness of breast tumors, endowing mammary gland cells with oncogenic features, as stemness properties, migration, invasion and chemoresistance.  Yet, YAP/TAZ mutations or genetic alterations of their known upstream regulators are relatively rare, raising the question of how YAP/TAZ are upregulated in cancer cells. To gain insights into novel TAZ regulators within the context of breast cancer, we conducted a series of loss-of-function CRISPR/Cas9 pooled genetic screens in vitro and in vivo on a selected subset of genes, previously identified in our laboratory as modulators of TAZ transcriptional activity.  With this study we aimed to identify genes crucial for breast cancer cells growth, start to investigate their mechanism of action and explore their potential functional relationship with YAP/TAZ dysregulation in cancer. Among the identified hits, we focused our attention on FERMT2 and performed an initial characterization of its pro-tumorigenic role as TAZ activator.","language":"eng","citation":"UNRAVELING TAZ REGULATION IN BREAST CANCER BY CRISPR SCREENING / A. Chiesa ; internal advisor: P.G. Pelicci ; tutor: S. Campaner ; phd coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2023 Dec 12. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12679.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1018289/2327276/phd_unimi_R12679.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1171155"},"title":"A RANDOMIZED STUDY OF THE GLUNOVO REAL-TIME CGM EFFECTIVENESS ON METABOLIC CONTROL IN PATIENTS WITH T2D","internalauthor":"LAZZARONI, ELISA","type":"Tesi di dottorato","year":"2025","abstract":"Objective: This study aimed to evaluate the effectiveness of the real-time continuous glucose monitoring (RT-CGM) system, Glunovo, in improving glycemic control and patient outcomes in individuals with poorly controlled type 2 diabetes (T2D) compared to traditional self-monitoring of blood glucose (SMBG).  Research Design and Methods: This prospective, open-label, randomized controlled trial included 178 patients with T2D from the Fatebenefratelli-Sacco Hospital in Milan. Participants were randomized into 2 groups: 89 patients received the Glunovo RT-CGM (case group), while 89 continued SMBG with standard glucometers (control group). The primary outcome was the change in HbA1c levels after 6 months. Secondary outcomes included time in range (TIR), time above range (TAR), time below range (TBR), mean glucose levels, Glucose Management Indicator GMI and patient satisfaction and well-being assessed by a numeric scale and the WHO-5 Well-Being Scale.  Results: After 6 months, the RT-CGM group showed a significant reduction in HbA1c levels (Δ -1.4%, p<0.001), compared to the control group (Δ -0.6% p<0.001). TIR significantly increased in the RT-CGM group (Δ +18.4%, p<0.001). TAR significantly decreased in the RT-CGM group (Δ -17.2%, p<0.001). There was no significant change in TBR in RT-CMG group. The GMI in the RT-CGM group dropped by 1.4% (p<0.001). Satisfaction with the RT-CGM significantly increased (p<0.001), but no significant improvements were observed in the well-being (WHO-5 index).  Conclusions: The use of the Glunovo RT-CGM system significantly improved glycemic control and patient satisfaction compared to SMBG. These findings suggest that Glunovo RT-CGM is an effective tool for managing poorly controlled T2D, providing a valuable option for enhancing both glucose regulation and patient self-management through improved dietary awareness and optimized therapy adherence.","language":"eng","citation":"A RANDOMIZED STUDY OF THE GLUNOVO REAL-TIME CGM EFFECTIVENESS ON METABOLIC CONTROL IN PATIENTS WITH T2D / E. Lazzaroni ; tutor: P. Fiorina, F. D'Addio ; coordinator: F. Cheli. Dipartimento di Scienze Biomediche e Cliniche, 2025 Jun 30. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13374.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1171155/3090527/phd_unimi_R13374.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1214355"},"title":"SMYD3: A PLAYER IN STEMNESS AND CHROMOSOME INSTABILITY IN TRIPLE NEGATIVE BREAST CANCER","internalauthor":"CAGLIO, FRANCESCA","type":"Tesi di dottorato","year":"2026","abstract":"The lysine methylase SMYD3 was shown to be overexpressed in various types of cancer and linked to the epithelial-mesenchymal transition (EMT) (1). Moreover, it is known that cancer stem cells (CSCs) are tumor initiating cells with importance in metastasis formation and a very strong link with EMT (2). With this state of the art, our goal was to investigate a possible link between CSCs and SMYD3 in triple negative breast cancer (TNBC), possibly through EMT. SMYD3 KO reduced the expression of stemness and EMT markers in MDA-MB-231 cells, reducing the ability of cells to form primary and secondary tumor spheroids. BT549 cells seem to be affected by SMYD3 depletion only in terms of proliferation and growth. RNA sequencing results deriving from MDA-MB-231 tumor spheroids revealed a possible SMYD3 involvement in chromosome instability (CIN), in the interferon response and in the cGAS-STING pathway. Cancer cells can be characterized usually by a high state of CIN, leading to the release of genomic DNA in the cytoplasm, associated with the activation of the cGAS-STING pathway, which acts as a pro-survival pathway (3). We investigated the link between SMYD3 and CIN, confirming that SMYD3 KO diminishes the activation of the cGAS-STING pathway, particularly the pro-survival one, upregulating the pro-apoptotic pathway that drives cell death instead, in both cell lines. Moreover, genomic DNA presence in the cytoplasm was evalu-ated and it revealed a high state of CIN, which diminishes following SMYD3 KO in both cell lines. Particularly in BT549, centrosomes were analysed, revealing a possible link between SMYD3 depletion and interference with their duplication process. Moreover, SMYD3 was found to be localized in the centrosomes. Finally, a SMYD3 interactor, Nucleophosmin (NPM1), was confirmed in BT549 cells, leading to a possible mechanism behind the involvement of SMYD3 in CIN.","language":"eng","citation":"SMYD3: A PLAYER IN STEMNESS AND CHROMOSOME INSTABILITY IN TRIPLE NEGATIVE BREAST CANCER / F. Caglio ; supervisore: G. Caretti ; coordinator: S. Ricagno. Dipartimento di Bioscienze, 2026 Feb 13. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13910.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 11-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1135686"},"title":"INTO THE STRUCTURE OF THE PERMIAN DEEP CONTINENTAL CRUST: A MULTISCALE APPROACH TO RECONSTRUCT MIGMATIZATION IN THE VALPELLINE SERIES (DENT BLANCHE TECTONIC SYSTEM, WESTERN ITALIAN ALPS)","internalauthor":"CASO, FABIOLA","type":"Tesi di dottorato","year":"2025","abstract":"Granulite and migmatite are widespread across different tectonic settings, such as those associated with collisional crustal thickening during orogenic events and post-collisional or back-arc lithospheric thinning. Studying these rocks provides an exceptional opportunity to observe the deep portions of the continental lithosphere and infer insights into the processes that control its evolution. In extensional settings, orogenic root delamination and lithospheric thinning cause asthenospheric upwelling, increasing heat flow and enhancing partial melting of the lithospheric mantle and deep crust. During the Permian, the Variscan lithosphere was affected by extension due to the Pangea break up followed by Tethys opening. This Thesis investigates the evolution of the Valpelline Series in the Dent-Blanche Tectonic System (Western Italian Alps) which represents an exceptionally preserved exposure of Permian deep continental crust, despite being involved in the subsequent Alpine-age reworking. It shows migmatitic metapelite with different mineral assemblages (i.e., garnet-, cordierite- and orthopyroxene-bearing), amphibolite and marble, intruded by aplite and pegmatite. Melt production in metapelite and locally in amphibolite occurred during the development of the regional foliation. Quantitative microstructural and mineral-chemical analyses allow identifying three tectono-metamorphic stages. The first (D1) is associated with an early foliation (S1) preserved within mafic boudins enclosed in migmatitic gneiss. The second (D2) is related to the dominant foliation in migmatitic gneiss (S2), coeval with the regional scale anatexis and growth of garnet, orthopyroxene and cordierite. The third (D3) is related to the late folding of S2 and the development of a sillimanite-rich axial plane foliation (S3) which wraps around garnet and cordierite. Meso- and microstructural analysis helped to identify melt migration pathways in the deep continental crust. These pathways, corresponding to high-strain zones such as the S3 sillimanite-rich foliation, exhibit distinct mineralogical and structural features indicative of melt-rock interaction processes during deformation. P–T conditions of migmatization in the Valpelline Series, recorded in different lithologies, are contrasting. Black amphibolite and orthopyroxene-migmatitic gneiss show peak conditions comprised between 800–900 °C and 0.8–1.0 GPa, while cordierite-migmatitic gneiss registered peak P–T conditions at 750–800 °C and ~0.5 GPa. These contrasting P–T conditions are associated with different ages. Multi-method geochronology revealed that migmatization peaked during the D2 stage at ~290 Ma and continued until ~285–280 Ma over a period of at least 5 Ma, as suggested by garnet diffusion modelling. The reconstructed tectono-metamorphic history reflects an evolution that originated from Variscan post-orogenic collapse and lithospheric extension during the late Carboniferous-early Permian.","language":"eng","citation":"INTO THE STRUCTURE OF THE PERMIAN DEEP CONTINENTAL CRUST: A MULTISCALE APPROACH TO RECONSTRUCT MIGMATIZATION IN THE VALPELLINE SERIES (DENT BLANCHE TECTONIC SYSTEM, WESTERN ITALIAN ALPS) / F. Caso ; tutor: M. Zucali ; co-tutor: F. Farina ; coordinatore: M.I. Spalla. Dipartimento di Scienze della Terra Ardito Desio, 2024 Jan 27. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13340.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1135686/2636398/phd_unimi_R13340.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/849040"},"title":"INVESTIGATING PLANT SENESCENCE: THE ROLE OF NAC TRANSCRIPTION FACTORS IN SOLANUM LYCOPERSICUM AND ARABIDOPSIS THALIANA","internalauthor":"FORLANI, SARA","type":"Tesi di dottorato","year":"2021","abstract":"THESIS OUTLINE  In the present thesis work, the senescence process in fruit and leaf has been investigated through the analysis of different mutant lines of Arabidopsis thaliana and Solanum lycopersicum. In particular, the work has focused on the downregulation of three NAC transcription factor genes, NAC058 (AT3G18400), NAC100 (AT5G61430, both analysed in Arabidopsis), and HEBE (Solyc12g036480), analysed in tomato. All of them have been selected for the analysis due to their putative role in senescence, e.g. their expression has been detected in senescing siliques (NAC058, NAC100) and in ripening berries (NAC100). In addition, HEBE is the putative ortholog in tomato of NAC058 of Arabidopsis.  The work has been divided in the following chapters:  - CHARACTERIZATION OF NAC058, A NEGATIVE SENESCENCE REGULATOR IN SILIQUES OF Arabidopsis thaliana - in this section, NAC058 is identified as fruit-specific negative regulator of senescence. Overexpression lines are analysed and NAC058 expression is localized in different tissues of  21  the siliques. Moreover, the bond between this transcription factor and phytohormones is preliminarly evaluated.  - NAC100, A NOVEL NAC TRANSCRIPTION FACTOR THAT NEGATIVELY REGULATES FRUIT SENESCENCE IN Arabidopsis thaliana – in this chapter, a comparison between transcriptomic data of Arabidopsis senescing siliques and tomato ripening berries allows to identify conserved NAC genes expressed during fruit maturation. 7 Arabidopsis lines carrying T-DNA insertions in these genes are analysed looking at senescence-related traits and, among them, nac100 is selected as putative negative regulator of silique senescence. In addition, NAC100 is found to affect silique development.  - HEBE, A NOVEL POSITIVE REGULATOR OF LEAF SENESCENCE IN Solanum lycopersicum – in this section, HEBE, the putative ortholog of NAC058 in tomato, is temporary silenced in tomato plants through Virus-Induced Gene Silencing (VIGS), resulting in a stay-green phenotype. The work has been published in 2020 (paper in attachment at the chapter).","language":"eng","citation":"INVESTIGATING PLANT SENESCENCE: THE ROLE OF NAC TRANSCRIPTION FACTORS IN SOLANUM LYCOPERSICUM AND ARABIDOPSIS THALIANA / S. Forlani ; tutor: S. Masiero. Dipartimento di Bioscienze, 2021 May 31. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12113.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/849040/1817689/phd_unimi_R12113.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1166919"},"title":"NUMERICAL, ANALYTICAL AND EXPERIMENTAL STUDY OF THE THERMAL BEHAVIOUR OF INNOVATIVE ENERGY GEOSTRUCTURES","internalauthor":"GEROLA, MARCO","type":"Tesi di dottorato","year":"2025","abstract":"\"This work aims to advance understanding and knowledge of the thermal behaviour of innovative Energy Geostruc-  tures (EGs), which serve a dual purpose: providing structural stability and supporting buildings or soil while  harnessing geothermal energy for the heating and/or cooling demands of buildings. Two innovative EG types were  investigated in this study: the Energy Quay Wall (EQW) and the Cutter Soil Mix (CSM) energy wall.  The EQW integrates zeta steel sections, so-called sheet piles, embedded in soil to stabilise river or canal banks,  with steel heat exchanger pipes welded onto the profiles to facilitate thermal energy exchange with both soil and  open water. This study builds upon a full-scale EQW test installed in Delft, the Netherlands, which incorporated  three distinct types of steel heat exchangers: (1) shallow loops and (2) add-on panels, both installed at a depth of  3 m, and (3) deep loops, positioned at a depth of 15 m.  Monitoring data from the full-scale test were analysed to evaluate the energy performance of each heat ex-  changer type, their impact on soil temperature, and the capability of deep loops to extract heat from open water  during summer for subsurface thermal energy storage. The results reveal that the shallow loops demonstrate the  highest heat extraction rate per activated quay wall surface area in most scenarios, with their performance closely  linked to the open water temperature. Additionally, shallow loops do not require recharging time to restore sur-  rounding temperatures, indicating stable long-term performance, yet are able to extract the least energy at the  coldest time periods of the year. In contrast, the deeper loops exhibit greater stability across varying open water  temperatures and achieve the highest total energy extraction per quay wall length. Based on these analyses, practi-  cal charts were developed to estimate energy extraction as a function of open water and heat exchanger fluid inlet  temperatures, providing a preliminary evaluation tool for assessing the thermal efficiency of EQW systems.  Two 3D numerical finite element (FE) models were developed to investigate the thermal behaviour of EQWs.  The first FE model, referred to as the \"\"Thermal Initialization\"\" model, evaluated the temperature distribution within  the soil prior to the thermal activation of the EQW. The second FE model, termed the \"\"Geothermal Activation\"\"  model, incorporated the heat exchanger pipes, which were represented in a one-dimensional framework. Both  numerical FE models were validated using measured data from the full-scale test. The Geothermal activation  model was subsequently employed to quantify the contributions of soil layers, open water, and air to the overall  energy performance of the system. Furthermore, it was used to analyse the effects of turbulent flow within the  heat exchanger pipes and the role of open water movement in optimising the thermal performance of the EQW  system. The results indicate that the primary source of energy gain is from open water, and the dominance of this  contribution is further increased by the presence of turbulent flow within the heat exchanger pipes. However, the  soil can play a key role in short term energy delivery. Furthermore, this study emphasises the importance of the  open water movement, revealing a 48% reduction in energy extraction for fully stationary water scenarios.  To explore the impact of design and site-dependent parameters on extracted energy and identify strategies  to enhance the energy performance of the EQW system, a sensitivity study using the Taguchi statistical method  was performed. This parametric analysis was conducted using a series of 3D FE numerical models derived from  the Geothermal activation model, accounting for configurations involving both steel pipes directly welded to zeta  profiles (as in the case of shallow and deep loops) and add-on panels. Results show that the most influential  design parameter is the number of U-loops connected in series, which can be adjusted within a reasonable range  to significantly improve performance. The effects of varying inlet fluid temperature, pipe cross-sectional area,  and heat exchanger fluid velocity are also critical for the energy output. Among site-specific factors, open water  body temperature and its depth are confirmed as pivotal for achieving high energy performance, while new insights  emerge regarding the contributions of open water flow velocity and soil thermal conductivity, particularly in short-  term EQW thermal output.  The second innovative EG type investigated is the CSM energy wall, constructed using the CSM technique.  This approach combines in situ soil with a cementitious binder slurry to produce a mortar-like material, commonly  employed for constructing cut-off and retaining walls. To enhance structural strength and resistance to bending  moments, CSM walls can be reinforced with steel beams or cages, which also provide a practical support for  mounting heat exchanger pipes. A full-scale CSM energy wall test site, located in Amstelveen, the Netherlands,  served as the basis for this study.  The thermal properties of the full-scale CSM wall were characterised through laboratory testing, then incor-  porated into a 3D FE numerical model. This model replicated the full-scale test geometry, including the heat  exchanger hydraulic system and soil layers, to accurately simulate the thermal exchange processes and thermal  performance of the CSM energy wall full-scale test. The 3D FE numerical model was validated using data from  the CSM full-scale test and applied to evaluate the short- and long-term energy performance of the CSM instal-  lation under various scenarios, including insulated and uninsulated horizontal pipes and different vertical loop  configurations and different energy demands. Findings indicate that energy demand significantly affects system  performance, with combined heating and cooling demands enhancing long-term heat exchange rates compared  to heating-only scenarios. The study demonstrates that non-insulated connection pipes increase overall heat ex-  change rates, especially under heating-only conditions, while reducing the number of U-loops decreases thermal  interaction and enhances energy extraction rates.  After numerically evaluating the energy performance of the CSM energy wall, analytical formulations were  developed to estimate one of the following parameters— outlet-inlet temperature difference, heat exchange rate,  or thermal diffusivity of the wall-soil system — when the other two are known. These formulations, derived using  the infinite plane source and shape factor methods, provide a simplified approach for designing the thermal system  of the CSM energy wall, eliminating the need for computationally intensive numerical models. By introducing  three advancements in the infinite plane source and shape factor methods, the predicted outlet temperature from  the heat exchanger pipes differs by 5.7% from the measured data under steady-state conditions. These findings  demonstrate the reliability and accuracy of the new analytical formulations.  Overall, the conducted research facilitated significant advancements for both EQW and CSM energy wall  installations by achieving the following:  • Advancing the understanding of heat exchange processes governing the thermal performance of EQW and  CSM systems.  • Improving thermal efficiency in both short- and long-term operational scenarios.  • Optimising the design process through the use of performance estimation charts for EQW systems and  analytical formulations for CSM systems.  These findings underscore the viability of EQW and CSM energy wall systems as sustainable and cost-efficient  technologies for harnessing shallow geothermal energy.\"","language":"eng","citation":"NUMERICAL, ANALYTICAL AND EXPERIMENTAL STUDY OF THE THERMAL BEHAVIOUR OF INNOVATIVE ENERGY GEOSTRUCTURES / M. Gerola ; advisor: F. Cecinato ;  co-advisor: J. Haasnoot ;  phd coordinator: G. Muttoni. Dipartimento di Scienze della Terra Ardito Desio, 2025 May 29. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13541.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1166919/3078300/phd_unimi_R13541.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1083408"},"title":"EXOTICIS TYPIS. GIAMBATTISTA BODONI (1740-1813) E LE COLLABORAZIONI EDITORIALI PER LE PUBBLICAZIONI IN LINGUE ORIENTALI","internalauthor":"SAVIOTTI, PIERFILIPPO","type":"Tesi di dottorato","year":"2024","abstract":"Giambattista Bodoni (1740-1813) was an admired and eulogised typographer during his lifetime and cel-ebrated from the first months after his death. As early as 1813 (but even a few years earlier), the first publications praising his typographic activity appeared, as well as the first official biographies, above all the Vita del cavaliere Giambattista Bodoni (1816) by Giuseppe De Lama. The first half of the 20th century was also characterised by great efforts in this regard, particularly on the 100th anniversary of his death (1913) and the 200th anniversary of his birth (1940), also exploited by the fascist regime for propaganda purposes. It was only with the second half of the 20th century, and especially with the foundation of the Museo Bodoniano in Parma (1963) and the consequent opening to the public of the extraordinary doc-umentary and material archive of Bodoni’s printing works, that a fruitful phase of scientific contribu-tions took hold, culminating in contemporary digital projects such as the Biblioteca Bodoni. While a great deal of effort has been devoted to the analysis of Bodoni’s typographic and political-cultural dimension, there is still room for investigation regarding the editorial aspects of his activity, especially in under-standing the dynamics that regulated his relationship with authors and editorial collaborators for the production of the most prestigious editions.  Of his biographical events, on the other hand, the period Bodoni spent in Rome (1758-1766) remains somewhat obscure, where he did his typographic apprenticeship at the Tipografia Poliglotta of Propa-ganda Fide, specialising in the engraving of characters from the Oriental alphabets (an activity that was also his flagship in his later years in Parma) and where he met the most important personalities on the Roman cultural scene with whom he forged bonds of friendship and collaboration that were the basis of his activity in the years that followed.  Having identified these two gaps after a careful study of previous bibliographical sources, the work was set out along two main paths: the reconstruction of the apprenticeship period that Bodoni spent in Rome at the Tipografia Poliglotta, subsequently attempting to analyse how the experiences he undertook and the relationships he matured bore fruit in his subsequent activity in Parma, and the investigation of certain aspects of his work from an editorial point of view through the main publishing collaborations for the realisation of the polyglot editions.  In addition to Giovanni Cristofano Amaduzzi (1740-1792), from 1770 superintendent of the Tipografia Poliglotta, who was Bodoni’s consultant both for the preparation of some Greek editions and for the constant work on the development of the ‘exotic’ types, the printer had fruitful editorial collaborations with the Hebrewist Giovanni Bernardo De Rossi (1742-1831) for the publication of the first prestigious editions printed with Oriental types, Tommaso Valperga di Caluso (1737-1815) for the publication of other Greek editions, as well as a Coptic grammar and a Hebrew one, and, by now in the twilight of his career, with Cardinal Giuseppe Mezzofanti (1774-1849) for the printing of the Oratio Dominca of 1806, the Lord’s Prayer printed in 155 different alphabets that represented the summa of the polyglot produc-tion of Bodoni’s printing house.  Although, at least in general terms, the definition of Bodoni as a typographer rather than a publisher remains firm (due to the lack of a unitary cultural and ‘identity’ project), the analysis of these collabora-tions has made it possible to highlight hitherto obscure aspects that, at least for the preparation of some individual editions, have brought to light typical characteristics of the publishing trade, according to both a humanistic and a modern definition, particularly with regard to the attention paid to all phases of book production, not just typography.","language":"ita","citation":"EXOTICIS TYPIS. GIAMBATTISTA BODONI (1740-1813) E LE COLLABORAZIONI EDITORIALI PER LE PUBBLICAZIONI IN LINGUE ORIENTALI / P. Saviotti ; tutor: L. Braida ; co-tutor: P. M. Cátedra García ; coordinatore: M. Soresina. - Milano. Università degli Studi di Milano, 2024 Sep 09. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12925.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1083408/2494674/phd_unimi_R12925.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/836391"},"title":"STRUCTURAL DETERMINANTS OF NF-Y INTERACTION WITH PARTNER TRANSCRIPTION FACTORS ON DNA","internalauthor":"SAAD, DANA","type":"Tesi di dottorato","year":"2021","abstract":"Gene expression is a complex set of events coordinated by a plethora of sequence-specific transcription factors (TFs) that bind and recognise regulatory elements of genes in a combinatorial fashion, and interface with chromatin structures. NF-Y is an ubiquitous eukaryotic TF composed by evolutionary conserved subunits (NF-YA, NF-YB and NF-YC), all necessary for specific binding of the CCAAT box, a widespread element occurring in 30% of genes promoters. NF-Y binding is critical in transcriptional regulation, establishing a permissive chromatin conformation and enabling master TF binding. Genome-wide analyses of TF locations in vivo unveiled NF-Y partnership with a defined set of TFs, some of them with precise binding-site (TFBS) arrangements with respect to the CCAAT box. Analysis of promoters of cancer “signature” genes pointed toward NF-Y and E2F TFBSs as the most enriched motifs in genes overexpressed in human tumours. Their significant co-localization in vivo further suggests NF-Y and E2Fs might functionally interact by building a landing platform for co- activators. With the long-term goal of controlling such TF interactions in cancer, in this thesis we initially focused on E2F structure, and then extended our studies to NF-Y interactions on DNA.    The E2F family of TFs, originally identified with E2F1 as master regulators of cell-cycle progression, bind DNA as heterodimers with the structurally related DP subunits. Their hallmark features consist of a DNA Binding Domain (DBD) connected through a short linker to the Coiled- Coil-Marked Box (CC-MB) dimerization domain, also involved in Rb tumour suppressor proteins interactions. As structural information is only available for the separated domains, we set out to obtain a coherent view of the linked domains on DNA, and produced the ensembles of DBD-CC-MB portions of E2F1/DP1. To structurally characterise the E2F1/DP1/DNA complex we applied an integrated approach that combines in-solution (SAXS) analyses with Molecular Dynamics simulations. We provide evidence for a high level of flexibility in the overall relative topology of the heterodimer, including in a newly identified part stabilizing DNA contacts.    Next, we applied EMSA experiments to characterise DNA binding of the CDC2 cell-cycle promoter, shown to be functionally dependent from both E2F and NF-Y. While results obtained indicate non-cooperative DNA association of NF-Y and E2F1, suggesting alternative mechanisms to elicit transcriptional synergy, we observed efficient assembly of stable ternary complexes. Together, our results and tools obtained in this work will be instrumental for future structural studies involving multi-protein complex assembly on DNA, and for defining the molecular bases of TFs interactions involved in architectural organisation of gene promoters.","language":"eng","citation":"STRUCTURAL DETERMINANTS OF NF-Y INTERACTION WITH PARTNER TRANSCRIPTION FACTORS ON DNA / D. Saad ; tutor: N. Gnesutta ; co-tutor: R. Mantovani. Dipartimento di Bioscienze, 2021 Apr 22. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11982.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/836391/1777374/phd_unimi_R11982.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/932508"},"title":"CLANKRIMINALITÄT: LE RAPPRESENTAZIONI SOCIALI E ISTITUZIONALI DI UN FENOMENO CRIMINALE IN EMERSIONE NEL CONTESTO BERLINESE","internalauthor":"MAZZENZANA, SARAH","type":"Tesi di dottorato","year":"2022","abstract":"\"This research project entitled \"\" Clankriminalität in Berlin: the social and institutional representation of an emerging criminal phenomenon” aims at investigating a recent criminal phenomenon whose presence is found within an environment often considered unrelated to the emergence of forms of organized crime: the German context. The theoretical framework of the research is structured around two thematic areas that are strongly interconnected with each other, namely the processes and dynamics of emergence of complex forms of organized crime on the one hand, and the controversial relationship existing between migratory processes and organized crime on the other hand. The study is carried out taking into consideration different sources that provide a representation of the phenomena, such as BKA and LKA reports, the archives of German newspaper and the scientific literature pubblished on the topic. The aforementioned sources are integrated with interviews to experts and privileged observers who cover a variety of roles, in order to ensure the heterogeneity of the sample and obtain multiple and diversified information. The ultimate goal is to put forward hypotheses about the factors that contributed to the construction of the social and institutional representation of the phenomenon.\"","language":"ita","citation":"CLANKRIMINALITÄT: LE RAPPRESENTAZIONI SOCIALI E ISTITUZIONALI DI UN FENOMENO CRIMINALE IN EMERSIONE NEL CONTESTO BERLINESE / S. Mazzenzana ; tutor: M. Massari ; coordinatore: F. Basile. Dipartimento di Studi Internazionali, Giuridici e Storico - Politici, 2022 Jul 11. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12334.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/932508/2047097/phd_unimi_R12334.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1210117"},"title":"«UN ARCHIVIO VIVO» PER «UNA STORIA IMMEDIATA». L'ISTITUTO ERNESTO DE MARTINO NELLO SCENARIO INTERNAZIONALE","internalauthor":"PARIS, CHIARA","type":"Tesi di dottorato","year":"2026","abstract":"This study investigates the history of the Ernesto de Martino Institute (IEdM) within the broader framework of the discovery and use of oral sources, a field shaped by shared practices and reflections that – often in fragmented and episodic forms – cut across transnational networks of researchers, institutions, artists, and intellectuals engaged in their documentation and enhancement. The Institute is examined both as a site of cultural elaboration, with its own orientation in cultural politics, and as a “political” archive, whose origins, structure, and evolution are interpreted considering the Italian and international context. The present PhD thesis develops along two main lines: on the one hand, an examination of the IEdM’s transnational relationships established with like-minded institutions and individuals in Europe and beyond; on the other, the exploration of the emergence and diffusion of oral history, with particular attention to potential intersections between its early promoters and the Institute’s experience. Adopting a transnational and comparative perspective, the research combines approaches from cultural and intellectual history, translocal microhistory, sound studies, and archival activism. It understands sound recording as a cultural process and knowledge as «in transit» between contexts and communities of thought. The dissertation is structured into a methodological introduction; a historical overview of Italian and international precedents in the use of sound testimony; an in-depth analysis of the IEdM’s cultural mandate, including a reconstruction of its network of contacts; and a final chapter on the 1970s–1980s, focusing on the Institute’s relationship with the so-called «Italian school of oral history». The documentary corpus includes correspondence, project files, printed materials, the Institute’s sound holdings, and fifteen interviews conducted between 2023 and 2024. Archival research was also carried out in Germany, Hungary, the United Kingdom, and Switzerland, following the circulation of books, records, tapes, and newsletters. The findings challenge the view of the Institute as an “insular” entity, showing instead its exchanges with a wide range of countries – most notably the United States, Great Britain, the German Democratic Republic, Hungary, Cuba, and China – within an antifascist, Third-Worldist, and internationalist cultural horizon. The IEdM engaged with institutions and intellectuals that, in some contexts, national historiographies identify as pioneers in the development of oral history. These transnational dynamics did not operate as one-way transfers but as horizontal exchanges involving books, recording formats, radio scripts, and theoretical essays, thereby generating a shared transnational framework of reference. The Institute’s cultural politics focused on its sound archive, conceived as an imperative to document the expressive forms of “subaltern” subjects. This dual mandate – at once political and cultural – highlighted the inseparability of the two dimensions. Studying the IEdM thus means tracing a practice that ranged from collection to description, preservation, collective re-elaboration, and public dissemination of sources – always conceiving recording as a cultural process and knowledge as “in transit” between contexts and intellectual-militant groups. This perspective is brought into focus through the analysis of the Institute’s first fieldwork campaigns, the Sound Archives record series, and community-based projects. In the context of the rise of oral history in Italy from the mid1970s, the thesis highlights the IEdM’s role in a field characterized by a persistent tension between militant circuits and the pursuit of academic recognition. Rejecting a teleological approach to the development of oral history – and engaging with the reflections of Graham Smith, Linda Shopes, and Daniel Kerr – the research sheds light on both anticipations and continuities in the ways sound sources were conceived, their narrative dimension, and the intersubjectivity of the interview. In doing so, it offers a new interpretation of the trajectories of oral history in Italy, emphasizing continuities, frictions, and processes of exchange and circulation.","language":"ita","citation":"\"«UN ARCHIVIO VIVO» PER «UNA STORIA IMMEDIATA». L'ISTITUTO ERNESTO DE MARTINO NELLO SCENARIO INTERNAZIONALE / C. Paris ; tutor: I. M. L. Piazzoni, F. Guidali ; coordinatore: P. Grillo. Dipartimento di Studi Storici \"\"Federico Chabod\"\", 2026 Jan 20. 38. ciclo, Anno Accademico 2024/2025.\"","filename":"phd_unimi_R13834.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 23-LUG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/916688"},"title":"INHERENT CHIRALITY AT WORK FOR APPLICATIONS IN CHIRAL ELECTROCHEMISTRY, CHIROPTICS AND SPINTRONICS.","internalauthor":"GRECCHI, SARA","type":"Tesi di dottorato","year":"2022","abstract":"This three-year thesis project is aimed to deeply investigate the potentialities of the inherently chiral strategy in the chiral voltammetry field, as well as in circular dichroism and magnetoelectrochemistry ones.   Voltammetric experiments must take place at chiral electrochemical interphases with the implementation of (inherently) chiral selectors, according to two strategies: i) exploitation of electrode surfaces modified with electrodeposited heterocycle-based inherently chiral oligomer films (with the stereogenic element responsible for chirality coinciding with the functional group responsible for the material specific properties); ii) use of enantiopure chiral media with high intrinsic order.  Concerning the modification of electrodes with inherently chiral oligomer films, several new inherently chiral monomers were studied with different techniques, in order to amplify the range of monomer structures studied and the combination of chiral selector/probe investigated (in fact, many new chiral probes, also of pharmaceutical interest were used in enantioselection tests, with different nature, chemical structures, bulkiness and reactivity). Enantioselection tests were discussed as a function of the experimental conditions; moreover, discussion of experiments with a systematic series of planar stereogenicity ferrocenes provided key clues concerning the probe-selector interactions in the process, while experiments on a systematic new family of inherently chiral monomers with different substituents on the N atoms in the biindole core enabled to study the effect of H bonds in the enantioselection process.   Finally, the inherently chiral oligomer films were discussed in advanced application for magnetoelectrochemistry experiments, employing an innovative experimental setup and resulting in impressive spin-related effects.   Also concerning the chiral media approach, several new chiral selectors were presented, employing them as low concentration chiral additives in achiral commercial ionic liquids or as bulk media, testing their performances in enantioselection experiments.   The performances of bio-based and synthetic chiral selectors were compared, studying different artificial inherently chiral media. The application of another kind of advanced chiral media were exploited, studying the enantioselection ability and properties of chiral Deep Eutectic Solvents (DESs) of natural origin. The DESs employed in this research project are composed of a mixture of at least two components, a hydrogen bond acceptor (HBA) and a hydrogen bond donor (HBD), which are able to self-associate to form a new eutectic phase characterized by a melting point (< 100°C) lower than that of each individual component and significantly lower than the predicted one for an ideal case.","language":"eng","citation":"INHERENT CHIRALITY AT WORK FOR APPLICATIONS IN CHIRAL ELECTROCHEMISTRY, CHIROPTICS AND SPINTRONICS / S. Grecchi ; tutor: P. R. Mussini ; supervisori:  T. Benincori, S. Arnaboldi. Dipartimento di Chimica, 2022 Mar 25. 34. ciclo, Anno Accademico 2021. [10.13130/grecchi-sara_phd2022-03-25].","filename":"phd_unimi_R12230.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/916688/2003412/phd_unimi_R12230.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1034711"},"title":"IN VITRO AND OMICS METHODOLOGIES APPLIED TO ANIMAL NUTRITION TO ADDRESS FEED-FOOD COMPETITION AND GREENHOUSE GAS EMISSIONS","internalauthor":"MANONI, MICHELE","type":"Tesi di dottorato","year":"2024","abstract":"Global population growth and the growing demand for animal-source food are two challenges for global food security and sustainability of agriculture and livestock production. Meanwhile, the use of food-competing feedstuffs and the greenhouse gas emissions from livestock are two major issues that challenge the global feed and food supply chain. Here, we applied several in vitro and omics methodologies to estimate the potential inclusion of alternative feeding strategies in the frame of the environmental sustainability of livestock production. We focused on two areas: i) the dietary inclusion  of food by-products (e.g. former food products) in the diet of piglets and pigs to  evaluate their impact on metabolism, and ii) the dietary inclusion of tannins to reduce methane production from enteric fermentation and ammonia in ruminants. The first research project involved the study of the metabolic impact of the dietary inclusion of salty and sugary former food products (FFPs) in pigs from the weaning phase to the finishing phase. To do this, we applied omics technologies to obtain a broad and  comprehensive picture of the metabolism of the pigs fed with FFPs. After assessing that both salty and sugary FFPs diets did not alter the growth performance and the feeding behaviour of the pigs, we observed a limited impact of FFPs on the modulation of the metabolome and the proteome-peptidome of piglets and pigs in multiple districts in liver and plasma. Indeed, we observed only a low number of modulated metabolites and proteins and a weak impact on the activation of specific metabolic pathways. We concluded that FFPs can be safely used as alternative and sustainable feed ingredients  to reduce the feed-food competition. The second research project involved the study of the effect of two tannin compounds, called gallic acid (GA) and ellagic acid (EA), on the composition of the rumen microbial community and on the end products of enteric fermentation, with methane and ammonia production under the spotlight. To do this, we simulated rumen fermentation using two in vitro approaches, named Hohenheim gas test (short-term batch culture) and Rusitec (long-term continuous culture). The GA and EA molecules, and the combination of both molecules, decreased methane and  ammonia production, but they influenced the overall rumen fermentation depending of the dosage used in terms of a reduced production of short-chain fatty acids and degradation of nutrients in rumen. Furthermore, we observed a strong modulation of the rumen bacterial community following tannins’ treatment, with limited impact on rumen archaea. The results of the two projects contributed to increase the validity of in vitro and omics evaluations as preliminary steps in searching innovative feeding strategies to increase the environmental sustainability of livestock production. Further work is needed to increase the robustness of these innovative and sustainable feeding strategies.","language":"eng","citation":"IN VITRO AND OMICS METHODOLOGIES APPLIED TO ANIMAL NUTRITION TO ADDRESS FEED-FOOD COMPETITION AND GREENHOUSE GAS EMISSIONS / M. Manoni ; tutor: L. Pinotti ; cotutor: M. Tretola ; chair of the doctoral program: F.Cheli. Dipartimento di Medicina Veterinaria e Scienze Animali, 2024 Mar 13. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12957.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1034711/2374239/phd_unimi_R12957.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/956777"},"title":"EXPLORING NOVEL SUSTAINABLE SYNTHETIC METHODOLOGIES WITH NITRO COMPOUNDS","internalauthor":"FAVERIO, CHIARA","type":"Tesi di dottorato","year":"2023","abstract":"The present thesis work is devoted to the study of four different topics, the reduction of nitroolefins employing ammonia borane as reductant, the enantioselective reduction of β,β-disubstituted nitroalkenes in deep eutectic solvents, the preliminary investigation of other enantioselective nitroalkenes reductions catalyzed by chiral organocatalysts and the study of mechanically interlocked molecules as organocatalysts in acylation reactions.   In particular, Chapter 1 introduces the concepts of green chemistry and of sustainable chemistry as they are the guiding threads of the whole manuscript. Moreover, the first chapter includes a brief overview about green metrics. The use of ammonia borane as reducing agent for the reduction of nitroolefins to nitroalkanes is described in Chapter 2, exploring the possibility to run the reaction both in traditional solvents and in deep eutectic solvents. The tests about the reuse of the DES in four subsequent reactions are also presented.   Chapter 3 reports our findings in the use of deep eutectic solvents as reaction media for the enantioselective reduction of β,β-disubstituted nitroalkenes catalyzed by Jacobsen-like catalysts. This is one of the first examples of a challenging transformation: a reaction in which the substrate, the catalyst and the reagents interact through hydrogen bonding in a reaction medium that is held together thanks to a hydrogen bonding network.  The preliminary studies about other enantioselective reduction catalyzed by chiral organocatalysts are the topic of Chapter 4, that reports the investigation of a novel activation mode of ammonia borane, trying to achieve its coordination by an enantiopure organocatalyst via hydrogen bonding to explore the enantioselective reduction of β,β-disubstituted nitroalkenes. Besides, the first findings about the regioselective and enantioselective reduction of nitro ester diene are reported.  Chapter 5 describes the work done during the six months period at the University of Southampton, in the group of Professor Stephen M. Goldup. In particular, the optimization of the synthesis of a novel catenane is discussed and the preliminary data about its use as an organocatalyst in acylation reactions are summarized.","language":"eng","citation":"EXPLORING NOVEL SUSTAINABLE SYNTHETIC METHODOLOGIES WITH NITRO COMPOUNDS / C. Faverio ; tutor: M. Benaglia ; coordinatore corso dottorato: D. Roberto. Dipartimento di Chimica, 2023 Mar 17. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12576.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/956777/2151495/phd_unimi_R12576.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1047710"},"title":"NANOTECHNOLOGICAL APPROACHES FOR CANCER DIAGNOSIS, TREATMENT AND MANAGEMENT: IMPLEMENTATION OF FERRITIN PROTEIN NANOPARTICLES FOR TUMOR TARGETING","internalauthor":"SEVIERI, MARTA","type":"Tesi di dottorato","year":"2024","abstract":"Despite the efforts performed in the field of cancer research, data concerning the incidence of this pathology in North America and Europe reveal that tumors still represent the second cause of death. In fact, the effectiveness of many drugs is often seriously affected by lack of specificity in hitting the therapeutic target, determining the onset of toxicity issues.  In this context, Nanomedicine aims to make a decisive contribution. Nanoparticle (NPs)-based drug delivery systems can enhance the physicochemical properties of a wide variety of drugs used in oncology to limit off-site side effects and improve their therapeutic efficacy, increasing drug accumulation in target tissue. Thus, through the development of nanocarriers capable of selectively recognizing and interacting with tumor cells and/or tissues, potential groundbreaking applications in the diagnosis, treatment and prevention of cancer could become feasible.  In my PhD project, I exploited the unique features of a NPs based on recombinant heavy-chain ferritin nanocages (HFn). HFn nanocages represent a promising protein- based class of NPs for drug delivery widely investigated by virtue of (1) their natural tumor homing and limited accumulation in off-target organs which leads to reduced off-target toxicity; (2) their biocompatibility; (3) their structure that allows the encapsulation of different types of drugs or fluorescent tracers; (4) their versatility to be modified at the surface both exploiting chemical and genetical strategies.  My work has been divided into three main studies aimed at implementing innovative strategies based on HFn nanocages both for diagnostic and therapeutic approaches in oncology.  In Study 1, I presented the exploitation of HFn nanocages as nanodevices for fluorescence image-guided surgery (FGS). This technique is gaining interest due to its potential to improve tumor margin visualization and real-time identification of tumor deposits, maximizing the benefits for patients. However, no tumor-targeted probe effectively capable of localizing tumor tissue is available to date. For this reason, we proposed a HFn-based nanotracer for the delivery of indocyanine green (ICG), which is the main fluorescent dye currently used in clinics for FGS. A novel variant of HFn was developed, extensively characterized in vitro and loaded with ICG for in vivo experiments demonstrating potentiality as tumor-targeted nanotracers for the identification of tumors.  In Study 2, HFn nanocages were exploited for the encapsulation of a chemotherapeutic drug, doxorubicin (DOX) obtaining FerOX nanoformulation. FerOX has been investigated by virtue of its natural tumor homing and limited accumulation in off- target organs which leads to reduced off-target toxicity of drugs herein incapsulated. In particular, the object of this study was to assess the efficacy of FerOX as an alternative formulation capable of preserving the proliferative potential of human lymphocytes and the potential impact in the generation of an adaptative immune response after treatment.  In Study 3, we focused on the use of HFn nanocages conjugated to the monoclonal anti-HER2 antibody trastuzumab (TZ). By exploiting the ability of HFn to cross the blood brain barrier (BBB), we achieved the delivery of TZ as a prophylactic treatment to tackle brain metastasis in HER2-positive advanced breast cancer.","language":"eng","citation":"NANOTECHNOLOGICAL APPROACHES FOR CANCER DIAGNOSIS, TREATMENT AND MANAGEMENT: IMPLEMENTATION OF FERRITIN PROTEIN NANOPARTICLES FOR TUMOR TARGETING / M. Sevieri ; tutor: S. Mazzucchelli ; coordinator: C. Sforza. Dipartimento di Scienze Biomediche e Cliniche, 2024 May 21. 36. ciclo, Anno Accademico 2023. [10.13130/sevieri-marta_phd2024-05-21].","filename":"phd_unimi_R12980.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1047710/2405021/phd_unimi_R12980.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1121915"},"title":"ONLINE LEARNING, UNIFORM CONVERGENCE, AND A THEORY OF INTERPRETABILITY","internalauthor":"ESPOSITO, EMMANUEL","type":"Tesi di dottorato","year":"2024","abstract":"This doctoral thesis covers various aspects of theoretical machine learning relative to two of its most fundamental paradigms: batch learning and online learning. In particular, we address the role of feedback models for multiple online learning problems, the sample complexity for uniform convergence, and a learning-theoretic approach to interpretable machine learning. First, we focus on online learning and investigate variants of the multi-armed bandit problem, including settings with feedback graphs, expert advice, and delayed feedback. We improve bounds on the minimax regret for undirected, strongly observable feedback graphs and develop nearly optimal algorithms for directed, stochastic feedback graphs without prior information on the distribution of the graphs. Additionally, we derive improved regret bounds for bandits with expert advice and explore the impact of intermediate observations in the delayed feedback setting, designing a meta-algorithm to achieve near-optimal regret which shows a reduced effect of the total delay. Second, we study the uniform convergence property of real-valued function classes with finite fat-shattering dimension. We provide an improved bound on the sample complexity of uniform convergence, closing the gap with existing lower bounds. Finally, regarding interpretability, we establish a taxonomy for approximating complex binary concepts with interpretable models such as shallow decision trees. Leveraging uniform convergence for Vapnik-Chervonenkis classes and von Neumann's minimax theorem, we achieve a surprising trichotomy for interpretable concepts while revealing connections between interpretable approximations and boosting.","language":"eng","citation":"ONLINE LEARNING, UNIFORM CONVERGENCE, AND A THEORY OF INTERPRETABILITY / E. Esposito ; supervisor: N. Cesa-Bianchi ; co-supervisor: M. Pontil ; coordinatore: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2024 Dec 05. 37. ciclo","filename":"phd_unimi_R13312.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1121915/2600332/phd_unimi_R13312.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1256795"},"title":"POLY(GLYCEROL SEBACATE) COPOLYMERS FOR DRUG DELIVERY","internalauthor":"ARNABOLDI, LUCA","type":"Tesi di dottorato","year":"2026","abstract":"Poly(glycerol sebacate) (PGS) is a biocompatible elastomer having high biomedical interest; however, its application in advanced drug delivery systems has been historically limited due to its inherent hydrophobicity and the resulting difficulties in the preparation of aqueous formulations. This thesis addressed this challenge by developing a versatile and scalable nanotechnological PGS platform based on a careful macromolecular design.  To overcome processability limitations a novel copolymer, poly(glycerol sebacate-co-oleic acid) (PGSO), was synthesized: the use of oleic acid as a monofunctional chain terminator allowed for the modulation of the polymer architecture, limiting uncontrolled crosslinking and enhancing the material's processability. This specific structural modification enabled the production of stable, high-concentration (10% w/w) aqueous dispersions via an inherently scalable and entirely solvent-free phase inversion technique. Process optimization highlighted the key role of triethanolamine (TEAOH), successfully employed not only as a salifying and stabilizing agent due to its steric hindrance, but also for its known function as a transdermal permeation enhancer.  The true potential of the system was investigated by addressing the encapsulation of curcumin, a molecule known for severe formulation criticalities related to low water solubility and a strong tendency towards crystalline self-aggregation. As classical physical approaches proved ineffective, this obstacle was overcome through a chemical compatibilization strategy. The PGSO matrix was combined with a custom-engineered active agent by synthesizing a novel Curcumin-Zinc-Oleate complex. Solid-state investigations (XRPD, FT-IR) alongside NMR spectroscopy confirmed the successful complexation which, by masking the groups responsible for hydrogen bonding, inhibited the drug's recrystallization. Concurrently, the lipophilic nature of the oleate ligand increased the thermodynamic affinity with the polymer core. This integrated approach ensured the formation of stable, homogeneously loaded and dimensionally controlled nanoparticles (~150 nm).  The formulation versatility of the platform was confirmed by its ability to encapsulate other lipophilic active ingredients, such as piroxicam and cinnamic acid. To complete the work, preliminary in vitro biocompatibility evaluations confirmed the absence of cytotoxicity for the empty nanocarrier and the preservation of the antiproliferative activity of the encapsulated complex. Furthermore, exploratory studies on the reactivity of the PGSO double bonds via photo-initiated thiol-ene chemistry provided encouraging indications regarding the feasibility of using this dispersion to develop in situ photo-crosslinkable biomaterials.  In conclusion, this thesis provides a robust methodological toolkit for the application of PGS. The results confirm how the synergy between controlled polymer synthesis, solvent-free formulation processes, and chemical engineering of the therapeutic payload represents a highly effective pathway for the development of targeted and industrially transferable nanocarriers.","language":"eng","citation":"POLY(GLYCEROL SEBACATE) COPOLYMERS FOR DRUG DELIVERY / L. Arnaboldi ; supervisor: M. Ortenzi ; cosupervisor: F. Selmin ; phd coordinator: L. Prati. Dipartimento di Chimica, 2026 Jun 23. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13940.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 23-DIC-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1248935"},"title":"FORCED DISPLACEMENT IN INTERNATIONAL CRIMINAL LAW","internalauthor":"PARSI, LAVINIA","type":"Tesi di dottorato","year":"2026","abstract":"Forced displacement is one of the most pressing phenomena of our time. According to UNHCR data, the number of forcibly displaced persons worldwide increased from 18.2 million to 117.3 million between 1993 and 2024 – more than six times higher in thirty years. Despite the scale and severity of the phenomenon, forced displacement has rarely been examined as a specific and coherent object of analysis within international criminal law. Existing legal scholarship has either approached the subject from a wider human rights perspective or tended to focus on specific political, historical or geographical contexts, rather than on displacement as a category of international crimes. This thesis represents a modest attempt to begin filling that gap by examining the constitutive elements of forced displacement within international criminal law and analysing the conceptual and structural tensions that emerge when contemporary configurations of displacement are confronted with existing legal categories.  The thesis addresses two central questions: what are the exact constitutive elements of the provisions governing forced displacement under the Rome Statute, and to what extent is the existing framework capable of capturing the diverse forms of displacement in contemporary contexts? The central argument is that international criminal law contains conceptual resources capable of addressing a wider spectrum of displacement practices than is commonly recognised. Prevailing doctrinal interpretations have often narrowed the scope of these crimes by associating them primarily with sudden episodes of mass expulsion and by insufficiently engaging with the structural power relations that shape displacement contexts. The thesis argues that the constitutive elements of crimes of displacement can only be adequately assessed when situated within the historical and political context in which displacement occurs, and in light of the power asymmetries that structure both the imposition of movement and the capacity to resist it.  The study proceeds in three parts. Part One reconstructs the historical genealogy of displacement crimes, tracing the gradual crystallisation of the prohibition against forced removal through a series of conventional instruments and judicial developments, culminating in its codification under the Rome Statute of the International Criminal Court – the legal framework that represents the primary reference for the prosecution of displacement crimes today. Part Two turns to the normative analysis of displacement and examines their constitutive elements. The analysis covers the elements common across crimes of displacement – including the relevance of the cross-border element, the forced character of the conduct, the lawful exceptions, the required mens rea, and the possible qualification as continuing or continuous offences – as well as the elements that differentiate them, with special consideration given to Article 8(2)(b)(viii) of the Rome Statute. Part Three centres around what the thesis terms ‘complex systems of displacement’ – configurations in which the movement or containment of populations forms part of broader political projects. Three types of systems are identified – settler colonialism, ethnic cleansing, and pre-entry removal as part of contemporary migration governance – each illustrated through a dedicated case study drawn from the Mediterranean region: the Moroccan occupation of Western Sahara, the policies of ethnic cleansing enforced by Israel in Gaza (and more broadly Palestine), and the Italian system of interceptions at sea in the Central Mediterranean.  The thesis adopts a critical legal methodology, combining historical, doctrinal and normative analysis, and drawing on insights developed within Third World Approaches to International Law (‘TWAIL’) scholarship. It proceeds from the conviction that rigorous doctrinal engagement and critical theoretical analysis are not mutually exclusive but mutually reinforcing: close attention to legal texts, jurisprudence and doctrinal debates gains analytical depth when situated within the historical, political and structural contexts that shape the production and interpretation of legal norms. This dual commitment informs the thesis's central ambition – to advance interpretations of displacement crimes that are both doctrinally grounded and responsive to the interests of communities most affected by forced displacement.  By reconstructing the historical genealogy of displacement crimes, analysing their doctrinal elements, and examining their operation within complex systems of displacement, the thesis seeks to demonstrate both the interpretive possibilities and the structural limits of the current legal framework – and to contribute to a more coherent and responsive understanding of crimes of displacement within international criminal law.","language":"eng","citation":"Forced Displacement in International Criminal Law / L. Parsi ; tutor: C. Meloni, F. Jeßberger co-tutor: S. Zirulia ;  coordinatrice di dottorato: F. Poggi. - Milano. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2026 May 28. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13931.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 26-NOV-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/994748"},"title":"THE POLITICS OF ECO-SOCIAL POLICIES: TOWARDS A JUST TRANSITION IN SPAIN AND IRELAND","internalauthor":"MANDELLI, MATTEO","type":"Tesi di dottorato","year":"2023","abstract":"Social and environmental challenges are deeply interconnected: it is indeed becoming increasingly evident how both climate change and green transition policies are giving rise to a new wave of social risk for the welfare state to address. Therefore, the so-called eco-social policies could represent suitable tools for the state to simultaneously pursue social and environmental goals in a synergic manner. This study concentrates on a particular type of eco-social policies, which are the ones designed to address the social consequences of decarbonisation and to achieve a just transition. Despite the importance that just transition policies could have in accompanying European countries’ net-zero transitions, these policies are not only still rarely diffused in reality but also undertheorized by political scientists, since the literature is currently dominated by prescriptive studies. Against this background, this Ph.D. thesis aims to contribute to the emerging debates about sustainable welfare and just transition by bringing in a so-far underdeveloped empirical-political perspective. Navigating a largely unexplored field, the thesis thus aspires to strengthen our analytical, theoretical and empirical understanding of just transition policies and related political dynamics. It does so, preliminarily, by proposing a novel conceptual-analytical framework; mapping existing just transition policies in European Union countries; and reflecting on the applicability of mainstream welfare state theories to potentially explain the emergence of just transition policies. Building on these preliminary insights, Spain and Ireland are selected as case studies for a comparison that aims to unveil the process culminating in the adoption and formulation of just transition policies in these two countries. The two cases are investigated through process tracing and qualitative methods, focusing on policy and politics analysis. In short, the thesis argues that national just transition policies are still relatively rare across the European Union and, with the notable exception of Spain, they are mostly formulated as narrow strategies, connected to investment-oriented instruments and to a governance that concentrates power in the hands of the government. The emergence of such policies can be explained as a result of a green-labour convergence among relevant socio-political actors engaging in political exchanges, with which political support for decarbonisation is traded for economic support to vulnerable societal groups.","language":"eng","citation":"THE POLITICS OF ECO-SOCIAL POLICIES: TOWARDS A JUST TRANSITION IN SPAIN AND IRELAND / M. Mandelli ; relatore: M.R.C. Jessoula ; coordinatore: M.R.C. Jessoula. Dipartimento di Scienze Sociali e Politiche, 2023 Sep 14. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12637.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/994748/2270030/phd_unimi_R12637.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/947209"},"title":"LONG-LASTING MOLECULAR ALTERATIONS FOLLOWING EARLY LIFE STRESS IN RATS: ROLE OF GUT MICROBIOTA AND INFLAMMATION","internalauthor":"LOPIZZO, NICOLA","type":"Tesi di dottorato","year":"2022","abstract":"It is well known that stress, especially when experienced early in life, affects the brain developmental trajectories leading to an enhanced vulnerability for several mental disorders later in life. The adverse outcomes depend on the timing of the stressful experiences, and in this contest, early stages, such as pregnancy and adolescence, represent key sensitive periods for brain development. Several studies in animal models have been carried out to understand the mechanisms underlying the negative outcomes associated with early adverse exposures. The presence of a chronic low-grade inflammatory status has been suggested to play a central role, however, a better knowledge of the inflammatory processes, as well as of the neurodevelopmental temporal window where such alterations become manifested, is still needed. Moreover, among the biological systems involved, the gut microbiota has recently been proposed to act at the interplay between the stress response system, brain functionality and inflammatory processes, through the gut-brain-immune axis communication.   To better elucidate the involvement of inflammation and the gut microbiota in the long-lasting functional effects of stress exposure, we have used the prenatal stress (PNS) paradigm, a well-established preclinical model of stress during pregnancy that causes impairments in self-care, motivation and sociability and we have investigated possible long-lasting alterations in the inflammatory mechanisms. Specifically, we found that adult animals exposed to PNS show a significant cortical activation status of the p38 MAPK, NF-kB, Neuroinflammation and Dendritic cell maturation signalling pathways. We also found that PNS causes the most pronounced alterations in inflammatory mechanisms already at adolescence, highlighting the biological vulnerability of this temporal window.   As we reported adolescence as the temporal window where biological vulnerability begins to manifest, we wanted to test whether pharmacological interventions during adolescence could modulate the impact of stress early in life. Therefore, we treated adolescent animals exposed to PNS with lurasidone, and we analysed their whole genome transcriptome. Our analyses indicated that none of the pathways related to pro-inflammatory processes were present in PNS animals treated with lurasidone, whereas we reported the implication of several processes related to inositol metabolism among the top involved mechanisms.    As we also aimed at investigating the role of the gut microbiota, we tested changes induced by PNS exposure in the gut microbiota composition during different temporal windows both in male and female offspring. We reported that the gut microbiota significantly evolves during ageing both in female and male rats and that restraint stress during the last week of gestation produced several short- and long-lasting changes in the gut microbiota composition with a significant modulation of bacterial taxa such as Parabacteroides, Lachnoclostridium, Eubacterium ventriosum, Eisenbergiella, Turicibacter, Lactobacillus, and Muribaculum.  As we observed that stress exposure during the prenatal period affects behaviour and it is associated with alterations in inflammatory mechanisms and in gut microbiota composition, we then wanted to evaluate the consequence of stress during a different temporal window (e.g., adolescence) on the same biological outcomes. Therefore, we investigated the effects of stress exposure during adolescence, by applying a social isolation paradigm, on central inflammation and gut microbiota. 16S sequencing analysis revealed that microbial changes were influenced by age in both isolated and control rats, regardless of sex, whereas social isolation impacted the microbial composition in a sex-dependent manner. Specifically, we found that social isolation induced short-term gut microbiota alterations in females but not in males. We also identified several stress-related bacterial taxa such as Odoribacter, Akkermansia, Parabacteroides, Ruminiclostridum 5. At the central level, we found a specific inflammatory pattern in dorsal and ventral hippocampus that significantly correlated with gut microbiota composition.  Overall, our findings support the notion that the negative behavioural outcomes related to early life stress exposure are associated with specific molecular signatures in inflammatory pathways and in the gut microbiota community structure and composition. The alterations become fully manifested in adolescence, pointing out this temporal window as the most sensitive and vulnerable period where interventions could be already effective. Indeed, we observed that a pharmacological treatment with lurasidone during this period moderates PNS-induced alterations in inflammatory processes, representing a possible intervention tool to restore or moderate the detrimental long-lasting effects caused by stress early in life exposure.","language":"eng","citation":"LONG-LASTING MOLECULAR ALTERATIONS FOLLOWING EARLY LIFE STRESS IN RATS: ROLE OF GUT MICROBIOTA AND INFLAMMATION / N. Lopizzo ; tutor: M.A. Riva ; co-tutor: A. Cattaneo ; coordinatore corso di dottorato: G. D. Norata. Dipartimento di Scienze Farmacologiche e Biomolecolari, 2022 Dec 12. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12642.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/947209/2104955/phd_unimi_R12642.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/819472"},"title":"EXPERIMENTAL CHARACTERIZATION OF LYSOZYME NUCLEATION THROUGH CONFOCAL DYNAMIC LIGHTSCATTERING","internalauthor":"SIMONETTO, FEDERICA","type":"Tesi di dottorato","year":"2021","abstract":"Any theory of nucleation requires two elements: first, a way to calculating properties of clusters such as their structure and free energies, and second, a dynamical description of fluctuations. Classical density functional theory has long been recognized to have the potential to provide the first element. cDFT has been used to determine the structure and energy of critical clusters for, first, nucleation of liquid droplets from a vapor and, later, that of crystallization.  The second element necessary to describe nucleation is a description of fluctuations. A natural framework for this is fluctuating hydrodynamics that is now a widely used tool applied to a range of subjects such as mode coupling theory, glass transition, and nucleation, and its foundations in more fundamental statistical mechanics have been established. The basic quantities used in the theory are the spatially varying local densities of each species as well as the velocity and temperature fields. For large particles, such as colloids or macromolecules, in a bath of smaller particles (e.g., water), an approximate effective description of the large molecules can be derived in which the effect of the smaller molecules is modeled as a combination of friction and a stochastic force.  In the present work, we focus on nucleation of protein crystals and clusters. Specific information on nucleation kinetics of protein molecules is not abundant, probably because the value of the nucleation stage was not realized by the protein crystallization community until recently. Protein crystal nucleation is a crucial problem in biological crystallography and other areas of science, technology and medicine; in particular: the in vivo nucleation process in the liquid{liquid region is also interesting for detection and understanding at the molecular level of illnesses related to protein aggregation. Protein molecules will be useful in the future for fundamental studies on nucleation because of their large size, which will permit visualization of the growth of crystals at the very beginning, when indirect information inferred from scattering studies is not very accurate.  Recent studies have demonstrated that protein crystal nuclei form within crucial precursors: protein-dense liquid clusters are regions of high protein concentration. They have been recently observed in solutions of several proteins. The typical cluster size varies from several tens to several hundreds of nanometers.","language":"eng","citation":"EXPERIMENTAL CHARACTERIZATION OF LYSOZYME NUCLEATION THROUGH CONFOCAL DYNAMIC LIGHTSCATTERING / F. Simonetto ; Tutor: M.A.C.Potenza. Dipartimento di Fisica Aldo Pontremoli, 2021 Mar 22. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11972.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/819472/1718274/phd_unimi_R11972.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/874185"},"title":"COMPUTATIONAL METHODS TO STUDY KNOWN AND NOVEL PROTEIN POST-TRANSLATIONAL MODIFICATIONS BY MASS SPECTROMETRY","internalauthor":"MASSIGNANI, ENRICO","type":"Tesi di dottorato","year":"2021","abstract":"A post-translational modifications (PTM) is the covalent modification of a protein after its synthesis, by either addition or removal of functional groups. PTMs significantly increase the complexity of the proteome by allowing each protein to exist in different forms, which can have different activity, stability or binding specificity. Because of their central role in protein regulation, PTMs are often deregulated in many diseases, especially cancer.  Since all PTMs introduce a change in the proteins mass, one of the leading techniques to study PTMs is Tandem Mass Spectrometry (MS/MS), which can measure the mass of molecules with high precision and resolution. Here, we apply computational methods to MS data, in order to study PTMs from two points of view.   In one project, we conducted a comprehensive analysis of Arginine (R) methylation at a global level. To achieve this, we significantly improved hmSEEKER, our in-house developed computational tool for the analysis of MS data from heavy methyl SILAC (hmSILAC) labelled samples, by implementing a machine learning model to identify methyl-peptides with high confidence. The hmSILAC-validated dataset was then combined with SILAC-based quantitative methyl-proteomics data from a set of SILAC experiments in which we profiled R methylation changes in response to different stimuli (e.g. Cisplatin treatment; inhibition of the major R methyltransferases; PRMT1 expression modulation) to generate the ProMetheus database (ProMetheusDB) of high-confidence methyl-sites. The in-depth analysis of R-methyl-sites inside ProMetheusDB reinforced the notion that protein R methylation modulates protein:RNA interactions but also provided new insights, such as the presence of several R-methyl-proteins involved in metabolism and immune response-related pathways or the fact that R methylation correlates differently with S/T-Y phosphorylation in response to different stimuli. Moreover, we employed computational methods to identify a number of protein:protein interactions that could be affect by this PTM and experimentally validated one of them. Finally, to fully exploit the potential of hmSILAC and hmSEEKER, we explored the application of our pipeline to the annotation of unconventional methyl-sites, which are largely uncharacterized.  Since MS has emerged as a powerful tool not only to characterize known PTMs but also to discover new ones, in a second project, we tried to expand the annotation of histone PTMs. Histone lysine (K) acetylation and methylation are routinely used identify cancer subtypes and assess their severity; however, the unbiased nature of MS analysis has revealed the existence of several additional modifications that have yet to be systematically studied. Although theoretically possible, using MS to profile all PTMs that can occur on histones is impractical at the moment, due to limitations in the post-acquisition processing of the MS data. As a matter of fact, the most common computational tools for the identification of modified peptides are not suited to search more than 5-6 PTMs at a time, and this impairs the analysis of the combinatorial nature and cross-talk of histone PTMs.   To overcome this limitation, we took advantage of a novel peptide search engine named ionbot, which can perform an “open modification search” to identify an arbitrarily large number of modifications. We reasoned that such a tool would be suitable for the detection of hyper-modified histone peptides. Upon filtering of the results, we were able to annotate not only novel histone PTMs, such as short-chain acylations, but also several amino acid substitutions that could have a biological impact on the interactions between histone and other proteins (i.e. DAXX).    The analysis presented here permitted us to better understand the extent, dynamicity and biological role of protein R methylation and identified several modifications and mutation events on histone proteins. We believe further optimization and application of these methods will lead to the discovery of novel regulatory axes and the development of new cancer therapies.","language":"eng","citation":"COMPUTATIONAL METHODS TO STUDY KNOWN AND NOVEL PROTEIN POST-TRANSLATIONAL MODIFICATIONS BY MASS SPECTROMETRY / E. Massignani ; added supervisor: G. Pavesi ; internal advisor: M. Pelizzola ; supervisor: T. Bonaldi. Università degli Studi di Milano, 2021 Dec 13. 33. ciclo, Anno Accademico 2021. [10.13130/massignani-enrico_phd2021-12-13].","filename":"phd_unimi_R12106.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/874185/1885866/phd_unimi_R12106.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/924603"},"title":"STUDYING THE PLAGUE: RETRIEVING INFORMATION FROM THE PAST","internalauthor":"NODARI, RICCARDO","type":"Tesi di dottorato","year":"2022","abstract":"Recently, due to COVID-19 pandemic, epidemic preparedness programs have received particular attention. Unfortunately, the importance of preparedness and rapid response to epidemic events reached politicians and the public only when it was too late to prevent or limit this infectious disease. This pandemic has rapidly exposed the enormous vulnerabilities of modern human societies; globalization, fast transport, climate change, high population density, and ecological transitions are all aspects of modern societies that can favour and influence the emergence of new and old human pathogens. Although it is currently impossible to predict the emergence of a new pathogen before it actually emerges, analysing past microorganisms and epidemics can allow us to learn from past successes and mistakes, so that present and future surveillance and monitoring programs can be improved.  With these premises, this thesis project incorporates biological and historical investigations to examine which information related to microorganisms and epidemics from the past can be derived from remains of organic material and historical records.  In the first part of the project, human teeth, recovered from an archaeological site dated to the period of the Milan plague of 1629-1631, were processed to investigate the presence of traces of Yersinia pestis, the causative agent of plague. Both DNA and proteins associated with the pathogen of interest have been searched. Preliminary results for these analyses were inconclusive, but the metagenomic analysis is still in progress and the results will be available in the next few months.  During the second part of the project, historical and epidemiological investigations were carried out on textual sources associated with past plague epidemics. The first study (Manuscript n. 1) involved the development of a new informatic tool aimed at extracting useful information from a huge amount of textual data. This tool was applied to derive information regarding the 1720–1722 plague of Marseille and the 1629–1631 plague in northern Italy. The analysis of text related to these two epidemic episodes revealed that plague-related words were associated with the words “merchandise”, “movable”, “tatters”, “bed” and “clothes”, while no association was found with rats. These results support the hypothesis of a role of human ectoparasites during the second plague pandemic. Moreover, the results suggested a potential future application of this tool for the prediction of pathogen, responsible for a described disease, in ancient texts.  The second study (Manuscript n.2) concerned the analysis of the progress of the plague epidemic that hit the city of Milan during the years 1629-1631. The registers of the deaths of the city of Milan for the year 1630 were digitized and subsequently used for the spatio-temporal analysis of the epidemic and historical events related to it; in particular, the effect that a religious mass gather had on the spread of the epidemic in the city was analysed.  The last part of the thesis project was focused on the research and study of the bibliography concerning the paleomicrobiological studies performed on ancient human microbiota (Manuscript n.3).","language":"eng","citation":"STUDYING THE PLAGUE: RETRIEVING INFORMATION FROM THE PAST / R. Nodari ; coordinatore: C. Bandi ; scientific tutor: S. Epis. Dipartimento di Bioscienze, 2022 May 24. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12388.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/924603/2025245/phd_unimi_R12388.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1208456"},"title":"'ORGANIZATIONAL HEALTH LITERACY'                                                                        COME MODELLO PER RIPENSARE L'OSPEDALE IN UN'OTTICA INCENTRATA SUL PAZIENTE","internalauthor":"PERRONE, PIER MARIO","type":"Tesi di dottorato","year":"2026","abstract":"\"INTRODUCTION  In the contemporary public health paradigm, health literacy (HL) is a pivotal determinant of health and a critical indicator of the quality of healthcare systems. Health literacy is defined as the set of cognitive and social skills that enable individuals to obtain, evaluate, and correctly interpret health information. It is the necessary condition through which citizens can exercise real decision-making autonomy in their own care pathway.  The significance of this construct is twofold: firstly, in terms of the individual dimension, and secondly, in terms of the patient's ability to act as an active partner in the healthcare setting. A solid health literacy promotes a symmetrical therapeutic alliance between the user and the operator, transforming the communication process into a collaborative and constructive environment. From this perspective, health literacy can no longer be regarded as a purely educational goal, but rather as a strategic asset with multidimensional impacts:  The clinical aspect is concerned with the reduction of errors and complications.  The overarching objective is to ensure social equity in access to services.  The objective is to optimise the allocation of resources and reduce waste resulting from the misuse of services, thereby achieving economic efficiency.  It is also important to note that the focus is now shifting from individual responsibility to system responsiveness through the concept of Organizational Health Literacy (OHL). This paradigm delineates the extent to which healthcare organisations are able to facilitate simplified access to their services, rendering information comprehensible and utilizable across all user levels. The transition to a \"\"literate\"\" structure necessitates a multidisciplinary approach, capable of integrating the vision of decision makers with clinical practice and the support of administrative and technological figures.  A study was conducted with two objectives in order to correctly analyse the aspect of OHL in the Italian context.  The objective of this study is to assess the presence and awareness of OHL measures within three hospitals, with a view to obtaining a representation of these measures within the Italian health service.  The provision of a toolkit is proposed, which would include a range of useful strategies. The aim of these strategies would be to improve or strengthen HL within a healthcare organisation. It is important to note that these strategies would be useful in both ordinary conditions and in emergency contexts.  MATERIAL AND METHODS  The cross-sectional, open study was conducted at three healthcare facilities in central and northern Italy. These were selected on the basis of specific characteristics, including the provision of high complexity of care (with a minimum of 500 beds), the presence of a Level II Emergency and Admissions Department (EAD), and their status as regional reference centres. Additionally, the study sites were chosen for their high quality, as determined by the criteria of the National Outcomes Plan (PNE), in the domains of patient-centred care and the integration of clinical care, training, and research. This selection criterion was particularly relevant given that the study sites are university hospitals.  A questionnaire was developed, comprising three sections. The first section sought to ascertain demographic and professional information. The second section utilised the Quality-Oriented Climate and Service Quality (QO-CSQ) scale to assess perceived service quality. The third section addressed the presence of the 10 attributes of a health-literate organisation. This section employed the Health-Literate Healthcare Organization (HLHO-10) questionnaire, an international questionnaire that had been translated and validated in Italian. The HLHO-10 questionnaire was modified to investigate the presence or absence of attributes within the organisation, rather than their frequency. This investigation employed Likert scales. Furthermore, in order to assess the quality of the service offered by the hospital to which the contacted staff belonged, 12 additional questions from the 2016 Romiti study were included in the questionnaire.  In order to evaluate the dimensional structure of the HLHO-10 scale, an exploratory factor analysis (EFA) was conducted. To this end, Principal Component Analysis (PCA) with Quartimax rotation and Kaiser normalisation were utilised. Concurrently, Kaiser-Meyer-Olkin (KMO) and Bartlett's sphericity tests were employed to ascertain the adequacy of the sampling. The internal consistency of the questionnaire was assessed using Cronbach's alpha index, with values greater than or equal to 0.7 being considered acceptable.  The correlations between HLHO and perceived quality of non-clinical care were analysed using Spearman's coefficient and Kruskal-Wallis tests for continuous and categorical variables, respectively.  In conclusion, in order to identify predictors of perceived quality (QUAL), three stepwise linear regression models were tested. The first model (Model 1) took into account demographic and contextual variables. The second model (Model 2) added HLHO_F1, a component of the HLHO-10 questionnaire that brings together seven items related to informative and communicative operating practices, to the demographic and contextual variables of Model 1. The third model (Model 3) added HLHO_F2, also a component of the HLHO-10 questionnaire, which brings together three items relating to the orientation of strategic directions towards health literacy issues in terms of institutional policy and staff training, to the variables in Model 2.  RESULTS  A thorough analysis of the completed questionnaires revealed that the majority of respondents were male, with an average age of 55.6 years (SD = 8.9 years). In terms of professional seniority, the average length of service in the healthcare sector was 30.4 years (SD = 9.2) years, with an average length of service in the current facility of 21.8 years (SD = 11.1) years and an average length of service in a managerial role of 13.6 years (SD = 7.7).   In relation to the two HLHO-10 components, the first (HLHO_F1) demonstrated a higher mean score than the second (HLHO_F2), with values of 4.74 and 3.74, respectively. However, the internal consistency index was lower for the first component (0.887) compared to the second (0.922).  In addition, Spearman's rank correlation indicated a positive association between both HLHO components and QUAL (for HLHO_F1: (ρ = 0.397, p = 0.003) and HLHO_F2: (ρ = 0.494, p < 0.001)).  The latter demonstrated an average score of 4.81 (SD = 1.78) and a significant correlation with the age of the respondents (ρ = 0.374, p = 0.005), years of professional experience in the healthcare sector (ρ = 0.309, p = 0.023), and years in a managerial position (ρ = 0.295, p = 0.031). Furthermore, Kruskal-Wallis tests revealed that QUAL scores varied significantly based on the number of staff managed (p = 0.023) and the frequency of direct contact with patients (p = 0.045), with higher QUAL scores among those who managed larger teams and had constant interaction with patients.  In relation to stepwise regression models, Model 1 revealed that the number of staff managed was the only significant predictor of QUAL (β = 0.287, p = 0.041). For Model 2, the HLHO_F1 component was identified as a statistically significant predictor (β = 0.325, p = 0.016), while the predictive significance of the number of staff members was found to decrease. In Model 3, the HLHO_F2 component emerged as the most robust predictor, with a beta coefficient of 0.377 and a p-value of 0.004. Conversely, the HLHO_F1 component exhibited a diminished statistical significance, with a beta coefficient of 0.204 and a p-value of 0.114.  CONCLUSIONS  In conclusion, while organizational health literacy must be integrated into strategic, training and decision-making processes in order to overcome fragmentation and isolated practices, it is clear that middle managers, thanks to their operational and managerial position, are crucial figures in converting health literacy (HL) objectives into concrete practices and resolving communication issues. Concurrently, front-office and public relations services represent a pivotal component in the effective management of patients. Consequently, enhanced integration of HL into these services has been demonstrated to improve the patient experience and institutional performance.  The present study underscores the necessity to acknowledge OHL as an integral component of healthcare, with the objective of addressing the suboptimal levels of HL prevalent in Italy. This approach emphasizes the promotion of clarity, accessibility, and involvement at all echelons of the healthcare system.\"","language":"ita","citation":"'ORGANIZATIONAL HEALTH LITERACY'  COME MODELLO PER RIPENSARE L'OSPEDALE IN UN'OTTICA INCENTRATA  SUL PAZIENTE / P.m. Perrone ; tutor: S. Castaldi ; coordinatore: F. Parazzini. - Milano. Dipartimento di Scienze Biomediche per la Salute, 2025 Sep 30. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13808.pdf","fileformat":"Adobe PDF","fileversion":"preprint","fileaccess":"Open from 14-LUG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/818976"},"title":"IN VITRO AND IN VIVO APPROACHES TO STUDY OXIDATIVE STRESS, ANEMIA AND DYSBIOSIS IN CHRONIC KIDNEY DISEASE","internalauthor":"ASTORI, EMANUELA","type":"Tesi di dottorato","year":"2021","abstract":"CKD is diagnosed when there’s a decreased kidney function shown by a GFR less than 60 ml / min (established for a reference man with 1.73 m² body surface area), or markers of kidney damage, or both, of at least 3 months duration. The severity of complications increases in parallel with the GFR decline. We focused on three comorbidities extremely common in CKD patients: oxidative stress and inflammation; anemia and dysbiosis. We investigated these CKD comorbidities both with in vitro and in vivo approaches. More in detail, regarding in vivo studies, we measured oxidative stress biomarkers in a population of ESRD patients before and after the hemodialysis treatment, comparing the results with a population of healthy subjects; we evaluated oxidative stress biomarkers in the plasma of HD patients before, during and after two type of iron treatments (intravenous and sucrosomial iron). Regarding in vitro experiments, we focused on two uremic toxins, urea and indoxyl sulphate, and we evaluated their effects on a human endothelial cell line (Human Microvascular Endothelial Cells 1, HMEC-1).","language":"eng","citation":"IN VITRO AND IN VIVO APPROACHES TO STUDY OXIDATIVE STRESS, ANEMIA AND DYSBIOSIS IN CHRONIC KIDNEY DISEASE / E. Astori ; tutor: I. Dalle Donne ; commissario interno: N. Gagliano ; commissario esterno: S. Moreno ; commissario esterno: A. E. Colombo ; head pf phd course: F. Ficetola. Università degli Studi di Milano, 2021 Feb 23. 33. ciclo, Anno Accademico 2020. [10.13130/astori-emanuela_phd2021-02-23].","filename":"phd_unimi_R11906.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/818976/1716850/phd_unimi_R11906.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1156175"},"title":"UP150 PROACTIVE OFFICE: THE OFFICE THAT EDUCATES ON EMPLOYEE CARE AND WELL-BEING THROUGH PHYSICAL EXERCISE FOR HEALTH","internalauthor":"SIGNORINI, GABRIELE","type":"Tesi di dottorato","year":"2025","abstract":"\"Systems thinking is a new area of knowledge that considers and integrates all the elements that must be considered to address complex public health problems, such as non-communicable disease prevention policy. Any intervention aimed at successfully preventing risk factors such as those caused by insufficient physical activity must be based on specific theories and scientific evidence and develop through active involvement in meaningful actions and interactions that consider the cultural and social context. For these reasons, the present study's structure is based on social theories contextualized in the sedentary working environment of desk workers to introduce a new company vision. In this vision, the working environment, where employees spend much time, is intended not only as a place for productivity but also a care and an educational environment to prevent a sedentary lifestyle. The aim of this study is to check with scientific and experimental experience how the traditional paradigm, stating that \"\"physical exercise intended as an active break out of context is opposed to useful and effortful work and represents a waste of time\"\", is no longer valid. The main idea is to incorporate physical exercise into the usual workflow to help employees increase their motivation to exercise and the amount of physical activity they do daily, with the aim of improving their health, physical literacy, and working wellness. Following the action research's vision, the present research project has been demonstrated to modify the local companies' welfare policies in which we proposed the intervention. Furthermore, the research structure following the design-based research paradigms has constituted an efficient road map to assess the effectiveness of the results of the proposed interventions. Finally, following the rationale of the system thinking approach, the research analyzed a wide range of variables (and their relationships) that can influence the analyzed reality to promote healthy lifestyles and long-term movement culture.\"","language":"eng","citation":"UP150 PROACTIVE OFFICE: THE OFFICE THAT EDUCATES ON EMPLOYEE CARE AND WELL-BEING THROUGH PHYSICAL EXERCISE FOR HEALTH / G. Signorini ; tutor: P.L. Invernizzi ; coordinator: C. Gozzoli. - Università Cattolica del Sacro Cuore, via Carducci 28 aula C014. Dipartimento di Scienze Biomediche per la Salute, 2025 Mar 26. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13451.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1156175/2730438/phd_unimi_R13451.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/811217"},"title":"RELATIONSHIP BETWEEN PLASMA LEVELS OF PCSK9, VASCULAR EVENTS AND MARKERS OF SUBCLINICAL ATHEROSCLEROSIS AND INFLAMMATION","internalauthor":"COGGI, DANIELA","type":"Tesi di dottorato","year":"2021","abstract":"Background and purpose: Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the main regulators of LDL receptor metabolism, has been associated with atherosclerosis development. Several studies have confirmed such association through both lipid and non-lipid pathways. However, the direct relationships between circulating PCSK9 and markers of subclinical and clinical atherosclerosis are still matter of debate. Therefore, we investigated the relationships between plasma PCSK9 levels and some indexes of subclinical (imaging markers) and clinical (vascular events; VEs) atherosclerosis. Another objective was the identification of the independent determinants of PCSK9, with particular attention to lipids and inflammatory biomarkers. Finally, we also assessed the relationship between some imaging markers and four SNPs of the PCSK9 gene, known to be associated with the presence of low levels of LDL-cholesterol. In order to validate the results obtained in this last part, the genetic analyses were replicated in an independent cohort recruited in the United Kingdom (UK).    Methods: The study was carried out taking advantage of databases, biobanks and imaging-bank of the IMPROVE study. 3,703 European subjects (54-79 years; 48% men), free of VEs at baseline and defined at high risk for the presence of at least three vascular risk factors, were recruited and followed-up for 36 months. PCSK9 was measured by ELISA and log-transformed prior to analyses. Conventional imaging markers [carotid intima-media thickness (cIMT) and carotid plaque-size], and emerging imaging markers [cIMT change over time, echolucency of the intima-media thickess of common carotid measured in plaque free areas (PF CC-IMTmean), echolucency of the biggest plaque detected in the whole carotid tree, and carotid calcium score (cCS)] were measured on ultrasonographic scans stored in the imaging-bank. In particular, echolucency was measured in terms of grey scale median (GSM) of pixels distribution of a specific region of interest, whereas cCS was calculated as sum of lengths of acoustic shadow cones generated by calcium within carotid plaques. Lipids were measured with enzymatic methods (except for LDL-cholesterol, which was calculated by Friedewald's formula). Among inflammatory markers, high-sensitivity C-reactive protein (hs-CRP) was measured by turbidimetry, whereas white blood cells (WBC) count and the leukocyte formula had already been measured locally. All the IMPROVE study and UK (n=22,179; 48% men) subjects have been genotyped.  Results: In the univariate analysis, PCSK9 was positively correlated with total, LDL-, and HDL-cholesterol, and with triglycerides and basophils (all p <0.0001), whereas was negatively correlated with neutrophils and eosinophils (both p=0.04). The positive correlations observed with hs-CRP and WBC count were just close to the statistical significance (p=0.060 and 0.064, respectively). Fibrates or statins therapies (positively; both p <0.0001), as well as male sex and family history of diabetes (negatively; both p <0.05) were the strongest independent predictors of plasma PCSK9 levels. In the unadjusted analysis, a negative correlation was observed between PCSK9 levels and basal cIMT variables (i.e. carotid IMTmean, IMTmax, IMTmean-max, and PF CC-IMTmean), a negative correlation between PCSK9 and cIMT change over time (Fastest-IMTmax-progr) and cCS (all p ≤0.01), whereas a positive trend was observed between PCSK9 and GSM of both PF CC-IMTmean and carotid plaque (both p ≤0.0001). The cCS (positively) and the GSM of PF CC-IMTmean (positively) were significantly (or almost significantly) associated with PCSK9 in several multivariate models (all p ≤0.064). All correlations observed in the univariate analysis between PCSK9 and basal cIMT variables, Fastest-IMTmax-progr and GSM of carotid plaque lost the statistical significance after adjustment for age, sex, latitude, and other potential confounders. During the follow-up [median (interquartile range): 3.01 (2.98; 3.12) years], 215 VEs were recorded: 125 coronary, 73 cerebral and 17 peripheral VEs. Among these, 37 were hard events (i.e. myocardial infarction, sudden death and stroke). In the unadjusted analysis, PCSK9 was positively associated with combined and coronary events (both p <0.01), but not with cerebrovascular events. Also in this case, however, all the associations observed lost the statistical significance after adjustment of the analyses for age, sex, and stratification for latitude. The lack of association with VEs was confirmed also in the model adjusted for all confounding factors considered, and in the analyses focused on hard events. With regard to the role of genetic variants, none of the four SNPs considered was correlated with cIMT (i.e. IMTmean, IMTmax, IMTmean-max) when the analysis was performed in the subjects recruited in the IMPROVE study. The rs11591147 variant, by contrast, was negatively correlated with IMTmax measured in the UK population (p=0.002). By combining the four genetic variants in a score, the relationship with cIMT was not significant in the IMPROVE study, whereas was negative and significant in the UK population (all p <0.01).  Conclusions: Plasma PCSK9 levels are not associated with VEs. Regarding markers of subclinical atherosclerosis, PCSK9 levels are associated neither with lesion size, nor with carotid plaque echolucency, but are associated with echolucency of carotid wall thickness and with carotid calcium score. Therefore, further studies are needed to better understand the role of such circulating proprotein in carotid wall thickness echolucency and in carotid calcium score. Fibrates or statins therapies, as well as male sex and family history of diabetes are the strongest independent predictors of PCSK9 levels. The associations, previously observed, between circulating PCSK9 and some lipid and inflammatory markers have been confirmed. The relationship between plasma levels of PCSK9 and other inflammatory markers (neutrophils, basophils and eosinophils) deserves further investigation, as does the association between the four selected PCSK9 variants and cIMT in the UK cohort, as it suggests a possible role of PCSK9 SNPs or gene polymorphisms in atherosclerosis and in its preventive strategies.","language":"eng","citation":"RELATIONSHIP BETWEEN PLASMA LEVELS OF PCSK9, VASCULAR EVENTS AND MARKERS OF SUBCLINICAL ATHEROSCLEROSIS AND INFLAMMATION / D. Coggi ; tutor: D. Baldassarre ; supervisore: D. Baldassarre ; coordinatore: A. L. Catapano. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2021 Feb 16. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12015.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/811217/1692937/phd_unimi_R12015.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1205653"},"title":"ACUTE ISCHEMIC STROKE: CANCER-RELATED STROKE AND MULTIMODAL ANALYSIS OF THROMBI.","internalauthor":"COSTAMAGNA, GIANLUCA","type":"Tesi di dottorato","year":"2026","abstract":"Background  Acute ischemic stroke (AIS) usually results from atherosclerosis or cardiac sources, but less frequent mechanisms, such as cancer-related stroke, play a role in some cases.  Studying these rarer causes of AIS is crucial for secondary prevention. Thrombi analysis provides a unique window into stroke biology. This thesis investigates (1) clinical features and outcomes of AIS in patients with active cancer (AC) and (2) histopathological and multi-omics profiles of retrieved thrombi from AIS patients with large vessel occlusion.    Methods  We examined AIS–cancer interactions using the Acute-Stroke-Registry-and-Analysis-of-Lausanne (ASTRAL, 2003–2024) and international collaborations, focusing on outcomes, antithrombotic and anticancer strategies, and the role of newly diagnosed vs known cancer. In parallel, we created the POLIclinico-Stroke-Thrombi-Analysis-Registry (POLISTAR) to prospectively collect thrombi with linked clinical, imaging, histological, and omics data. Histology assessed fibrin/red blood cell content and immune-cell composition. Proteomic and transcriptomic analyses explored convergent pathways and cross-platform signatures.    Results  Among 464 AIS patients with AC from ASTRAL, anticoagulation at discharge did not reduce recurrent AIS compared with antiplatelets. Newly diagnosed cancer doubled mortality risk (adjusted common HR 2.11, 95% CI 1.38–3.21) compared with having a known AC. Initiating or resuming cancer treatment within 3 months after AIS reduced 3-month mortality both before (aHR 0.39, 95% CI 0.28–0.56) and after (aHR 0.33, 95% CI 0.13–0.80) propensity score matching. Histology of 82 thrombi showed no significant compositional differences by clot permeability or between embolic stroke of undetermined source and cardioembolic subtypes, with 74% fibrin-prevalent. Multi-omics analyses of four thrombi revealed enrichment of platelet activation, neutrophil degranulation, complement cascades, and metabolic rewiring. Integrative proteomic–transcriptomic networks identified central hubs (FN1, GAPDH, HSP90AA1, ACTB, MYH9) linking immune and stress-response modules.    Conclusions  These studies show how AC, its subtypes and its therapies shape AIS prognosis. Thrombus histology alone cannot discriminate stroke etiologies, while omics highlight convergent immune, platelet, and metabolic programs. Integrating large registries, pathology, and molecular biology may advance precision medicine in AIS, especially in cancer-related and cryptogenic subgroups.","language":"eng","citation":"ACUTE ISCHEMIC STROKE: CANCER-RELATED STROKE AND MULTIMODAL ANALYSIS OF THROMBI / G. Costamagna ; tutor: G. Comi ; cotutor: S. Corti ; coordinatore: S. M. Clerici. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2025 Jan 15. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13881.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 07-LUG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/968780"},"title":"UNDERSTANDING AND DETECTING DAIRY RUMINANT MASTITIS: RECENT FINDINGS ON MICROBIAL IDENTIFICATION METHODS, DIAGNOSTIC MARKERS, AND THE MICROBIOME","internalauthor":"PENATI, MARTINA","type":"Tesi di dottorato","year":"2023","abstract":"Mastitis is one of the most economically impactful diseases in dairy farming. It may cause severe qualitative-quantitative losses in milk production, adversely affect animal welfare, and lead to early culling of animals. Mastitis can present itself in different forms, often due to the different causative agents. Two main manifestations of the disease are clinical, which is easier to detect due to the use of semi-quantitative techniques or simple examination of the udder, and subclinical , which has no obvious symptoms and requires milk testing to discover mastitis indicators. The focus of this thesis work is to understand dairy ruminant mastitis with a focus on recent findings on microbial identification methods, diagnostic markers of mastitis, and the impact of intramammary antibiotic treatment due to the presence of mastitis on the gut microbiome. The first study was focused on improving the identification of etiologic agents, focusing on the highly prevalent non-aureus staphylococci (NAS), with the application of PCR–RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism) and MALDI-TOF MS (Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry) for improving the detection of intramammary infections (IMI). We applied MALDI‐TOF MS and gap PCR–RFLP to 204 NAS and mammaliicocci (NASM) and to 57 streptococci isolated from the milk of sheep and goats with mastitis to compare their respective results. The study revealed a high level of agreement between MALDI‐TOF MS and PCR–RFLP in identifying the most prevalent NASM and streptococci causing small ruminant mastitis. The second study aimed to conduct a systematic review to synthesize all the literature on the topic and improve the understanding of the diagnostic accuracy of protein marker-based immunoassays for mastitis detection. Currently, the most widely used tool for monitoring mastitis is the somatic cell count (SCC), expressed as the number of cells per ml of milk. Using SCC as a monitor has two major drawbacks. First, it has low specificity, and this limitation is particularly relevant in small ruminants, especially goats, as the SCC increases physiologically with parity and lactation number. The other major drawback is the difficulty of using this system to monitor mastitis in dairy herds of non-bovine species, for which clear reference values are unavailable. This has led to the search for new markers with higher specificity and suitability for easy measurements. Among the most studied are the protein molecules produced by the infected host in the context of inflammation and released in the milk, which makes them directly and easily detectable by techniques that exploit antigen-antibody interaction (immunoassay). To provide a general overview of their application in the different dairy species, we carried out a systematic review of the scientific literature using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. Based on 13 keywords combined into 42 searches, we extracted 523 manuscripts from three scientific databases. After screening for duplicates and pertinence, we summarized the main findings in 33 selected articles for the different markers. Where available, we reported their results in comparative tables, including sample selection criteria, marker values, and diagnostic performances. Finally, we reported the study limitations and bias assessment findings. The third study addressed the impact of mastitis on the calf gut microbiome, particularly concerning the impact of calf feeding with waste milk (WM). The risks associated with using WM as a feed source for calves have recently been highlighted. WM is a by-product of the dairy sector that, due to its physical, chemical, and microbiological properties and the presence of antibiotic residues from the treatment of lactating cows, cannot be marketed for human consumption. This milk may be a resource for calf feeding. Although  WM represents an economically advantageous alternative and offers a viable solution to the environmental disposal of this product, it may present risks in terms of antibiotic resistance selection and may impair the healthy development of the calf gut microbiota. In particular, the administration of WM containing antimicrobial residues could contribute to  select and maintain resistant bacteria in the animal's gut. In addition to presenting issues in terms of health and management of the animals themselves, this could pose a public health risk: calves, by becoming reservoirs of resistant bacteria, would contribute to the spread of these microorganisms through the environmental release of their feces. The trial assessed the longitudinal effect of unpasteurized WM containing residual cefalexin monohydrate on calf intestinal health and fecal microbiota in an 8-week trial. The feeding trial included 12 male Holstein Friesian calves. After colostrum, which lasted 3 days, 6 calves were fed waste milk (WM group), and 6 calves were fed normal bulk tank milk (NM group) for two weeks. At the end of this first phase, all calves were fed reconstituted whey powder and starter feed, according to standard farm protocols, for another six weeks. For the first two weeks, and then every two weeks until the end of the trial, calves were monitored and weighed, and fecal and swab samples were taken. Our results suggest that feeding pre-weaned calves with unpasteurized WM containing antibiotics leads to significant changes in the fecal microbiota composition, further discouraging this practice despite its short-term economic advantages.","language":"eng","citation":"UNDERSTANDING AND DETECTING DAIRY RUMINANT MASTITIS: RECENT FINDINGS ON MICROBIAL IDENTIFICATION METHODS, DIAGNOSTIC MARKERS, AND THE MICROBIOME / M. Penati ; phd supervisor: M. F. ADDIS ; phd coordinator: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2023 May 12. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12517.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/968780/2196477/phd_unimi_R12517.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1236515"},"title":"INTEGRATED AND MULTI-SCALE CHARACTERISATION OF GEM MATERIALS LACKING LONG-RANGE ORDER. THE CASE STUDIES OF CHRYSOCOLLA AND ANDEAN BLUE OPAL","internalauthor":"MONICO, SARA","type":"Tesi di dottorato","year":"2026","abstract":"The PhD research project was focused on the integrated and multi-scale characterisation of gem materials lacking long-range structural order. These materials, positioned between crystalline and completely amorphous systems, present significant challenges in terms of classification and characterisation, due to their intrinsic heterogeneity and complexity, which conventional analytical techniques are often unable to investigate properly. However, these characteristics are often responsible for the particularly attractive aesthetic qualities of these materials, which also determine their value in the field of gemmology. The study aimed to address some unresolved issues in the field of gemmology concerning two varieties of material lacking a long-range structural order, chrysocolla and Andean blue opal.   Chrysocolla is a hydrated copper silicate (Cu2-xAlx(H2-xSi2O5)(OH)4·nH4O), known for its vivid blue–green colour and its millennial use (Bianucci et al., 2009; Clark, 2021; Torpy et al., 2021). Its classification remains debated (both in mineralogy and gemmology) because of its variable composition and uncertainties regarding its crystal structure (Frost and Xi, 2013; Torpy et al., 2021; Dold et al., 2023; Kahou et al., 2025).   Andean blue opal is a particular gemmological variety of hydrated silica (SiO2·nH2O), extracted in southern Peru and of strong cultural value since pre-Hispanic times (Hyršl, 2001; Caucia et al., 2015). It is appreciated for its intense colours, ranging from milky blue to green, but the causes of its colouration, as well as its structural and compositional features, are still not fully understood (Gaillou et al., 2008b; Caucia et al., 2015).   The in-depth study of chrysocolla was carried out through a multidisciplinary and multiscale approach, made necessary by the complex and strongly heterogeneous nature of the mineral. The methodological strategy involved the integration of conventional techniques, commonly used in the study of crystalline materials (e.g., X-ray diffraction), with advanced approaches specifically suited to nanocrystalline or amorphous systems, such as X-ray Total Scattering and transmission electron microscopy (TEM). Given the spatial heterogeneity of the samples, spot analyses at the micrometric scale were also adopted, including micro-Raman spectroscopy and electron microprobe analysis in wavelength-dispersive mode (EMPA-WDS) (using a multivariate analysis approach (PCA) for in-depth investigation of chemical data). The experimental protocol was structured as a progressive workflow across different scales of investigation, from macroscopic observations to nanoscale characterisations, ensuring a hierarchical and integrated view of the mineralogical system. The selected samples, from two reference deposits – Capo Calamita mine (Elba Island, Italy) and Cornwall mine (Pennsylvania, USA) – were investigated in terms of chemical composition, microstructure, degree of crystallinity, and associations with other phases involved in the formation process. Particular attention was paid to the identification of potential compositional fingerprints of chrysocolla, while at the same time addressing the analytical challenges posed by its nature and optimising the analytical procedures. Finally, thermodynamic models of the Cu–SiO2–SCOH system (T = 298 K, P = 1 atm) were developed to define the stability fields of the mineral, providing insights into the chemical and physical conditions favourable to its genesis.   The investigation of Andean blue opal was developed through a multiscale and integrated strategy, aimed at combining mineralogical characterisation, textural observations, and detailed chemical analyses. A preliminary petrographic study made it possible to identify the main textural features of the Andean blue opal and to highlight the distribution of mineral inclusions, which served as a basis for further investigation. Mineralogical characterisation was carried out using high-resolution X-ray diffraction, integrated with micro-Raman spectroscopy, in order to define the opaline matrix and the accessory phases present. Raman mapping and X-ray microtomography (micro-CT) were used to investigate the spatial distribution of inclusions and their relationships within the silica matrix. Compositional analysis was carried out at different levels: EMPA-WDS for the determination of major and minor elements, and LA-ICP-MS (Laser Ablation Inductively Coupled Plasma Mass Spectrometry) for the quantification of trace elements, thus providing a detailed and quantitative picture of the chemical variability. Finally, the data obtained were subjected to multivariate statistical analysis (PCA), useful for highlighting internal heterogeneities and possible correlations between composition, inclusions, and genetic processes. The integration of these methodologies made it possible to build a coherent and hierarchical picture of the studied variety, addressing the complexity of opal through a structured approach.","language":"eng","citation":"INTEGRATED AND MULTI-SCALE CHARACTERISATION OF GEM MATERIALS LACKING LONG-RANGE ORDER. THE CASE STUDIES OF CHRYSOCOLLA AND ANDEAN BLUE OPAL / S. Monico ; tutor: N. Marinoni ; co-tutor: G. D. Gatta ; coordinatore: G. Muttoni. - Milano. Dipartimento di Scienze della Terra Ardito Desio, 2026 Apr 28. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13885.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 21-OTT-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1198279"},"title":"SYNTHETIC-LETHAL PHARMACOLOGICAL INTERACTIONS IN MYC-DRIVEN LYMPHOMAS: A ROLE FOR GLUCOCORTICOIDS IN TARGETED THERAPY","internalauthor":"GHSEIN, AYA","type":"Tesi di dottorato","year":"2025","abstract":"Diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma, includes aggressive subtypes that remain difficult to treat. One of the molecular features associated with poor prognosis is the presence of chromosomal translocations that activate the MYC oncogene, in particular when associated with concurrent activation of BCL2, which leads to an aggressive disease subtype commonly known as double-hit lymphomas (DHL). Since direct targeting of MYC remains challenging, we sought to unravel synthetic-lethal vulnerabilities as alternative therapeutic options against MYC-driven tumors. Toward this aim, we performed an unbiased high-throughput pharmacological screen in a murine B-lymphoid cell line with conditional MYC activation and identified a set of compounds that preferential kill MYC-overexpressing cells. Unexpectedly, these included glucocorticoids (GCs) with Budesonide scoring as the top candidate. Targeted experiments confirmed that MYC also sensitizes B-cells to another GC, Prednisolone, the active metabolite of Prednisone, itself an integral component of the frontline therapeutic regimen R-CHOP. Functional assays revealed that MYC activation markedly sensitizes B cells to GC-induced apoptosis through the intrinsic mitochondrial pathway. Transcriptomic profiling confirmed that MYC differentially modulates the transcriptional response to GCs, reinforcing the activation of stress and apoptotic programs while attenuating the repression of proliferative and metabolic genes, thus providing a mechanistic basis for MYC-specific cytotoxicity. Guided by these findings, we uncovered a strong synergy between GCs and the selective BCL2 inhibitor Venetoclax (ABT199) in killing a human DHL cell line, providing a rationale for combining these drugs against this aggressive lymphoma subtype. Additional combinatorial experiments showed that Prednisolone contributes to the cytotoxicity of the pharmacological CHOP backbone in MYC-overexpressing B-cells. Collectively, our data identify GCs as potent MYC-synthetic lethal agents, mechanistically linked to MYC-driven remodeling of GC-regulated transcription, revealing an unexpected mechanism of action for these long-standing therapeutic agents.","language":"eng","citation":"SYNTHETIC-LETHAL PHARMACOLOGICAL INTERACTIONS IN MYC-DRIVEN LYMPHOMAS: A ROLE FOR GLUCOCORTICOIDS IN TARGETED THERAPY / A. Ghsein ; tutor: B. Amati ; co-tutor: G. Donati ; internal advisor: S. Minucci ; external advisor: L. Soucek ; coordinator: D. Pasini. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Dec 17. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13514.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 25-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1216635"},"title":"MICROBIAL AND BOTANICAL STRATEGIES TO SUPPORT HUMAN DIGESTION AND GUT MICROBIOTA.","internalauthor":"DUNCAN, ROBIN","type":"Tesi di dottorato","year":"2026","abstract":"The interaction between diet, digestion, and the gut microbiota has become a central topic in nutrition and health research. Growing scientific and commercial interest has focused on functional foods and supplements that aim to support digestion, influence microbial communities, and provide health benefits without disrupting ecological balance. Developing products that are both effective and microbiome-compatible requires experimental models capable of capturing physiologically relevant conditions.  This PhD project examined three categories of microbiome-related interventions: (1) spore-forming probiotics, (2) fungal enzyme supplements, and (3) botanical extracts. A central methodological approach was the application of standardized in vitro models, in particular the INFOGEST 2.0 protocol, which simulates the human gastrointestinal environment and provides reproducible digestion studies. These experiments were complemented by fecal microbiota incubations and targeted microbial cultures to assess viability, metabolic activity, and community responses. The overarching aim was to evaluate how specific products, including Heyndrickxia coagulans LMG S-24828, two fungal enzyme blends, and three botanical extracts, interact with gut-related processes. Emphasis was placed on safety, functional performance during digestion, and effects on selected commensal or probiotic strains. The findings contribute to the development of evidence-based strategies for improving digestive efficiency and maintaining microbial balance through microbiome-compatible supplements.","language":"eng","citation":"MICROBIAL AND BOTANICAL STRATEGIES TO SUPPORT HUMAN DIGESTION AND GUT MICROBIOTA / R. Duncan ; tutor: S. D. Guglielmetti ; tutor: R. Russo ; coordinatore: D. Mora. Università degli Studi di Milano, 2025 Feb 09. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13679.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1216635/3253194/phd_unimi_R13679.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1196419"},"title":"PROBABILISTIC AND DEEP LEARNING APPROACHES TO MODELING BIOLOGICAL SYSTEMS","internalauthor":"MILITE, SALVATORE","type":"Tesi di dottorato","year":"2025","abstract":"This thesis investigates probabilistic and deep learning methods for modeling biological systems across various scales, with a specific focus on cancer. The aim is to develop models that are both quantitatively rigorous and biologically meaningful.    In the first part, I present a hierarchical Bayesian extension of MOBSTER, a model-based clustering approach for subclonal deconvolution. By introducing a probabilistic hierarchical structure, this method accounts for observational noise, for shared uncertainty across karyotypes, and allows inference on a substantially bigger proportion of the genome. I then apply it to a large cohort of whole-genome sequencing data, where I analyze clonal dynamics, mutation rates, and driver selection patterns.    The second part deals with single-cell and multi-omic data integration, as well as the study of cancer cell plasticity and resistance to therapy. I present MIDAA, a deep archetypal analysis method that provides interpretable latent representations and show its performance on two different hematopoiesis multiomics datasets. Building on this, I present a computational analysis of lentivirally barcoded patient-derived organoids to show that epigenetic heritability plays a key role in drug resistance. This leads to a unified view where stable epigenetic differences drive diverse cell states and adaptive responses to treatment.    The final part focuses on spatial and temporal modeling. I develop the Mixture of Neural Cellular Automata as a stochastic framework for simulating tissue growth and image morphogenesis. I then show some preliminary results on designing an agent-based deep learning model to capture cell fate decisions from spatial transcriptomics data.    Overall, this work shows how combining probabilistic and deep learning approaches can provide new ways to study complex biological processes, from cancer evolution to tissue organization, and offers general frameworks that can be applied to a broad range of problems in computational biology.","language":"eng","citation":"PROBABILISTIC AND DEEP LEARNING APPROACHES TO MODELING BIOLOGICAL SYSTEMS / S. Milite ; tutor: A. Sottoriva, G. Caravagna ;  coordinatore: D. Pasini. Dipartimento di Scienze della Salute, 2025 Oct 10. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13490.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 18-NOV-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/956498"},"title":"PHENOTYPIC AND MOLECULAR CHARACTERIZATION OF A NOVEL P63ALPHA;KO MOUSE MODEL","internalauthor":"URCIUOLI, GLORIA","type":"Tesi di dottorato","year":"2023","abstract":"The transcription factor p63, a p53 gene family member, plays a crucial role in embryonic development of stratified epithelia where it can function either as an activator or a repressor. In the epidermis, p63 is a master regulator of epidermal gene expression and is crucial for cell proliferation, cell adhesion and stratification. Here we describe a new p63α-/- mouse model in which we delete exon 13 leading to the expression of the p63β isoform. Newborn p63α-/- mice die soon after birth and are characterised by cleft palate and digit malformations but exhibit normal skin. Our study indicates that p63α and p63β are not interchangeable in palate and limb development during embryogenesis, whereas expression of either one allows normal skin development, laying the foundation for a better understanding of the contribution of each p63 isoforms to mouse development. Compared to previously generated p63 knock-out mice, morphological and molecular impairment in p63α-/- model are mainly caused by alterations in the expression of genes involved in cell-cell and cell-matrix interactions. Taken together, these novel findings shed light on the function of both the alpha and the beta isoforms, and indicate that p63α is specifically required for limb and palate development, whereas p63β can replace p63α in skin development and in the adulthood.","language":"eng","citation":"PHENOTYPIC AND MOLECULAR CHARACTERIZATION OF A NOVEL P63ALPHA;KO MOUSE MODEL / G. Urciuoli ; supervisor: C. MISSERO ; internal supervisor: B FRANCO ; external supervisor: M. MIKKOLA. Università degli Studi di Milano, 2023 Mar 02. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12426.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/956498/2149086/phd_unimi_R12426.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1175518"},"title":"CLINICAL AND LABORATORY CHARACTERISATION OF ACQUIRED VON WILLEBRAND SYNDROME","internalauthor":"CIAVARELLA, ALESSANDRO","type":"Tesi di dottorato","year":"2025","abstract":"Background: Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder due to reduced or dysfunctional VWF in individuals without a personal or familial bleeding history. It is associated with systemic diseases such as lymphoproliferative (LPDs) and myeloproliferative neoplasms (MPNs), cardiovascular, and autoimmune conditions. The underlying biological processes differ across clinical contexts and remain incompletely defined, complicating both diagnosis and management.  Aim: To characterize AVWS based on clinical presentations and laboratory profiles, with particular focus on bleeding phenotypes, multimer patterns, and underlying disease mechanisms.  Methods: This cross-sectional study included patients diagnosed with AVWS between 2014 and 2025 at a single center. Clinical and laboratory data, including ISTH-BAT score, FVIII:C, VWF:Ag, VWF:RCo, VWF:GPIbR, VWF:CB, VWFpp, multimer distribution, and intraplatelet VWF, were analyzed. Comparative and correlation analyses were conducted between MPNs and LPDs subgroups. Additional analyses explored associations between functional VWF assays and clinical bleeding severity.  Results: Among 140 patients diagnosed with AVWS, 76% had MPNs and 19% LPDs. Clinically relevant bleeding was more frequent and severe in LPDs, with higher ISTH-BAT scores and predominant mucosal and gastrointestinal bleedings. LPDs showed more profound laboratory alterations, including reduced VWF activity, pronounced multimeric loss, and elevated VWFpp/VWF:Ag ratios, suggesting selective clearance of high molecular weight multimers potentially associated with proteolysis. In contrast, MPNs displayed milder abnormalities, with relatively preserved multimer structure, supporting a mechanism of platelet-mediated adsorption, and reduced intraplatelet VWF content. Notably, among the two assays measuring the platelet-dependent VWF activity, VWF:RCo better correlated with bleeding severity in LPDs, while VWF:GPIbR was more sensitive in detecting qualitative functional defects in MPNs.  Conclusions: AVWS is characterized by distinct pathogenetic patterns in MPNs and LPDs, that may variably involve clearance, cellular absorption, and proteolysis. Detailed investigation of these processes is essential to support targeted, mechanism-oriented management strategies.","language":"eng","citation":"CLINICAL AND LABORATORY CHARACTERISATION OF ACQUIRED VON WILLEBRAND SYNDROME / A. Ciavarella ; tutor: F. Peyvandi ; coordinator: M. S. Clerici. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2025 Jun 18. 36. ciclo","filename":"phd_unimi_R12854.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1175518/3110660/phd_unimi_R12854.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1049189"},"title":"ALLE ORIGINI DEL CIMENTO: RETI METEOROLOGICHE E INTELLETTUALI IN TOSCANA ALLA METÀ DEL SEICENTO","internalauthor":"PACE GRAVINA, RUGGERO","type":"Tesi di dottorato","year":"2024","abstract":"The main objective of this thesis is to reconstruct the context in which the Accademia del   Cimento arose. The first chapter will therefore retrace the intellectual origins of the group:   starting from the study of a peculiar documentary corpus of lists of books and authors, the   main philosophical-natural references of the academicians will be identified, as well as their   self-perception in the Republic of Letters.    The second chapter, on the other hand, is dedicated to the analysis of many documents   related to meteorology which importance is fundamental for achieving the underlying   objective. Keeping the focus on the figure of Grand Duke Ferdinand II de' Medici, a great   connoisseur of the subject, the events of the circle of scholars who gravitated around him   will be retraced, as well as the first european meteorological network he founded in 1654.   Particular attention will be paid to the historical-political context in which it was born and   the modalities of data transmission.    Finally, in the third and last chapter we will focus on the observations and theoretical   writings on meteorological topics directly referable to the Cimento, thus reknitting the   thread between the Accademia and the intellectual and experimental context before it.","language":"ita","citation":"ALLE ORIGINI DEL CIMENTO: RETI METEOROLOGICHE E INTELLETTUALI IN TOSCANA ALLA METÀ DEL SEICENTO / R. Pace Gravina ; tutor: G. Giannini ; coordinatore: M. Soresina. - Milano. Dipartimento di Studi Storici, 2024 May 31. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12910.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1049189/2408914/phd_unimi_R12910.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1212648"},"title":"IL RUOLO DELLA CORTE COSTITUZIONALE NELLO SPAZIO DELLA DISCREZIONALITÀ LEGISLATIVA: LA GIURISPRUDENZA A ¿RIME OBBLIGATE¿ E A ¿RIME ADEGUATE¿","internalauthor":"PANIGADA, NICCOLO","type":"Tesi di dottorato","year":"2026","abstract":"The research addresses the contested issue of the relationship between the Italian Constitutional Court and the legislature, analyzing the dialectic between respect for political discretion and the protection of fundamental rights. The theoretical foundation of this tension lies in the principle of separation of powers, which has led the Court, in certain circumstances, to exercise self-restraint through decisions of inadmissibility or outright annulment, thereby creating regulatory gaps. While such rulings preserve the legislative domain, they raise the question of the Court’s actual capacity to ensure the supremacy of the Constitution. At the same time, constitutional jurisprudence has progressively expanded its decisional arsenal, introducing manipulative techniques and experimenting with novel forms of intervention—sometimes unsuccessful—in order to strengthen the protection of rights. This dynamic brings into focus a central issue: the limits of the Court’s creative power and the pursuit of a balance between self-restraint and manipulative intervention.  The dissertation investigates whether the Court’s decisions can achieve a genuine balance between legislative discretion and constitutional primacy, with particular attention to the opposition—and at times the overlap—between rime obbligate decisions (mandatory rhymes), grounded in the Crisafullian doctrine, and rime adeguate decisions (adequate rhymes). The analysis, focusing especially on constitutional jurisprudence from 2018 to 2025, begins with the historical and normative foundations of constitutional justice, first addressing the consolidation of the Crisafullian doctrine of rime obbligate, and then tracing the jurisprudential evolution that led to the legitimation of rime adeguate decisions. The most recent period, inaugurated by judgment no. 222 of 2018, is examined in detail, highlighting how the Court has favored manipulative interventions, often in the field of criminal law, with significant implications both for institutional legitimacy and for the stability of its relationship with the legislature.  This reconstruction brings to light the overcoming of the rime obbligate dogma and, at the same time, the emergence of new perspectives: from a possible return to more rigorous forms of self-restraint, as evidenced by certain recent decisions, to the debate on normative or institutional instruments better suited to align the role of the Court with that of the legislature, thereby ensuring the effective protection of rights without undermining the centrality of political representation. In this perspective, the research aims to provide an updated interpretive framework for the relationship between the Constitutional Court and Parliament, within the context of the most recent transformations of Italian constitutional justice.","language":"ita","citation":"\"IL RUOLO DELLA CORTE COSTITUZIONALE NELLO SPAZIO DELLA DISCREZIONALITÀ LEGISLATIVA: LA GIURISPRUDENZA A \"\"RIME OBBLIGATE\"\" E A \"\"RIME ADEGUATE\"\" / N. Panigada ; tutor: M. E. D'Amico ; co-tutor: G. Arconzo ; coordinatrice: F. Biondi. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2026 Feb 02. 38. ciclo, Anno Accademico 2024/2025.\"","filename":"phd_unimi_R13681.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 06-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1062951"},"title":"(POST)COLONIAL INTERFERENCES: ETHNICITY, GENDER, AND CLASS IN CONTEMPORARY DANISH LITERATURE ABOUT GREENLAND","internalauthor":"TURRI, FRANCESCA","type":"Tesi di dottorato","year":"2024","abstract":"During the last two decades, Greenland has progressively become a hot topic within the international public debate, and this same interest has characterized Danish literature – in a variety of forms ranging from autofictional and historical texts to genre-fiction. Kim Leine, Iben Mondrup, and Lotte Inuk stand out as three significant representatives of this wave, also due to their peculiar experience as migrants in Greenland. The present work is concerned with the narratives that have characterized Danish literature and discourses about Greenland since the cultural encounter between former colonizer and colonized and investigates whether the three authors’ ‘internal’ viewpoint has led to literary understandings of Danish-Greenlandic relations that do not necessarily rely on stereotypical stances or on a binary opposition between ‘us’ and ‘them’. Two discourses – both central to postcolonial studies pertaining to the Danish-Greenlandic context – are at the core of my inquiry: 1) the ‘othering’ dynamics that fall under the name of «Arctic orientalism», concept theorized by Kirsten Thisted in the 1990s and 2) the so-called «exceptionalism», i.e., the rhetoric of self-absolution promoted on Danish side with regard to colonial presence and responsibility in Greenland.   The (possible) deconstruction of these narratives in a selection of novels by Leine, Mondrup, and Inuk has been analyzed by taking into consideration three different categories of social difference: ethnicity, gender, and class. The joint attention for these aspects – all deeply intertwined with understandings of identity – presupposes an ‘intersectional’ viewpoint on Greenlandic society and how it is represented in these literary works. Although in the course of my research I also refer to the notion of «intersectionality» – first employed by the jurist Kimberlé Crenshaw in an attempt to «contrast the multidimensionality of Black women’s experience with the single-axis analysis that distorts these experiences» (Crenshaw 1989: 139) – I rather tend to employ Ingunn Moser’s adjoining term, «interference». ‘Interference’ points to the fact that «the different processes that construct gender, class and dis/ability not only mechanically sustain and reinforce each other (as the metaphor of intersections suggests), but may also clash, come into conflict and neutralize each other» (Lykke 2010: 84). Moser’s expression, suggesting a certain degree of ‘fuzziness’, thus seems to leave more room for possible inconsistencies.  The ‘intersectional’ nature of my work unfolds through the creation of a ‘cumulative’ structure for the last three chapters – preceded by chapter 1, conceived as a historical introduction to the context and genre here scrutinized. While chapter 2 solely revolves around the ethnic dimension, chapter 3 and 4 – respectively focusing on gender and class – are essentially ‘multidimensional’, as they build on concepts and observations made in the previous sections of the dissertation. Thus, the category of ethnicity constantly dialogues with those of gender and class; gender-related matters are also discussed in chapters 2 and 4, although they are perhaps less pervasive than discourses on ‘Danishness’ and ‘Greenlandicness’, at the center of dansk grønlandslitteratur.","language":"eng","citation":"(POST)COLONIAL INTERFERENCES: ETHNICITY, GENDER, AND CLASS IN CONTEMPORARY DANISH LITERATURE ABOUT GREENLAND / F. Turri ; tutor: C.C. Storskog ; co-tutor: K. Thisted ; coordinator: L. Pinnavaia. Università degli Studi di Milano, 2024 Jun 21. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12892.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1062951/2440481/phd_unimi_R12892.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/946381"},"title":"AMYLOID FIBRILS INDUCE GLYCOCALYX MEDIATED MECHANOTRANSDUCTION IN MELANOMA","internalauthor":"FARRIS, FRANCESCO","type":"Tesi di dottorato","year":"2022","abstract":"PMEL is an amyloidogenic protein found overexpressed in melanoma compared to healthy skin. PMEL expression correlates with unfavorable prognosis, but the mechanism beyond the adverse disease outcome is still unknown. Recently, our lab established a link between the presence of PMEL amyloid fibrils in the metastatic melanoma secretome and YAP activation, driving cancer proliferation and drug resistance.  In this study, we show that PMEL amyloid fibrils, secreted by cancer cells, are component of the extracellular matrix and modify its stiffness thus activating mechanosignalling.   We highlight the signaling pathway that connects PMEL fibrils to YAP activation. In particular, we show that Agrin is part of the extracellular amyloid plaques, interacts with PMEL amyloid fibrils and it is necessary to drive PMEL dependent YAP activation. To further dissect the signaling cascade triggered by amyloids we also overexpressed LATS1 or/and LATS2, key members of Hippo pathway downstream of Agrin. The overexpression of LATS2 does not affect YAP activation, while LATS1 overexpression abrogates PMEL dependent YAP activation indicating that this kinase is a downstream inhibitor of the amyloid mediated mechano-response. We demonstrate that PMEL amyloid fibrils activate YAP in a ROCK independent fashion. Finally, we demonstrated that the presence of amyloid fibrils in the extracellular space enhances the migration and invasion capacity of melanoma cells.   Our study uncovers the mechanism by which amyloid fibrils drive YAP activation impacting on migration and invasion of melanoma cells. These data suggest that inhibitors capable to reduce the formation of extracellular amyloid fibrils could interfere with melanoma progression.","language":"eng","citation":"AMYLOID FIBRILS INDUCE GLYCOCALYX MEDIATED MECHANOTRANSDUCTION IN MELANOMA / F. Farris ; internal advisor:  M. Mapelli ; tutor: A. Bachi ; coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2022 Dec 16. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12417.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/946381/2100158/phd_unimi_R12417.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1205495"},"title":"WESTMINSTER LEGACY? EXECUTIVE AGENDA CONTROL AND LEGISLATIVE TIME IN A MULTIPARTY PARLIAMENTTHE ISRAELI KNESSET IN COMPARATIVE-HISTORICAL PERSPECTIVE","internalauthor":"ELOVITS, TAL YEHEZKEL","type":"Tesi di dottorato","year":"2026","abstract":"\"This dissertation resolves a central puzzle in comparative politics: how Israel’s parliament, the Knesset, built on a consensual electoral framework, exhibits the powerful executive agenda control characteristic of a majoritarian Westminster system. I argue this paradox is sustained by a path-dependent hybrid system where individual-centric procedural rules function as the trigger for powerful, party-centric control.  This argument is tested using a mixed-methods design, grounded in a novel, manually-coded dataset covering 1,699 bills and the universe of over 29,500 associated amendments from 2009 to 2022.  The statistical analysis uncovers a stark asymmetry in the procedural power of amendments: those from the opposition cause significant legislative delay, while those from the governing coalition produce no significant delay. This is explained by a \"\"pre-emptive negotiation\"\" mechanism, where ideologically diverse coalitions resolve disputes in private to avoid the high costs of public infighting. The analysis also reveals a predictable lifecycle of this conflict, driven by government alternation and legislative timing.  The dissertation traces this hybrid framework to its origins in Israel’s founding (1948–1951), where two distinct inheritances were combined: a consensual system from the pre-state political culture, and an executive-centric procedural core from the British Mandate.  Ultimately, this research makes several distinct contributions. For legislative studies, it introduces a comprehensive new dataset and an integrated model of the strategic lifecycle of legislative conflict. For Israeli studies, it offers a historically-grounded institutional lens for interpreting contemporary political conflicts. Finally, for comparative politics, it provides the first systematic classification of Israel's agenda control powers using Döring's framework, empirically grounding its paradoxical institutional placement, and argues for repositioning Israel as a critical, and often overlooked, case in the study of Westminster-inflected systems.\"","language":"eng","citation":"Westminster Legacy? Executive Agenda Control and Legislative Time in a Multiparty Parliament. The Israeli Knesset In Comparative-Historical Perspective / T.y. Elovits ; supervisor: A. Pedrazzani ; cosupervisor: A. Cassani ; doctorate program coordinator: F. Franchino. - Milano. Dipartimento di Scienze Sociali e Politiche, 2026 Jan 29. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13689.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 05-LUG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1020471"},"title":"DISORDERING IN PYROCHLORE PHASES FOR RADIONUCLIDES DISPOSAL: A MULTISCALE STRUCTURE STUDY","internalauthor":"DI BIASE, ARMANDO","type":"Tesi di dottorato","year":"2023","abstract":"Oxides with the general formula A2B2O7 and the pyrochlore structure have drawn much attention in the field of radionuclides immobilization. The Gd2Zr2O7 composition, in particular, has demonstrated high radiation resistance, making it an ideal host-matrix for encapsulating radioactive elements within the crystal structure. Despite the average structure, chemical composition can induce intrinsic structural distortions and control the degree of ordering of cations and anions in pyrochlore oxides, defining their response towards irradiation. To understand the origin of such   distortions, an in-depth study of the structure at both the average and local scales is required. In the present thesis, a systematic investigation of three solid solutions related to the Gd2Zr2O7 composition is performed. Namely, the following solid solutions are examined: Gd2(Ti1-xZrx)2O7, (Nd1-xGdx)2Zr2O7 and Gd2(Zr1-xCex)2O7. All the samples are produced by solid-state synthesis and structural changes as a function of chemical composition are studied through High-resolution X-ray Diffraction (HR-XRD), laboratory Raman spectroscopy and the analysis of Pair Distribution Function (PDF). Cation antisite and anion Anti-Frenkel defects accumulate at the average scale as cations become similar in size. These defects are   symptoms of structural distortions at the local scale and a weberite-type model is invoked for the description of the short-range order in the Gd2(Ti1-xZrx)2O7 system. Nevertheless, the deviation from the average structure at the local scale in disordered compositions appear to be more complex than a single structural model can describe.","language":"eng","citation":"DISORDERING IN PYROCHLORE PHASES FOR RADIONUCLIDES DISPOSAL: A MULTISCALE STRUCTURE STUDY / A. Di Biase ; tutor: C. Castellano ; co-tutor: M. Scavini ; coordinator: D. Passarella. Dipartimento di Chimica, 2023. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12749.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1020471/2333873/phd_unimi_R12749.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1196908"},"title":"DISSECTING THE ROLE OF GOLGI TRAFFIC IN BRAIN DEVELOPMENT ACROSS HEALTH AND DISEASE: A LESSON FROM COG5-CDG STUDIES","internalauthor":"POLENGHI, MARTINA","type":"Tesi di dottorato","year":"2025","abstract":"Neurons forming the neocortex are generated during embryonic development from two main classes of neural progenitor cells: apical and basal progenitors (APs and BPs, respectively). The cell fate switch from AP to BP is accompanied by changes in polarization and intracellular architecture. Interestingly, Golgi apparatus (GA) is differentially positioned in APs and BPs. GA is the main hub for glycosylation and defects in GA and associated glycosylation are observed in a group of rare multi system diseases collectively referred to as Congenital Disorders of Glycosylation (CDGs). Notably, brain development impairments, such as primary microcephaly, are described in most CDG patients. Despite the increased number of diagnosed patients, the cell biological mechanisms linking defective Golgi glycosylation and neurodevelopmental manifestations are currently unknown.  Here we try to fill this gap by investigating the influence of GA on cell identity and fate transition during brain development.   In this study we show that pharmacologically induced GA fragmentation results in a premature cell fate switch from apical to basal progenitors, prompting to a link between Golgi apparatus homeostasis and cell identity and fate in brain development.  Using ML-guided automated microinjection we prove that the premature cell fate switch is caused by an increase in symmetric differentiative divisions of AP cells.   To specifically study GA polarization in APs and GA-related glycosylation in physiology and disease in humans, we select COG5 as a target for functional manipulation. COG5 is a subunit of the Conserved Oligomeric Golgi Complex (COG) whose mutation is associated with primary microcephaly and glycosylation impairments.   We first use electroporation in organoids to knock down COG5 and we observe that depletion of COG5 affects Golgi integrity and causes an increase in BPs and in Ctip2+ neurons suggesting that targeted GA perturbation influences the program of cell proliferation vs differentiation.   To gain more insights into the cellular logic linking GA and cell fate switch we generate human brain organoids from two patients harboring a novel COG5 mutation that causes reduced levels of COG5 protein and of its COG7 interactor. Concomitantly, reduction of glycosphingolipid (GSL) subtypes is observed.   In the brain organoids of the COG5 CDG patients, an impairment on APs Golgi structure is observed. This is paralleled by changes in the apical progenitor cells division plane, that ultimately affect NPCs and neuronal populations abundance. These observations are consistent with the microcephalic clinical phenotype described for the two patients.    Finally, we show that COG5 mutation can differentially regulate cell fate switch trajectories, possibly by influencing signaling pathways determinants trafficking, and we specifically propose a role of ACBD3-mediated Notch/Numb pathway.  In conclusion, our data suggest that GA is linked to cell fate switch during brain development and that GA is crucial for the control of cell proliferation vs differentiation possibly by influencing the trafficking of cell fate determinants.","language":"eng","citation":"DISSECTING THE ROLE OF GOLGI TRAFFIC IN BRAIN DEVELOPMENT ACROSS HEALTH AND DISEASE: A LESSON FROM COG5-CDG STUDIES / M. Polenghi ; tutor: E. Taverna ;  supervisore: G. Testa ;  coordinatore: G. Testa, D. Pasini. - Human Technopole. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Dec 16. 37. ciclo, Anno Accademico 2025.","filename":"phd_unimi_R13497.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1196908/3186343/phd_unimi_R13497.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1125557"},"title":"THE EXPERIENCE OF CANCER PAIN: DEVELOPING INTEGRATED SUPPORT SYSTEMS FOR BREAST CANCER PATIENTS WITH CHRONIC PAIN INFORMED BY PATIENT AND CAREGIVER INSIGHTS","internalauthor":"FILIPPONI, CHIARA","type":"Tesi di dottorato","year":"2025","abstract":"Introduction: Chronic pain (CP) significantly affects the quality of life (QoL) of cancer patients and their informal caregivers, necessitating a multidimensional approach to address its complexities. This doctoral thesis synthesizes findings from four years of research, focusing on cancer-related CP, particularly in breast cancer survivors and their caregivers.  Methods: The research began with a narrative review (Study 1) that synthesized existing data on the impacts of CP on both patients’ and caregivers’ QoL. Subsequent studies utilized a mix of qualitative and quantitative methods. Online platforms (Study 2) and focus groups (Study 3) collected data on patients' and caregivers' unmet needs, emotional responses, and treatment preferences concerning CP, particularly in breast cancer survivorship. The final study (Study 4) evaluated the usability of PainRELife, a novel digital health tool for managing breast cancer CP and enhancing patient engagement in treatment decisions.  Results: Study 1 revealed an overall reduction in QoL and emphasized the need for a bidirectional perspective on CP’s impacts. Study 2 identified distinct emotional and practical needs through online community data. Study 3’s focus groups highlighted significant barriers to pain management, the need for psychosocial support, and caregiver emotional challenges. Study 4 demonstrated the PainRELife app’s effectiveness, showing improved pain self-efficacy, reduced pain intensity, and enhanced patient engagement in shared decision-making processes.  Discussion: The studies revealed the complexity of CP management, particularly in breast cancer, highlighting diverse needs between patients and caregivers. Digital tools like PainRELife show potential for enhancing CP self-management and outcomes, underscoring the need for holistic, patient-centered approaches in cancer care.","language":"eng","citation":"THE EXPERIENCE OF CANCER PAIN: DEVELOPING INTEGRATED SUPPORT SYSTEMS FOR BREAST CANCER PATIENTS WITH CHRONIC PAIN INFORMED BY PATIENT AND CAREGIVER INSIGHTS / C. Filipponi ; supervisor: G. Pravettoni ; added supervisor: M. Masiero ; internal advisor: K. Mazzocco. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Jan 21. 36. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13138.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1125557/2610989/phd_unimi_R13138.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1052208"},"title":"RELIGION AS A CULTURAL CONTEXT OF INTOLERANCE: ASSESSING THE INFLUENCE OF CULTURAL(IZED) FORMS OF RELIGION ON ATTITUDES TOWARDS IMMIGRATION ACROSS EUROPEAN COUNTRIES","internalauthor":"TURKOVIC, ANDREA","type":"Tesi di dottorato","year":"2024","abstract":"In the 21st century, Europe experienced a surge in immigration, fostering both ethnic and religious diversification of European societies. In addressing the dynamic landscape of inter-group relations within this evolving context, existing research is primarily grounded in social identity theory and ethnic competition theory, where values and beliefs are perceived as resources in understanding inter-group dynamics. From such a perspective, immigrants become further separated from the national identity and Christian heritage of European societies through their generalised association with Islam, which is often instrumentalized, highlighting religion's role in inter-group relations. Despite the ongoing discussion on secularization and the decline in the significance of religion, the multifaceted nature of these processes must be recognized, as religion appears to transform from its purely religious meaning into a more cultural, institutional, and political force that continues to shape identities indirectly.  This thesis proposes to assess and explain the role that religion and religiosity play in the formation of intolerance towards immigrants in European societies as they are becoming increasingly ethnically and religiously heterogeneous, while simultaneously recognising the transformation of religion and its meanings across different contexts.  Comprising three studies, the thesis explores the impact of culturalized religion on intolerance, investigates religion's instrumentalization in political discourse across European countries, and analyses religious contexts in Serbia, Italy, and the UK.   The first study delves into individual-level manifestations of culturalized religion, examining how cultural affiliation and religious practice influence intolerance towards immigrants across European countries. Findings highlight the nuanced nature of individual religiosity, with nominal affiliation and irregular practice among the unaffiliated exhibiting significant associations with intolerance, especially in Orthodox contexts where the cultural practice of religion stands out the most.  The second study shifts focus to political elite discourse, investigating religion's instrumentalization in public discussions on immigration in Europe. Results reveal two mechanisms: general notions of religion influence intolerance for affiliates, irrespective of their practice; while specific identification of Muslims activates broader civilizational identity instigating intolerance for all, regardless of their religious affiliation and practice. The findings suggest that individual religiosity may not substantially mediate the relationship between individual intolerance towards immigrants and the instrumentalization of religion in political elite discourse, highlighting the complexity of these dynamics across various religious contexts.  The third study adopts a smaller-scale comparative approach, exploring religious contexts in Serbia, Italy, and the UK. Results reveal distinct patterns in the relationship between religiosity types and intolerance towards immigrants, showcasing variations in both the definition of immigrant groups and the types of religiosity that emerge across these three distinct contexts.   To answer the posited research questions, the microdata from the 9th wave of the European Social Survey was applied across all three studies. Additionally, contextual-level data supplemented the first two studies, where multilevel regression modelling was employed to explore cross-contextual differences in the relationship between intolerance and religiosity. The third study adopted a small-scale comparative design, employing linear regression modelling separately on samples from three countries: Serbia, Italy, and the UK.   As its primary objective, this research emphasizes the transformation of religion, its culturalization, and its evolving role as an identity marker across European countries, surpassing its purely religious connotations. In conclusion, the thesis contributes to the discourse on the transformation and culturalization of religion, providing insights into the complexity of these processes and their context dependency. The research advocates for nuanced analyses of religiosity, political discourse, and cultural contexts to comprehend the intricate relationship between religion and intolerance in contemporary societies.","language":"eng","citation":"RELIGION AS A CULTURAL CONTEXT OF INTOLERANCE: ASSESSING THE INFLUENCE OF CULTURAL(IZED) FORMS OF RELIGION ON ATTITUDES TOWARDS IMMIGRATION ACROSS EUROPEAN COUNTRIES / A. Turkovic ; tutor: F. Biolcati Rinaldi (University of Milan), C. Nardella (University of Milan) ; coordinator: P. A. Rebughini (University of Milan). - Aula Seminari (latto Passione), University of Milan, Via Conservatorio 7, 20122 Milano. Università degli Studi di Milano, 2024 Jun 04. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12913.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1052208/2407991/phd_unimi_R12913.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1259216"},"title":"MSC-LADEN SCAFFOLDS FOR OSTEOCHONDRAL REPAIR","internalauthor":"ROBERTS, LAUREN MARTINE INGRID","type":"Tesi di dottorato","year":"2026","abstract":"Osteochondral defects disrupt the functional unit formed by articular cartilage, subchondral bone, and their interface. Current clinical strategies do not reliably restore this complex organisation, creating a need for scaffolds that combine cell compatibility, tunable material properties, biochemical cues, and spatial organisation. The aim of this thesis was to develop and evaluate modular silylated sol–gel hydrogels as candidate mesenchymal stromal cell-laden scaffolds for osteochondral repair.  Gelatin, hyaluronic acid, and chitosan were functionalised with alkoxysilane groups to generate single-component and multicomponent hydrogels within a shared sol–gel crosslinking framework. Hydrogel composition modulated precursor viscosity, viscoelastic properties, swelling, and stability. Extrusion-based evaluation showed that favourable rheological behaviour did not directly translate into reliable printability, mainly because dynamic sol–gel crosslinking created a narrow processing window between flow, gelation, and post-deposition stabilisation. The hydrogels showed good cytocompatibility, and N-terminal silylation of bioactive peptides improved peptide retention within a model Si-Gel network. Preliminary cell attachment and differentiation assays produced limited and non-sequence-specific responses, highlighting the need to optimise peptide presentation and biological assay conditions.  This work provides a foundation for the future development of spatially organised, peptide-functionalised, cell-laden osteochondral constructs.","language":"eng","citation":"MSC-LADEN SCAFFOLDS FOR OSTEOCHONDRAL REPAIR / L.m.i. Roberts ; supervisors: S. Pellegrino, G. Subra ; co-supervisors: C. Echalier, E. Perrier-Groult ; PhD course coordinator: G. Vistoli. - Université de Montpellier, Montpellier, France. Dipartimento di Scienze Farmaceutiche, 2026 Jul 16. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R14297.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 06-GEN-28"}
,{"handle":{"url":"https://hdl.handle.net/2434/816309"},"title":"NUCLEAR FRAGMENTATION CROSS SECTIONS MEASUREMENTS FOR HADRONTHERAPY: IMPLEMENTATION AND OPTIMIZATION OF A BEAM MONITORING SYSTEM","internalauthor":"DONG, YUNSHENG","type":"Tesi di dottorato","year":"2021","abstract":"The FOOT project is a nuclear physics experiment that aims to measure the differential cross sections (d2σ/dΩ·dE) of the nuclear interactions involved in particle therapy and space radioprotection. The final experimental data will be adopted as benchmark for the MC simulation tools, to improve the current particle therapy treatment planning systems and to develop a new shielding design suitable for the future space missions.   The FOOT project consists of two different experimental setups and in both of them a drift chamber is adopted as Beam Monitor to measure the projectile direction and position, to count the total number of delivered particles and to reject the pre-target fragmentation events.  In this Ph. D. project, which has contributed to the construction and start of the FOOT experiment, the drift chamber has been finalized, tested, calibrated and operated in the experiment.   A multi-track reconstruction algorithm has been developed taking advantages of the Legendre transformation properties combined with a χ2 minimization algorithm. The software has been tested and optimized both on experimental and on MC simulated data and it has been included within the FOOT global reconstruction code.  The detector has been used in different tests and data takings. In particular, an extensive calibration and performance assessment has been conducted with protons at 228 and 80 MeV. In this occasion, the overall Beam Monitor efficiency, spatial resolution and active area have been measured.  In addition, the space-time relations of the drift chamber have been measured and the results have been adopted as benchmark for a self calibration method developed to estimate the space-time relations using only the Beam Monitor hits and tracks.   The detector has been successfully operated in the FOOT data takings performed with both the experimental setups. In particular, in the framework of the emulsion spectrometer measurements, the Beam Monitor has been employed to measure the profile of the irradiation pattern and to count the total number of delivered particles. Then, during the test performed with the electronic spectrometer, the drift chamber has been used with the FOOT general DAQ system to measure the incoming beam direction and position.   In addition, the Beam Monitor has performed a characterization of the GSI 700 MeV/u carbon ion beam, measuring the transverse spot size, the rate and the angular spread of the incoming beam.  The final part of the project has been devoted to a detailed study of the performances of the detector in view of the work for the data analysis of the FOOT experiment. In particular, different selection criteria have been studied to identify and reject the pre-target fragmentation events and the impact of the drift chamber spatial resolution on the cross section accuracy has been estimated by means of MC simulations.","language":"eng","citation":"NUCLEAR FRAGMENTATION CROSS SECTIONS MEASUREMENTS FOR HADRONTHERAPY: IMPLEMENTATION AND OPTIMIZATION OF A BEAM MONITORING SYSTEM / Y. Dong ; supervisor: G. Battistoni, F. Camera ; coordinator: M. Paris. Dipartimento di Fisica Aldo Pontremoli, 2021 Mar 08. 33. ciclo, Anno Accademico 2020. [10.13130/dong-yunsheng_phd2021-03-08].","filename":"phd_unimi_R11860.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/816309/1709049/phd_unimi_R11860.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1068920"},"title":"IL CONTROLLO GIURISDIZIONALE DELLE MISURE DI APPLICAZIONE DEL DIRITTO DELL'UNIONE EUROPEA","internalauthor":"AGRATI, GIULIA","type":"Tesi di dottorato","year":"2024","abstract":"In the absence of any relevant elements of innovation within the Treaty of Lisbon, the primary law approach to the issue of the application of EU law never seems to have deviated from the dichotomy between the ordinary cases of indirect administration of EU law by MS and the (rare) cases of direct administration by the EU (see Art. 291(2) TFEU and Art. 4(3) TEU). More recently, however, the emergence of new organizational and procedural forms has led to an ever-increasing intertwining of the national and EU administrative levels. It has resulted in an intense network of formal and informal collaboration techniques between the EU and the MS and, consequently, in a kind of implementing measures of a progressively more hybrid nature, composed of a national and an EU part. This phenomenon has also been accompanied by the simultaneous appearance of “new sources of law”, markedly atypical and with socially relevant mandatory force. Overall, there has been a gradual de facto erosion of the traditional binary system of implementation of EU law, in favor of the emergence of a third, new, model, called the co-administration. While the latter meets inescapable enforcement needs, it seems to have given rise to many questions regarding the theme of judicial protection against acts of application of EU law.   Against this background, this thesis proposes to investigate the issue of judicial review of measures of implementation of EU law, with the aim of understand whether the system outlined by the Union can be said to be satisfactory and respectful of the principles of effectiveness and completeness of judicial remedies set forth in Article 47 Charter and Article 19 TEU.   After a description of the current integrated system of application of EU law, it will proceed, first of all, to the investigation of the mechanisms of the jurisdictional control, that is, of the subjects in charge, at different levels, of carrying out this function and of the means through which it is carried out, then the work will be completed by a study of the ways in which the judge, who is competent to control the executive measure, carries out his review, especially with reference to the parameters and intensity of the latter. This is always in the light of the principles set forth in Article 47 Charter and Article 19 TEU, thus with the aim of understand whether, once the party has had access to the judge, the breadth of the control exercised by the latter over the acts of implementa- tion of EU law can be considered satisfactory or whether, on the other hand, criticalities (still) remain, such as to realize areas (more or less justified) of “jurisdictional immunity”.","language":"ita","citation":"IL CONTROLLO GIURISDIZIONALE DELLE MISURE DI APPLICAZIONE DEL DIRITTO DELL'UNIONE EUROPEA / G. Agrati ; tutor: M. Condinanzi ; coordinator: F. Biondi. - Università degli Studi di Milano. Università degli Studi di Milano, 2024 Jul 09. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12946.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1068920/2457753/phd_unimi_R12946.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1042070"},"title":"COLOR CHARACTERIZATION: NOVEL ASPECTS IN DISPLAYING, MODELING AND INTERACTION WITH LIGHT","internalauthor":"SARTI, BEATRICE","type":"Tesi di dottorato","year":"2024","abstract":"The central theme of the thesis is color. Within this overarching theme, we explore research lines in three areas: Displaying color, Modeling color sensation and Light and Color Interaction.  Regarding the first area, the research focused on color reproduction in the digitization of cinematographic films. Two different approaches were followed. The first involves reconstructing the gamut of analog films based on the sensitometric data released by various production houses in the case of chromogenic films, or based on dye recipes in the case of films colored using the tinting method. The second approach involves comparing the different results of digitizing a cinematographic film with various scanners from different manufacturers in different archives and laboratories, highlighting the presence of glare and other issues related to the lack of standards in this field.  Concerning the second area, the focus is on modeling color sensation in image processing, specifically exploring the application of ACE (Automatic Color Equalization), one of the Spatial color algorithms (SCAs) derived from the Retinex theory, to hyperspectral imaging. ACE is commonly used on the three channels in RGB image processing but has never been applied in the hyperspectral domain, where the spectral information defines the third dimension of the image.  Finally, for the third area, the Spectra Divergence CRI (SDCRI) is proposed as a new easy-to-calculate metric to replace the color rendering index (CRI). Over the years, CRI has shown significant drawbacks in assessing lighting fidelity, especially with advancements in colorimetry and LED lighting. However, despite numerous attempts with new fidelity metrics, it has never been replaced. Different from all the methods in the literature, SDCRI relies on a spectral approach to calculate color fidelity.","language":"eng","citation":"COLOR CHARACTERIZATION: NOVEL ASPECTS IN DISPLAYING, MODELING AND INTERACTION WITH LIGHT / B. Sarti ; tutor: A. Rizzi ; coordinatore: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2024 Apr 17. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13000.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1042070/2391031/phd_unimi_R13000.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1021110"},"title":"ENVIRONMENTAL IMPACT OF LIVESTOCK ACTIVITIES IN THE PO VALLEY AND MITIGATION PATHWAYS EVALUATION","internalauthor":"COSTANTINI, MICHELE","type":"Tesi di dottorato","year":"2023","abstract":"\"In Italy, livestock production is of great importance within the agricultural sector, driven by social, economic and cultural factors, with the Po Valley hosting approximately 80% of the national dairy and beef cattle, and pig populations. The link between animal production and the environment is increasingly recognized as a critical issue, requiring a thorough understanding of their interaction.  This thesis aimed to evaluate different mitigation strategies to reduce on-farm emissions of greenhouse gases and air pollutants, specifically examining air treatment technologies in pig housing facilities and some waste management measures for the cattle sector. Focus was made on the two above environmental aspects due on the one hand to the strong relationship that these have with the sector under analysis and on the other to their relevance in the Italian and the broader European context. To provide a comprehensive understanding of these issues, the approach included (i) direct measurements during field campaigns on farms to assess emissions; (ii) life cycle assessment (LCA) methodology using primary production data collected through surveys, complemented by secondary data from literature and estimation models; and (iii) large-scale modeling based on regional/national statistics and general activity factors, to estimate the potential resulting from widespread adoption of mitigation practices.  The relationship between livestock in Italy and air pollution, with a focus on ammonia emissions, was explored through three different studies. The first focused on the evaluation of the evolution of atmospheric concentrations of ammonia (NH3) in Northern Italy during the COVID-19 pandemic. Ground-based and satellite data were analyzed for the year 2020 and compared with data from previous years, and it was concluded that, unlike some other air pollutants, the anti-COVID-19 measures affecting human activities did not lead to a reduction in NH3 air concentrations, confirming its strong relationship with agriculture, whose activities were not significantly interrupted during the pandemic.  The other two studies focused instead on the adoption of abatement strategies in pig farms to reduce ammonia and particulate emissions from housing facilities. This phase of the agricultural cycle is very influential on the total emissions of these pollutants, but mitigation technologies aimed at it are not widespread in the Italian context. LCA has been used to  quantify the environmental impact of pig production in a \"\"standard\"\" production context and to compare it with the production when implementing two air treatment technologies aimed at reducing pollutant emissions: i) wet scrubber; ii) dry scrubber. Inventories have been made of the technical performances of farms in Italy and Spain. Operation of the two technologies have been obtained from experimental trials carried out during the Life- MEGA project. Both technologies tested showed their potential to reduce emissions in the pig housing phase, which had an impact on all the categories affected by air pollutant emissions, such as particulate matter formation, acidification and eutrophication. At the same time, different trade-offs were observed with impact categories related to energy and resource use. The dry scrubber was found to be the most favorable option when considering the balance with the trade-offs.  The third study explored the effect that the large-scale implementation of air cleaning technologies (with a focus on wet acid scrubbers) for pig housing facilities could have in and endpoint perspective in the European Union. Emissions related to the housing stage of NH3, PM10, NMVOC and indirect N2O from large pig farms (>1000 heads of sows or fattening pigs) were first estimated in the actual situation (current scenario - CS), considering implementation rates and removal efficiencies of the different emission abatement techniques available. Subsequently, alternative scenarios were simulated with a growing implementation rate of the wet acid scrubber (35% and 65% of the concerned pig farms in all Member States). In conclusion, scrubber technologies are promising for mitigating the environmental impacts of pig production and the emission reduction achievable with increased implementation rates across the EU would have a largely positive endpoint effect on human health, and lead to significant alleviation of current environmental costs on society of air pollution related to intensive pig farming. Future research should focus on more issues related to these technologies, including optimizing cost-effectiveness, impact on animal welfare and production performance, on farm worker working conditions, and effluent management.  Subsequently, two studies were developed focused on the analysis of potential strategies for reducing greenhouse gas emissions from cattle farming waste management, one on the dairy and one on the beef sector. For the dairy sector, a direct measurement approach was adopted, through a campaign that included an on-farm trial lasting several months, adopting    slurry treatment through the commercial additive SOP Lagoon and specific technologies for on-site control of emitted gases from slurry storage tanks. Although the effectiveness of emission reduction varied throughout the trial, the results were positive, particularly for methane, as three months after the first applications of the additive, the treated storage tank showed statistically significant lower emissions than the untreated tank.  As for the beef cattle sector, on the other hand, a case study was developed to analyze a beef cattle farm integrating on-farm renewable energy production technologies by combining life cycle assessment and emissions modeling. The implementation of anaerobic digestion system on farm is shown to considerably enhance the environmental and energy performance of beef production. This study, to the authors' knowledge, was the first to quantify the possible environmental benefit deriving from such integrated management of livestock and energy production on a beef farm.  Overall, this work has provided valuable context-specific insights into the technologies evaluated, highlighting the benefits and limitations of their application. It goes without saying that none of them can fully address the environmental challenges of animal production if implemented in isolation, as integrated interventions are required.  LCA was confirmed as a valuable tool for identifying areas for improvement within the value chain and for highlighting trade-offs, ensuring that improvements in one aspect of a product's life cycle do not inadvertently shift environmental burdens to another phase or impact category. However, due to some of its limitations discussed in the course of the work, it cannot stand alone in guiding decision making and environmental policy development. This again underlines the importance of a holistic approach to assessing the environmental impacts of livestock production, as a key challenge is to capture the complexity and variability of farming systems where local practices and conditions vary widely.\"","language":"eng","citation":"ENVIRONMENTAL IMPACT OF LIVESTOCK ACTIVITIES IN THE PO VALLEY AND MITIGATION PATHWAYS EVALUATION / M. Costantini ; tutor: M.P.M. Guarino, J. Bacenetti ; coordinatore: G.F. Ficetola, M.P.M. Guarino. Dipartimento di Scienze e Politiche Ambientali, 2023. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12961.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1021110/2336320/phd_unimi_R12961.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1177958"},"title":"MAKING UP URBAN SPACE. A COMPARATIVE ETHNOGRAPHY OF SOCIAL DISTANCING ON PUBLIC TRANSPORT","internalauthor":"LA BRUNA, FEDERICO","type":"Tesi di dottorato","year":"2025","abstract":"While social distancing has emerged as a global strategy in addressing the COVID-19 pandemic, its relevance in social science, particularly as a category for the study of everyday life, remains a subject of debate. This research, relying on the complementary aspects of interactionist studies, neo-materialism, and neo-Marxist perspectives, delves into phenomena and ecologies of social distancing on public transport within Milan, Amsterdam, and New York City. The study, moving beyond the pandemic context, addresses two primary inquiries: how does social distancing emerge from public transport experience? Furthermore, what insights can the relationship between social distancing and public transport provide about urban space as a whole? This ethnographic investigation explains how social distancing produces – and simultaneously is produced by – urban territories through material and symbolic negotiation of geographical, geometrical and imagined distances. This project, approaching the field from different angles, examines social distancing in the choreographies of mobility practices on Milan’s public transit, the configurations of unequal urban experiences in Milan and Amsterdam, and the narratives and collective imaginaries of public transport in Milan and New York. Each case highlights how the ways that people deal with social distancing are situational and mediated by a plurality of heterogeneous actors. This exploration prompts a shift from binary interpretations of material and immaterial realms to a deeper and more comprehensive understanding of urban space.","language":"eng","citation":"MAKING UP URBAN SPACE. A COMPARATIVE ETHNOGRAPHY OF SOCIAL DISTANCING ON PUBLIC TRANSPORT / F. La Bruna ; supervisor: P. A. Rebughini ; co-supervisor: G. Semi ; director of doctoral program: P. A. Rebughini. - Milano. Dipartimento di Scienze Sociali e Politiche, 2025 Sep 18. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13247.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1177958/3119800/phd_unimi_R13247.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1041477"},"title":"UNA REPUBBLICA SENZA DEMOCRAZIA. PER UNA STORIA TRANSNAZIONALE DEL MODELLO REPUBBLICANO CONSERVATORE TRA FRANCIA, SANTO DOMINGO E STATI UNITI ((1793 - 1804).","internalauthor":"MAFFEI, AMANDA","type":"Tesi di dottorato","year":"2024","abstract":"The aim of this research project is to investigate and evaluate the transnational nature of the conservative republican model at the end of the 18th century. Moreover, this project examines how this conservative sentiment was conveyed between France, Santo Domingo and the United States through white Santo Domingo exiled settlers’ strategies and political organizations. Their adaptation to the profound changes of the colonial situation, accompanied by their lobbying action between the years 1794 and 1804, propose a new reading of the Atlantic reconfiguraion: originated by the reconquest of their plantations, soon the reflection would be articulated around the concepts of republic and modernity, republic and property, and, consequently, republic and hierarchization of the human beings according to supposed scientific bases.","language":"ita","citation":"UNA REPUBBLICA SENZA DEMOCRAZIA. PER UNA STORIA TRANSNAZIONALE DEL MODELLO REPUBBLICANO CONSERVATORE TRA FRANCIA, SANTO DOMINGO E STATI UNITI ((1793 - 1804) / A. Maffei ; tutor: A. De Francesco ; co-tutor: P. Serna. - Milano. Dipartimento di Studi Storici, 2024 Apr 02. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12595.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1041477/2389032/phd_unimi_R12595.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1040118"},"title":"INTEGRATED MOLECULAR INVESTIGATIONS OF MYRF AND SFRP2: UNVEILING REGULATORY MECHANISMS OF ER STRESS AND ECM REMODELLING IN PANCREATIC CANCER","internalauthor":"ARCO, FABIANA","type":"Tesi di dottorato","year":"2024","abstract":"Pancreatic ductal adenocarcinoma (PDAC) stands out as the most prevalent type of pancreatic tumors and the deadliest among common solid malignancies. One of the causes of this high lethality is the significant intratumor cell diversity, highlighting the need for enhanced molecular understanding. Indeed, PDACs are ensembles of three different subtypes with distinct morphology and gene expression programs that coexist in variable proportions in every tumor.  Following the identification of transcriptional regulatory networks in the various biotypes, we decided to better characterize two pivotal proteins controlling specific hallmarks of pancreatic cancer biology, like evading growth suppression and activating invasion.  First, we focused on the regulation of the myelin regulatory factor (MYRF), a poorly characterized transcription factor. Previous studies conducted in our laboratory demonstrated that MYRF, an endoplasmic reticulum (ER) transmembrane protein, maintains the homeostasis in the ER of pancreatic secretory glandular cells. After trimerization and self-cleavage, MYRF releases the N-terminal fragment which translocates into the nucleus to exert its transcriptional role by regulating the expression of genes encoding secretory proteins. However, the role of C-terminal fragment which remains inserted in the ER is unclear. Since the regulation of MYRF release from the ER membrane is still unknown, our hypothesis is that this fragment may interact with proteins in the ER lumen and regulate MYRF trimerization and cleavage. Using enzyme-catalyzed proximity labeling followed by biotin pull-down and mass spectrometry, we identified MYRF proximal interactors in the ER lumen. Currently, we were able to obtain a first validation of MYRF interaction with UGGT1, which could provide quality control for MYRF folding.  Furthermore, in order to investigate the role of MYRF C-terminal fragment in the maintenance of ER functionality, we generated clonal cell lines lacking one of the two critical MYRF functional domains – DNA binding or transmembrane domains - by CRISPR/Cas9-mediated in-frame deletion. The analysis of the gene expression profile of MYRF domain-specific mutants revealed that MYRF has a structural functionality in the ER that is independent of its transcriptional activity.  Additionally, we focused on the role of SFRP2 as a potential regulator influencing the characteristics of PDAC transitional cells. One of the key aspects of transitional cancer cells is the ability to contribute to the extracellular matrix (ECM) remodeling: we observed that SFRP2 led to a noteworthy augmentation in this process, along with increased migratory and invasive capabilities of PDAC cells. We also demonstrated that the abundance of ECM components contributes to different tissue density and rigidity, leading cells to mount a mechanoresponsive transcription program.  This work could provide i) a mechanistic understanding of MYRF in the regulation of ER activity. Considering the impact of ER stress on cancer cell fitness and drug-induced toxicity, the possibility to influence ER regulation by modulating MYRF trimerization and cleavage by targeting UGGT1 may provide therapeutic opportunities; ii) a better characterization of SFRP2 and its functional effects on PDAC transitional cells, improving anti-cancer therapies.","language":"eng","citation":"INTEGRATED MOLECULAR INVESTIGATIONS OF MYRF AND SFRP2: UNVEILING REGULATORY MECHANISMS OF ER STRESS AND ECM REMODELLING IN PANCREATIC CANCER / F. Arco ; tutor: G. Natoli ; co-tutor: D. Pasini ; phd coordinator: S. Minucci. Dipartimento di Scienze della Salute, 2024 Apr 11. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12690.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1040118/2385548/phd_unimi_R12690.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1232969"},"title":"STUDIO DELLA COMPOSIZIONE CHIMICA DEL DEPOSITO DI PARTICOLATO ATMOSFERICO E DELLA SUA INFLUENZA SULLA CONDUCIBILITÀ ELETTRICA DEGLI ISOLATORI DELLA RETE DI TRASMISSIONE","internalauthor":"BORELLI, MATTIA","type":"Tesi di dottorato","year":"2026","abstract":"Saline pollution represents a risk factor for the power networks. In this study a comprehensive chemical characterization of electric insulator deposits is presented. The two main locations were Milan, which, according to IEC 60815, resulted in a lightly polluted site, and Latina, a coastal mediumly-polluted site. Weathering, face of the insulator, vertical profile of and the presence of a hydrophobic coating were the studied factors. Weathering effect was predominant and synergic with the complex system of phenomena in act: vertical profile was in fact responsive to rain wash-off, while correlation with face factor was masked. The coating was responsible of high-risk situations during the hot period. Significative differences were observed between air particulate matter composition and deposits composition because of deposition itself and evolution phenomena: the deposit, despite atmospheric PM composition, is enriched in bicarbonates, calcium, sodium and chlorides while lacking largely ammonium sulphate and nitrate, newborn seasonality was also observed. Regarding carbonaceous, OC/EC ratio proved to be a peculiar characteristic in deposits being higher than in air up to a factor 10. The main campaigns were supported by intensive ones. Finally, a national campaign gave an idea of pollutant distribution over insulator throughout Italy: OC is more abundant in the southern, while EC in the northern. This work poses the basis for alert systems based on modelling tools. It is unparalleled in Italy and represents a step towards the resilience of the Italian electrical system.","language":"eng","citation":"STUDIO DELLA COMPOSIZIONE CHIMICA DEL DEPOSITO DI PARTICOLATO ATMOSFERICO E DELLA SUA INFLUENZA SULLA CONDUCIBILITÀ ELETTRICA DEGLI ISOLATORI DELLA RETE DI TRASMISSIONE / M. Borelli ; tutor: P. Fermo ; co-tutor: G. Pirovano ; coordinator: D. Passarella. Dipartimento di Chimica, 2026. 38. ciclo","filename":"phd_unimi_R13851.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 10-OTT-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1123757"},"title":"SARCOPENIA, LIVER AND CARDIOVASCULAR ALTERATIONS IN A MULTICENTRIC COHORT OF PATIENTS WITH MASLD: EVALUATION OF CLINICAL PRESENTATION AND GENETIC PREDISPOSITION","internalauthor":"CESPIATI, ANNALISA","type":"Tesi di dottorato","year":"2024","abstract":"Background and Aims: Sarcopenia, characterized by the progressive loss of skeletal muscle mass (SMM), strength, and function, is not solely an age-related condition but is also associated with several diseases, including chronic liver disease (CLD) and cardiovascular (CV) disease. Metabolic-dysfunction associated steatotic liver disease (MASLD) is defined by the presence of liver steatosis combined with, at least, one cardiometabolic risk factor, with liver fibrosis serving as a critical determinant of liver-related and CV-related events and mortality. Sarcopenia is highly prevalent in advanced MASLD, although recent studies have highlighted myosteatosis, the accumulation of fat within muscle, as a key driver of liver disease progression. Studies conducted mainly in Asia have reported a high prevalence of sarcopenia even in early MASLD, though it is not routinely assessed. Both sarcopenia and MASLD contribute to atherosclerotic CV damage, especially in the presence of advanced liver fibrosis, and share common pathogenetic mechanisms such as insulin-resistance (IR), low-grade chronic systemic inflammation, mitochondrial dysfunction, and oxidative stress. Additionally, genetic predisposition plays a role in MASLD, with specific polymorphisms in PNPLA3, TM6SF2, MBOAT7, and GCKR promoting severe liver disease, while the HSD17B13 variant appears protective against MASLD. Despite this background, most studies evaluating the relationship between sarcopenia, MASLD, and CV disease are cross-sectional, primarily involving Asian populations, limiting the generalizability of findings and the ability to determine whether the relationship is bidirectional. Furthermore, the absence of standardized criteria for diagnosing sarcopenia in MASLD complicates comparisons across studies, leading to conflicting results. To date, no studies have yet explored the role of genetic variants predisposing to MASLD in the risk of developing sarcopenia and CV damage. This project aims to address these gaps by 1) evaluating the impact of sarcopenia on liver and CV damage in non-cirrhotic MASLD patients, 2) investigating the influence of MASLD-related genetic variants on muscle mass and CV damage, and 3) assessing changes in muscle, liver, and CV parameters over a 5-year follow-up in a subset of patients.  Methods: 856 non-cirrhotic MASLD patients were recruited from liver outpatient clinics in Milan, Palermo, and London. At enrollment, anthropometric, demographic, and laboratory data were collected. Liver steatosis was assessed using abdominal ultrasound (US) and controlled attenuation parameter (CAP) measurements via Fibroscan, while liver fibrosis was evaluated using liver stiffness measurement (LSM) at Fibroscan. Severe steatosis was defined as CAP > 280 dB/m, and advanced fibrosis was identified as LSM ≥ 8 kPa. Liver biopsies were performed on 370 patients. Sarcopenia was assessed using bioelectrical impedance analysis (BIA), a non-invasive and radiation-free technique, with the skeletal muscle index (SMI) calculated as SMM/height^2. Patients were divided into gender-specific tertiles based on SMI (lowest, middle, and highest). CV damage was evaluated using carotid doppler US, with carotid intima-media thickness (cIMT) ≥ 0.9 mm or carotid plaques indicating CV damage. In 502 patients, epicardial fat thickness (EFT) was measured via echocardiography, and carotid-femoral pulse wave velocity (cfPWV) via tonometry. EFT ≥ 9.5/7.5 mm in men/women was considered a marker of visceral adiposity, while EFT ≥ 5.2 mm was associated with coronary artery disease. cfPWV > 10 m/sec was used as a marker of arterial stiffness. CV risk was calculated for all patients using SCORE2 and SCORE2-OP algorithms according to European Society of Cardiology (ESC) guidelines, with SCORE2-Diabetes applied to diabetic patients. Genetic polymorphisms in PNPLA3, TM6SF2, MBOAT7, GCKR, and HSD17B13 were analyzed in 437 patients. Finally, 104 patients underwent a 5-year follow-up to reassess muscle mass at BIA, CAP and LSM, cIMT and carotid plaques, and EFT.  Results: Patients had a mean age of 51 years, with 63% males. Patients in the lowest SMI tertile were older (54 vs 48 years, p<0.001), had lower body mass index (BMI) (27 vs 33.4 kg/m2, p<0.001), lower waist circumference (WC) (99 vs 110 cm, p<0.001), higher prevalence of dyslipidemia (56% vs 46%, p=0.03) compared to those in the highest tertile. Regarding liver damage, patients in the lowest SMI tertile had lower CAP (293 vs 317 dB/m, p<0.001), LSM (4.9 vs 6.4 kPa, p<0.001), grade 3 fibrosis prevalence (20% vs 25%, p=0.009), and MASH rates (30% vs 53%, p=0.04) compared to those in the highest tertile. For CV damage, patients in the lowest SMI tertile had a higher percentage of patients with increased cIMT (p=0.01). No significant associations were observed between SMI and the genetic polymorphisms studied. In the lowest SMI tertile, PNPLA3 CG/GG variant was linked to increased LSM (OR 1.82, p=0.03), lower cIMT (OR 0.39, p=0.04), and increased cfPWV (OR 2.1, p=0.01). The TM6SF2 wild-type allele was associated with increased cIMT (OR 3.4, p=0.004), while the CT/TT variant correlated with reduced hypertension (OR 0.09, p=0.02) and lower WC (OR 0.25, p=0.02) in the lowest SMI tertile. In multivariate analysis, low SMI was significantly associated with lower BMI (OR 0.61, p<0.001), lower WC (OR 0.92, p=0.001), female sex (OR 2.21, p=0.008), increased cIMT (OR 2.10, p=0.02), and slightly older age (OR 1.04, p=0.002). Among hypertensive MASLD patients, low SMI was independently associated with increased cIMT (OR 2.06, p=0.03) and cfPWV (OR 2.73, p=0.03). In non-diabetic MASLD patients, low muscle mass was associated with increased cIMT (OR 1.66, p=0.03), carotid plaques (OR 1.56, p=0.02), less fibrosis on histology (OR 0.29, p=0.04), lower ALT levels (OR 0.54, p=0.001), higher LDL (OR 4.38, p=0.02), and lower HDL (OR 1.03, p=0.002). At 5-year follow-up, a significant reduction in mean BMI (29.1 vs 28.4, p=0.001), a decrease in patients in the lowest SMI tertile (42% vs 22%, p<0.001), and a regression of steatosis in 9% of patients, with significant reductions in CAP (300 vs 289 dB/m, p=0.02) and LSM≥8 kPa prevalence (17% vs 7%, p<0.001) were observed. Regarding CV damage, a significant increase in carotid plaques (34% vs 54%, p<0.001), mean EFT (7.5 vs 9.0 mm, p<0.001), and high CV risk categorization (56% vs 63%, p=0.004) were observed. Baseline low muscle mass was significantly associated with changes in delta LSM (HR 2.30, p=0.013), BMI (HR 0.61, p=<0.001), and dyslipidemia (HR 5.74, p=0.007) at follow-up.   Discussion: This multicentric study revealed a significant independent relationship between sarcopenia and increased markers of atherosclerotic damage in non-cirrhotic MASLD patients, particularly among those with hypertension and without diabetes. Notably, patients with low muscle mass exhibited a lower prevalence of liver damage, possibly due to reduced visceral adiposity. However, longitudinal analysis demonstrated that low muscle mass was independently associated with an increase in mean LSM, suggesting that sarcopenia contributes to liver damage progression over time. Additionally, while persistent low muscle mass appeared to exacerbate CV damage, a definitive independent association was not observed, possibly due to the relatively short duration of follow-up. The study also identified a protective effect of the TM6SF2 polymorphism against CV damage, underscoring its potential role in mitigating CV risk.   In conclusion, this research highlights the importance of integrating imaging techniques to evaluate both liver and CV damage alongside genetic profiling for a more holistic understanding of the interplay between sarcopenia and CV damage in non-cirrhotic MASLD patients. Preserving muscle mass emerges as a key strategy for preventing both liver and CV diseases, and future public health initiatives should prioritize interventions aimed at supporting and enhancing muscle mass health.","language":"eng","citation":"SARCOPENIA, LIVER AND CARDIOVASCULAR ALTERATIONS IN A MULTICENTRIC COHORT OF PATIENTS WITH MASLD: EVALUATION OF CLINICAL PRESENTATION AND GENETIC PREDISPOSITION / A. Cespiati ; tutor: A L. Fracanzani ; supervisore: R. Lombardi ; coordinatore: M. Del Fabbro. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2024 Dec. 37. ciclo","filename":"phd_unimi_R13405_1.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1123757/2606091/phd_unimi_R13405_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1207835"},"title":"NOVEL THERAPEUTIC APPROACHES EMERGING FROM HCN CHANNELS STRUCTURAL AND FUNCTIONAL STUDIES","internalauthor":"CASTELLI, ROBERTA","type":"Tesi di dottorato","year":"2026","abstract":"Hyperpolarization-activated cyclic-nucleotide gated 1 (HCN1) channels are the molecular determinants of the cationic Ih current that regulates spontaneous electrical activity and synaptic integration in neurons. Mutations in the HCN1 gene have been linked to Early Infantile Epileptic Encephalopathy (EIEE) and a spectrum of neurodevelopmental disorders (ND). Despite the growing number of identified HCN1 variants, the mechanisms by which they alter channel function and contribute to pathogenesis remain poorly understood. Here, we combine molecular, cellular, and system-level neuroscience approaches to functionally characterize HCN1 mutations and explore targeted strategies for therapeutic rescue. Using in vitro electrophysiology in HEK293 cells, we analyze a panel of patient-derived variants, and we propose a systematic classification of HCN1 mutations into four distinct classes (I-IV) according to their functional properties. This framework reveals correlations between mutation location, channel dysfunction, and clinical phenotype. Interestingly, we identify a novel correlation between loss-of-function mutations in the pore-helix / selectivity filter domain of HCN1 that are associated with ND and no history of seizures. We further explore the use of pore blockers and allosteric modulators to restore wild-type-like function in mutant HCN1 channels in vitro, highlighting the potential of precision medicine approaches tailored to mutation-specific phenotypes. Extending these studies ex vivo, we demonstrate that the allosteric modulator J&J12e effectively rescues altered intrinsic properties and excitability in hippocampal CA1 pyramidal neurons from a knock-in mouse model carrying the HCN1 M153I mutation. Additionally, we show that NB6 can modulate native Ih currents in native brain tissue, underscoring its promise as a peptide-based therapeutic tool. At the system level, in vivo electrophysiological recordings reveal increased interictal spike activity in knock-in mice, which is further amplified following lamotrigine administration. Sleep architecture is also disrupted in these animals, suggesting that HCN1 dysfunction impacts broader aspects of brain function beyond seizure susceptibility. Together, these findings provide a comprehensive understanding of the functional impact of HCN1 dysfunction and lay the basis for the development of targeted, mutation-specific therapies aimed at restoring normal channel function and improving clinical outcomes in patients with HCN1-related disorders.","language":"eng","citation":"NOVEL THERAPEUTIC APPROACHES EMERGING FROM HCN CHANNELS STRUCTURAL AND FUNCTIONAL STUDIES / R. Castelli ; scientific supervisor: A. Moroni ; coordinator: S. Ricagno. - Dipartimento di Bioscienze, Milano. Dipartimento di Bioscienze, 2026 Jan 27. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13671.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 12-LUG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1220555"},"title":"LA GIUSTIZIA TRIBUTARIA TRA EFFICIENZA E CERTEZZA DEL DIRITTO NELLA PROSPETTIVA DEL GIUSTO PROCESSO","internalauthor":"DIDONI, STEFANO","type":"Tesi di dottorato","year":"2026","abstract":"The above PhD thesis aims to conduct an in-depth and critical analysis of the Italian tax jurisdiction system, with particular regard to the significant reforms introduced in the recent historical period, especially through L. 31 August 2022, n. 130 and L. 9 August 2023, n. 111. These normative interventions are part of the broader context of structural renewal promoted by the National Recovery and Resilience Plan (PNRR), which identifies the reform of justice, including tax justice, as a strategic axis for the relaunch of the Country. The investigation is structured around the complex interrelation and, at times, the dialectical tension, between the pressing need for efficiency of the judicial system (intended as the ability to resolve disputes in a timely and effective manner) and, at the same time, legal certainty (conceived as the predictability of the legal consequences of the actions of individuals and entities). The evaluation of these profiles is constantly conducted through the prism of the correlation between the above-mentioned principles and the principles of the fair trial, as provided by the Italian Constitution and international sources, as the European Convention on Human Rights (Art. 6) and the Charter of Fundamental Rights of the European Union (Art. 47).  The first chapter is dedicated to the analysis of the legal status of the tax judge, considered as a condicio sine qua non for the establishment of an authentically efficient and credible jurisdiction. Starting from an examination of the historical evolution of the tax judiciary, the analysis focuses on the most relevant innovation introduced by L. n. 130/2022, namely the establishment of a professional tax judiciary. The guarantees set to protect the fundamental requirements of the magistrate's status are examinated in detail, such as the autonomy of the tax judicial order, the independence of the individual magistrate, as well as the professionalism of the tax judge, through a comparison, mainly, with the canons of the ordinary judicial order. The second chapter mean to analyze the factors that contribute to determining the efficiency and overall quality of tax justice in relation to the correlated objective of legal certainty, maintaining the reference to the perspective of the fair trial. The examination begins by considering the search for high quality standards through the promotion of the coherence of judicial decisions, as well as the need to improve the quality of rulings as a starting point for an efficient jurisdiction. The crucial role of the availability of legal knowledge and the value, not formally binding but de facto persuasive, of jurisprudential precedent in the Italian system is discussed, evaluating its specificity and problematic application in the context of the tax trial. The attention thus focuses first on the role of governance and organizational structures within the Tax Courts of Justice (Corti di giustizia tributaria), functional to the management of workloads and the definition of performance objectives; second on the establishment of structures deemed suitable to promote interpretative uniformity, discussing the risk of judicial conformism, as well as comparing them with some significant foreign experiences. The chapter continues by examining the role, in relation to the stated objectives, of the transparency of the judicial system. A reflection is made on the accessibility of legal data and the promotion of transparency through public legal databases, with particular reference to the impulse given by L. n. 111/2023 to the creation of a database of tax case law decisions (Banca Dati della Giurisprudenza Tributaria), analyzing its technical characteristics, potential, and critical issues related to the completeness and representativeness of the data, as well as reflecting on the risks associated with judicial open data in light of the experiences and debates underway in other European countries. The last part of the chapter is dedicated to the analysis of the use of algorithmic systems in the justice sector and, specifically, to the impact that these can generate in the processes of interpreting legal rules and in decision-making ones. The opportunities and risks deriving from the use of artificial intelligence (AI) in the justice sector and, in particular, of predictive systems, are examined, in light of the European (EU Reg. 2024/1689) and national (L. 23 September 2025, n. 132) framework, according to which the use of such tools in the judicial sector can involve risks in relation to the objective of protecting fundamental rights. The declination of predictive justice in tax matters is explored in depth, analyzing the intrinsic critical issues of predictive systems developed in this area. The third chapter focuses on the institutional dialogue between the merits courts and the superior courts, introducing the concept of preliminary ruling as a mechanism of jurisdictional cooperation and analyzing it as a potential tool to promote the efficiency of the jurisdiction and interpretative uniformity. Starting from experiences in other European legal systems (e.g., the saisine pour avis to the French Cour de Cassation) and grasping their similarities and differences, the analysis focuses on the institution of the preliminary ruling to the Italian Court of Cassation (Corte di cassazione) provided for in the Italian system by art. 363-bis of the Code of Civil Procedure introduced by the so-called “Cartabia Reform” (D.lgs. n. 149/2022). Its legislative history is first reconstructed, and then a reflection is made, by virtue of the declared objectives, on the procedural choices made by the legislator as well as, in relation to the canons of the fair trial, on the binding effect attributed to the principle of law enunciated by the Court of Cassation, even though detached from the typical context of an appeal. Finally, the issues relating to the relevance of the factual reconstruction in the preliminary ruling proceedings are addressed. It is emphasized how, despite concerning “exclusively legal” issues, the ruling of the superior Court is inevitably conditioned by the representation of the facts offered by the referring judge, highlighting the need for a complete and defined factual reconstruction before the referral, also in light of the limited possibility for the Court of Cassation to integrate or review such reconstruction.  The conclusions of the thesis draw an overall balance of the investigation. It is recognized that the reforms initiated constitute a significant step towards the modernization of tax justice, although some perplexities remain due to the persistent organic and functional link with the Ministry of Economy and Finance. It is observed how the legislator, in pursuing the PNRR objective to increase the efficiency of tax trial system, seems to have privileged strategies aimed at increasing the coherence of judicial decisions and the stabilization of jurisprudential orientations. This approach manifests itself through interventions on governance (National Digest Tax Case Office – Ufficio del Massimario Nazionale, Tax Section of Court of Cassation – Sezione Tributaria della Corte di cassazione), accessibility to case law (databases of tax case law), the development of technological tools based on AI (predictive justice in tax field) and the introduction of procedural mechanisms such as the binding preliminary ruling. It is highlighted how this emphasis on the “predictability” and “bindingness” of case law, although moved by positive intentions of legal certainty, may present the risk of a conformist flattening of case law on precedents (real or “predictable”) and come into friction with the fundamental principles of the fair trial, in particular by limiting the interpretative independence of the merits judge. It concludes by hoping for a rethinking that values more the role of the individual judge, his legal culture and his ability to interpret the law in the specific context of the dispute, as the ultimate guarantee of a “fair” justice as well as efficient.","language":"ita","citation":"LA GIUSTIZIA TRIBUTARIA TRA EFFICIENZA E CERTEZZA DEL DIRITTO NELLA PROSPETTIVA DEL GIUSTO PROCESSO / S. Didoni ; tutor: G. Ragucci ; co-tutor: F.V. Albertini ; coordinatore: E. Damiani. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2026 Feb 26. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14025.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1220555/3263266/phd_unimi_R14025.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1146615"},"title":"HEALTH CONSEQUENCES OF URBANIZATION: EFFECTS OF AIR AND ELECTROMAGNETIC POLLUTION ON THE PREVALENCE OF OBESITY, DIABETIC COMPLICATIONS AND OLFACTORY DYSFUCTION IN DIABETIC PATIENTS.","internalauthor":"CARDELLA, ARIANNA","type":"Tesi di dottorato","year":"2025","abstract":"Introduction  The health consequences of increasing urbanization are calling for clinicians’ attention. Both air and electromagnetic (EM) pollution have been associated to type 2 diabetes mellitus (T2DM). This study aims to evaluate the effects of such pollutants on the prevalence of obesity, T2DM complications and olfactory dysfunction (OD) in two groups of T2DM patients living in different areas of the Lombardy region of Italy with different pollution exposure.    Materials and Methods  Two comparable groups of T2DM patients coming from an area characterized by a higher level of air and EM pollution in the past 10 years (Milan) and one with a lower level of pollution (Sondrio) were analyzed. Each patient underwent standard diabetology evaluation, ENT exam, psychophysical olfactory testing and filled in a questionnaire on olfactory-related quality of life (QoL). Statistical analysis used non-parametric tests and logistic regression.    Results  The prevalence of diabetic complications (48.5% vs.25%, p=0.007) and of OD (60.3% vs. 41.2%, p=0.039) was significantly higher in patients from Milan than from Sondrio, while no significant difference was found for obesity (p=0.716). The group with a greater prevalence of OD also reported worse olfactory-related QoL. Regression analysis showed a significant association between OD and the presence of diabetic complications (OR: 3.021; CI: 1.302 – 7.255; p=0.011) and between complications and T2DM duration (OR: 1.186; CI: 1.095 – 1.301; p<0.001). Pollution exposure was a weak independent predictor for both OD and complications in T2DM patients.    Conclusions  Our study showed that T2DM patients subject to a higher exposure to pollution were more frequently affected by diabetic complications and OD and reported a poorer olfactory-related QoL compared to patients with a lower exposure. We were also able to highlight a strong association between OD and T2DM complications and gathered evidence to support the hypothesis that pollution exposure is associated both with OD and complications in T2DM patients.","language":"eng","citation":"HEALTH CONSEQUENCES OF URBANIZATION: EFFECTS OF AIR AND ELECTROMAGNETIC POLLUTION ON THE PREVALENCE OF OBESITY, DIABETIC COMPLICATIONS AND OLFACTORY DYSFUCTION IN DIABETIC PATIENTS / A. Cardella ; tutor: L. Luzi, F. Mozzanica ;  coordinatore: M. Del Fabbro. Dipartimento di Scienze Biomediche per la Salute, 2025 Feb 28. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13644.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1146615/2676410/phd_unimi_R13644.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1153936"},"title":"OPTIMIZING MICROCLIMATE CONTROL STRATEGIES IN PRECISION AGRICULTURE USING MACHINE LEARNING TECHNIQUES AND IOT SENSORS DATA","internalauthor":"ZANCHI, MARCO","type":"Tesi di dottorato","year":"2025","abstract":"The overarching aim of this PhD thesis is to push the boundaries of microclimate monitoring in precision agriculture through the application of machine learning to IoT sensor data. The sensors provide vast amounts of detailed microclimatic information, which can be effectively processed by machine learning algorithms to optimize control strategies for precision agriculture.  The thesis aims to advance the state of the art in microclimate control by integrating machine learning techniques with sensor data, focusing on two key dimensions: spatial and temporal.    The scientific work presented in this thesis was developed in collaboration with DNDG srl, a company specialized in the development of fully customized, high performance IoT industrial systems business solutions and digital products, and a partner of the multinational Finder Group.    From a spatial perspective, this thesis aims to optimize microclimate monitoring in outdoor agricultural fields with a complex terrain conformation, such as vineyards. As will be discussed in the Introduction, microclimate monitoring can be performed using either remote sensing or networks of IoT sensors. While remote sensing provides highly accurate results at continuous spatial scales, it is expensive and does not allow for continuous, real-time monitoring. IoT sensor networks offer a more affordable solution for real-time monitoring of specific locations within a field. However, these measurements are localized and may miss significant microclimatic patterns elsewhere in the field. An ideal solution would involve deploying a large number of sensors, but this would significantly increase maintenance costs. To address this, zones with similar microclimatic patterns need to be identified, allowing for the strategic placement of sensors within each zone.  The literature currently lacks a clear strategy to achieve this. Thus, there is a need for a method that can use IoT data to continuously reconstruct microclimatic variations and identify characteristic patterns. Given the mathematical complexity of modelling the physical behaviour in this task, the approach is based on data-driven methods such as neural networks and machine learning clustering algorithms.  This thesis tackles the problem in two steps: (1) using neural networks trained on IoT sensor data to obtain a continuous description of microclimate variations at the meter scale across the entire field; and (2) identifying spatial areas with similar microclimate variations using a machine learning clustering algorithm.    From a temporal perspective, this thesis proposes the application of neural networks tailored for time series forecasting to enhance time-based monitoring of microclimate effects on precision agriculture systems. The temporal aspect is addressed through two distinct scenarios.  First, a case study is presented regarding the use of neural networks to monitor milk production data in a commercial dairy farm equipped with Automatic Milking Systems, with a focus on the influence of microclimate conditions. Milk production is highly sensitive to the microclimatic conditions experienced by dairy cows. To improve production and enhance animal welfare, precision agriculture should implement strategies that forecast milk production based on the relationship between past microclimate conditions and production data. This thesis applies a modern neural network for time series forecasting (Time-Series Mixer) to predict future milk production, demonstrating how AI can be utilized to optimize production for commercial dairy farms.  The second scenario focuses on developing a strategy to improve weather forecasting for local agricultural sites, with a particular emphasis on predicting hazardous events that could impact agricultural production. Accurate knowledge of future weather conditions is crucial for optimizing risk management strategies. Numerical weather predictions generate forecasts at global or regional scales, which lack precision at the local agricultural level. This thesis advances the field by proposing the application of a modern neural network (Time-Series Mixer), specifically designed for time series forecasting, that integrates past local weather data with future numerical weather predictions. The framework has been tested on six agricultural sites in Northern Italy.    In addition, precision agriculture is intricately connected to public health, especially when considering the impact of pollutants like heavy metals in water. Indeed, heavy metals absorbed by plants, after irrigation, can enter the food chain, posing significant risks to human health. Metals like chromium and lead are known carcinogens and can affect the kidney, liver, and nervous system even at low concentrations.  Therefore, a critical aspect of precision agriculture is the need to address pollution in both water and soil, with a focus on continuous monitoring using big data analysis of sensor networks. These sensors provide valuable information on pollutant levels, capturing both temporal and spatial variations. Effective monitoring of environmental contaminants is vital for safeguarding public health and ensuring the sustainability of agricultural practices.  This thesis tackles this challenge by investigating the temporal and spatial trends of heavy metal contamination in the waters of Lombardy, covering the period from 2017 to 2020. This analysis aims to provide a comprehensive overview of contamination patterns and identify potential risks associated with heavy metal pollution, informing strategies for improved environmental management and policy development.","language":"eng","citation":"OPTIMIZING MICROCLIMATE CONTROL STRATEGIES IN PRECISION AGRICULTURE USING MACHINE LEARNING TECHNIQUES AND IOT SENSORS DATA / M. Zanchi ; supervisore: C.A.M. La Porta ; tutor: P. Di Nunzio ; coordinatore: M. Guarino. Dipartimento di Scienze e Politiche Ambientali, 2025 Mar 25. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13594_1.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1153936/2713376/phd_unimi_R13594_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/946184"},"title":"IMMUNOLOGICAL CHARACTERIZATION OF SEVERE INFERTILE MEN REVEALED ALTERATIONS OF THE LYMPHOID AND MYELOID COMPARTMENTS","internalauthor":"BOERI, LUCA","type":"Tesi di dottorato","year":"2022","abstract":"Background: Infertility is the inability of a sexually active, non-contraceptive couple to achieve spontaneous pregnancy in one year. It is estimated to affect worldwide up to 15% of couples; overall, a male infertility factor has been found in at least 40% of infertile couples. Several studies have shown that infertile men have a higher incidence and prevalence of cancer, chronic non-malignant morbidities, endocrinological and autoimmune disorders, and overall a higher mortality risk compared to fertile age-matched men. Various hypotheses have been considered to explain the factors underlying male health status and male factor infertility, including genetic, endocrinological, and metabolic abnormalities. Recent evidence has shown that the immune testicular cells are different among infertile and fertile individuals. Testicular tissue of infertile men showed a pro-inflammatory phenotype which was not found in fertile controls. Moreover, a senescent phenotype was observed in azoospermic somatic cells of infertile men but not in those from the control group. The previously reported findings in infertile men documented a shift from the immune-privileged status to a proinflammatory testicular environment, eventually associated with iNOA. From a translational point of view, the pro-inflammatory status of testicular cells and the senescent phenotype characterized by decreased T cells number and higher level of inflammatory cytokines observed in infertile men could be associated with the infertility status per se, an exhausted pattern of circulating immune cells and it could predispose to future risk of developing malignancies and chronic diseases.  However, a detailed characterization of the local (e.g. testicular) and systemic immune status of infertile and fertile men has never been investigated.  Our main hypothesis that infertile men have alterations/defect of the immune system has been pursued  with the following specific aims:  AIM 1. To assess lymphoid and myeloid cell distribution in seminal fluid and peripheral blood of  fertile and infertile men.  AIM 2. To evaluate the presence of regulatory cells in seminal fluid and peripheral blood.  AIM 3. To evaluate the presence of potential biomarkers of an inflammatory/exhausted immune  status of infertile men.  Methods. We enrolled 38 infertile men with a diagnosis of oligo-astheno-teratozoospermia (OAT), 13 infertile men with idiopathic non-obstructive azoospermia (iNOA) and 40 age-matched fertile controls that provided comprehensive medical data, peripheral blood (PB) and seminal fluid (SF) samples. Clinical data was collected. We defined the leukocyte composition and the presence of different subsets of myeloid cells in the peripheral blood and seminal fluid by multiparameter flow cytometry. The levels of several cytokines and chemokines were measured in serum and seminal plasma by multi-beads array, and T cell responsiveness was performed on peripheral blood mononuclear cells (PBMC) isolated by density gradient centrifugation.  Results. Groups were comparable in terms of age, testosterone level and metabolic parameters. As expected, testicular volume and FSH values were worse in infertile men.  Seminal plasma  Myeloid cells represented the major leukocyte subsets in the seminal fluid. OAT and iNOA men had higher neutrophil cells compared to fertile controls. A significant higher rate of pro-inflammatory cDC2 was observed in OAT participants compared to fertile controls. Of the cytokines analyzed, we observed an overall upregulation of myeloid-derived pro-inflammatory cytokines and of IL-10 in the seminal fluid of infertile compared to fertile men. On the contrary, chemokines involved in leukocyte recruitment, such as MCP-1, MIP1b, RANTES, Eotaxin, and IL-8, were detected at lower or comparable concentration in samples from infertile men compared to fertile ones.  Peripheral blood  The analysis of leucocyte subsets in the peripheral blood revealed a higher frequency of neutrophils in infertile men compared to fertile controls reaching statistical significance for OAT. Of note, CD4+ and CD8+ cells were lower in OAT compared to fertile controls. Of note, the analysis of the pro-inflammatory DC subset revealed that the rate of cDC1 was higher in OAT men as compared to fertile controls while the proportion of cDC2 was comparable between infertile and fertile men. CD4+ and CD8+ cells of infertile men showed a higher expression of markers of exhaustion compared to fertile controls.  Conclusion. Although still preliminary, this study highlights novel evidence that male infertility is associated with a deregulation of the immune system without defect of the regulatory compartment (DC-10 and Tr1 cells) and with a pro-inflammatory signature that leads to the expansion of exhaustion T cell compartment. Moreover, the reduced levels of CD4+ and CD8+ T cells, along with the higher pro-inflammatory and exhausted signatures seem to depict a senescent phenotype for infertile men. These data could help the understanding of the pathophysiological mechanism underlying male factor infertility and the possible link behind the lower overall health status of infertile men compared to fertile individuals.","language":"eng","citation":"IMMUNOLOGICAL CHARACTERIZATION OF SEVERE INFERTILE MEN REVEALED ALTERATIONS OF THE LYMPHOID AND MYELOID COMPARTMENTS / L. Boeri ; TUTOR: E. MONTANARI ; CO-TUTOR: G. AMODIO. Dipartimento di Scienze Cliniche e di Comunità, 2022 Dec 14. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12681.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/946184/2099138/phd_unimi_R12681.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1037988"},"title":"IMPACT OF AGING ON MAMMALIAN INTRA- AND EXTRA-CELLULAR ENVIRONMENTS","internalauthor":"DE IORIO, TERESINA","type":"Tesi di dottorato","year":"2024","abstract":"Aging is a physiological process characterized by a gradual decline in cell, tissue, and organ functions. Although a significant amount of information is available on the senescence-related processes that take place in the cellular compartment, little is known about the role of the extracellular matrix (ECM) and its changes. Given the close relationship between the ECM and the cells residing within it, as well as the well-known ability of cells to interact with the surrounding matrix, it can be hypothesized that age-related modifications in the extracellular microenvironment might compromise cell behaviour, affecting tissue homeostasis and causing organ dysfunctions. This thesis has the specific aims to:  -study the role of the ECM in cell differentiation.  -identify age-related ECM changes.  -generate age-specific ECM-based bio-scaffolds.  -assess whether age-related ECM modifications may influence cell behaviour.  -take advantage of ECM-derived biomechanical cues to develop/support novel rejuvenating strategies.  I adopted the porcine ovary as experimental model, based on its complex microanatomy and heterogenous architecture, and used a decellularization protocol previously developed in the Laboratory hosting my PhD activities to generate ECM-based bio-scaffolds. These were then repopulated with different sets of cells, namely a) freshly isolated porcine ovarian cells, b) high-plasticity cells and c) cells previously rejuvenated with soluble factors.  The obtained results demonstrate that aging directly impact on the ovarian ECM that shows significant changes in its composition and organization with collagen, glycosaminoglycans, and laminins significantly incremented, and elastin, as well as fibronectin, decreased. This is accompanied by a dynamic response in the expression levels of key ECM and protease-related genes, suggesting a direct impact of aging on the transcriptional machinery. The ECM-based 3D bio-scaffolds generated preserved the structural changes occurring in vivo demonstrating their ability to act as a powerful high predictive in vitro model for reproductive aging and its prevention. When ECM-based scaffolds were repopulated, they were able to properly drive the differentiation, fate and viability of all cells tested. In particular, aged cells previously rejuvenated with miRNA or young cell-derived factors stably maintained the newly acquired phenotype when engrafted onto young ECM-based scaffolds. This suggests that an adequate young environment is able to stabilize miRNA and EV-mediated rejuvenation and implies a synergistic interaction among molecular effectors and ECM-derived bio-mechanical stimuli.  Altogether, these data indicate that the experimental model here developed may represent a useful tool to finely dissect the several biochemical and biomechanical cues driving tissue and organ aging.","language":"eng","citation":"IMPACT OF AGING ON MAMMALIAN INTRA- AND EXTRA-CELLULAR ENVIRONMENTS / T. De Iorio ; tutor: G, Pennarossa ; co-tutor: T. Al Brevini ; coordinatore:  F Ceciliani. - Facoltà di Medicina Veterinaria, Via dell'Università, 6 -26900- Lodi (Italy). Dipartimento di Medicina Veterinaria e Scienze Animali, 2024 Mar 20. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R12975.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1037988/2380350/phd_unimi_R12975.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1194439"},"title":"DISSECTING THE POLYGENIC LANDSCAPE OF HUMAN COMPLEX TRAITS AND DISEASES IN A SOUTHERN ITALIAN COHORT","internalauthor":"SANTONASTASO, FEDERICA","type":"Tesi di dottorato","year":"2025","abstract":"Complex traits and diseases are shaped by the combined effects of common and rare genetic variants, yet their contribution to risk is still poorly characterised in Southern European populations. This thesis addresses this gap by analysing the genetic architecture of traits and diseases in Italy, leveraging the Moli-sani cohort, a large population-based study from Southern Italy. The aim is to clarify the role of genetic variation in disease risk and to evaluate its potential for improving prediction models with applications in precision medicine and public health.  In the first part, genome-wide association analyses of quantitative traits showed overall consistency with findings from other European populations, while also revealing population-specific features, such as the persistence of strong-effect alleles at the HBB locus. We then assessed the transferability of polygenic scores derived from Northern European datasets to the Italian context, finding that predictive accuracy was reduced for several traits. However, incorporating variants specific to the Italian population improved performance in some cases, highlighting the value of population-tailored models.  The second part explored the predictive potential of polygenic risk scores (PRS) for major diseases using long-term follow-up and electronic health records. PRS stratified lifetime risk for conditions such as coronary heart disease and breast cancer, and when combined with demographic factors such as age and sex, achieved performance comparable to SCORE2, the standard clinical risk model. Unlike traditional risk factors, PRS are fixed at birth and can be calculated early in life, enabling lifelong risk stratification and supporting prevention strategies that can be tailored to the individual.  The final part of this thesis focused on rare variants identified through whole-genome sequencing. Gene-based analyses of 52 quantitative traits yielded 95 significant associations, approximately one third of which were replicated in the GeneBass resource. A leave-one-variant-out analysis further prioritised 238 alleles likely driving these signals, including rs730882080 (FH Naples-3) in LDLR, a pathogenic variant first reported in Southern Italy and associated with elevated LDL cholesterol levels and an increased risk of coronary heart disease.   These findings demonstrate the value of studying underrepresented populations to characterise their unique genetic architecture, improve the accuracy of genomic prediction, and identify variants with direct clinical relevance. By integrating analyses of common and rare variants, polygenic scores, and sequencing data, this thesis contributes to the foundations of precision prevention and highlights the potential of genomics to inform public health in Italy.","language":"eng","citation":"DISSECTING THE POLYGENIC LANDSCAPE OF HUMAN COMPLEX TRAITS AND DISEASES IN A SOUTHERN ITALIAN COHORT / F. Santonastaso ; tutor: N. Soranzo ; co-supervisor: N. Pirastu ; internal advisors: B. Soskic, E. Di Angelantonio phd coordinator: D. Pasini. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Oct 29. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13500.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 10-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/987709"},"title":"MULTISCALE GEOCHEMICAL STUDY OF THE CORNO ALTO COMPLEX (ADAMELLO BATHOLITH)","internalauthor":"MOSCONI, ANGELICA","type":"Tesi di dottorato","year":"2023","abstract":"Granitoid batholiths are important end products of the Earth’s long-term compositional differentiation, representing either the addition of juvenile material to the crust or the reworking of older crustal components. The nature and composition of crustal granitoids significantly changed at the Archean-Proterozoic boundary highlighting major changes in the mechanisms of continental crust formation/differentiation throughout the Earth’s history. In particular, the transition from the typical Archean TTG rocks to the post-Archean calc-alkaline granitoids is marked, in all cratons, by the occurrence of distinctive rocks called sanukitoids. These latter have been linked to subduction-related partial melting of enriched mantle and hence signal the onset of the modern plate-tectonic regime. In this context, modern analogues of the Archean granitoids provide valuable clues for investigating continental crust formation/differentiation and its secular evolution.   This study focuses on the Corno Alto complex, the oldest intrusion of the Adamello batholith and also the oldest known intrusive complex of the whole Periadriatic magmatism. The Corno Alto intrusion is crucial to shed light on the tectono-magmatic conditions active at the onset of alpine magmatism; conditions that are not yet fully understood.  In the field, three distinct types of granitoid rocks have been recognized, ranging in composition from tonalite to granodiorite and without encompassing the trondhjemitic terms described in the literature. Whole-rock chemistry reveals peculiar features with respect to the other units of the Adamello batholith, and to typical I-type and S-type granitoid rocks. The Corno Alto rocks exhibit the highest SiO2 contents, K2O+Na2O up to 7.2%, a strong enrichment in Ba and to a minor extent in Sr (Ba + Sr ≈ 1100-1900 ppm). Other geochemical features include a moderately-to-strong enrichment in LREE over HREE (LaN/YbN > 20) and Y (Sr/Y > 40).   U-Pb geochronology on zircon shows an east-west trend of decreasing ages in the intrusive complex, with three main recurring age peaks, at c. 44 Ma, c. 42 Ma, and c. 39 Ma. The different zircon domains have significantly distinct Hf isotopes (up to 18 ƐHf units of variation) with some values trending towards the isotopic composition of the depleted mantle (DM). The evidence of multiple components in the petrogenesis of the Corno Alto is also supported by the occurrence of multiple plagioclase populations as suggested by their crystals zoning and the intense chemical disequilibria for major and trace elements, as well as for Sr isotopes (determined in situ by LA-ICP-MS).   The new geochronological data presented in this study indicate an incremental assembly of the Corno Alto complex by multiple and possibly discrete magma injections in a time span of about ~5 Myr. These results refine the current knowledge of the Corno Alto complex emplacement as a single event at 43 Ma. Noticeably, the observed age trend parallel that observed on a larger scale by Ji et al (2019) being perpendicular to the direction of the Giudicarie line, which is located right above the European slab edge (Sun et al., 2019; Zhao et al. 2016). The new data suggest that the NW migration of the magmatism observed at the orogen scale as a consequence of the Eocene-Oligocene slab steepening is also evident at the scale of Corno Alto complex.   Major-trace element mineral chemistry, Hf isotope on zircon and Sr isotope on plagioclase suggest that the Corno Alto is the product of a multi-stage and multi-component process involving a high Ba component with high Sr and La/Yb ratios and a juvenile component. The overall geochemical signature of the Corno Alto rocks resembles that of a peculiar group of Phanerozoic rocks known as high Ba-Sr granites which are considered as modern analogues of the Archean sanukitoids. The relatively high thermal gradient required to generate such peculiar melts, typical of the Archean, are likely ensured during the Eocene by the thermal perturbation induced by rising asthenospheric material along the slab tear in response to slab edge effects.","language":"eng","citation":"MULTISCALE GEOCHEMICAL STUDY OF THE CORNO ALTO COMPLEX (ADAMELLO BATHOLITH) / A. Mosconi ; tutor: M. Tiepolo ; coordinatore: M.I. Spalla. Dipartimento di Scienze della Terra Ardito Desio, 2023 Jul 25. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12654.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/987709/2252963/phd_unimi_R12654.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1156561"},"title":"TOWARDS A SUSTAINABLE NUTRACEUTICAL TREATMENT: CARDIOMETABOLIC EFFECTS OF AGRO-FOOD WASTE EXTRACTS ON HUMAN IN VITRO MODELS","internalauthor":"TOLAJ KLINAKU, FATIONA","type":"Tesi di dottorato","year":"2025","abstract":"\"Metabolic Syndrome often leads to cardiovascular disease and diabetes. Beyond lifestyle changes and conventional therapy, nutraceuticals offer a promising approach for disease prevention and management. The primary aim is to evaluate the in vitro effects of two agro-food waste extracts obtained through sustainable techniques. Specifically, hepatic, adipocyte and intestinal human cell-based models are utilized, contributing to novel treatments and food waste reduction.  After screening various agro-food extracts, the A781B herbal extract was tested on HepG2, SW872 and Caco-2 cell models. Secondly, P. domestica extract was tested on normal and dysfunctional models of human SW872 adipocytes, cell models rendered dysfunctional-like with oleic acid addition or spontaneous differentiation strategies. The SW872 in vitro cell models were first characterized by lipid content, gene expression, oxidative stress, and glucose uptake. The effects of the extract were then assessed based on viability changes and modulation of the above indicated cardiometabolic pathways.  Characterization revealed a dysfunctional metabolic phenotype in oleic acid-treated and spontaneously differentiated models. None of the extracts showed toxicity in all cell lines and stimulated glucose uptake. P. domestica reduced ROS species and lipid accumulation, and positively modulated gene expression, mostly in a dose-dependent manner.  The findings suggest that extracts from agri-food waste can positively influence cardiometabolic health, and the selected cell models are appropriate for such studies. Further validation is needed for the cell models, as well as exploring the full potential of these extracts to improve metabolic syndrome pathophysiology and contribute to food waste management, in alignment with the \"\"One Health\"\" principles.\"","language":"eng","citation":"TOWARDS A SUSTAINABLE NUTRACEUTICAL TREATMENT: CARDIOMETABOLIC EFFECTS OF AGRO-FOOD WASTE EXTRACTS ON HUMAN IN VITRO MODELS / F. Tolaj Klinaku ; supervisor: P. Magni ;  cosupervisor: G. Guercilena ; PhD coordinator: G. D. Norata. - Milan, Italy. Università degli Studi di Milano, 2025 Apr 11. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13560.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1156561/2736896/phd_unimi_R13560.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/809284"},"title":"APPLICATIONS OF BACTERIOPHAGES FOR THE CONTROL OF PATHOGENIC ESCHERICHIA COLI","internalauthor":"MANGIERI, NICOLA","type":"Tesi di dottorato","year":"2021","abstract":"Some Escherichia coli are characterized by virulence factors that can cause disease in humans. With the spread of antibiotic resistance genes in E. coli as well, the researchers are studying different solutions. One of the most promising alternatives to control pathogenic bacteria is the application of bacteriophages.   The main purpose of this PhD work was to control pathogenic E. coli through the application of bacteriophages.   Twenty phages were isolated from feces, sewage, and bedding material from livestock. The viral particles have been shown not to carry genes that encode for Shiga-toxins and intimin and have been therefore used against Shiga toxin-producing E. coli (STEC). No STEC showed resistance to all phages, but some strains revealed weak sensitivity. Among the most effective phages and based on their different RAPD (Random Amplification of Polymorphic DNA), three (which were used to make the “cocktail”), were used at different multiplicity of infection (MOI = 0,1, 1, and 10). Significant differences  (p < 0,05) were reported in the mean values of optical density compared with the control. The best performance was obtained with the highest MOI. Additionally, the phage cocktail was tested on fresh cucumbers. The results showed a reduction in pathogenic E. coli of 1,97–2,01 log CFU/g at 25ºC and of 1,16–2,01 log CFU/g at 4ºC during 24 h.  Bacteriophages alone or in a cocktail were used to prevent biofilm formation at 4 different MOI (1, 2, 10, 100). The crystal violet assay showed a 43,64% reduction in biofilm formation of the analyzed strains compared to the control. The most effective was a cocktail composed by six phages. This phage cocktail was also used in trials to remove already formed biofilm. The results showed no significant differences between the control and samples (p<0,05).   The isolated phages were also used to control bacteria related to urinary tract infections (UTIs), after being screened for the presence of inducible prophage (17,43% have a prophage). The results indicated that at least one phage was effective against 262 out of 270 bacteria. Sequencing and TEM images showed that the bacteriophages used belonged to the Myoviridae family; no pathogenesis or lysogenesis related genes were found in phage genomes.   Three STEC strains were studied for prophage release, by real time qPCR, after a stress related to cheese making process: addition of NaCl at 1, 1,5 and 2% w/v, lactic acid at 0,5, 1,5 and 3% (v/v), anaerobic condition, pasteurization, UV, and after exposure to ciprofloxacin, nalidixic acid and norfloxacin. Induction of the prophages showed that the addition of NaCl at 1,5 and 2% significantly increased the phages release compared to the control, while lactic acid addition at the three concentrations tested had a significant repressing effect on phage release.   In conclusion, the positive results obtained in this work in the control of pathogenic E. coli, prevention of biofilm formation, together with the genetic characteristic of phages, suggest that the isolated phages could be used to improve food safety.","language":"eng","citation":"APPLICATIONS OF BACTERIOPHAGES FOR THE CONTROL OF PATHOGENIC ESCHERICHIA COLI / N. Mangieri ; tutor: C. Picozzi ; phd  dean: A. Pagliarini. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2021 Feb 18. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12028.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/809284/1687019/phd_unimi_R12028.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/920269"},"title":"THE MMR VACCINE-AUTISM CONTROVERSY IN THE POST-TRUTH ERA: A CORPUS-ASSISTED DISCOURSE ANALYSIS OF A NEWSPAPER AND FACEBOOK CORPUS","internalauthor":"FIAMMENGHI, CARLOTTA","type":"Tesi di dottorato","year":"2022","abstract":"The present dissertation is a corpus-assisted (critical) discourse analysis (Baker 2006; KhosraviNik and Unger 2016) of the UK newspaper coverage of the MMR vaccine-autism “controversy”. This “controversy” concerns the alleged link between the triple MMR vaccine and the onset of autism, that was first suggested in 1998 by Andrew Wakefield and his colleagues in a paper published in the prestigious British medical journal The Lancet. Despite having been subsequently discredited and retracted, and despite the fact that Andrew Wakefield was stripped of his medical license by the British General Medical Council, the paper has arguably contributed greatly to the negative perception of vaccines by the British public: it fostered a climate of scepticism towards experts and authorities, and it effectively created a public debate, re-presented in the mass media, where objective facts and evidence were pitted against emotions and personal beliefs (see, for example: Boyce 2006; Clarke 2008; Stöckl and Smajdor 2017). In this sense, the MMR vaccine-autism debate may also be interpreted considering more recent discussions about a post-truth epistemology (D’Ancona 2017) and the spreading of mis/disinformation and fake news.   In order to explore the discursive characteristics of this debate, a corpus of news articles from major UK newspapers was built and analysed; the quantitative analysis was carried out using the corpus analyser AntConc (Anthony 2020), while the qualitative analysis was carried out manually through close reading. The analysis aimed at exploring the way in which proponents and opponents of vaccination used language – and especially evaluation (Bednarek 2006a, 2006b), polyphony (Fløttum and Gjerstad 2013) and argumentative storytelling (Carranza 2015) – to legitimize their views and delegitimize their opponents’. To this end, special attention was paid to editorials and readers’ letters, which were largely ignored by previous studies (Clarke 2008) but are here seen as argumentative texts (Richardson 2007) allowing for reader participation and engagement, where audiences can publicly react to the news and discuss it.  The second part of the research is devoted to the analysis of a corpus of users’ comments taken from the Guardian and the Daily Mail Facebook pages, with the aim of carrying out a comparison between online and offline debates about the MMR vaccine. Such a comparison is proposed as one possible way to explore the role played by the internet and social media in re-presenting medical debates and in shaping the so-called “post-truth” society.  The results of the analyses point to a marked polyphony in newspaper articles, where multiple social actors are re-presented (chiefly children, parents, medical doctors, and the government), often using largely the same linguistic strategies and frames; thus, different views are equally quoted and legitimised, irrespective of the amount of scientific evidence supporting them. Social actors themselves exploit participatory genres such as letters to the editor and Facebook comments to foster their own views using a variety of linguistic and argumentative means, the most distinctive of which is argumentative storytelling, whereby personal experiences with vaccinations are used as evidence to support one’s positions towards the medical procedure. Moreover, online participants regularly refer to each other using labels such as pro-vaxxer and anti-vaxxer (which, on the other hand, are infrequent in the newspaper corpus) used to summarise one own’s identity and system of beliefs. Thus, trust in vaccines is transformed into a polarising, partisan, and ultimately profoundly ideological issue.","language":"eng","citation":"THE MMR VACCINE-AUTISM CONTROVERSY IN THE POST-TRUTH ERA: A CORPUS-ASSISTED DISCOURSE ANALYSIS OF A NEWSPAPER AND FACEBOOK CORPUS / C. Fiammenghi ; tutor: L. Pinnavaia ; coordinatrice del corso di dottorato: M. V. Calvi. Dipartimento di Lingue, Letterature, Culture e Mediazioni, 2022 Apr 06. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12310.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/920269/2013969/phd_unimi_R12310.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1245579"},"title":"THE DIRECT EFFECT OF SOCIAL ORIGIN. A SCOPING REVIEW AND TWO COMPARATIVE ANALYSES","internalauthor":"CARTAGINI, DAVIDE","type":"Tesi di dottorato","year":"2026","abstract":"The work examines the Direct Effect of Social Origin (DESO), i.e. the intergenerational transmission of occupational status independent of individual education, or human capital. Building on the Blau-Duncan (1967) framework, foundational to current social stratification research, this work addresses persistent questions about why modern societies, despite meritocratic sorting systems, continue to exhibit substantial inequality of opportunity rooted in social origin. The dissertation includes three chapters, aiming at systematizing existing knowledge, describing cross-national patterns, and investigate the possible mechanisms underlying this aspect of social stratification. Chapter one presents a scoping review of sixty years of quantitative research on DESO, documenting theoretical developments, methodological evolutions, geographical scope, and empirical operationalizations that have shaped the field. The second chapter adopts a descriptive, macro-level approach to analyse cross-country variations in DESO across more than twenty European countries spanning over eighty years, examining how macro-level factors are associated with class differentials in opportunity structures and their evolution over time. The third chapter employs panel data from four countries (United States, Russia, Switzerland, and Germany) to assess the life-course patterns of the DESO in comparative perspective, accounting for individual random effects and (possibly) shedding light on the possible mechanisms that generate unequal outcomes across social backgrounds. By integrating systematic knowledge consolidation, extensive cross-national description, and longitudinal analysis, this dissertation contributes to the longstanding debate on meritocracy versus social reproduction, advancing understanding of the mechanisms, patterns, and determinants of intergenerational inequality in status attainment in contemporary societies.","language":"eng","citation":"The Direct Effect of Social Origin. A scoping review and two comparative analyses / D. Cartagini ; supervisor: G. Ballarino ; director of doctoral program: M. Guerci. Dipartimento di Economia, Management e Metodi Quantitativi, 2026 Jun 09. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13682.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1245579/3332424/phd_unimi_R13682.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/926213"},"title":"LO STATO DELLA CHIESA TRA DIRITTO INTERNO E INTERNAZIONALE NELLA PRIMA METÀ DELL'OTTOCENTO. LA FIGURA E IL PENSIERO POLITICO DI PELLEGRINO ROSSI","internalauthor":"TOSCANO, VINCENZO","type":"Tesi di dottorato","year":"2022","abstract":"The first part of the nineteenth century was a crucial moment for the European context, which was first forced to reckon with the last consequences of the great revolutionary wave, and then - directly - with France's most unscrupulous son; that petit diable arrived from Corsica and become emperor. In these years the Papal States experienced some of the most delicate moments of their existence (suffice it to think of the direct annexation to the French Empire or the deportation of Pius VII), without having the material strength to oppose such vicissitudes.  The work carried out by the European representatives in Vienna, during the famous Congress, attempts to implement a “forced” and precarious return to the past, which will prove to be incapable of withstanding the spirit of the new times. The Papal State - this was the new denomination adopted after the great meeting of 1814-1815 (as if to eliminate the aura of sacredness destined to become increasingly uncomfortable in the following decades) - was faced with the urgent need to reorganise its institutional apparatus, aware that it could not definitively cancel the parenthesis of the years that had just passed. In a century that will see the disappearance of the temporal dominion of the popes, it was only one of the challenges with which the State of central Italy was called to confront. In fact, these events took place in a constantly evolving international scenario, where even the great powers were often called upon to deal with unexpected events, but were always attentive to the dynamics of balance and the balancing of interests at stake.  For a reality that is not only a state entity, but also the centre of the Catholic world and the seat of the successor of Peter, accepting to change its “nature” is not easy. Allowing lay people access to the upper echelons of the bureaucracy, setting up “truly” representative bodies, or thinking of promulgating a fundamental charter, has been a recurring mirage for years. Although the need to modernise the internal administration of the State is echoed on many fronts, on the administrative, economic and, above all, judicial fronts, the line of intransigence and immobility seems to triumph almost always. It is true that action is sometimes taken, but more out of complacency than real conviction, having to take account of internal and external pressures. Pressure that sometimes comes from increasingly widespread discontent, sometimes from the interference of the large European states.   The aim of this research work was therefore to analyse the main (especially legal) events - internal and external - that involved the Church State in the first half of the nineteenth century. A path developed along multiple lines, starting from the background of the great historical events of recent years, and intertwined with the vicissitudes of some great protagonists: popes, secretaries of state, heads of government, monarchs. A look not only at the domestic front, but also at the international one. Understanding how Rome tries to manage its foreign relations in a supranational context that in recent decades has seen the emergence of new states (e.g. Belgium), significant changes (e.g. France in 1830, with the beginning of the Orleanist monarchy, or the independence achieved by the countries of South America), or strong dynastic disputes (e.g. the Iberian Peninsula), is important to understand how it must also deal with governments that, depending on the case, take on markedly conservative characteristics or with strong liberal tendencies. Despite the Roman Curia's natural inclination, “closeness” to reactionary positions, relations with powers such as Russia or Austria don’t remain idyllic.  However, the line just described was not the only one followed in the development of this research. As if wishing to proceed on two parallel tracks, we have also focused on the figure and political thought of one of the most important jurists of the first half of the century: Pellegrino Rossi. A jurist of course, although this expression is not enough to encapsulate the greatness of an “Italian son”, born and raised when united Italy did not yet exist. Much has already been said, or rather written, about this multifaceted character, and about his life spent between Italy, Switzerland, France and then back on the peninsula, working at the Roman court as a French representative, and then as a minister of His Holiness.  And yet these aspects have been precisely useful in this work, looking at lesser-known but absolutely important aspects. These were, for example, the most important moments Rossi spent in Switzerland (as a member of the Geneva Representative Council and as an envoy to the Diet of Lucerne in 1832), or the major speeches he made at the Chamber of Peers in Paris between 1840 and 1844. The same can be said about the delicate events that involved the jurist during his tenure at the papal court. It was here, first as ambassador, and then as the pivot of the new government formed in September 1848, that the multifaceted Italian tried to shake the Roman State out of its torpor and pull it towards a more modern and truly constitutional order.","language":"ita","citation":"LO STATO DELLA CHIESA TRA DIRITTO INTERNO E INTERNAZIONALE NELLA PRIMA METÀ DELL'OTTOCENTO. LA FIGURA E IL PENSIERO POLITICO DI PELLEGRINO ROSSI / V. Toscano ; tutor: C. STORTI ; co-tutor: M. NACCI ; coordinatore: C. LUZZATI. Dipartimento di Diritto Privato e Storia del Diritto, 2022 May 17. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12148.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/926213/2029186/phd_unimi_R12148.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1157159"},"title":"METABOLIC IMPROVEMENT AFTER EXERCISE TRAINING IN CHILDREN WITH OBESITY: POSSIBLE ROLE OF THE SIX-MINUTE WALKING TEST","internalauthor":"GIOVANELLI, LUCA","type":"Tesi di dottorato","year":"2025","abstract":"Objective: To assess in a group of children with obesity whether a simple test such as Six-Minute Walking Test (6MWT) may be helpful in evaluating the effectiveness of an online supervised training program in modulating lipid and glucose metabolism, given that exercise-based interventions can be considered effective when they are able to modulate the pathogenetic processes underlying the obesity complications.  Study design: 35 Caucasian children with obesity (aged 8-13) were assessed before (T0) and after (T1) a 12-week online supervised exercise training protocol. Every participant underwent the following evaluations: cardiovascular fitness (by means of 6MWT), metabolic biochemical profile, lifestyle (with ad hoc questionnaires focusing on physical activity, nutrition, sedentariness, sleep hours and quality, health perception), Cardiac Autonomic Regulation (CAR). Spearman correlations between the variations in the studied outcomes were explored.  Results: After intervention, the distance covered during 6MWT significantly increased (p <0.001), and nutrition quality improved slightly but significantly (p=0.03). The improvement in the 6MWT performance was shown to significantly correlate with the reduction of insulin levels (r=-0.455; p=0.02), HOMA-IR Index (r=-0.452; p=0.02), total cholesterol values (r=-0.549; p=0.004) and Atherogenic Index of Plasma (AIP) (r=0.422; p=0.04). Besides, there was a significant correlation between the improvement in 6MWT and health perception (r=0.578; p=0.002).  Conclusion: We observed that the improvement in the 6MWT performance correlates with metabolic profile betterment after exercise training in children with obesity, thus suggesting that this relatively simple test is capable of unveiling relevant changes in pathogenetic processes underlying obesity.","language":"eng","citation":"METABOLIC IMPROVEMENT AFTER EXERCISE TRAINING IN CHILDREN WITH OBESITY: POSSIBLE ROLE OF THE SIX-MINUTE WALKING TEST / L. Giovanelli ; tutor: D. Lucini ;  cotutor: M. Bonomi. Università degli Studi di Milano, 2025 Mar 24. 37. ciclo","filename":"phd_unimi_R13646.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1157159/2743503/phd_unimi_R13646.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1155095"},"title":"WATER ECONOMY: SUSTAINABILITY IN BOTTLED WATER SUPPLY CHAIN. THE ROLE OF CONSUMER AND ENTERPRISE TO ENHANCE SUSTAINABILITY IN THE FOOD SYSTEM.","internalauthor":"FROLA, ENRICA NADIA","type":"Tesi di dottorato","year":"2025","abstract":"Water is the planet’s most precious natural resource, essential for all life forms and economic activities. Despite covering 70% of the Earth's surface, freshwater represents only 2.5% of total water resources, with just 1% readily available for human use. Population growth, shifting consumption patterns, and climate change are intensifying pressures on this finite resource. This thesis examines environmental sustainability in the water economy, with a particular focus on the bottled water sector, before expanding the analysis to broader sustainability challenges in food consumption.    The first part of the research explores sustainability within the bottled water industry, using Italy—one of the world’s largest consumers of bottled water—as a case study. The study identifies a gap in understanding sustainability across the production side of the bottled water value chain. Through an analysis of industry practices, including eco-design, recycled and bio-based materials, and logistics improvements, the research highlights how enterprise-led innovations can contribute to systemic change. Supported by insights from Sanpellegrino, the findings indicate that companies are increasingly adopting sustainable solutions, with European regulatory frameworks playing a crucial role in shaping industry practices. The role of consumer behavior is also considered, emphasizing the importance of environmental labels and certifications in promoting transparency and informed choices.    Building on this sector-specific analysis, the research extends to the sustainability of food consumption, focusing on the Water Footprint (WF) of dietary choices in Italy. Using real consumption data from 2005 to 2021, the study reveals a shift away from the traditional Mediterranean Diet (MD), with an overconsumption of red meat and lower vegetable intake contributing to an elevated WF. Through a Sustainable Diet Model (SDM), the research demonstrates that adopting alternative dietary patterns—such as the Atlantic Diet or plant-based diets—can significantly reduce WF. The findings, published in Renewable Agriculture and Food Systems (2024), contribute to the debate on how dietary choices impact water sustainability.    The thesis further broadens its scope by assessing the Carbon Footprint (CF) and Ecological Footprint (EF) of Italian food consumption. The analysis confirms that deviations from the MD amplify environmental pressures. Using the SDM, the study evaluates alternative dietary scenarios, showing that flexitarian, pesco-vegetarian, and predominantly plant-based diets significantly lower CF and EF. An unexpected yet significant finding highlights the economic dimension of dietary shifts: sustainable diets, including MD-aligned and plant-based patterns, are more affordable than the current Italian diet. This challenges the misconception that environmentally sustainable diets are costly and positions affordability as a key driver for dietary change. These results were published in Ecological Economics (2023).    Finally, the research explores the alignment between supply and demand in promoting sustainability. A study conducted at Université Grenoble-Alpes examines the impact of educational campaigns—Nutri-Score labeling and plant-based meal promotions—on employee food choices in collective catering. While these interventions improved awareness, behavioral shifts remained limited due to entrenched consumption habits and supply constraints. The findings underscore the necessity of coordinated efforts between consumer awareness and structural supply-side changes to drive sustainable dietary transitions.    Overall, this thesis provides a comprehensive examination of sustainability in the bottled water and food sectors, highlighting the interconnectedness of production and consumption. By integrating industry practices, policy frameworks, and consumer behavior insights, the research contributes to ongoing discussions on sustainability strategies and policy interventions necessary for systemic change.","language":"eng","citation":"WATER ECONOMY: SUSTAINABILITY IN BOTTLED WATER SUPPLY CHAIN. THE ROLE OF CONSUMER AND ENTERPRISE TO ENHANCE SUSTAINABILITY IN THE FOOD SYSTEM / E.n. Frola ; tutor: F. D'Alessandro; co-tutor: A. Banterle. - Milano. Dipartimento di Scienze e Politiche Ambientali, 2025 Mar 28. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13592.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1155095/2717289/phd_unimi_R13592.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/918917"},"title":"THE POLITICS OF SANCTIONS COMPLIANCE. EXPLAINING SANCTIONS EFFECTIVENESS THROUGH THE LENS OF DOMESTIC VETO PLAYERS. EMPIRICAL EVIDENCE FROM THE CASES OF ERITREA, IRAN, AND SUDAN.","internalauthor":"CORDA, TIZIANA","type":"Tesi di dottorato","year":"2022","abstract":"Sanctions scholarship overwhelmingly expects that authoritarian states defy and resist the demands attached to sanctions imposed on them. In practice, however, authoritarian states do sometimes accommodate to sanctions-related demands and offer political concessions consistent with them. What explains their choice of compliance or defiance? When do they decide to offer political concessions aligned with sanctions-related demands, and why are those concessions sometimes short-lived and not robust, and why can they be more or less expedited? This research project argues the answer lies in the domestic configuration of institutional and political constraints, also called veto players, of the states under sanctions. As a contribution to the domestic-politics branch of the literature on international sanctions, which has become increasingly more relevant in light of the evolution of sanctions from comprehensive to targeted, this research project aims to investigate the under-researched application of a typically public-policy approach such as the veto player analysis to the literature on international sanctions and understand if and how domestic constraints such as veto players, who cut across regime type classifications that are frequently –but often inconclusively– used in the literature on sanctions, affect the effectiveness of sanctions in achieving the desired political concessions. Differently from previous studies, this project intends to examine this interaction along three different dimensions of the targeted state’s aggregate policy response to sanctions, that are the direction, robustness, and expedition of the policy change which together describe the overall effectiveness of sanctions. To test how three different elements of the configuration of the targeted state’s veto players such as the concentration of the agenda power, the congruence of policy preferences, and the internal cohesion, can affect those three outcome dimensions, the project adopts different methodological strategies. After performing some statistical analyses which expose some issues which remain largely unaddressed by the extant literature and probe alternative hypotheses, the project builds on those findings to develop a new theoretical framework and related spatial model which is applied to few selected comparative case studies to trace how veto power operates inside a state targeted by sanctions and test the hypotheses identified, one per dimension of the policy response to sanctions. This empirical part aims to verify the empirical support for the hypotheses and illustrate how the explanatory power of the veto player lens outperforms explanations that focus instead only on regime type classifications in decoding the politics of sanctions compliance.","language":"eng","citation":"THE POLITICS OF SANCTIONS COMPLIANCE. EXPLAINING SANCTIONS EFFECTIVENESS THROUGH THE LENS OF DOMESTIC VETO PLAYERS. EMPIRICAL EVIDENCE FROM THE CASES OF ERITREA, IRAN, AND SUDAN / T. Corda ; tutor: A. Carati ; coordinatore del dottorato: M. Jessoula. Dipartimento di Studi Internazionali, Giuridici e Storico - Politici, 2022 Apr 13. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12149.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/918917/2009914/phd_unimi_R12149.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/966059"},"title":"FROM DARK MATTER TO THE DARK SECTOR: SEARCH FOR NEW PHYSICS IN FINAL STATES WITH A PHOTON AND MISSING TRANSVERSE MOMENTUM, AT THE ATLAS EXPERIMENT","internalauthor":"PIAZZA, FEDERICA","type":"Tesi di dottorato","year":"2023","abstract":"The Dark Matter (DM) problem is one of the main open questions in physics, and an hint of the incompleteness of the Standard Model (SM) of elementary particles. Among the several proposed DM models, one of the most explored DM candidate is the WIMP (Weakly Interacting Massive Particle), while an appealing scenario which is gaining growing interest, predicts the existence of a full Dark Sector, with its own internal gauge structure and particle content.   This thesis focuses on WIMP and Dark Photon searches in proton-proton collisions at 13 TeV at the Large Hadron Collider (LHC), using the 139 fb-1 of full Run-2 data collected by the ATLAS experiment between 2015 and 2018. Final states involving a photon and missing transverse momentum (ETmiss), an imbalance in the total transverse momentum of the final state due to undetected particles, are considered, the latter being a potential signature of DM or Dark Sector particles.     The first search targets mono-photon final states (photon+ETmiss), interpreting the results in terms of pair-production of weakly interacting DM candidates via an s-channel decay of an axial-vector or vector mediator.     The second part of this work present two searches for a Dark Photon (H->yyd) (predicted as the gauge boson of a new U(1) symmetry group of the Dark Sector) produced via the decay of a (SM or BSM) Higgs boson, . The search is performed, at first, targeting Higgs boson production in association with a leptonically decaying Z boson (), and then reinterpreting the mono-photon analysis in terms of the same decay for a BSM Higgs with masses between 400 GeV and 3 TeV, in the gluon-gluon fusion and Vector Boson Fusion production modes.     These analyses are part of a huge effort carried on within the ATLAS collaboration, towards the understanding of DM nature. Collider searches have a key role in this field, ensuring good complementarity with Direct Detection and Indirect Detection strategies, which is of fundamental importance to extend the possible reach of research in probing the extremely wide range of possible DM models and masses.","language":"eng","citation":"FROM DARK MATTER TO THE DARK SECTOR: SEARCH FOR NEW PHYSICS IN FINAL STATES WITH A PHOTON AND MISSING TRANSVERSE MOMENTUM, AT THE ATLAS EXPERIMENT / F. Piazza ; tutors: S. Resconi, M. Fanti ; coordinatore: M. Paris. Dipartimento di Fisica Aldo Pontremoli, 2023 Apr 17. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12674.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/966059/2183780/phd_unimi_R12674.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1048817"},"title":"TESTI SCOLASTICI DELLA LOMBARDIA DEL XIV E XV SECOLO.TENDENZE KOINEIZZANTI E INDIZI DI GRAMMATIZZAZIONE DEL VOLGARE LOMBARDO","internalauthor":"SOMA, ANNA","type":"Tesi di dottorato","year":"2024","abstract":"This work aims to study the vernacular language used in school texts intended for the teaching of Latin in Lombardy in the 14th and 15th centuries. Starting in the 14th century, bilingual textbooks in Latin and the vernacular began to appear in schools, in which the vernacular was used for the (practical) purpose of making the Latin text accessible.   The research aims, on the one hand, to provide an analysis of the vernacular language used in these texts to describe certain tendencies towards the koineisation of Old Lombard, and, on the other, to investigate the relationship between Latin and vernacular in school texts and its evolution. The reflection on Latin grammar led teachers and students of the time to confront themselves with linguistic problems that were also applicable to their mother tongue. An attempt was made to ascertain the extent to which these reflections influenced the process of grammatisation and normativisation of Old Lombard at the time.","language":"ita","citation":"TESTI SCOLASTICI DELLA LOMBARDIA DEL XIV E XV SECOLO.TENDENZE KOINEIZZANTI E INDIZI DI GRAMMATIZZAZIONE DEL VOLGARE LOMBARDO / A. Soma ; cotutor: G. Polimeni ; tutor: R. Wilhelm ; coordinatore: F. Slavazzi. Dipartimento di Studi Letterari, Filologici e Linguistici, 2024 Sep 30. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13191_1.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1048817/2407890/phd_unimi_R13191_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1197837"},"title":"DTI-ALPS REFLECTS WHITE MATTER DIFFUSION ANISOTROPY AND MICROSTRUCTURAL HETEROGENEITY RATHER THAN GLYMPHATIC FLOW: INSIGHTS FROM MULTI-MODAL MRI","internalauthor":"SACCHI, LUCA","type":"Tesi di dottorato","year":"2025","abstract":"The glymphatic system plays a critical role in the clearance of metabolic waste and pathological proteins such as amyloid-β and tau from the brain, and its dysfunction has been increasingly implicated in the pathogenesis of neurodegenerative diseases, making its in vivo characterization a major research priority. The diffusion tensor imaging–analysis along the perivascular space (DTI-ALPS) has been widely adopted as a putative non- invasive MRI biomarker of glymphatic flow. However, the biological specificity of the DTI- ALPS index remains unclear, and recent evidence has raised concerns that it may primarily reflect white-matter (WM) microstructure rather than perivascular fluid transport. In this study, we sought to clarify the determinants of DTI-ALPS and to assess whether this metric primarily reflects WM microstructural damage rather than glymphatic activity.  A total of 100 participants were recruited from individuals referred to the Neurodegenerative Diseases Unit of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan (Italy) for suspected dementia. All the participants underwent the same 3T MRI protocol comprising high-resolution T1-weighted and FLAIR imaging, double-shell diffusion-weighted imaging (b=1000 and 2000 s/mm2), and multi-echo gradient-echo sequences for quantitative susceptibility mapping. Within standard centrum semiovale regions of interest, we computed DTI-ALPS together with fractional anisotropy (FA), mean diffusivity (MD), mode of anisotropy (MA), and neurite orientation and density imaging (NODDI) metrics, including the orientation dispersion index (ODI), neurite density index (NDI), and isotropic volume fraction (FISO). We also computed the T1/FLAIR signal ratio and the diamagnetic component of susceptibility (DCS) derived from DECOMPOSE within the same ROIs, as complimentary structural metrics of WM damage.  Lower DTI-ALPS values were associated with higher FA and MD (|r|=0.40–0.60), with stronger effects observed at b=2000 than at b=1000. The DTI-ALPS index correlated strongly and inversely with MA (r=–0.84 at b=1000; r=–0.86 at b=2000) and positively with ODI (r=0.73), and both metrics remained strong independent predictors after correction for age and sex. Moderate associations were observed with structural markers—direct with the T1/FLAIR ratio (r 0.33) and inverse with DCS standard deviation (r -0.50) —consistent with altered myelin integrity and increased microstructural heterogeneity. Exploratory factor analysis demonstrated that DTI-ALPS did not form a separate latent component but clustered with MA and ODI, indicating shared variance related to axonal geometry rather than to perivascular flow.  Collectively, these findings demonstrate that DTI-ALPS predominantly reflects WM architecture—specifically, loss of crossing fibers, increased diffusion coherence, and reduced orientation dispersion—rather than the dynamics of glymphatic transport. Although DTI-ALPS may still capture secondary effects of glymphatic impairment arising from WM injury, the present results suggest that it cannot be considered a direct biomarker of glymphatic function. Its use as a surrogate measure of glymphatic flow should therefore be approached with caution and re-evaluated through direct validation against intrathecal contrast-enhanced MRI or other physiological reference methods.","language":"eng","citation":"DTI-ALPS REFLECTS WHITE MATTER DIFFUSION ANISOTROPY AND MICROSTRUCTURAL HETEROGENEITY RATHER THAN GLYMPHATIC FLOW: INSIGHTS FROM MULTI-MODAL MRI / L. Sacchi ; tutor: D. Galimberti ; tutor clinico: A. Arighi ; direttore del corso: M. Del Fabbro. Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, 2025 Dec 19. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13981.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1197837/3188856/phd_unimi_R13981.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/982848"},"title":"PRENUPTIAL AGREEMENTS E AUTONOMIA NEGOZIALE: UN PERCORSO COMPARATISTICO.","internalauthor":"NOVELLO, FEDERICA","type":"Tesi di dottorato","year":"2023","abstract":"The interest in prenuptial agreements is part of the broader debate aimed at enhancing private autonomy in relations between spouses with particular reference to the moment of marriage crisis and its patrimonial consequences.  An examination of the space that private autonomy has conquered over time in the Italian system and the role it has played in the English system will make it possible to highlight the attitude that the two systems have shown toward prenuptial agreements.  The analysis conducted from a comparative-historical perspective will make it possible to observe the approach of the two systems, one of civil law, the other of common law, to the subject matter of the doctoral dissertation and to carry out some reflections about the possibility of sustaining the validity of prenuptial agreements in the Italian legal landscape without the need for any intervention by the legislature.","language":"ita","citation":"PRENUPTIAL AGREEMENTS E AUTONOMIA NEGOZIALE: UN PERCORSO COMPARATISTICO / F. Novello ; tutor: R.E. CERCHIA ; co-tutor: A. MANIACI ; coordinatore: G. LUDOVICO. Dipartimento di Diritto Privato e Storia del Diritto, 2023 Jul 07. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12668.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/982848/2240753/phd_unimi_R12668.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/814055"},"title":"PROCESS ANALYTICAL TECHNOLOGY APPROACHES FOR DAIRY INDUSTRY","internalauthor":"STRANI, LORENZO","type":"Tesi di dottorato","year":"2021","abstract":"This thesis work wants to answer the need of dairy industry to increase productivity while satisfying the consumers request for higher quality products. In order to do that, dairy companies need innovative methods to improve the understanding and the monitoring of production processes. Process Analytical Technology (PAT) approaches are the perfect tool for this purpose, as they use green, fast, non-invasive and non-destructive sensors that allow to perform measurements in real time. The most used techniques in this field are Near- and Mid-Infrared (NIR and MIR, respectively) spectroscopy, whose probes can be directly installed in critical points of the process providing both physical and chemical information of the product. However, these techniques have the drawback of providing results (spectra) difficult to be interpreted without proper statistical tools. In this context, Chemometric methods and algorithms allow the extraction of relevant information from spectroscopic data, providing a better understanding of the studied system.   The first part of the present work focused on the monitoring of the coagulation process, one of the most critical moments of cheesemaking. To this aim, an FT-NIR spectroscopy system was used, acquiring spectra along the rennet coagulation process. According to a Box-Behnken experimental design, several coagulation trials were carried out, changing crucial technological factors, such as temperature, fat content and pH. Through Multivariate Curve Resolution optimized by Alternating Least Squares (MCR-ALS) algorithm it was possible to both have a reliable description of the three different coagulation phases and, most importantly, to build Multivariate Statistical Process Control (MSPC) charts, able to detect failures from the first moment of the process. Moreover, ANOVA-Simultaneous Component Analysis (ASCA) method was applied on spectral data to obtain a better understanding of the process, highlighting in which way each physicochemical parameter affects the process.  In the second part of the work, FT-NIR spectroscopy was tested as a possible tool to replace the golden standards of coagulation ability, i.e. Formagraph. Coagulation trials were carried out using different milk powder samples. The use of MCR-ALS algorithm permitted the assessment of the best powder in terms of coagulation attitude and, in addition, it highlighted the non-significant effect on coagulation occurrence of CaCl2 concentration and of heat treatment on reconstituted milk. Finally, experimental trials carried out with mixtures of skimmed milk and reconstituted milk showed a slower coagulation time when a higher reconstituted milk percentage was used.   The last part of the work regarded the use of MIR spectroscopy to monitor Galactooligosaccharides (GOS) production from cheese whey, in order to avoid the waste of this compound and to optimize the studied process. To do so, Partial Least Square (PLS) regression was used to predict the specific compounds resultant from the different enzymatic reaction studied.   In conclusion, the application of the proposed methods will implicate, with a modest environmental impact, an efficient control of the process, satisfying at the same time law requirements and consumers’ needs. Furthermore, reliability of PAT approaches could be strengthened by future industrial applications.","language":"eng","citation":"PROCESS ANALYTICAL TECHNOLOGY APPROACHES FOR DAIRY INDUSTRY / L. Strani ; supervisor: E. CASIRAGHI ; phd coordinator: A. PAGLIARINI. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2021 Feb 19. 33. ciclo, Anno Accademico 2020. [10.13130/strani-lorenzo_phd2021-02-19].","filename":"phd_unimi_R11978.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/814055/1702807/phd_unimi_R11978.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1221309"},"title":"SUGAR EDITING FOR THE SYNTHESIS OF GLYCOMIMETICS","internalauthor":"CAVAZZOLI, GIANLUCA","type":"Tesi di dottorato","year":"2026","abstract":"This doctoral thesis explores strategies for the synthesis of structurally advanced glycomimetics. The first project focuses on the design of selective antagonists of C-type lectins, specifically targeting L-SIGN over DC-SIGN, two closely related receptors involved in viral recognition and SARS-CoV-2 infection. Inspired by the selective ligand Man84, a library of C2-triazole-modified mannosides bearing guanidine isosteres was synthesized. Structure–activity relationship studies combined with SPR assays identified several potent and selective L-SIGN ligands, including Man96, Man97, and Man102, displaying low micromolar affinity. X-ray crystallography of the L-SIGN/Man96 complex revealed the key interactions determining affinity and selectivity, highlighting the important role of residues E370, F325, and N385 in L-SIGN CRD. The second project develops a nickel-photoredox methodology for the synthesis of α-C-arylglycosides via deoxygenative arylation of unprotected anomeric hydroxyl groups. By replacing expensive iridium photocatalysts with sustainable organic dyes such as 5CzBN, an efficient and economical catalytic system was established. The protocol proved compatible with various monosaccharides and (hetero)aryl bromides, affording α-selective C-arylglycosides under mild conditions. Mechanistic investigations, including fluorescence quenching experiments, supported a radical pathway initiated by reductive quenching of a sugar–NHC adduct. The third project investigates racemic crystallization as a novel strategy for structural studies of glycans. Through automated glycan assembly, both D- and L-enantiomers of a galactosylated xyloglucan hexasaccharide were synthesized. Preliminary results suggest that racemic crystallization may overcome longstanding challenges in glycan structural analysis.   Overall, this work expands the chemical space of glycomimetics, introduces sustainable synthetic methodologies for C-arylglycosides, and pioneers structural approaches for complex oligosaccharides, contributing to the advancement of medicinal and structural glycoscience.","language":"eng","citation":"SUGAR EDITING FOR THE SYNTHESIS OF GLYCOMIMETICS / G. Cavazzoli ; tutor: A. Bernardi ;  coordinator: D. Passarella. - Aula V1, Settore Didattico, via Venezian 15, 20133 Milano (MI). Dipartimento di Chimica, 2026 Mar 03. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13900_6.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 04-SET-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1151337"},"title":"MULTISTAKEHOLDER GOVERNANCE FOR SUSTAINABILITY.NORMATIVE INSIGHTS FROM A DELIBERATIVE PERSPECTIVE","internalauthor":"ITOLLI, FILIPPO","type":"Tesi di dottorato","year":"2025","abstract":"This dissertation critically examines the legitimacy and effectiveness of multistakeholder governance (MSG) in sustainability, arguing that power asymmetries undermine the transformative potential of these governance models. While MSG frameworks, particularly Multistakeholder Initiatives (MSIs), have been promoted as inclusive and participatory responses to global challenges, empirical evidence suggests that they frequently fail to address key Sustainable Development Goals (SDGs), such as poverty reduction (SDG 1), inequality mitigation (SDG 10), and climate action (SDG 13). The core problem identified is that corporate actors, while positioned as central stakeholders, exercise disproportionate influence, shaping governance mechanisms in ways that prioritize commercial interests over broader social and environmental objectives.  Building on governance studies, business ethics, and deliberative democratic theory, this dissertation argues that deliberative democracy offers a viable normative and institutional framework to address these imbalances. By emphasizing reasoned justification, inclusion, and other essential deliberative principles, this normative perspective can help mitigating corporate dominance in MSIs. The research employs a mixed-method approach, combining conceptual analysis with case studies of the Forest Stewardship Council (FSC), the Roundtable on Sustainable Palm Oil (RSPO), and the Accord on Fire and Building Safety in Bangladesh. These cases reveal structural limitations in current MSG frameworks, particularly in their accountability mechanisms and their ability to empower marginalized stakeholders.  As a response, the dissertation proposes a deliberative reform agenda, including the institutionalization of mini-publics and stronger mechanisms for stakeholder empowerment. By bridging deliberative democratic theory with global sustainability governance, this work contributes to the debate on corporate legitimacy and the need for democratic oversight in transnational regulatory frameworks.","language":"eng","citation":"MULTISTAKEHOLDER GOVERNANCE FOR SUSTAINABILITY.NORMATIVE INSIGHTS FROM A DELIBERATIVE PERSPECTIVE / F. Itolli ; tutor: R. Ruffini ; co-tutor: V. Cecchini Manara, P. Francés-Gómez, L. Crema ; coordinatore: L. Sacconi. - Milano. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2025 Apr 07. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13396.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1151337/2705975/phd_unimi_R13396.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1259255"},"title":"LAKEMAGING: GEOPHYSICAL DATA INTEGRATION FOR GROUNDWATER MODELLING","internalauthor":"GALLI, STEFANO","type":"Tesi di dottorato","year":"2026","abstract":"Groundwater models are often affected by strong uncertainties because hydrogeological information is commonly derived from sparse boreholes, local hydraulic tests, and indirect observations that do not adequately describe subsurface heterogeneity. In this context, geophysical methods, and especially electrical and electromagnetic techniques, provide spatially continuous information that can improve conceptualization of aquifer systems. However, their integration into hydrogeological workflows remains challenging because geophysical datasets may differ in scale, sensitivity, and acquisition time, and because electrical properties are only indirectly related to hydraulic parameters.  This thesis develops methodological frameworks for integrating geophysical data and for transferring geophysical information into groundwater modelling. The first part addresses joint inversion of concordant, discordant, and geologically constrained datasets. It shows that combining datasets with complementary sensitivities can reduce non-uniqueness and improve subsurface characterization, while robust inversion strategies based on asymmetric generalized minimum support can mitigate the influence of inconsistent or outdated ancillary data without discarding them entirely. The integration of geological constraints within 3D inversion further improves the structural plausibility of the recovered models in complex settings.  The second part focuses on waterborne transient electromagnetic data and their use in groundwater modelling. A dedicated inversion workflow is developed to account for bathymetry, sharp resistivity contrasts, and depth-dependent damping. Synthetic tests and field applications show that these elements are essential to correctly image the water–sediment interface and reduce inversion artifacts in lacustrine environments. The resulting models are then incorporated into groundwater simulations through two complementary approaches: direct petrophysical translation and structurally guided calibration. Two case studies demonstrate that geophysical information can improve aquifer parameterization, preserve mapped heterogeneity, and reduce conceptual uncertainty, although the reliability of direct petrophysical conversion remains strongly site dependent.  Overall, the thesis shows that geophysics can play a more active role in groundwater modelling, not only as a qualitative support tool but as a quantitative source of constraints for inversion, model building, and uncertainty reduction.","language":"eng","citation":"LAKEMAGING: GEOPHYSICAL DATA INTEGRATION FOR GROUNDWATER MODELLING / S. Galli ; tutor: G. Fiandaca ; co-tutor: M. Giudici ; coordinatore: G. Muttoni. Dipartimento di Scienze della Terra Ardito Desio, 2026. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13838.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1259255/3366343/phd_unimi_R13838.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1152107"},"title":"INFLUENCE OF THE INTERACTION SCION X ROOTSTOCK ON GRAPEVINE RESPONSE TO DROUGHT STRESS AS A TOOL IN NEW GRAPEVINE ROOTSTOCKS BREEDING PROGRAMS.","internalauthor":"MODINA, DAVIDE","type":"Tesi di dottorato","year":"2025","abstract":"Viticulture is expected to face several challenges related to current and future climate changes. Particularly, the vine-growing areas experiencing severe drought stress are expected to increase in the coming years. This could affect grape quality and yield, as well as the character and style of wines, and, more generally, the viticultural potential of many regions. Many studies suggest adaptive strategies to address changing environmental conditions, and the use of drought-tolerant rootstocks is considered an effective mid-term solution to mitigate and manage these negative impacts. However, the range of available rootstocks is limited, and most of them were selected in the late 19th century, when grapevine cultivation practices vastly differed from those of today. As a result, there is a growing demand for drought-tolerant rootstocks that are suitable for modern viticulture. In response to this request, some new genotypes have been released in recent years. Among those, the M-series by University of Milano has shown promising performances in different viticultural contexts.  A deep insight into the behaviour of these new rootstocks under water stress conditions, especially in comparison to traditional ones, could provide valuable information, useful at different levels. On one hand, a better understanding of rootstocks performance under drought stress would support winegrowers in making informed decisions when planning new vineyards. On the other hand, it would provide breeders with crucial data on the grapevine responses to water stress, with particular regard to the complex interaction between scion and rootstock, allowing them to better direct their research efforts. To address these questions, three experiments were conducted. The first study evaluates the scion x rootstock interaction effect on drought tolerance, considering two grapevine varieties characterized by different physiological strategies against water stress. More in detail, the study aimed to: (a) analyse the behaviour of ungrafted rootstocks (1103P, M4) and own-rooted vines (Sangiovese, Montepulciano) under increasing water deficit conditions and after rewatering; (b) evaluate the behaviour of the four grafting combinations in the same experimental conditions; and (c) assess the response of the four grafting combinations to different drought dynamics. The second experiment delves into the specific water stress tolerance strategies employed by the two grafting combinations of Pinot Blanc with 1103P and M4, focusing particularly on changes in morphology of the scion, including leaf, petiole and xylem vessels induced by rootstocks. The third experiment examines the influence of rootstock on grapevine production and quality. When selecting a rootstock, it is important not only to assess its tolerance to water stress but also to consider its impact on grape quality, taking into account environmental conditions and oenological objectives. This study analysed six different grafting combinations of Chardonnay with 1103P, SO4, M1, M2, M3, M4, all cultivated in the same vineyard over a four-year period. Data on production per plant, vine vigour, and must quality (sugar content, pH, total acidity, K⁺ concentration) were collected. Furthermore, micro-vinifications of the six combinations were produced in two years and wines sensorial characteristics were evaluated.  The results generally highlight the crucial role of the interplay between rootstock, scion, and water stress intensity in shaping drought response mechanisms. Specifically, differences in leaf gas  exchange are primarily driven by the variety under moderate water stress and by the rootstock under severe water stress and after rewatering. In particular, M4 outperforms 1103P, demonstrating a superior response under severe water stress conditions and a faster recovery following rehydration. This pattern is consistently observed across all three grafted combinations: Pinot Blanc, Sangiovese, and Montepulciano.  The differing responses of the two rootstocks appear to be influenced by both chemical and morphological factors. In particular, variations in osmolyte content and mobilization patterns were observed. On the other hand, an interaction between rootstock genotype and water stress level was identified for Pinot Blanc. Under water stress, 1103P induced a higher density of vessels with smaller diameters, whereas M4 did not cause any notable changes in xylem anatomy. Additionally, a loss of hydraulic conductivity was observed in the stems and petioles of vines grafted onto 1103P, indicating a greater vulnerability to cavitation compared to those grafted onto M4.  Finally, the results of productive and qualitative parameters collected in open field on six grafting combinations of Chardonnay, highlight a statistically significant influence of the rootstock on most of the analysed parameters. Differences were found also in the sensory characteristics of the wines, highlighting the critical role of rootstock selection in achieving the desired oenological goal.  In conclusion, this work analysed various aspects related to the role of the rootstock and its close interaction with the scion in the grapevine's response to water stress. In particular, the rootstock can induce different morphological and physiological responses in the plant under water deficit conditions, which can determine a varying degree of tolerance to water stress of the different grafting combination. In this context, it is important to highlight how this knowledge could be important for farmers in making optimal rootstock x scion choices for their vineyards and for breeders for the selection of new rootstocks tailored to specific cultivars or environmental conditions","language":"eng","citation":"INFLUENCE OF THE INTERACTION SCION X ROOTSTOCK ON GRAPEVINE RESPONSE TO DROUGHT STRESS AS A TOOL IN NEW GRAPEVINE ROOTSTOCKS BREEDING PROGRAMS / D. Modina ; tutor: L. Brancadoro ; co-tutor: G. Cola ; coordinatore: S. Pilu. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2025 Mar 21. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13575.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1152107/2708007/phd_unimi_R13575.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1156015"},"title":"L¿ESECUZIONE DELLA PENA E L¿ORDINAMENTO PENITENZIARIO PER IMINORENNI: L¿EVOLUZIONE E LE NUOVE PROSPETTIVE ALLA LUCEDEL D.LGS. 2 OTTOBRE 2018, N. 121","internalauthor":"VALENTE SARDINA, ENRICA","type":"Tesi di dottorato","year":"2025","abstract":"This paper analyses the regulation of the execution of the sentence, and particularly the prison system, in respect of juvenile offenders (rectius: those who had not reached the age of majority, at the time of the commission of the offence), in the light of the enactment of Legislative Decree No 121 of 2 October 2018.   The latter implemented Article 1(81), (83) and (85)(p) of Delegated Law No. 103 of 23 June 2017, constituting a turning point in the Italian legal system, as an ad hoc discipline of juvenile prison law was introduced for the first time, filling an internal gap in the system, already felt since Law No. 354 of 26 July 1975.   In fact, while awaiting the great reform of prison law in 1975, a transitional provision had been envisaged, which allowed the application of the general discipline, even to those who had committed the offence as minors, with the assurance, however, that this use would cease as soon as possible with the enactment of legislation dedicated to them (Article 79 of Law 354/1975).  Despite the solicitations of European and supranational sources, the complaints of merit of juvenile judges and the vain attempts represented by numerous draft laws, for more than forty years, our legal system has suffered from the lack of a separate discipline, making it necessary for the Constitutional Court to make substantial adjustments to the rules that prevented a constitutionally oriented interpretation of the principle of favor minoris.  These pronouncements, however, became more numerous from the 1990s onwards, in the face of the boost provided by the far-sighted Presidential Decree of 22 September 1988, no. 448 of 22 September 1988, which, by forging the system of a criminal trial aimed exclusively at under-eighteen-year-olds, endorsed some of the cardinal principles of juvenile matters, of which this thesis intends to give an enucleation: in particular, the specialisation of judges and other professionals who have contact with young defendants, the individualisation of each procedure and the need for differentiated judicial outcomes.   The same guarantees, a fortiori, also deserved to be applied to the trial segment following sentencing, specifically oriented towards the recovery and resocialisation of the young offender.  The first part of the research work is, therefore, aimed at analysing, the wise work of differentiation between the penitentiary system of adults and that of juveniles, conducted by the Constitutional Judge, starting from the well-known judgment of 25 March 1992, no. 125, which discussed the legitimacy of art. 79, Ord. Penit, in the part in which it did not differentiate the applicability of alternative measures to detention (and other penitentiary benefits) to young prisoners, compared to the more rigid provisions provided for adult offenders.   The Constitutional Court, while ruling that the question was inadmissible, took the opportunity to denounce the parity of the two systems, stressing that ‘the application also to juveniles of the limits of inflicted and [...] served sentences, provided for probation and semi-release’ compromised ‘the need for specific individualisation and flexibility of treatment’ that the young person's personality, still in the making, would have required.   The incisiveness of the 1992 ‘warning judgement’ was not enough to spur the Italian legislature on this point, further corrective measures by the Judge of Laws being necessary.  From the joint reading of some of these judgments it is possible to deduce the common thread that slowly led the delegating legislator to include within the so-called Orlando Reform also the directives to be transposed, in the drafting of a new juvenile prison system.  The merit of the sentences that the research intends to highlight, concerns the interpretation given to certain fundamental principles of the Constitutional Charter, contained in the provisions of Articles 3, 27 paragraph 3 and 31 paragraph 2.  Thus, starting from the assumption that serving an intramoenia sentence makes it, in practice, more complex to prepare the minor, effectively, for future experience in society, the constitutional judges have oriented their decisions in two directions.    On the one hand, in fact, it was recognised that the stay in juvenile penal institutions should always be the extreme ratio, definitively opening the doors to any alternative measure to detention. In this wake, the judges of the Constitutional Court severely censured any form of automatism that prevented, in practice, those who were minors at the time of the crime, from benefiting from measures less segregating than prison.  The motivations underlying these decisions find their common denominator in the interpretation of Article 3 of the Constitution, in the light of the principle of the protection of childhood and youth: the principle of substantive equality, in fact, requires differential treatment in the face of conditions - such as minor and adult age - that are profoundly different. To this is added the need, in the light of the principle of favor minoris, ‘to adapt the treatment of the convicted person in relation to individualised assessments and prognoses anchored to the concreteness of the case’.   With regard, then, to the second guideline followed, in the work of correction of the prison system, the Court specified that, in the residual hypotheses in which the stay in prison cannot be avoided, the intramuritary execution should present diversified and flexible characteristics, in order to allow an individualised prison experience, suitable for the maturation and re-socialisation of each young prisoner. To make this principle explicit, once again, it was necessary to reinterpret the rule of Article 27, paragraph 3 of the Constitution, enhancing the protection and social rehabilitation of the juvenile, with respect to the punitive needs of the State.   The next part of the work investigates, therefore, the extent to which the delegated legislator followed the directives enucleated in the eight points, contained within art. 1, paragraph 85 letter p) of the delegated law of 23 June 2017 no. 103, which, in turn, borrowed the warnings of the Consulta and the solicitations of the supranational and European legislators.  The main aspects that should have committed the delegate concerned, first of all, the extension of the entire juvenile discipline also to the so-called young-adults, with a view to not abruptly halting the re-educational path undertaken; the provision of alternative measures to detention, really different from those aimed at adults and more easily accessible the elimination of any automatism or preclusion with respect to prison benefits, linked to absolute presumptions (linked to the title of offence); the strengthening of activities aimed at education or vocational training, as well as the increase of contacts with the outside world.   With a view to assessing the success of the reform and, on the other hand, the aspects that have disappointed the expectations of the delegator, the paper focuses, firstly, on the regulation of external criminal execution and, secondly, on the regulation of intramoenia execution.   The choice is not causal, as it recalls the topographical placement of the regulations of Legislative Decree no. 121/2018, the result, in turn, of a happy decision of the delegated legislator to give prevalence, first, to the ‘new’ community-based criminal measures, relegating, as a last resort, the discipline of intramoenia detention.   Nonetheless, the approach to the reform is mainly critical since, in fact, the resulting decree appears to be mostly a slavish re-proposal of the ordinary prison regulations, presenting only a few differences, more quantitative - with reference to the application prerequisites - than qualitative.   The thesis, therefore, proposes to compare the matter of external criminal enforcement, as reformed in 2018, with the ‘traditional’ alternative measures to detention, regulated in Chapter IV of Title I of Law no. 354/1975.  A further element of comparison is provided, moreover, by the solicitations coming from the States General of Penal Enforcement, which dedicated an ad hoc table to the juvenile matter. Even the first Draft of the decree, presented by the Cascini Commission, had appeared far more ambitious in freeing the juvenile prison system, from that aimed at adults, than the work that resulted in 2018.  In studying the new provisions of the decree, which have been the subject of criticism by the first commentators, it is necessary to look at the reform through the lens of the legislator of the 1988 Code of Juvenile Criminal Procedure, which, on the contrary, had introduced innovative forms of diversion, which kept in mind the psychophysical condition of a young defendant. It is believed that certain provisions contained in that far-sighted piece of legislation can still be borrowed today when rethinking some of the institutions of prison discipline.   This is also true in the third part of the paper, which, as anticipated, aims to investigate the intramoenia discipline in the various Juvenile Penal Institutions located on the Italian territory, in the light of the new ‘educational’ project.   Without prejudice to the fact that recourse to intramurary detention remains an obligatory choice in extremely residual hypotheses, there are two aspects on which the research work intends to focus.   In the first place, it is considered essential - even though the final decree has been described in only one rule - to take the utmost care in maintaining relations with the juvenile's family and, more broadly, to protect affectivity and contacts with the outside world (whether represented by relatives or other persons close to the detainee, as well as by volunteers of the institution itself): the aim is to redesign the execution of the juvenile sentence with a view to a progressive rapprochement to society.  Secondly, it is necessary to investigate the core of activities that can be selected - both by the specialised judiciary and by the social services - and included in the treatment programme. It is believed that this last aspect represents what can distinguish the juvenile offender's enforcement process, marked by his gradual maturation, from that of the adult, mostly aimed, instead, at the containment of dangerousness.  In this regard, also thanks to the opportunity of participating in a project held at the ‘Cesare Beccaria’ Juvenile Penal Institute in Milan, the re-educational power of theatrical activity within prisons is assessed, under multiple aspects: the cathartic and emotional one, the educational and cultural one and, lastly, the one concerning re-socialisation and relations with others.   The work closes with an analysis of the Flemish juvenile criminal law, which was carried out during a research period at the KU Leuven University. The comparison with that legislation, which in some aspects is profoundly different from ours, allows us to explore margins of improvement for the domestic discipline, with particular regard to the concrete translation of the extreme ratio of detention and, on the other hand, allows us to emphasise which Italian practices can be proudly taken as an example also abroad.","language":"ita","citation":"L¿ESECUZIONE DELLA PENA E L¿ORDINAMENTO PENITENZIARIO PER IMINORENNI: L¿EVOLUZIONE E LE NUOVE PROSPETTIVE ALLA LUCEDEL D.LGS. 2 OTTOBRE 2018, N. 121 / E. Valente Sardina ; tutor: L. Camaldo ; coordinatore: F. Poggi. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2025 Mar 25. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13414.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1156015/2725709/phd_unimi_R13414.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/922688"},"title":"L'EDITING GENETICO GERMINALE UMANO, TRA PROBLEMI ETICI E QUESTIONI DI GOVERNANCE.","internalauthor":"BONOMELLI, SARA","type":"Tesi di dottorato","year":"2022","abstract":"The dissertation aims at identifying and analyzing the scientific, legal, and ethical issues raised by the perspective of intentional modification of human germline by the potential future use of gene editing techniques in the context of human reproduction.   Such a study makes it possible to formulate some critical considerations about human germline gene editing governance. The dissertation claims that the best option to regulate the use of this biotechnological innovation for reproductive purposes consists of a regulation on a state-by-state-basis, which should however be developed within an international governance framework. Several arguments are suggested to underpin this thesis, and some recent initiatives adhering to such governance pattern are examined.  The research is organized in three chapters.  The first chapter, which is introductive to the real research, focuses on the scientific and technical aspects of the thesis topic. More specifically, this chapter aims at laying the foundations for the subsequent discussion, by defining and explaining the notions of i) DNA, gene, chromosome; ii) genetic mutation and genetic disease; and iii) gene therapy and gene editing. Special attention is paid to this latter technology and especially to its potential use on the human germline. Such use is highly controversial, mainly – but not exclusively – since, unlike modifications made by somatic gene editing, those affecting germinal cells – namely, gametes and zygotes – are transmitted to descendants, and thus to next generations.  The second chapter is divided into two sections. The first section reconstructs and analyses the existing regulations in the field of human germline gene editing at international, supranational and national level, stressing their vagueness, fragmentation and lack of specificity. Given the impossibility of extensively examining all relevant domestic laws, guidelines and policies, those of four countries only – the USA, the UK, China and Italy – have been considered in detail. This choice is motivated by the geographical and cultural representativeness of their respective regulations, as well as by the fact that, except for Italy, those countries conducted nearly all the experiments carried out so far in the field of human germline gene editing. The second section of the chapter precisely focuses on these experiments – both for research and reproductive purposes. Jiankui He’s experiment – which resulted in the birth of the world’s first gene-edited babies in 2018 – and Denis Rebrikov’s germline gene editing clinical trial project are thoroughly described and analyzed.   The third and last chapter deals with the ethical issues raised by the perspective of the potential future implementation of germline gene editing interventions in the context of human reproduction. This chapter too is articulated into two sections. The first section provides the theoretical bases for the subsequent ethical analysis, by dividing the possible future uses of germline gene editing techniques into three categories: i) therapeutic interventions; ii) medical enhancement interventions; and iii) non-medical enhancement interventions. Such categorization is paramount, since the various ethical issues related to human germline gene editing do not always involve all three of these categories, and, even when they do, they tend to carry different connotations according to each category. This becomes clear in the second section of the chapter, which critically explores six main ethically problematic areas related to this biotechnological innovation and their numerous articulations.  Finally, the dissertation argues that the scientific, legal and ethical issues identified and examined throughout the research must be taken into account by proper germline gene editing governance mechanisms, which should be the result of parallel and complementary regulatory initiatives promoted both at national and international level.","language":"ita","citation":"L'EDITING GENETICO GERMINALE UMANO, TRA PROBLEMI ETICI E QUESTIONI DI GOVERNANCE / S. Bonomelli ; tutor: F. Poggi; tutor: C. Vázquez Rojas; coordinator: C. Luzzati. Università degli Studi di Milano, 2022 May 13. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12266.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/922688/2020422/phd_unimi_R12266.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1040119"},"title":"TERMINATION OF EXTRAGENIC TRANSCRIPTION BY THE RESTRICTOR COMPLEX: DISSECTING RNA BINDING SPECIFICITY","internalauthor":"POLIZZESE, DANILO","type":"Tesi di dottorato","year":"2024","abstract":"Controlling the precise spatiotemporal utilization of genomic information is crucial across all kingdoms of life. Dealing with the complexity of eukaryotic genomes is challenging due to the multitude of transcription initiation events generated by hundreds of thousands of cis-regulatory elements. Unchecked pervasive transcription can be costly, potentially compromising genome integrity by increasing the threats posed by transcription and disrupting the regulation of non-coding RNAs (ncRNAs).  In this context, we recently identified the Restrictor complex, which plays a critical and non-redundant role in the termination of extragenic RNA Polymerase II (Pol II). The complex is composed of WDR82, an RNA Polymerase II-binding protein, and its RNA-binding partner ZC3H4. Restrictor predominantly terminates extragenic transcription, with limited impact on protein-coding genes.   Numerous aspects of the functionality of the Restrictor complex remain enigmatic. My thesis work focused on the specific contribution of ZC3H4 to the activity of the complex.  Through acute and rapid degron-mediated depletion of ZC3H4, I observed a significant upregulation of thousands of ncRNAs, many of which are polyadenylated and spliced. The extent of the upregulation was underestimated due to the unstable nature of Restrictor’s target RNAs, which normally are rapidly degraded. Analysis of the nascent transcriptome after DRB treatment and release revealed a greater number of targets regulated by ZC3H4, and that they are transcribed slower than protein-coding transcription units.   Moreover, the genomic distribution of ZC3H4 revealed that it was recruited immediately downstream of transcription start sites, coinciding with the genomic distribution of initiating and early elongating Pol II, thus confirming that Restrictor acts in an early termination mechanism.  In line with its reported RNA binding activity, the in-frame deletion of the putative RNA binding domain of ZC3H4 induced a partial upregulation of Restrictor targets. I further assessed its RNA binding activity both in vivo and in vitro, both of which yield a candidate binding motif for ZC3H4.  This thesis highlights the role of sequence-specific recognition of nascent RNAs in the termination activity of the Restrictor complex.","language":"eng","citation":"TERMINATION OF EXTRAGENIC TRANSCRIPTION BY THE RESTRICTOR COMPLEX: DISSECTING RNA BINDING SPECIFICITY / D. Polizzese ; tutor: G. Natoli, D. Pasini ; phd coordinator: S. Minucci. Dipartimento di Scienze della Salute, 2024 Apr 11. 35. ciclo","filename":"phd_unimi_R12703.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1040119/2385549/phd_unimi_R12703.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1198095"},"title":"STRUCTURE-BASED APPROACHES TO DATA-DRIVEN PROTEIN FOLDING, AGGREGATION, AND SELF-ASSEMBLY","internalauthor":"BACIC TOPLEK, FRAN","type":"Tesi di dottorato","year":"2025","abstract":"Predicting protein dynamics on a molecular level is central to understanding and ultimately controlling the biomolecular machines that govern life. Despite advances in molecular dynamics and AI-based structure prediction, the accurate and efficient simulation of complex self-assembly processes - such as protein aggregation, protein folding, and the dynamics of intrinsically disordered proteins - remains a limitation of most approaches due to system size and sampling limitations. This work presents the development and application of the multi-eGO model, a data-driven, hybrid structure-based approach designed to overcome these barriers. By combining an informative prior with high-resolution structural information or lower-resolution experimental data, the multi-eGO force field learns conformational ensembles across multiple energy minima while maintaining atomistic resolution. Applications include the folding dynamics of protein G and X11-PDZ1-PDZ2, the structural ensemble of amyloid-b42 the aggregation of transthyretin peptides, and the self-assembly of ferritin complexes. Complementary to these studies, conventional molecular dynamics simulations are used to research the effect of electric fields on the dynamics of amyloid b42 fibrils, revealing the potential of electric fields to disrupt assembly and secondary nucleation. Results demonstrate that multi-eGO can reproduce equilibrium, out-of-equilibrium, and kinetic features, and integrate heterogeneous data sources, such as SAXS and PRE NMR data, to refine the model without the need for explicit training. At the same time, limitations such as finite-size effects and kinetic trapping for intermolecular processes highlight the need for further refinement.","language":"eng","citation":"STRUCTURE-BASED APPROACHES TO DATA-DRIVEN PROTEIN FOLDING, AGGREGATION, AND SELF-ASSEMBLY / F. Bacic Toplek ; tutor: C. Camilloni ; coordinatore: S. Ricagno. Dipartimento di Bioscienze, 2025 Nov 24. 38. ciclo","filename":"phd_unimi_R13841.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1198095/3190199/phd_unimi_R13841.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/850186"},"title":"BIOCONTROL STRATEGIES AGAINST PLANT PATHOGENS","internalauthor":"SHAHZAD, GUL I RAYNA","type":"Tesi di dottorato","year":"2021","abstract":"It is a known fact that the whole agriculture system is suffering from the diseases caused by plant pathogens, affecting negatively the crop yield production, food security, biodiversity, agricultural ecosystem and hence agricultural economy. In many countries, the containment strategies of plant pathogens are still depending on chemical pesticides that cause adverse effects in the long term. According to the implementations reinforced by European council 2009/128/EC, biocontrol strategies are considered as the most profound and integrated approach for sustainable disease management. Defining biocontrol in terms of plant pathology, it is the purposeful utilization of beneficial microbes, or its molecules, to suppress phytopathogens’ ability to colonize or induce symptoms in the host. In spite of their lesser shelf-life and unreliability as compared to conventional pesticides, their targeted biological interaction with the phytopathogens reduces the possibility of affecting non-target organisms, environment and the development of resistance in the pathogen.  In this context, exploitation of bacterial endophytes has gained much attention during the past decades. Endophytic plant growth promoting bacteria (ePGPBs) mediate their biocontrol efficacy by targeting species through a multitude of direct or indirect biological interactions, often employing both modes of action, such as plant growth promotion, host’s resistance induction, allelochemicals secretion, and nutrients and niche competition. Another strategy that has gained popularity is the exogenous application of double stranded RNA (dsRNA), which is considered as the key trigger molecule of RNA interreference (RNAi), a post-transcriptional gene silencing mechanism, and has been shown to provide protection without the need for integration of dsRNA-expressing constructs as transgenes.  In the present doctoral thesis, the above-mentioned biocontrol strategies were adapted, utilizing “ePGPBs as microbial inoculants” and “exogenously applied dsRNA as RNAi based natural product”, against several phytopathogens belonging to different families of viruses and fungi.  Regarding ePGBPs as microbial inoculants, the objective of this study was to extend our understanding of five endophytic bacterial strains; Pantoea agglomerans (255-7), Pseudomonas syringae (260-02), Lysinibacillus fusiformis (S4C11), Paraburkholderia fungorum (R8), Paenibacillus pasadenensis (R16); that have shown a promising result in previous studies. In the present doctoral study, these strains were tested in planta to evaluate their role in providing plant growth promotion and broad-spectrum protection against two target pathosystems (viruses and fungi) that might have direct, indirect or simultaneous effects,  proceeded with two following aims: (Aim 1) action against viruses: Cymbidium ringspot virus (CymRSV), Cucumber mosaic virus (CMV), Potato virus X (PVX), and Potato virus Y (PVY) on Nicotiana benthamiana plants, comparing their effects with those of three chitosan-based products, which are known to induce resistance in plants; and (Aim 2) action against fungal pathogens: Rhizoctonia solani, Pythium ultimum and Botrytis cinerea on Lactuca sativa plants, comparing their effects with Bacillus amyloliquefaciens strain (CC2) and Trichoderma spp. based product, under controlled conditions.  To test the priming efficacy of ePGPBs against target viruses, several phenotypic parameters were observed along with the evaluation of three plant defense related genes (EDS1, PR2B and NPR1) on Nicotiana benthamiana plants. Interestingly, the symptoms reduction was successfully registered against CymRSV and CMV with increased heights of the plants. Some of the treatments were shown correlation between severity of symptoms and the virus concentration in the plants. Furthermore, the molecular interaction indicated the involvement of a salicylic acid (SA) mediated defense pathway as evidenced by the increased expression levels of EDS1 gene in strains R16 and 260-02. Whereas, strain S4C11 showed downregulation of PR2B gene, suggesting that SA-independent pathways could be involved. These findings opened queries regarding the duration of the protective effect, host-plant- pathogen interaction, and epidemiological implications of the use of similar biocontrol strains, that reduce the symptoms but not the concentration of virus in the host.  To test the ePGPBs role against target fungi (pre- and post-harvest stage), several experiments were conducted including phenotypic paraments, gene expression analysis (PR1, PAL, ThlP3, ERF1 and ACCS1), microbiota analysis in bulk soil, rhizosphere, and root associated with Lactuca sativa in the presence or absence of the inoculants, and nutritional quality parameters at time of harvest and during shelf-life of Romaine lettuce. The results were accompanied in terms of symptoms reduction by strain R16 (P. ultimum, R. solani, B. cinerea) and strain 260-02 (R. solani, B. cinerea); % seed germination by strains R16, 260-02, 255-7, S4C11 in some healthy and R. solani infected lettuce varieties; inhibition of R. solani population in soil and rhizosphere soil by strains R16, 260-02 and 255-7. Furthermore, composition of the bacterial microbiota was radically different in the rhizosphere and the root endosphere among treatments, while the bulk soil formed a single cluster regardless of treatment, indicating that the use of these treatments did not have an ecological impact outside of the plant. Also, these strains were able to contribute to the maintenance of nutritional quality indexes of lettuce at harvest and during storage. All the obtained results indicated that these    strains were involved directly (via antibiosis) and indirectly (via SA or ET/JA) in the observed reduction of symptoms. Particularly, strain R16 upregulated both PAL and ACCS1 gene in R. solani infected L. sativa (suggesting co-activation of SA- and JA/ ET mediated ISR resistance); strain 260-02 upregulated PAL gene in R. solani infected romaine lettuce and showed higher levels of ascorbic acid (AsA) production in B. cinerea infected romaine lettuce (suggesting the activation of SA- and AsA-mediated antioxidant resistance); and strain 255-7 triggered PAL and ThlP3 gene up-stream expression levels indicating SA mediated pathways in R. solani infected romaine lettuce. These findings affirmed the previous conclusions and added valuable pieces of information regarding the traits these ePGPB carried, most importantly, in individuating different mode of action of the different strains in different host plants with or without the presence of pathogen.  Regarding the second approach, non-transgenic strategy was employed to induce resistance against Tomato Aspermy Virus (TAV) in N. benthamiana plants. DsRNA molecules for coat protein (CP) gene was produced by a two-step PCR assay followed by in vitro transcription and purification and was exogenously applied. The implementation of CP-derived dsRNA TAV was not successful in reducing observed symptoms (mosaics, blisters, crinkling, leaf distortion, and systemic vein clearing), regardless of treatments or days of post inoculation. Only a slight difference was found in plant heights indicating that the treatment managed to reduce stunted growth of the plant at dilution 01:10 (6 and 12 dpi). The reasons could involve inappropriate concentration of dsRNA inoculum. Therefore, future studies will be conducted to optimize in vitro dsRNA molecules production to obtain higher concentrations or more specific sequences, and more suitable viral genes.  Both strategies have shown interesting outcomes and gave us the future direction which will help us in designing the adequate trials (in planta or semi-field) for the disease management and diseases control through the application of ePGPBs as a microbial inoculants and dsRNA-based product individually or in combination.","language":"eng","citation":"BIOCONTROL STRATEGIES AGAINST PLANT PATHOGENS / G.i.r. Shahzad ; tutor: P. Casati ; coordinatore: D. Bassi. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2021 Jun 14. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11928.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/850186/1820783/phd_unimi_R11928.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1038194"},"title":"CROSSTALK BETWEEN TUMOUR VASCULATURE AND OVARIAN CANCER STEM CELLS: THE ROLE OF L1CAM.","internalauthor":"BARONIO, MICOL","type":"Tesi di dottorato","year":"2024","abstract":"Ovarian cancer is the most lethal gynaecologic tumour, mainly due to relapse and chemoresistance, two events fuelled by ovarian cancer stem cells (OCSC). The tumour microenvironment (TME) is thought to act as a niche for OCSC, preserving stem cells properties and sustaining tumour recurrence. The crosstalk between TME and OCSC, therefore, offers a source of new targets and mechanisms to overcome the limitations of current treatments. We identified L1CAM, an adhesion glycoprotein, expressed both in tumour endothelium and epithelial cancer cells, as a mediator of the interaction between the vascular TME (vTME) and OCSC. L1CAM expression correlates with metastatic spread and poor outcome, because of its ability to induce cancer proliferation and chemoresistance, together with the increase of vessels permeability and neo-angiogenesis. Notably, endothelial cells express a new isoform of L1CAM (L1-ΔTM), that is released as a soluble factor. We found that endothelial L1-ΔTM enhances stem-like properties in OCSC, a process mediated by IL6/JAK2/STAT3 signalling axis. Furthermore, the RNA-sequencing analysis revealed that L1-ΔTM confers a proinflammatory phenotype on OCSC, able to support cancer initiation, proliferation and progression. Moreover, I have setup a perivascular niche-on-chip confirming the capability of L1-ΔTM-expressing vessels to foster proliferation and spreading in the tumoral compartment. Our approach highlights L1-ΔTM as a druggable target in the crosstalk between vTME and OCSC. Indeed, our findings could provide the rationale for exploring novel L1CAM-based therapeutic approaches aimed at the eradication of OC through the elimination of its stem cell compartment.","language":"eng","citation":"CROSSTALK BETWEEN TUMOUR VASCULATURE AND OVARIAN CANCER STEM CELLS: THE ROLE OF L1CAM / M. Baronio ; supervisor: U. Cavallaro ; internal advisor: G. Scita ; phd coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2024 Apr 11. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12768.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1038194/2380880/phd_unimi_R12768.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/917092"},"title":"EPIGENETIC CHARACTERIZATION OF TUMOR INFILTRATING CD4+ T REGULATORY CELLS","internalauthor":"BASON, RAMONA","type":"Tesi di dottorato","year":"2022","abstract":"In recent years, the role of CD4+ regulatory T cells (Treg cells) in inhibiting the anti cancer activity of effector T cells has become increasingly evident and they are therefore currently considered promising targets for cancer immunotherapy. Despite Treg cell depletion has been reported to increase anti-tumor specific immune responses and to reduce tumor burden, some relevant issues still remain to be addressed, for a safer, more effective clinical application of these therapies.  Previous findings in our lab identified unique transcriptional profiles of human Treg cells infiltrating colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) supporting the existence of an underlying regulatory hubs that specifically shape tumor Treg identity and represent potential target for their functional modulation specificially in the tumor microenvironment.  Treg cell transcriptome represents just a layer of the machinery that drive the acquisition of their tumor cell state. Ultimately, a comprehensive understanding of the regulatory networks that govern tumor Treg gene expression programs can provide insights on how a more selective inhibition can be achieved by interfering with the hubs that translate the cues coming from the tumor microenvironment.  To define the epigenetic blueprints specific for tumor infiltrating Treg cells we have integrated distinct histone marks (H3K4me3, H3K4me1, H3K36me3, H3K27ac, H3K27me3) with ATAC-seq derived chromatin accessibility data we generated in Treg cells isolated from peripheral blood, normal and tumor tissues. To infer genome chromatin states we have employed ChromHMM a machine learning based approach that predicts the molecular structure of promoters and enhancers based on data from chromatin accessibility assays and a set of histone modification. We focused in particular on active enhancer regions, characterized by the co-presence of H3K27Ac and H3K4me1. Transcription factor footprinting analysis on the identified regulatory regions showed TF groups with distinct binding activity profile across Treg populations that are clearly lost or gained specifically in tumor Treg cells. Based on our findings we are implementing CRISPR based epigenetic modulation of selected enhancers that represent a novel strategy to reverse Treg mediated immunosuppression in the tumor microenvironment.  The new knowledge coming from this project cues will lead to a better understanding of tiTreg plasticity and to the identification of novel potential targets that can guide the rational development of tiTreg reprograming and innovative therapeutics for cancer with increased efficacy and reduced adverse effects.","language":"eng","citation":"EPIGENETIC CHARACTERIZATION OF TUMOR INFILTRATING CD4+ T REGULATORY CELLS / R. Bason ; tutor: M.Pagani ; supervisor: G.Rossetti ; director: N. Landsberger. Università degli Studi di Milano, 2022 Apr 21. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12321.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/917092/2004546/phd_unimi_R12321.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/842501"},"title":"HETEROGENEITY OF DUODENAL NEUROENDOCRINE TUMORS: NATURAL HISTORY AND PROGNOSTIC FACTORS IN A LARGE COHORT PROSPECTIVELY FOLLOWED-UP","internalauthor":"ROSSI, ROBERTA ELISA","type":"Tesi di dottorato","year":"2021","abstract":"Background and aims. The natural history, clinical characteristics and optimal management of duodenal neuroendocrine neoplasms (dNENs) are unclear. Present multicenter study was aimed at analyzing the natural history of patients with dNENs. The secondary goal was to evaluate the overall (OS) and progression-free survival (PFS), according to the histological features, stage at initial diagnosis, and other possible prognostic parameters.  Methods. This is a retrospective analysis of patients with histologically confirmed diagnosis of dNENs, managed at five Italian tertiary referral Centers in Italy.  Results. From 2000 to 2017, 108 patients were included in this study. Seventy-one patients had G1, 21 G2, 4 G3 dNENs (12 Ki-67 not available). Fifty-four patients showed metastases at diagnosis, and 20 patients developed metachronous metastases. Thirty patients had a functioning dNEN (14 metastatic). Fifty-seven patients had the dNEN surgically resected, 16 endoscopically, 23 metastatic, received medical therapy + surgery or endoscopy. Seven patients underwent liver-directed therapies, and one patient had PRRT. Median OS was 187 months. During a median follow-up of 76 months, 20 patients died (19 of disease-related causes). At Cox’s multivariate proportional hazard regression, grading and age were the only variables independently related to OS. Median PFS was 170 months. Grading and staging at the initial diagnosis were independently related to PFS. No differences in terms of OS and PFS were observed between patients treated surgically or endoscopically.  Conclusions. dNENs prognosis may be highly variable. These tumors can be metastatic in up to 50% of cases at the time of first diagnosis and can develop metastases thereafter. Functioning neoplasms express high metastatic potential. Nuclear imaging should be performed to exclude distant metastases in all dNENs. Endoscopy and surgery play a primary role in the management of the disease. Further prospective studies are needed.","language":"eng","citation":"HETEROGENEITY OF DUODENAL NEUROENDOCRINE TUMORS: NATURAL HISTORY AND PROGNOSTIC FACTORS IN A LARGE COHORT PROSPECTIVELY FOLLOWED-UP / R.e. Rossi ; tutor: M. Vecchi ; coordinatore: E. Berti. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2021 May 14. 33. ciclo, Anno Accademico 2020. [10.13130/rossi-roberta-elisa_phd2021-05-14].","filename":"phd_unimi_R11840.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/842501/1797232/phd_unimi_R11840.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/947210"},"title":"PROBING BAND MAGNETISM IN DIFFERENT DIMENSIONS: ENERGY, SPIN AND TIME-RESOLVED STUDIES","internalauthor":"DE VITA, ALESSANDRO","type":"Tesi di dottorato","year":"2022","abstract":"This thesis completes my work as doctoral student of the Scuola di Dottorato in Fisica, Astrofisica e Fisica Applicata at the Università degli Studi di Milano, that has been carried out since November 2019 at the Istituto Officina dei Materiali of the Consiglio Nazionale delle Ricerche (IOM-CNR) in the premises of the Elettra - Sincrotrone Trieste and FERMI@Elettra infrastructures and in the framework of the NFFA facility.  My experimental activity employed complementary spectroscopy and polarimetry techniques oriented to address the characterisation of electronic and spin properties of systems with decreasing dimensionality. This programme has been conducted by exploiting state-of-the-art infrastructures to generate visible, UV and EUV ultrashort pulses (tabletop lasers and HHG at NFFA-SPRINT laboratory) and soft X-ray synchrotron light (at Elettra, Diamond and ESRF synchrotron light sources).  I used photoemission as the main tool in my investigation, supplementing my results with absorption spectroscopy. I focused on three materials, Fe(001)-p(1x1)O/MgO(001), EuSn2P2 and VI3, of high interest in modern and next-generation magnetic devices.  In the three systems I studied the electronic band structure to identify key features hinting at the bound electrons behaviour. I investigated the properties of the magnetically ordered phases and found evidence of the reduced dimensionality in the emergence of atypical spin ordering and the increasingly manifest electron correlation phenomena. The information retained by band electrons is critical to access the spin polarisation of the bands and to give insight into the effects of spatial confinement on the spin degree of freedom.","language":"eng","citation":"PROBING BAND MAGNETISM IN DIFFERENT DIMENSIONS: ENERGY, SPIN AND TIME-RESOLVED STUDIES / A. De Vita ; tutor: G. Rossi, G. Panaccione ; coordinatore: M. Paris. Dipartimento di Fisica Aldo Pontremoli, 2022 Dec 02. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12675.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/947210/2104958/phd_unimi_R12675.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1003368"},"title":"DISSECTING THE INTERACTION OF a-SYNUCLEIN WITH TUBULIN/MICROTUBULES","internalauthor":"KOTHUIS, JOSINE MARIE","type":"Tesi di dottorato","year":"2023","abstract":"Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation and misfolding of α-synuclein. Remarkably, PD is even the fastest-growing neurological disorder; by 2040, the number of PD patients worldwide is expected to exceed 12 million. Despite tremendous scientific research and financial investments in PD, a cure for this devastating disorder remains elusive. Therefore, a better understanding of the biological mechanisms involved in PD is crucial for the discovery of disease-modifying therapies. Here, we focus on the interaction between α-synuclein and tubulin/microtubules and its potential role in neurodegeneration. Under physiological conditions, α-synuclein is proposed to function as a so-called microtubule dynamase, by interacting with tubulin α2β2 tetramer and promoting both microtubule growth rate and catastrophe frequency in vitro. However, the interaction of PD-associated α-synuclein mutations with tubulin, and its role in PD pathogenesis has not been fully elucidated yet. In this work, we report, for the first time, that tubulin directly interacts with various PD-related α-synuclein variants and diminishes tubulin polymerization in cell-free systems. Moreover, α- synuclein aggregation is reduced in the presence of purified tubulin, suggesting that tubulin could modulate α-synuclein pathology by inhibiting its aggregation through its interaction with α-synuclein. An advanced live-cell imaging approach in a cellular model demonstrated that α- synuclein does not impact microtubule dynamics in axon-like processes. Interestingly, the expression of α-synuclein-A53T, one of the most aggregation-prone PD-related α-synuclein mutations, reduced the velocity and processivity of APP-vesicle transport along microtubules in neuronally differentiated cells. Remarkably, we disclosed that treatment with an α-synuclein aggregation inhibitor can rescue these deficits in axonal transport, suggesting that α-synuclein inclusions impact vesicle transport. In addition, we present a novel α-synuclein aggregation inhibitor that effectively inhibits α-synuclein oligomeric species in cells, which could potentially function as a disease-modifying therapeutical drug in PD. To conclude, in this study we emphasize the importance of the α-synuclein/tubulin interaction, which directly or indirectly may play a major role in neurodegeneration.","language":"eng","citation":"DISSECTING THE INTERACTION OF a-SYNUCLEIN WITH TUBULIN/MICROTUBULES / J.m. Kothuis ; tutor: G. CAPPELLETTI ; co-tutor: R. BRANDT. Dipartimento di Bioscienze, 2023 Sep 22. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12789.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1003368/2290529/phd_unimi_R12789.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/956986"},"title":"THE 2019 EP ELECTION CAMPAIGN AS SEEN FROM TWITTER","internalauthor":"PAGANO, GIOVANNI","type":"Tesi di dottorato","year":"2022","abstract":"\"The end of May 2019 saw European citizens go to the polls to choose a new   European Parliament (EP). These elections marked a crucial moment for European democracy, as they took place in a context of significant challenges and upheavals, including the aftermath of the economic and financial crisis that had impacted the EU in the preceding decade, the refugee crisis that had tested the EU's capacity to manage migration and asylum, and the departure of the United Kingdom from the EU. These events had far-reaching implications for the political landscape of the EU, and the election campaign was shaped by the issues and concerns that they raised, as well as the parties and candidates who sought to address them. Against this backdrop, the 2019 EP election campaign was marked by a high degree of contentiousness and uncertainty, with many parties and candidates seeking to position themselves in response to the shifting political and economic landscape    Moreover, the 2019 EP election campaign was characterized by the significant role of social media in political communication, a phenomenon that had not been as prominent in previous campaigns. This transformation was due to the widespread dissemination of digital communication technologies, which had granted European citizens unprecedented access to information and new opportunities for political participation. As a result, political parties and politicians have greatly increased the number of available communication channels in order to disseminate information online and mobilize party members and supporters, making the use of social media a critical aspect of election campaign activity. Virtually every political party in Europe had a presence on social media, highlighting the importance of these platforms in modern-day political communication. The literature has recognized the significance of social media in shaping the outcome of election campaigns and has examined its role in creating new opportunities for political participation, promoting transparency and responsiveness between citizens and their representatives.    An online election campaign offers a “window of opportunity” where behaviors and interactions between parties, candidates and citizens can be observed in condensed form. In the case of European Parliament elections, the view can embrace 28 different countries simultaneously in the same campaign context and in the same digital arena. Despite its many promises however the online dimension of EP campaigns is still relatively understudied.     In this dissertation I present three distinct studies, each addressing a different   dimension of the multifaceted and complex phenomenon of the 2019 EP online campaign.    In the first chapter I examine the role of candidates and parties in online election campaigns, given the increasing importance of social media platforms. Specifically, the study investigates the prevalence of Twitter usage among candidates for the 2019 European Parliament election, as well as the factors that influence adoption and use of the platform. The study takes a comparative approach, analyzing data from all 28 member states of the European Union, and it aims to contribute to the ongoing “equalization vs.   normalization” debate on the impact of social media on election campaigns. In particular, I investigate whether social media can be viewed as a force that equalizes the resource gaps between candidates and parties, or its use is being normalized into the EP campaign. To accomplish this, the study considers both individual-level and party-level factors that may influence Twitter adoption and use during the EP 2019 campaign.    Chapter 2 investigates the dynamic nature of online communication between European Parliament (EP) candidates and their audiences during the 2019 EP campaign in the five largest Western European countries: France, Germany, Italy, Spain, and the United Kingdom. The study uses online communication data from both candidates and regular users to investigate the question of \"\"who leads whom\"\" in the communication process. Drawing on the literature on competing principals, the study explores who the \"\"principal\"\" is in the online communication between candidates and their audiences.  Rather than relying on self-reported policy positions or roll-call votes, the study proposes a text-based measure at the level of individual tweets to determine the distance between the positions of political elites and those of their audience. The measure is then used to assess the extent to which EP candidates and Members of the European Parliament (MEPs) are faced with competing pressures from their audience, their party, and their EP group.  The findings of the study contribute to the literature at the intersection of EU studies and legislative studies that focuses on the role of MEPs as agents with multiple principals. Additionally, the study contributes to the debate on the potential of social media to promote responsiveness and transparency between citizens and their representatives.    In Chapter 3, the focus shifts towards the audience of the Twitter campaign, analyzing how the public reacts to campaign content by examining the replies to candidates' Twitter messages. A significant concern in recent years has been the rise in animosity and hostility across partisan lines, which has developed in parallel with the changes in media environments. The investigation covers campaign communication originated by the candidates of four EU member states: France, Italy, Spain, and the United Kingdom. The study addresses how interactions between candidates and the public might fuel reinforcing spirals of polarization dynamics along partisan lines, highlighting patterns of affective polarization in the context of the EP 2019 election campaign.  Research on affective polarization has typically relied on survey questionnaires or experimental settings to measure partisan animosity and positive partisanship. However, most existing studies lack a comparative perspective and tend to focus on the mass level, thereby neglecting the crucial aspect of the interaction between citizens and political elites. To address these gaps, the study leverages behavioral data from Twitter to test how citizens react to elite messages in the context of an election campaign. A text-as-data approach is developed to analyze Twitter communication from more than 350,000 Twitter users, collected as they interact with hundreds of political candidates in the four countries. This measure is then used to unpack the mechanisms behind affective polarization and to shed light on its main drivers.\"","language":"eng","citation":"THE 2019 EP ELECTION CAMPAIGN AS SEEN FROM TWITTER / G. Pagano ; supervisor: L. CURINI; direttore PhD: M. Jessoula. Dipartimento di Scienze Sociali e Politiche, 2022 Oct 25. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12340.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open from 01-GEN-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/946529"},"title":"HYBRID DEEP LEARNING AND RADIOMICS MODELS FOR ASSESSMENT OF CLINICALLY RELEVANT PROSTATE CANCER","internalauthor":"ISAKSSON, LARS JOHANNES","type":"Tesi di dottorato","year":"2022","abstract":"Precision medicine holds the potential to revolutionize healthcare by providing every patient with personalized treatments and decisions tailored to his or her individual needs. This might be enabled by the large influx of potentially diagnostic information from new sources such as genetics and modern imaging techniques, provided the relevant information can be extracted. One such framework that has started to demonstrate promise in radiology, especially in the assessment of cancer, is radiomics; the practice of characterizing images by extracting a substantial amount of quantitative mathematical descriptors. This success has largely been enabled by artificial intelligence (AI) and machine learning developments that are capable of handling the big data arrays. Using radiomics, researchers have been able to build prediction models capable of assisting and informing doctors in important decisions such as risk assessment or the choice of treatment. But even though radiomics has shown promise in preliminary studies, there is still a long way to go before radiomics and related AI applications can become routine tools in clinics. The road from patient admission to release is long, and all its intricate steps need to be studied in detail to establish the AI models' benefits and safety.       Deep learning is an incredibly powerful AI technique that has revolutionized many areas of science and industry such as recommender systems and protein folding. The technique has demonstrated particular capabilities in image analysis, such as the ability to drive cars autonomously and generate realistic-looking images from scratch. However, the recent advances in deep learning have largely been segregated from the radiomics domain, even though they can synergize with radiomics by performing complementary tasks such as image segmentation and denoising. There is considerable potential for DL and radiomics to cooperatively reinforce each other that so far has been majorly unexplored.      This thesis investigates the application of radiomics and deep learning in the context of prostate cancer. It focuses on the clinical perspective of where machine learning implementations are most likely to have a beneficial real-world impact. A key contribution is the deployment aspect: the models are not simply proofs of concept but are conceived and applied in a practical scenario, from patient admission to treatment decision. The specific areas studied include automatic organ segmentation in medical images, automatic quality assurance of segmentations, image processing, and radiomic feature analysis. Finally, a comprehensive study is performed on predicting essential pathological variables with AI, which so far has not been studied previously. Taken together, the methods outlined in this thesis constitute a concrete pathway of how AI can be used to bolster the steps along the patient's clinical trajectory. Successful applications of these methods hold the potential to reduce the workload of clinicians and improve patient outcomes.","language":"eng","citation":"HYBRID DEEP LEARNING AND RADIOMICS MODELS FOR ASSESSMENT OF CLINICALLY RELEVANT PROSTATE CANCER / L.j. Isaksson ; internal advisor: S. Gandini ; external advisor: A. Bhalerao ; phd coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2022 Dec 16. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12392.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/946529/2101308/phd_unimi_R12392.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1233218"},"title":"DESIGN AND DEVELOPMENT OF RNA-BASED DRUGS USING MOLECULAR DYNAMICS SIMULATIONS AND ARTIFICIAL INTELLIGENCE METHODS","internalauthor":"ALBANI, MARCO","type":"Tesi di dottorato","year":"2026","abstract":"RNA-based therapeutics represent a powerful class of drugs offering precise targeting for genetic disorders, cancer, and infectious diseases. Several RNA-based modalities have been developed, including messenger RNAs (mRNAs), small interfering RNAs (siRNAs), microRNAs (miRNAs), antisense oligonucleotides (ASOs), circular RNAs (circRNAs), and aptamers. Despite their significant potential, these therapeutics face important limitations, including susceptibility to RNase degradation, high net negative charge, and rapid renal clearance. To address these challenges, advanced chemical modifications, such as Xeno Nucleic Acids (XNAs) and 2-OH modifications, along with specialized delivery systems, including viral vectors and lipid nanoparticles (LNPs), have been introduced.  The design of these advanced ligands increasingly relies on computational approaches, including structure-based drug design (SBDD), molecular dynamics (MD) simulations, and machine learning (ML). This thesis presents a comprehensive in silico framework for the design and optimization of nucleic acid therapeutics targeting three distinct systems.  First, autophagy inhibition was pursued by targeting the LC3B RNA-binding motif using novel Peptide Nucleic Acids (PNAs) to disrupt cancer cell survival mechanisms. Second, XNA sequences were optimized to target the DNA-binding domain of the oncogenic protein HMGB1. Third, aptamers were designed to bind the CD4-binding site of the HIV-1 envelope glycoprotein GP120, thereby blocking viral entry.  All projects followed a multi-step computational and experimental pipeline. Protein structures retrieved from the Protein Data Bank (PDB) were prepared and used for docking studies to identify ligand binding sites. Subsequently, MD simulations were performed to evaluate the stability of ligand–target complexes, and binding free energies were estimated using MM/GBSA methods. Additionally, an Active Learning (AL) model was developed to analyze multi-dimensional (1D–4D) molecular descriptors for ligands targeting LC3B. This workflow was adapted and optimized for each target system.  The results demonstrate that targeting the LC3B RNA-binding motif can disrupt LC3B–mRNA interactions, preventing lysosome-mediated degradation of tumor suppressors such as PRMT1 and limiting cancer cell survival. Microscale thermophoresis (MST) experiments on the PNA ligand AATAAA revealed a dissociation constant in the low nanomolar range. For HMGB1, sequence optimization of the initial ATAG motif led to a twofold improvement in predicted binding affinity. The lead Tyr2 analog of GAGG-opt exhibited a binding free energy of –149.3 ± 6.3 kcal/mol and a Kd of 26.9 ± 1.36 µM against the HMGB1 A-box domain. In the HIV-1 system, the designed aptamers targeting the GP120 CD4-binding site highlighted the critical role of sequence length and composition in achieving high affinity. Furthermore, glycan interactions were essential for aptamer stability, and backbone optimization was strongly dependent on both sequence and folding.  In conclusion, this work demonstrates that the integration of computational chemistry, machine learning, and experimental validation provides an effective strategy for the rational design of nucleic acid therapeutics targeting complex biological systems.","language":"eng","citation":"DESIGN AND DEVELOPMENT OF RNA-BASED DRUGS USING MOLECULAR DYNAMICS SIMULATIONS AND ARTIFICIAL INTELLIGENCE METHODS / M. Albani ; tutor: G. Grazioso, G. Roda ; coordinatore: G. Vistoli. Dipartimento di Scienze Farmaceutiche, 2026 Apr 17. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R14147.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1233218/3299280/phd_unimi_R14147.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/869186"},"title":"APPROCCIO INTEGRATO ALLO STUDIO DEL GLAUCOMA: DALLA CLINICA ALL'INDAGINE BIOCHIMICO-MOLECOLARE","internalauthor":"FARCI, ROBERTA","type":"Tesi di dottorato","year":"2021","abstract":"\"Glaucoma is a neurodegenerative disease caused by ganglion cells death by apoptosis. It represents the leading cause of irreversible blindness in the world. Although the mechanisms triggering the neuronal degeneration in glaucoma have not yet been fully understood, a chronic inflammatory condition at the retinal level, sustained by abnormal IOP, is considered today a main factor in glaucoma pathogenesis.  The aim of this PhD project was a multidisciplinary approach to glaucoma investigation, both clinical and bio-molecular.   Firstly, a prototype of visual field analyzer (Compass, Centervue, Padua, Italy) was implemented, primarily by developing a demographic database of healthy subjects for 30-2 perimetric test.  Subsequently, the test-retest reliability of the device was assessed by performing the \"\"New Grid\"\" visual field six straight times in a group of patients clustered according to the MD, resulting in a good inter-test reliability. The agreement between three different reviewers was also calculated: they independently examined Compass visual fields and the fundus photos, establishing whether or not the glaucomatous pathology worsened, as well as the agreement between the remote analysis and the standard clinical visit of glaucoma patients. The results highlighted an excellent agreement among the Reviewers and between remote analysis and the clinical examination.   In order to establish the Compass’ point-by-point accuracy, a 10-2 visual field was performed in patients affected by geographic atrophy, finding an accurate correspondence of the perimetric scores with the underlying retinal image.  Ultimately, the osmometry and all the clinical parameters of the tear film were analyzed in patients suffering from asymmetric glaucoma.   Afterwards, for the biochemical and molecular approach, the analysis of gap-junction protein connexin 43 in the aqueous humor of affected and unaffected glaucoma patients was performed: a nearly double expression of the protein was found in glaucomatous subjects, even if there were no statistically significant differences, probably due to the small number of samples.    An innovative method of biochemical analysis was introduced in this doctorate thesis: the metabolomics, a scientific branch that deals with the analysis of <1.5 kDa metabolites deriving from specific cellular processes in human samples. Vitreous samples of patients operated by vitrectomy were analyzed by 1H-NMR Nuclear Magnetic Resonance Spectroscopy, and an increase in acetone and methanol was observed in glaucomatous eyes.\"","language":"ita","citation":"APPROCCIO INTEGRATO ALLO STUDIO DEL GLAUCOMA: DALLA CLINICA ALL'INDAGINE BIOCHIMICO-MOLECOLARE / R. Farci ; CURATORE E SUPERVISORE DELLA TESI:  M. FOSSARELLO (UNIVERSITA DEGLI STUDI DI CAGLIARI) CURATORE: C. BATTAGLIA CURATORE:  A. RATTI COORDINATORE DEL DOTTORATO: M. SAMAJA. Dipartimento di Scienze della Salute, 2021 Oct 07. 33. ciclo, Anno Accademico 2020. [10.13130/farci-roberta_phd2021-10-07].","filename":"phd_unimi_R11922.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/869186/1872086/phd_unimi_R11922.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1165835"},"title":"ECO-FRIENDLY HYDROXYAPATITE-BASED MATERIALS AS METAL ADSORBENTS: OPTIMIZATION OF SURFACE PROPERTIES FOR WATER AND WASTEWATER REMEDIATION","internalauthor":"AVOLA, TIZIANA","type":"Tesi di dottorato","year":"2025","abstract":"Water protection is a global priority due to its critical role in human health and environmental sustainability. One of the 17 United Nations Sustainable Development Goals (SDGs) focuses on clean water and sanitation, with a key target of improving water quality by reducing pollution and limiting the release of hazardous chemicals.  This doctoral dissertation, conducted in collaboration with the national water management company A2A, addresses the challenge of water pollution by focusing on hexavalent chromium (Cr(VI)) contamination – an environmental hazard known for its high toxicity even at low concentrations. Among available remediation techniques, reductive adsorption is gaining attention as it combines both reduction and adsorption into a single process, necessitating the development of tailored adsorbent materials.  The aim of this work is to design and develop tin-modified calcium phosphate-based adsorbents for the removal of Cr(VI). Two distinct synthetic approaches were employed, yielding two different materials: (i) Sn-modified hydroxyapatite (Sn/HAP) – prepared by surface deposition of tin species on preformed hydroxyapatite – and (ii) tin-enriched calcium phosphate (Sn-CaP) – prepared by a one-pot co-precipitation. A comprehensive characterization study using XRPD, N2 adsorption/desorption isotherms, XPS, 119Sn Mӧssbauer spectroscopy, TEM, and HAADF-STEM/EDS provided insights into tin speciation, structural composition, and morphological features, revealing structural differences between the materials. Sn/HAP was found to be crystalline, indicating that Sn surface deposition did not alter the crystalline structure of HAP. In contrast, the one-pot synthesis strategy resulted in a multiphasic material (Sn-CaP), which contained both amorphous and crystalline phases, specifically amorphous calcium phosphate, hydroromarchite (Sn6O4(OH)4), and cassiterite (SnO2).  Despite their structural differences, both adsorbents proved to be efficient in the reductive adsorption of Cr(VI), underlining the crucial role of tin species. In particular, the oxidation state of Sn was found to be a key factor, with Sn2+ playing a pivotal role in the reductive adsorption process. Remarkably, the adsorbents maintained their Cr(VI) removal efficiency even in the presence of competing ions, highlighting their potential for real-world water treatment applications.  In addition to Cr(VI) removal, this thesis explored strategies for the valorization of spent adsorbents, including recycling and upcycling approaches. Notably, spent Sn-CaP was successfully repurposed as a catalyst for environmental gas-phase reactions. Specifically, the upcycled catalyst exhibited moderate activity in the oxidation of NO to NO2, a key reaction in NOx abatement. This finding underscored the potential for circular economy applications by transforming spent adsorbents into functional materials for environmental use.  Overall, this dissertation advances current water treatment strategies by demonstrating the feasibility of Sn-modified calcium phosphate adsorbents for treating Cr(VI)-contaminated water, even in complex matrices. Furthermore, the successful upcycling of spent adsorbents into catalysts aligns with sustainability principles, offering a promising route for waste valorization in environmental applications.","language":"eng","citation":"ECO-FRIENDLY HYDROXYAPATITE-BASED MATERIALS AS METAL ADSORBENTS: OPTIMIZATION OF SURFACE PROPERTIES FOR WATER AND WASTEWATER REMEDIATION / T. Avola ; tutor: A. Gervasini ;  co-tutor: S. Campisi, L. Ferruti coordinatore: L. Prati. Dipartimento di Chimica, 2025 May 30. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13625.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1165835/3075169/phd_unimi_R13625.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/958477"},"title":"THE METHIONINE CYCLE AS A NOVEL THERAPEUTIC TARGET IN NPM1C DRIVEN ACUTE MYELOID LEUKEMIA","internalauthor":"POLAZZI, ANDREA","type":"Tesi di dottorato","year":"2023","abstract":"Acute myeloid leukemia (AML) is the most common leukemia in adults and its prognosis is usually poor. Patients are still treated with conventional chemotherapy, which induces disease cure in <40% of patients. The main culprit of therapy failure is the genomic and biological heterogeneity of the disease and the lack of specific targeting-approaches. NPM1 is the most frequently mutated gene in AMLs (~30% of cases). Though the role of the NPM1 mutation (NPM1c) in the maintenance of the leukemic state is well characterized, little is known about underlying molecular mechanisms of oncogenesis. Most notably, the mutation causes an aberrant cytoplasmic localization of the protein, which is otherwise a nucleus-cytoplasmic protein mainly localized in the nucleolus and in the nucleoplasm.  Unpublished data generated in our lab have shown that ectopic expression of NPM1c in Murine Embryonic Fibroblasts (MEFs) leads to an unbalanced methionine-cycle with decreased ratio between S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), key metabolites of the methionine cycle. Decreased SAM/SAH ratio is known to inhibit cellular methyltransferases activity. Consistently, the majority of NPM1c regulated genes (e.g. HoxA cluster) and enhancers in MEF cells result markedly hypomethylated and overexpressed or active, respectively.  Here, we show that SAM exogenous supplementation in NPM1c-MEF cells increases DNA methylation at specific loci and reverts significantly expression and activity of NPM1c-targeted promoters and enhancers. We then investigated the effects of SAM supplementation in NPM1c-AML blasts, and demonstrated that SAM reverts the NPM1c transcriptional signature, promotes monocytic differentiation and cell death in vitro and inhibits AML growth in vivo, suggesting that restoration of a physiological SAM/SAH ratio reverts the malignant phenotype of NPM1c-AMLs. Using engineered AML cells that allow degradation of NPM1c or its ectopic expression, we demonstrated that NPM1c is directly responsible for: i) the cytoplasmic mis-localization of Methionine Adenosyltransferase 2A (MAT2A), the key enzyme that catalyzes SAM production, leading to SAM/SAH ratio unbalance; ii) the SAM/SAH ratio unbalancing; and iii) the sensitivity to SAM treatment. To explore alternative approaches to increase the SAM/SAH ratio,  we used Metformin, known to activate adenosylhomocysteinase (SAHH) and reduce SAH levels, and showed that it synergizes with SAM, inhibits growth and promotes monocytic differentiation of NPM1c-AML growth in vitro.  In summary, in this PhD project, we demonstrate that the SAM/SAH unbalance is at the basis of the NPM1c-dependency of AML blasts, thus paving the way for the therapeutic use of SAM as specific targeting approach in NPM1c-AMLs.","language":"eng","citation":"THE METHIONINE CYCLE AS A NOVEL THERAPEUTIC TARGET IN NPM1C DRIVEN ACUTE MYELOID LEUKEMIA / A. Polazzi ; tutor: P. G. Pelicci ; co-tutor: E. Colombo. Dipartimento di Oncologia ed Emato-Oncologia, 2023 Apr 13. 34. ciclo","filename":"phd_unimi_R12382.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/958477/2159967/phd_unimi_R12382.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/828194"},"title":"L¿ANNESSIONE DELLA CRIMEA ALLA FEDERAZIONE RUSSA NELLE PAROLE DELLA STAMPA. PRATICHE DISCORSIVE E COSTRUZIONE DELL¿IDENTITÀ NAZIONALE","internalauthor":"VOLPI, FRANCESCA","type":"Tesi di dottorato","year":"2021","abstract":"The mass media play a central role in contemporary societies, being the news a fundamental actor in shaping our identities as citizens and our worldviews. Through the stories and representations built by journalists, public opinion produces and reproduces a shared cognition of reality.  The main argument of this doctoral thesis is Crimea’s annexation to the Russian Federation as it was represented by some of the prominent Russian national newspapers. Crimea became a Russian republic in March 2014 following a bitterly contested by the international community referendum, which generated a crisis in relations between Russia and the West still far away from being resolved.  The aim of the thesis is two-fold. The first one is to analyze the narrative and linguistic strategies through which discourses of the annexation, along with their cultural and ideological implicatures, have circulated through the print media. The second goal is to verify whether and to what extent it is possible to identify alternative and competing narratives in the Russian press. To the purpose, a corpus of texts has specifically been prepared. The corpus consists of one hundred and eighty news and commentary articles retrieved from six national newspapers. The newspapers selection was based on popularity and circulation criteria. The analysis involves three dimensions: the representation of national identity, the representation of social actors and the representation of reported speech.   The methodology adopted draws from Critical Discourse Analysis, Discourse Historical Approach and the model for the representation of social actors developed by Theo van Leeuwen (1996).  Overall, a considerable degree of uniformity characterizes the newspapers analyzed. Due to their loyalty to the Kremlin, Izvestija, Rossijskaja Gazeta, Komsomol’skaja Pravda, and – to some extent – Kommersant ‘’ reproduced or even anticipated, the discourses circulated by the political elite. Novaya Gazeta and Vedomosti take a different line, albeit with distinct nuances, consistent with their ideological position as part of the so-called systemic opposition.   Regarding the representation of national identity, the whole discourse was built on the polarization between the Russian nation and an external enemy, namely all those who do not recognize Russia the status of a ‘Great Nation’. In this ‘Great Nation’ conceptualization, a foreground position is given to ethnic belonging, which is made to coincide with linguistic identity. The discursive strategies employed by journalists can be summarized as follows: emphasis on the difference between ‘us’ and ‘them’, emphasis on the alleged historical similarity between the present time and the Second World War, black and white description of the enemy, delegitimization of the Ukrainian state, shift of blame and responsibility by reversing the victim/culprit scheme.  Concerning the second dimension – the representation of social actors – the strategies and narrative schemes adopted in no small extent duplicate the representation of the national identity. The discourse is articulated around an intense polarization between an in-group, namely the ethnic Russians, and an out-group, namely all the rest. An example of such polarization is the use of epithets drawing from the memory of the WWII – in particular banderovcy, and opolcency -, to leverage the emotional sphere of public opinion and to exclude from the discourse any possible articulated positions, distinctions, or identities that eschew binary representation.  The third analytical dimension has highlighted to what extent reported speech constitutes a significant issue in many texts. The preferred tendency is that of direct quotation, isolated from the text by graphic signs such as quotation marks or hyphens. A second element is the tendency to favour neutral verba dicendi to introduce speakers’ utterances: zajavit ‘, skazat’, ob’jasnit’ are those that appear to have the most significant number of occurrences. The reason for that is two-fold. Firstly, the need to give the article a tone of objectivity and, at the same time, drama, especially in cases where words with a strong emotional connotation, spoken by ordinary citizens who participate in the events are reported. The second reason – more relevant – is connected to the argumentative function that journalists attribute to reported speech in their articles.  In conclusion, the research has outlined how the media discourse relating to Crimea has essentially framed according to binary logic. The polarization around the dichotomies us or them, friend or enemy, good or evil, has contributed to the impoverishment and the trivialization of the entire public discourse.","language":"ita","citation":"L¿ANNESSIONE DELLA CRIMEA ALLA FEDERAZIONE RUSSA NELLE PAROLE DELLA STAMPA. PRATICHE DISCORSIVE E COSTRUZIONE DELL¿IDENTITÀ NAZIONALE / F. Volpi ; tutor: R. Vassena; coordinatore: M. V. Calvi. Dipartimento di Lingue e Letterature Straniere, 2021 Mar 29. 33. ciclo, Anno Accademico 2020. [10.13130/volpi-francesca_phd2021-03-29].","filename":"phd_unimi_R11839.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/828194/1747873/phd_unimi_R11839.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1070048"},"title":"MICROCLIMATE AND HERITAGE CONSERVATION: PROBABILISTIC DAMAGE FUNCTIONS AS RISK ASSESSMENT TOOLS","internalauthor":"MELADA, JACOPO","type":"Tesi di dottorato","year":"2024","abstract":"The conservation of cultural heritage stands as an essential priority to safeguard our cultural legacy for future generations. Within this framework, microclimatology emerges as a cornerstone in comprehending and managing environmental conditions within museum and monumental settings. This study aims to delve into current methodologies for assessing microclimatic conditions and ensuring the preservation of artworks and monuments. Its primary objective is to develop a theoretical and practical framework for applying damage functions within the realm of hazard assessment. In the field of microclimatology for cultural heritage, there is a shift towards dynamic approaches that consider specific environmental factors and associated degradation processes, departing from static approaches relying on optimal universal values for material conservation. The precise identification and evaluation of these factors are pivotal in crafting targeted risk management strategies and averting long-term damage. This study endeavors to contribute to a deeper understanding of these dynamics and provide pragmatic guidelines for optimal cultural heritage conservation through microclimatic analysis.  Several case studies have been meticulously chosen to represent various cultural heritage contexts and illustrate potential monitoring strategies. These encompass Parco del Paradiso in Chiavenna, the Archives of Bressanone, the Studio-Museum Francesco Messina in Milan.   The methods employed include the assimilation of monitored microclimatic data through specifically crafted protocols for each case study, coupled with climate data obtained from reanalysis models or meteorological stations, following correction and validation.  Key research findings encompass the characterization of microclimatic conditions through a transdisciplinary lens, the applicability of damage functions, and the crucial interplay with the principles and practices of risk analysis. On a practical level, this involves defining a straightforward methodology for utilizing damage functions to assess the suitability of the microclimate for conservation, with potential applicability to past data to assess the evolution of environmental conditions and degradation processes over time.  Among the original contributions lies the introduction of a new damage function pertaining to paper-damaging insects and the implementation of a novel algorithm utilizing infrared thermography to examine the effects of biofilms on stone substrates. These contributions offer fresh perspectives and methodologies for evaluating and managing risk in the conservation of cultural heritage.","language":"eng","citation":"MICROCLIMATE AND HERITAGE CONSERVATION: PROBABILISTIC DAMAGE FUNCTIONS AS RISK ASSESSMENT TOOLS / J. Melada ; tutor: M. Giudici ;  co-tutor: N. Ludwig, T. Apuani ;  coordinatore: M. I. Spalla. Dipartimento di Scienze e Politiche Ambientali, 2024 Jul 08. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13097.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1070048/2460592/phd_unimi_R13097.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/816787"},"title":"NOVEL APPROACHES IN COLOR ASSESSMENT: FROM POINT-WISE COLORIMETRY TO FILM RESTORATION","internalauthor":"PLUTINO, ALICE","type":"Tesi di dottorato","year":"2021","abstract":"Colorimetry is the science which studies the quantification, reproduction and management of color from its optical, chemical, physical, but also physiological and perceptual point of view. Today, colorimetry has been standardized and color management can count on a robust workflow in point-wise conditions, thus when a color stimulus is considered under specific constraints (e.g., standard illumination and observation). As a consequence, the rigorous application of standard colorimetry is insufficient to reproduce and manage color in real conditions with non-uniform illumination and with complex spatial arrangements. This work of research is organized into three threads of work, which follow the standard pipeline of color signal evaluation: color assessment, color acquisition and processing, and quality assessment.  In the first Part of this study, the assumptions and constraints of standard colorimetry are recalled, together with specific comments on their limits in non-standard and practical applications. The open problems and misuses of colorimetry discussed from the theoretical point of view are supported by preliminary tests and experiments, aiming at highlighting the limits of the application of standard colorimetry in cultural heritage field.  In the second Part of this work, the standard digitization workflow is analyzed, and the issues and effects which could affect the acquisition of contrast and tones in imaging systems are discussed. In particular, the limits of hyperspectral imaging have been tested and examined, in order to assess the main source of noise in the acquisition and to evaluate the reliability of the acquired data. Subsequently, an implementation of the digitization protocol for film restoration is proposed and different methods to perform image enhancement and processing have been examined. For this aim, the family of Spatial Color Algorithms (SCAs), derived from Retinex, has been found successful for cultural heritage applications and a novel approach to film restoration is proposed. This specific family of algorithms, enhance colors according to the spatial distribution of pixel values in the scene, thus include the visual spatial mechanisms in color computation, overcoming the main constraints of standard colorimetry. Nevertheless, SCAs present high computational costs. To address this problem, in this Thesis a new speed-up algorithm is presented in order to allow the enhancement of video streams.   Regarding quality assessment thread, an overview of image quality metrics is presented, and different metrics and measures have been examined and tested, to define which metrics could be the most effective and usable for cultural heritage applications. In this context, a new framework of image quality measures has been presented and applied on historical images and videos.  The field of cultural heritage has been particularly suitable to underline the limits in the application of standard colorimetry, because, in this context, color is never observed as isolated phenomenon, but always inside a spatial arrangement. In this work, film digital restoration has been the main field of application and different approaches and alternative methods have been proposed to overcome the limits of standard color analysis. Anyway, the highlighted limits and solutions are applicable to film restoration, as well as to many other fields, where color sensation cannot be limited to point-wise colorimetry.","language":"eng","citation":"NOVEL APPROACHES IN COLOR ASSESSMENT: FROM POINT-WISE COLORIMETRY TO FILM RESTORATION / A. Plutino ; supervisor: A. Rizzi, B. R. Barricelli ; coordinator: P. Boldi. Dipartimento di Informatica Giovanni Degli Antoni, 2021 Mar 22. 33. ciclo, Anno Accademico 2020. [10.13130/plutino-alice_phd2021-03-22].","filename":"phd_unimi_R12108.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/816787/1710436/phd_unimi_R12108.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1171175"},"title":"COMPUTATIONAL APPROACHES IN STUDYING INHIBITOR DEVELOPMENT IN HAEMOPHILIA A PATIENTS","internalauthor":"CHAND, HIMANI","type":"Tesi di dottorato","year":"2025","abstract":"Haemophilia A is an X-linked recessive bleeding disorder caused by mutations in the F8 gene, resulting in deficiency or dysfunction of coagulation Factor VIII (FVIII). A major clinical complication in severe cases is the development of neutralizing alloantibodies, known as inhibitors, which undermine treatment efficacy and increase morbidity. This doctoral thesis uses a multidisciplinary approach by combining computational biology, bioinformatics, and high-throughput immunological assays, to investigate the mechanisms of inhibitor development and identify predictive biomarkers for clinical risk stratification.  The first study employs a novel IgG epitope mapping method using a random peptide phage-display library in the SIPPET cohort. Mimotope-variation analysis (MVA) was used to characterize FVIII-specific antibody repertoires, and predictive models based on LASSO logistic regression and random forest algorithms achieved strong performance (C-statistics ~0.78–0.80), supporting their utility in pre-treatment risk assessment.  The second study explores molecular mimicry by aligning FVIII mimotopes with pathogen-derived B-cell epitopes from the Immune Epitope Database (IEDB). Although some homologies were observed, no significant enrichment was found, providing no support for molecular mimicry as a driver of inhibitor formation.  The third study involves genome-wide DNA methylation analysis to identify epigenetic differences associated with inhibitor risk. Differentially methylated CpG sites were found in genes linked to immune regulation and tolerance, suggesting epigenetic contributions to FVIII immunogenicity.    Overall, this thesis demonstrates the value of integrative computational approaches in elucidating immune responses in Haemophilia A and contributes to the development of predictive tools and personalized treatment strategies in translational medicine.","language":"eng","citation":"COMPUTATIONAL APPROACHES IN STUDYING INHIBITOR DEVELOPMENT IN HAEMOPHILIA A PATIENTS / H. Chand ; tutor: F. Peyvandi ;  co-tutor: R. Palla ; coordinator: M. Clerici. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2025 Jun 18. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13656.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1171175/3090605/phd_unimi_R13656.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1132756"},"title":"ETHNOBOTANICAL SURVEYS IN LOMBARDY (ITALY): A MULTIDISCIPLINARY APPROACH TO STUDYING THE PAST TO IMPROVE THE FUTURE.","internalauthor":"MILANI, FABRIZIA","type":"Tesi di dottorato","year":"2025","abstract":"In the thesis presented herein, three case studies, with focus on ethnobotanical investigations conducted in Lombardy (North of Italy), are described. Considering ethnobotany as a multidisciplinary and cyclic science, the main phases of an investigation (the field, the laboratory, and the return to the population phases) are considered and the case studies are designed to cover them all.  The case studies are the following:  1. Case study Milan: a peculiar historical investigation on the majolica jars preserved at the Ca' Granda Ospedale Maggiore Policlinico, once used to store plant ingredients and medicinal remedies administered to the patients of the hospital. The thorough analysis of the inscriptions of the jars and extensive research on literature of the time allowed to hypothesize the medicinal species once potentially cultivated in the Hortus simplicium (Garden of Simples) of the hospital. Research in current scientific literature represented a starting point for the theoretical validation or rejection of the ancient remedies of the jars.  2. Case study Valle Imagna (Bergamo): the starting point of this case is the previous analysis of an ancient 18th century manuscript containing medicinal remedies. The diachronic comparison of the medicinal uses retrieved from historical sources with the traditional ones recorded during an ad hoc ethnobotanical investigation conducted on the territory of upper Valle Imagna allowed for the selection of a plant species symbol of the territory. The subsequent a multi-step laboratory survey was aimed at the thorough examination of the selected species, Agrimonia eupatoria L. (Rosaceae), from a micromorphological, phytochemical, and pharmacological standpoints.  3. Case study Alpine Lombardy: the case was developed along different Alpine territories: Sondalo (Valtellina, Sondrio), Valmalenco (Sondrio), and the neighboring Valposchiavo (Canton of Grisons, Switzerland). The field investigations of the three territories are presented. Additionally, the case involved the laboratory phase conducted in continuity with a previous PhD project in Valmalenco on the species Achillea erba-rotta subsp. moschata (Wulfen) I.Richardson and the nutritional analyses on six wild edible species collected in Valmalenco. Finally, different strategies for the return to the population phase are outlined and discussed.  Finally, in the Appendix attached to the main thesis, all the activities of dissemination of the scientific results and third mission of the three-year PhD project are thoroughly described.","language":"eng","citation":"ETHNOBOTANICAL SURVEYS IN LOMBARDY (ITALY): A MULTIDISCIPLINARY APPROACH TO STUDYING THE PAST TO IMPROVE THE FUTURE / F. Milani ; tutor: G. Fico ; phd coordinator: G. Vistoli. - DISFARM - UNIMI - Milano. Dipartimento di Scienze Farmaceutiche, 2025 Jan 29. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13301_2.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1132756/2632974/phd_unimi_R13301_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1138896"},"title":"LONG TIME BEHAVIOR OF LINEAR AND NONLINEAR WAVES:LARGE LARGE AMPLITUDE TRAVELING QUASI-PERIODIC SOLUTIONS IN FLUID MECHANICS AND DYNAMICS OF LINEAR WAVE EQUATIONS","internalauthor":"TERRACINA, SHULAMIT","type":"Tesi di dottorato","year":"2025","abstract":"In this thesis we study quasilinear PDEs on tori and we prove existence results of quasi-periodic large amplitude solutions for fluid-dynamic models in more than one space-dimension  and a stability result for the linear Klein-Gordon Equation with a small quasi-periodic perturbation.    In the first part of the thesis, where we consider two different models on $\\mathbb{T}^2$: the non-resistive Magnetohydrodynamics (MHD) system and the 2D-Euler equation for rotating fluids ($\\beta$-plane equation), both in presence of a large amplitude traveling wave external force with large velocity speed $\\lambda \\omega$, where $\\lambda \\gg 1$ is a large parameter.    For both equations we prove the existence of large amplitude traveling quasi-periodic solutions. In particular, for the MHD system we construct solutions which are bi-periodic and stationary in a moving frame, while for the case of the $\\beta$-plane equation we also prove the stability of the solutions, provided that the external force fulfills some additional algebraic property.      Due to the presence of small divisors, the proofs rely on a nonlinear Nash-Moser scheme tailored to construct nonlinear waves of large size.    The key point in this strategy is to study the invertibility of the linearized operator at a quasi-periodic approximate solution, giving ``good'' tame estimates. In both cases the linearized operator are unbounded diagonal operators plus a large amplitude perturbation and therefore for the invertibility of the linearized operator new ideas are required.   Another key obstruction is the fact that the problems are high dimensional.    For the MHD system   the principal symbol of the linearized operator has super-linear growth. The invertibility procedure is then   performed by using tools from micro-local analysis and normal forms together with a sharp analysis of high and low frequency regimes w.r.t. the large parameter $\\lambda$.   Moreover, to the best of our knowledge, this is the first result in which global in time, large amplitude solutions are constructed for the 2D non-resistive MHD system with periodic boundary conditions.    For the $\\beta$-plane equation the invertibility of the linearized operator   requires completely different strategy since the equation is dispersive and the dispersion relation is sub-linear.  The main difficulty is due to the fact that the dispersion relation is highly degenerate - indicating an infinite-dimensional kernel for the linear principal operator.  This degeneracy challenge is overcome by implementing a novel normal form methods based on the sub-linear growth of the unperturbed frequencies, the traveling-wave structure and the conservation of momentum which allows to cancel out some resonant terms.    The third result proved in this thesis regards instead a model which finds applications in General Relativity. We consider the     linear Klein-Gordon (KG) equation $\\psi_{tt}-\\psi_{xx}+\\mathtt{m}\\psi+\\mathcal{Q}(\\omega t)\\psi=0  $ on $\\mathbb{T}$ where  $ \\mathcal{Q} (\\omega t)$ is a quasi-periodic differential operator of {\\it order $ 2 $}.   Under suitable condition on this perturbation we prove that all the solutions are {\\it almost periodic} in time and  uniformly bounded  for all times.  This result is obtained by reducing the KG equation to a diagonal constant coefficient system with purely imaginary eigenvalues.  The main difficulty is the presence in the perturbation $ \\mathcal{Q} (\\omega t) $  of the maximal order.  This requires a normalization procedure of the highest order which is particularly delicate due to the linear dispersion relation which implies a strong interaction between space derivative and time derivative. This is delicate from a quantitative point of view.","language":"eng","citation":"Long time behavior of linear and nonlinear waves: Large amplitude traveling quasi-periodic solutions in fluid mechanics and dynamics of linear wave equations / S. Terracina ; tutor: R. Feola, R. Montalto. Dipartimento di Matematica Federigo Enriques, 2025 Feb 21. 37. ciclo","filename":"phd_unimi_R13516.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1138896/2647229/phd_unimi_R13516.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/809893"},"title":"REPRODUCTION AND PERINATOLOGY IN COMPANION ANIMALS INVESTIGATED BY USE OF NONINVASIVE MATRICES","internalauthor":"FUSI, JASMINE","type":"Tesi di dottorato","year":"2021","abstract":"Reproduction in companion animals is a topic of growing interest for scientific research, but knowledge about some aspects is still lacking. This is likely due to the need of collecting a large number of serial samples in order to perform longitudinal studies of the longer-lasting reproductive phases, which is now incompatible with the current concept of animal welfare, according to which any distress must be avoided, especially where pregnant and neonatal subjects are concerned. For these reasons, complying with the need of respecting animal welfare and aiming to study reproductive phases that are still incompletely explored in companion animals, the project lines of the present PhD thesis were focused on three crucial phases of reproduction: pregnancy and post-partum, perinatology and puberty. This was achieved by using matrices, like coat and the claws, and, to a lesser extent, fetal fluids obtained by noninvasive sampling. The sudden Covid-19 pandemic and the consequent lockdown rules have partially impaired the sample collection and laboratory analyses, but some interesting and satisfactory data were provided nonetheless. In the pregnancy and post-partum study, the results showed changes in the concentrations of cortisol (C) in coat from mating to 60 days post- partum, in line with what was reported for cats, suggesting that canine maternity could be considered as a challenge for the bitches, and dehydroepiandrosterone-sulfate DHEA(S) was also analyzed. About perinatology, the claws concentrations of C, DHEA(S), E2 and T tended to decrease from birth until 60 days of age, adding precious information about the perinatal physiology. In fetal fluids, leptin amniotic concentrations were higher in smaller-seized breeds, highlighting the role of breed body-size in affecting the intrauterine fetal metabolism. In the puberty study, in cats 17β-estradiol (E2) and testosterone (T) concentrations were assessed in coat and dewclaws. The concentrations of T in coat significantly differed between pubertal males and females and between gonadectomized males and females. The concentrations of T in coat were higher in pubertal than prepubertal male cats. In dogs, the analyses of the concentrations of C, DHEA(S), T and E2 in coat showed lower DHEA(S) concentration in pubertal than prepubertal and gonadectomized female dogs. In males, T concentrations in coat were higher in pubertal than prepubertal dogs, and C concentrations in coat were higher in pubertal than prepubertal and gonadectomized dogs, suggesting that pubertal status leads to a higher activation of the HPA axis in male dogs. The results shown in the present thesis evidenced the usefulness of these matrices for longitudinal and long-term hormonal studies of reproduction in dogs and cats, providing useful data about crucial reproductive phases and new interesting insights. Further investigations are needed to better understand some pending questions about the use of these matrices.","language":"eng","citation":"REPRODUCTION AND PERINATOLOGY IN COMPANION ANIMALS INVESTIGATED BY USE OF NONINVASIVE MATRICES / J. Fusi ; tutor: M. C. Veronesi ; PhD Program Coordinator: V. Grieco. Dipartimento di Medicina Veterinaria, 2021 Jan 28. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11878.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/809893/1688686/phd_unimi_R11878.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/831719"},"title":"MAY A PHARMACOLOGICAL MODULATION OF LIPIDS ALTER PROTUMORIGENIC SIGNALING OF EXTRACELLULAR VESICLES? A LONG JOURNEY IN EVS DIMENSIONAL, LIPIDIC AND PROTEIC CHARACTERIZATION FROM A METASTATIC MELANOMA CELL LINE'","internalauthor":"ACCATTATIS, FELICE MARIA","type":"Tesi di dottorato","year":"2021","abstract":"New insights into size, protein and lipid composition may help in characterizing functionality of Extracellular Vesicles (EVs) and infer with their fast development as delivery tools. Unfortunately, despite latest size-based classifications which divide EVs in small (50-80nm) or large (80-120nm) exosomes, microvesicles (<1000nm) and the new smallest (<50nm) population (exomeres), overlapping of different EV populations and unproper separation methods impair the comprehension of their biological role. In addition (EVs) are a very attractive pharmacological target, due to their involvement in cell-cell communication in physiological and pathological conditions. Among lipids, cholesterol and BisMonoacylGlyceroPhosphate (BMP) play a paramount role in EV biogenesis since their interplay drive endosomes towards the secretory or recycling pathway. We used as model a lymph node metastatic cell line (LM-16).  1)We set up a reproducible ultracentrifugation (UC) method for a size-based separation of different EV populations by 5 UC steps, in which physical and dynamic parameters are determined by an algorithm developed by Livshits et al. 2) In vitro treatment LM-16 cells with simvastatin and/or KT182, respectively inhibitors of cholesterol biosynthesis and of BMP degradation, was carried for 3 days with 10% FCS and for 3 days in serum free conditions. In this case we only isolated two fractions according to canonical EVs isolation method, namely 10K (microvesicles) and 100K (exosomes). EVs were further characterized by Nanosight, Zetasizer, Confocal and Electron microscopy. Quantitative proteomic analysis was performed by mass spectrometry and results analyzed by Ingenuity Pathway Analysis (IPA) while lipid analysis was carried out by gas-liquid chromatography.  1) Zetasizer and TEM analysis documented the existence of 5 different EV populations, whose relative % in saturated fatty acids gradually and continuously increased from larger to smaller EV (from 37.21±0.21 to 64.79±9.47). Proteomics identified a total of 2003 proteins differentially distributed (or even unique) among the 5 EV populations (n=697, 819, 1079, 1621 and 1654, respectively). IPA analysis of these distributions revealed different characteristics signaling pathways. 2) Treatment with simvastatin (0.1µM) and KT182 (50nM) alone or in combination did not affect cell proliferation, and EVs size and counts. Proteomics identified 1294 and 1192 proteins respectively for 100K and 10K, showing different significant expression patterns, compared to control, with several proteins up- and down regulated. IPA showed that treatments specifically decreased the expression of proteins involved in cellular movement, migration, proliferation and cytoskeleton arrangement, both in 100K and 10K fractions, with typical and striking differences and patterns.  Melanoma-released EVs include vesicles of different size, fatty acid and protein composition. These differences may translate into distinct behaviors and functions in biological fluids and help to define the role of specific EV populations in physiological and pathological processes. Cholesterol and BMP modulation of melanoma cells dramatically alters the protein content of released EVs, possibly leading to altered EVs functionality, suggesting the potential of lipid modulation in reshaping tumor cell-released EVs to develop new therapeutic approaches. Finally, these results pave the road to new pharmacological treatments to modulate EVs functions or to use EVs as pharmaceutical tools or melanoma biomarkers.","language":"eng","citation":"MAY A PHARMACOLOGICAL MODULATION OF LIPIDS ALTER PROTUMORIGENIC SIGNALING OF EXTRACELLULAR VESICLES? A LONG JOURNEY IN EVS DIMENSIONAL, LIPIDIC AND PROTEIC CHARACTERIZATION FROM A METASTATIC MELANOMA CELL LINE' / F.m. Accattatis ; coordinatore: A. L.Catapano ; coordinatore: G. D. Norata ; tutor: A. Llorente, A. Corsini ; co-tutor: L. Arnaboldi. Dipartimento di Scienze Farmacologiche e Biomolecolari, 2021 Apr 23. 33. ciclo, Anno Accademico 2020. [10.13130/accattatis-felice-maria_phd2021-04-23].","filename":"phd_unimi_R12008.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/831719/1760207/phd_unimi_R12008.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1149755"},"title":"OPTIMIZING MONOGASTRICS AND RUMINANTS GUT HEALTH TO FACE WEANING TRANSITION CHALLENGES","internalauthor":"MARCHETTI, LUCA","type":"Tesi di dottorato","year":"2025","abstract":"The weaning transition represents one of the most critical phases of the cycle of production, in which monogastrics and ruminants are susceptible to environmental, social, and nutritional stressors that may favor the outburst of multifactorial diseases. Among them, gastroenteric pathologies represent a major cause of economic loss and antimicrobials usage. Feed additives represent a key tool to shape the gut health of monogastrics and ruminants during weaning transition. As depicted by current European legislation, antimicrobials and pharmacological dosages of zinc and copper for growth-promoting purposes are no longer allowed due to public health and environmental issues which brought lower limits of inclusion in feeds, especially concerning zinc and copper. Continuous research of different solutions able to guarantee an effective modulation of gut health is strongly needed. Weaning changes in the gut environment involves a dynamic interplay between the gut barrier and the microbiota. Nevertheless, the balance among microbial niches and the enteric environment can be perturbed during weaning. The purpose of the present thesis was to evaluate different nutritional strategies based on feed additives and verify their effects on gut health and microbiota of piglets and dairy calves during weaning. In chapter 6 is described an in vitro characterization of a blend of carvacrol, tannic acid and medium chain fatty acids (MCFAs) supplemented in weanling piglets. Published results showed the potential of the blend in ameliorating gut barrier integrity and morphological characteristics, having notable reflexes in terms of salivary cortisol as biomarker of intestinal health, fecal score and gut microbiota composition. After the ban on pharmacological dosages of zinc and copper, the need to deeply investigate their relationship in dietary interventions was particularly evident. In chapter 7, the administration of different ratios of zinc and copper administered via specialty oxide sources in weanling piglets was evaluated. The unbalanced administration of Zn and Cu can be detrimental to intestinal permeability and immune parameters during early post-weaning phases, as confirmed also by evident microbiota variations in terms of compositional distances and taxa. The dietary supplementation of Bacillus spp. strains has not been extensively investigated in calves during weaning. A third study (chapter 8) was focused on the administration of Weizmannia faecalis strain DSM32016 in Italian female Holstein calves’ diet. Results highlighted the effectiveness of the treatment in conditioning the circulating immunoglobulins level, the antioxidant status and the fecal microbiota features, ameliorating growth performance and fecal score. The possibility to evaluate further alternative strategies to counterattack diarrheal disorders in piglets was explored during a 6-month secondment at the Department of Animal and Veterinary Sciences of Aarhus University (Denmark). In particular, an immunostimulant parenteral vaccine targeting secretory IgA production was tested to prevent E. coli induced post weaning diarrhea. As this project is on-going, a brief report of this experience is reported in chapter 9. As discussed in chapter 10, the tested solutions outlined their validity as a preventive tool to enhance gut health and animals’ performance during weaning also by establishing a balanced microbiota, possibly promoting the reduction of antimicrobial-based treatments and decreasing the manifestation of gastroenteric disorders.","language":"eng","citation":"OPTIMIZING MONOGASTRICS AND RUMINANTS GUT HEALTH TO FACE WEANING TRANSITION CHALLENGES / L. Marchetti ; coordinatore: F. Ceciliani ; tutor: V. Bontempo. - Dipartimento di Medicina Veterinaria e Scienze Animali, Via dell'Università 6, Lodi. Dipartimento di Medicina Veterinaria e Scienze Animali, 2025 Mar 17. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13323.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1149755/2693883/phd_unimi_R13323.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1133055"},"title":"NANOSTRUCTURED COMPOSITE FILMS FOR BRAIN-MACHINE INTERFACE APPLICATIONS","internalauthor":"PROFUMO, FILIPPO","type":"Tesi di dottorato","year":"2025","abstract":"Biohybrid electronic technologies, fostering information flow and processing between natural and artificial components [1] are essential for developing energy-efficient, compact interfaces that integrate bioelectrical activity for personalized medicine. In this frame, advances in thin-film sensors and non-invasive signal processing enable wearable systems to monitor brain and peripheral neural activity [2] in view of the development of efficient Brain-Machine Interfaces (BMIs) [3]. While the quality and quantity of signal recordings have improved [4], managing and processing large data volumes in real-time necessitates significant hardware and software advancements. Crucial concern is also the mechanical matching and biocompatibility of the materials used in Micro Electrode Arrays (MEAs) and other recording devices, as well as the proper device geometries and scaling for in vivo brain activity.           Nanostructured Cluster Assembled Films (NCAFs) are of particular interest for the development of artificial systems showing neuromorphic behaviors and as the basis for BMIs. Au NCAFs show nonlinear electrical properties and resistive switching behavior [5], [6]. ZrOx NCAFs are biocompatible, and they have been used as substrates for the growth of neural cells. Thanks to their controlled nanoscale roughness, they can be used to induce phenotypic modifications via mechanotransductive signaling [7], [8], [9], [10].          My work was focused on combining these two aspects by fabricating and characterizing a nanocomposite Au-ZrOx system showing resisting switching behavior and capable of enabling a suitable information coding/decoding protocol in view of the development of BMIs.           I developed planar layered Au/ZrOx two terminal systems, on glass substrates [11]. An electrical characterization highlighted hysteretic I-V curves, and two separate resistance states explored with alternated polarity pulses. This system showed neuromorphic properties such as short-time memory with stretched-exponential relaxation, and potentiation/depotentiation for subsequent applied voltage pulses. I characterized the bilayered NCAF conduction processes, suggesting a memristive-like model to explain the system's hysteresis characteristics taking into account the competition of a Poole-Frenkel (PF) and a Schottky conduction mechanisms [12]. Layered Au/ZrOx devices can be interfaced with biological systems, but their electrical resistance is very high (around 1 GΩ), being prohibitive for noise and readout operations. Furthermore, their electrical properties are strongly dependent on the characteristics of the 2-D interface between the two films, making it hard to control tuning geometry and deposition parameters.           For these reasons, I worked on the development of a deposition system able to produce composite NCAFs where Au and ZrOx clusters are interspersed. I have demonstrated a two-source Supersonic Cluster Beam Deposition Apparatus [Filippo Profumo et al., submitted] and I fabricated by this technique nanocomposite Au/ZrOx NCAFs with different zirconia contents. Their electrical properties, monitored in-situ during fabrication, resulted strongly related to zirconia concentrations and ranged from insulating characteristics for high ZrOx content to those of Au NCAFs. By the ex-situ electrical characterization of nanocomposite devices, I highlighted a “soft” activation of resistive switching with a gradual resistance transition, enhanced resistance retention, and the presence of Negative Differential Resistivity (NDR). Through an in-situ thermal TEM analysis of the morphological rearrangements of composite NCAFs with varying zirconia contents, combined with molecular dynamics simulations, I have addressed the improved stability of composite electrical properties to zirconia clusters acting as an insulating matrix and reducing the thermally driven diffusivity of gold atoms. [Andrea Falqui et al., submitted].          Since NCAFs exhibit complicated quasi-random electrical activity, a different neural signal processing approach than those described for other memristive devices [13] is needed to proceed toward a BMI application. The Inter-Switch Interval (ISI) analysis [14], [15] has been used to analyze the switching features of Au NCAFs under constant applied voltage [5], [16]. However, I mainly focused on pulsed stimuli, producing current traces with non-Gaussian distributions if applied on composite NCAF, and incompatible with an ISI analysis.           I thus investigated the autocorrelation function of current traces following a power law decrease, as reported for similar gold nanoparticle systems [15], and sensitive to voltage and alternated polarity of pulses capable of varying its decay trend. To identify distinctive parameters of current recordings and their relationship with input pulse parameters, I introduced the use of a time-series analysis capable of comparing a large number of statistical methods at once [17]. I evinced that the voltage and polarity of applied pulses influence significantly other statistical features of the current trace recorded from the nanocomposite devices and that general voltage input signals (input-timeseries) are mapped into current recording (output-timeseries) with new statistical features.           Exploiting this input/output map, I have demonstrated the possibility of classifying, in real-time, in-vivo neural recordings of rats according to their registration location and activity (normal or abnormal) [Filippo Profumo, submitted], representing a step towards the decoding of neuronal signals by the intrinsic processing of neuromorphic devices and thus towards the development of NCAF-based BMI.        References    [1] S. Vassanelli and M. Mahmud, ‘Trends and Challenges in Neuroengineering: Toward “Intelligent” Neuroprostheses through Brain-“Brain Inspired Systems” Communication’, Front. Neurosci., vol. 10, Sep. 2016, doi: 10.3389/fnins.2016.00438.  [2] A. Mikhaylov et al., ‘Neurohybrid Memristive CMOS-Integrated Systems for Biosensors and Neuroprosthetics’, Front. Neurosci., vol. 14, p. 358, Apr. 2020, doi: 10.3389/fnins.2020.00358.  [3] L. F. Nicolas-Alonso and J. Gomez-Gil, ‘Brain Computer Interfaces, a Review’, Sensors, vol. 12, no. 2, pp. 1211–1279, Jan. 2012, doi: 10.3390/s120201211.  [4] E. Musk, ‘An integrated brain-machine interface platform with thousands of channels’, 2019.  [5] M. Mirigliano et al., ‘Complex electrical spiking activity in resistive switching nanostructured Au two-terminal devices’, Nanotechnology, vol. 31, no. 23, p. 234001, Mar. 2020, doi: 10.1088/1361-6528/ab76ec.  [6] M. Mirigliano and P. Milani, ‘Electrical conduction in nanogranular cluster-assembled metallic films’, Advances in Physics: X, vol. 6, no. 1, p. 1908847, Jan. 2021, doi: 10.1080/23746149.2021.1908847.  [7] C. Schulte et al., ‘Conversion of nanoscale topographical information of cluster-assembled zirconia surfaces into mechanotransductive events promotes neuronal differentiation’, J Nanobiotechnol, vol. 14, no. 1, p. 18, Dec. 2016, doi: 10.1186/s12951-016-0171-3.  [8] C. Schulte, A. Podestà, C. Lenardi, G. Tedeschi, and P. Milani, ‘Quantitative Control of Protein and Cell Interaction with Nanostructured Surfaces by Cluster Assembling’, Acc. Chem. Res., vol. 50, no. 2, pp. 231–239, Feb. 2017, doi: 10.1021/acs.accounts.6b00433.  [9] A. Previdi et al., ‘Micropatterning of Substrates for the Culture of Cell Networks by Stencil-Assisted Additive Nanofabrication’, Micromachines, vol. 12, no. 1, p. 94, Jan. 2021, doi: 10.3390/mi12010094.  [10] A. Previdi et al., ‘Nanotopography and Microconfinement Impact on Primary Hippocampal Astrocyte Morphology, Cytoskeleton and Spontaneous Calcium Wave Signalling’, Cells, vol. 12, no. 2, p. 293, Jan. 2023, doi: 10.3390/cells12020293.  [11] F. Profumo, F. Borghi, A. Falqui, and P. Milani, ‘Potentiation and depression behaviour in a two-terminal memristor based on nanostructured bilayer ZrO x /Au films’, J. Phys. D: Appl. Phys., vol. 56, no. 35, p. 355301, Aug. 2023, doi: 10.1088/1361-6463/acd704.  [12] D. Cipollini, F. Profumo, L. Schomaker, P. Milani, and F. Borghi, ‘Conduction mechanisms in a planar nanocomposite resistive switching device based on cluster-assembled Au/ZrOx films’, Front. Mater., vol. 11, May 2024, doi: 10.3389/fmats.2024.1385792.  [13] I. Gupta, A. Serb, A. Khiat, R. Zeitler, S. Vassanelli, and T. Prodromakis, ‘Real-time encoding and compression of neuronal spikes by metal-oxide memristors’, Nat Commun, vol. 7, no. 1, p. 12805, Sep. 2016, doi: 10.1038/ncomms12805.  [14] M. Karsai, K. Kaski, A.-L. Barabási, and J. Kertész, ‘Universal features of correlated bursty behaviour’, Sci Rep, vol. 2, no. 1, p. 397, Dec. 2012, doi: 10.1038/srep00397.  [15] J. B. Mallinson, S. Shirai, S. K. Acharya, S. K. Bose, E. Galli, and S. A. Brown, ‘Avalanches and criticality in self-organized nanoscale networks’, Science Advances, vol. 5, no. 11, p. eaaw8438, Nov. 2019, doi: 10.1126/sciadv.aaw8438.  [16] G. Nadalini, F. Borghi, T. Košutová, A. Falqui, N. Ludwig, and P. Milani, ‘Engineering the structural and electrical interplay of nanostructured Au resistive switching networks by controlling the forming process’, Sci Rep, vol. 13, no. 1, Art. no. 1, Nov. 2023, doi: 10.1038/s41598-023-46990-4.  [17] B. D. Fulcher, M. A. Little, and N. S. Jones, ‘Highly comparative time-series analysis: the empirical structure of time series and their methods’, Journal of The Royal Society Interface, vol. 10, no. 83, p. 20130048, Jun. 2013, doi: 10.1098/rsif.2013.0048.","language":"eng","citation":"NANOSTRUCTURED COMPOSITE FILMS FOR BRAIN-MACHINE INTERFACE APPLICATIONS / F. Profumo ; supervisor: P. Milani ; co-supervisor: F. Borghi ; director of the school: A. Mennella. - Dipartimento di Fisica Aldo Pontremoli. Dipartimento di Fisica Aldo Pontremoli, 2025 Jan 27. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13418.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1133055/2629934/phd_unimi_R13418.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1151338"},"title":"IMPACT OF KETOGENIC DIET TREATMENT IN GLUT1 DEFICIENCY SYNDROME: DISCOVERY OF MOLECULAR MECHANISMS RESPONSIBLE FOR PHENOTYPE CHANGES IN BOTH PEDIATRIC AND ADULT PATIENTS","internalauthor":"MAURI, ALESSIA","type":"Tesi di dottorato","year":"2025","abstract":"GLUT1 deficiency syndrome (GLUT1-DS) is a rare, effectively treatable, neurometabolic disease. It is caused by loss-of function mutations in the SLC2A1 gene, encoding GLUT1 protein, which supplies glucose to the brain. A genetic defect in this transporter leads to cerebral energy deficiency, resulting in a complex spectrum of neurological symptoms, including seizures and movement disorders.   Although many clinical and molecular features have been deeply studied, there are still some not completely understood aspects, including (i) clinical variability and wide spectrum of SLC2A1 variations, (ii) phenotype age-related changes, and (iii) response to ketogenic diet (KD) treatment, which are investigated in this research study through a multi-omics approach.  Firstly, we explored the clinical, biochemical and molecular data of 27 pediatric patients with GLUT1-DS, identifying (1) different clinical phenotypes (from early- to late-onset), (2) 25 disease-related SLC2A1 variants of which 10 never reported before, (3) a mutational hotspots in exon 4, suggesting a vulnerable region for glucose uptake associated to clinical manifestations, and (4) strong correlations between variant types, clinical and biochemical severity patterns.  Next, we analyzed the transcriptional profiles and isoform switches in GLUT1-DS patients, before and after KD, focusing on three comparisons: (a) adults versus children, both untreated; (b) children in pre- versus post-KD; and (c) responders versus non-responders to KD in GLUT1-DS children. Overall, enrichment analysis revealed a reduction in inflammatory pathways in GLUT1-DS patients who experienced clinical improvements in seizure frequency and severity, whether in response to KD or during adulthood. These processes involve type I IFN signatures, which have an impact on mitochondrial function and signaling, suggesting a specific role in GLUT1-DS pathogenesis. Supporting these suggestions, the detected lncRNAs are also related to inflammatory response, as RMRP and LINC02555, or to ketone biosynthesis and oxidative phosphorylation processes, like PAX8-AS1, for which emerges its potential regulatory role in KD response. Another significant molecular pathway contributing to mitigate clinical signs is the alternative splicing of ion channel genes, such as P2X7 receptor which is, in turn, liked to inflammasome pathway. As well as this, the methylome profiles, performed by ONT, revealed altered methylation patterns in similar genes, like GRIN3A, suggesting also in this analysis an ion channel signaling deregulation.  Lastly, these novel and suggestive findings underline the complex interplay that transcriptional variations, isoform switching and methylation patterns may have in the phenotype age-dependent changes and response to KD in patients with GLUT1-DS.","language":"eng","citation":"IMPACT OF KETOGENIC DIET TREATMENT IN GLUT1 DEFICIENCY SYNDROME: DISCOVERY OF MOLECULAR MECHANISMS RESPONSIBLE FOR PHENOTYPE CHANGES IN BOTH PEDIATRIC AND ADULT PATIENTS / A. Mauri ; tutor: G.V. Zuccotti, C. Cereda ;  coordinatore: F. Cheli. Dipartimento di Scienze Biomediche e Cliniche, 2025 Mar 26. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13562_3.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1151338/2706000/phd_unimi_R13562_3.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1143775"},"title":"TRAUMATIC ORTHOPEDIC DISEASES IN UNOWNED CATS: TEACHING PERFORMANCE INVESTIGATION FOR UNDERGRADUATE TRAINING AND COHORT CLINICAL STUDY.","internalauthor":"FERRARI, FRANCESCO","type":"Tesi di dottorato","year":"2025","abstract":"In the last decades, there has been an increasing interest in the medical management of unowned cats within small animal practice. Trauma is a common cause of hospitalization and mortality in unowned cats, frequently resulting in traumatic orthopedic and craniomaxillofacial injuries.  However, the current veterinary literature lacks epidemiological data and prognostic factors for unowned cats suffering from such injuries. Craniomaxillofacial fractures, a common sequela of trauma in cats, present diagnostic challenges due to their anatomical complexity. Meanwhile, both human and veterinary medicine have increasingly explored novel educational strategies to enhance students’ learning. Among these, 3D-printed models have demonstrated their utility in the understanding of fractures affecting complex bone structures.  In this scenario, this research project had two primary objectives. The first was to investigate the outcomes of unowned cats affected by orthopedic traumatic injuries referred to the Veterinary Teaching Hospital of the University of Milan (VTHUM). Data on signalment, injury patterns, and treatments were analyzed to identify correlations with clinical outcomes. The second aim was to evaluate the effectiveness of 3D-printed feline skull models as a learning tool for the radiographic interpretation of craniomaxillofacial traumatic injuries in cats.  Unowned cats suffering from traumatic orthopaedic injuries referred by the veterinary public service over three-year period were retrospectively evaluated for inclusion. Clinical variables were retrospectively collected from the medical records and analysed using nominal logistic regression. A total of 48 unowned cats were enrolled, with a median estimated age of 24 (1-180) months and a body weight of 3 (0.7-5) kg. Thirty-four (71%) patients reached complete functional recovery (CFR). Several factors were significantly associated with CFR, including estimated age, body weight, time from trauma to therapeutic intervention, spinal involvement, presence of comorbidities, hospitalization time, and radiographic score. A longer interval between trauma and therapeutic intervention seemed to be associated with a better outcome. For the second part of the project, fourth- and fifth-year veterinary students were randomly assigned to two groups (2D and 3D) and completed a pre-test consisting of multiple-choice questions (MCQs). Both groups attended a recorded lesson on feline skull radiographic anatomy and traumatic lesions, after which the 3D group received 3D-printed skulls models, both normal and with traumatic lesions. Finally, all students completed a post-test. The MCQs included orthogonal feline skull radiographs representing three different trauma patterns and assessed knowledge of normal anatomy and lesion recognition. Twenty-three (25.6%) fourth-year and 67 (74.4%) fifth-year students participated. Post-test scores significantly improved in both groups compared to pre-test scores. However, no significant differences were observed between the 2D and 3D groups in the post-test scores, suggesting that 3D-printed models did not improve the students’ ability to recognize anatomical structures and traumatic lesions of the feline skull.   In the unique academic setting of the VTHUM, that melts education, research, and clinical activity, further studies are warranted to refine teaching strategies for complex clinical topics. Moreover, this project provides the bases for establishing an evidence-based algorithm for managing traumatic orthopedic injuries in unowned cats.","language":"eng","citation":"TRAUMATIC ORTHOPEDIC DISEASES IN UNOWNED CATS: TEACHING PERFORMANCE INVESTIGATION FOR UNDERGRADUATE TRAINING AND COHORT CLINICAL STUDY / F. Ferrari ; tutor: D. Stefanello ; phd coordinator: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2025 Feb 28. 36. ciclo","filename":"phd_unimi_R12950.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1143775/2666208/phd_unimi_R12950.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1038969"},"title":"OPTIMISATION AND THERAPEUTIC-TARGET-DISCOVERY ORIENTED ANALYSIS OF CRISPR-CAS9 SCREENS","internalauthor":"VINCETI, ALESSANDRO","type":"Tesi di dottorato","year":"2024","abstract":"The emergence of CRISPR-Cas9 technology has revolutionized cancer research by enabling targeted genome modifications in tumour cells, offering insights into cancer biology and potential treatment targets. My PhD research focuses on developing tailored tools and pipelines to enhance the analysis of CRISPR-Cas9 screens for identifying cancer therapeutic targets.  CRISPR-Cas9 screens are vital in cancer research, allowing precise gene knockout and unveiling genes critical for cancer cell survival. However, challenges persist in experimental setup optimization and data analysis. My work addresses these challenges by optimizing CRISPR-Cas9 screens and developing advanced analysis tools.  Key challenges include addressing biases from copy number alterations and distinguishing between core-fitness and context-specific fitness genes. Identifying context-specific genes is crucial for personalized cancer treatments.  Additionally, cancer dependency datasets derived from CRISPR-Cas9 screens on large cell line panels offer valuable insights into cancer vulnerabilities, guiding cancer and fundamental biology research.  In conclusion, optimised methods and analytical tools for CRISPR-Cas9 screens are pivotal in cancer research. My research aims to overcome challenges in experimental setup and data analysis, facilitating the identification and validation of novel therapeutic targets. These tools not only enhance screen accuracy but also provide valuable resources for the scientific community, advancing cancer treatment and fundamental biological understanding.","language":"eng","citation":"OPTIMISATION AND THERAPEUTIC-TARGET-DISCOVERY ORIENTED ANALYSIS OF CRISPR-CAS9 SCREENS / A. Vinceti ; tutor: F. Iorio ; co-tutor: G. Testa ; coordinatore: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2024 Apr 11. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12758_1.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1038969/2382873/phd_unimi_R12758_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1132397"},"title":"EXPLORING PHYSIOLOGICAL, PATHOLOGICAL AND PARAPHYSIOLOGICAL BRAIN ACTIVITY ACROSS SCALES WITH SIMULTANEOUS INVASIVE AND NON-INVASIVE EEG","internalauthor":"ZAULI, FLAVIA MARIA","type":"Tesi di dottorato","year":"2025","abstract":"\"This thesis explores the integration of non-invasive high-density electroencephalography (hd-EEG) with invasive stereoelectroencephalography (SEEG) to enhance understanding of brain electrophysiology in pathological, physiological and paraphysiological contexts. The combination of these two methods, known as \"\"co-registration,\"\" leverages the high temporal resolution and full-brain coverage of hd-EEG with the spatial precision of SEEG, allowing for a more comprehensive view of brain activity. The thesis is divided into three primary areas of investigation.  First, it examines pathological brain activity, specifically focusing on interictal epileptiform discharges (IEDs). These discharges, often difficult to detect with scalp EEG alone, were successfully localized using co-registration. By guiding hd-EEG analysis with SEEG data, hidden epileptic activity was revealed, contributing to more accurate non-invasive identification of epileptic foci, which is critical for surgical planning in drug-resistant epilepsy cases.  Second, the study investigates physiological brain responses to sensory stimuli using median nerve stimulation. Co-registration enabled the analysis of how brain signals propagate from primary sensory regions to higher-order areas involved in perception. While hd-EEG captured fast, large-scale activity, SEEG provided detailed recordings from deep cortical structures. This integration revealed both phasic and tonic gamma band brain responses, offering new insights into sensory processing and conscious perception.  Third, the thesis evaluates brain responses to artificial stimulation via single-pulse electrical stimulation (SPES), which evoked cortico-cortical evoked potentials (CCEPs). Co-registration allowed for a detailed analysis of how artificial stimulation propagates through brain circuits. While SEEG detected localized responses, hd-EEG captured broader patterns of brain activation, enhancing the understanding of brain connectivity and reactivity to external stimuli.  Overall, the combination of hd-EEG and SEEG offers unique advantages, providing a more accurate and detailed picture of brain dynamics. This method not only refines neuroimaging techniques but also holds promise for improving clinical diagnostics and treatments, particularly in epilepsy. In essence, this thesis demonstrates that co-registration can bridge the gap between non-invasive and invasive brain recordings, offering significant benefits for both neuroscience research and clinical applications.\"","language":"eng","citation":"\"EXPLORING PHYSIOLOGICAL, PATHOLOGICAL AND PARAPHYSIOLOGICAL BRAIN ACTIVITY ACROSS SCALES WITH SIMULTANEOUS INVASIVE AND NON-INVASIVE EEG / F.m. Zauli ; tutor: M. Massimini ; supervisori: A. Pigorini, E. Mikulan ; PhD coordinator: F. Guala. - DIPARTIMENTO DI SCIENZE BIOMEDICHE E CLINICHE \"\"LUIGI SACCO\"\" (MILANO). Dipartimento di Scienze Biomediche e Cliniche, 2025 Jan 16. 37. ciclo, Anno Accademico 2024.\"","filename":"phd_unimi_R13198_2.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1132397/2628037/phd_unimi_R13198_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1196540"},"title":"STUDI SULLA TRADIZIONE ESEGETICA ED ERUDITA INTORNO AGLI IDILLI DI TEOCRITO.","internalauthor":"BUZZI, GIOVANNI BATTISTA","type":"Tesi di dottorato","year":"2025","abstract":"This research project focuses on the early exegetical tradition of Theocritus' Idylls, with a detailed examination of most of the papyri which feature traces of commentaries to the poetic text. A key achievement of the project is the creation of comprehensive entries for each papyrus, including critical editions, physical descriptions, and line-by-line analysis. These entries shed light on the relationship between the papyri and the scholia vetera. Furthermore, future studies on the scholia recentiora could offer new insights into the transmission of exegetical texts related to Theocritus’ works, by systematically comparing papyri and scholia. The project also led to the discovery and publication of previously unknown Latin marginalia on the text of Theocritus, written by cardinal Pietro Bembo. These annotations, preserved in a manuscript (Neap. II F 43) copied by Zacharias Calliergis, offer a valuable example of humanistic exegesis and shed new light on the reception of Greek pastoral poetry during the Renaissance.","language":"ita","citation":"Studi sulla tradizione esegetica ed erudita intorno agli Idilli di Teocrito / G.b. Buzzi ; supervisore: S. Martinelli Tempesta (UniMI) correlatore: F. Vendruscolo (UniUD) coordinatore: M. Faraguna. Dipartimento di Studi Letterari, Filologici e Linguistici, 2025 Nov 28. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13375.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 18-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1212644"},"title":"LA CITTÀ PERSONIFICATA NEL BASSO MEDIOEVO TRA CULTURE POLITICHE CITTADINE ED ESPANSIONISMO TERRITORIALE","internalauthor":"DEMICHELIS, LUCIA","type":"Tesi di dottorato","year":"2026","abstract":"Late medieval depictions of cities as female figures, attested in Italy from the thirteenth century onwards and present in paintings, sculptures, miniatures and coins, have so far been neglected by studies devoted to political iconography. Through the collection and study of the earliest Italian examples of these images, dating from the 13th to the 15th centuries, this thesis aims to shed light on a particular – but widely used – way in which cities constructed their identity, communicated it and transmitted its memory in the late Middle Ages. However, this is neither a study of art history nor an investigation into changes in iconography over the centuries: city personifications will instead be used to investigate the contexts in which they were produced and on which they acted.  The personification of cities is a long-standing phenomenon, which since its inception in the ancient world has continued to re-emerge sporadically to the present day, producing numerous examples, especially in Europe. However, this thesis only considers examples from central and northern Italy from the 13th to the 15th century. This is an area and a period in which not only did cities maintain their centrality, thus ensuring the spread of city personifications, but in which there were also successive types of government (communes, lordships, multi-city states) interested in interacting in one way or another with cities and their personifications. This allows us to use city personifications as a new key to understanding the changes taking place at the time, including the relationship between the different forms of government and the city, and that between cities and the surrounding territory.","language":"ita","citation":"\"LA CITTÀ PERSONIFICATA NEL BASSO MEDIOEVO TRA CULTURE POLITICHE CITTADINE ED ESPANSIONISMO TERRITORIALE / L. Demichelis ; tutor: A. Gamberini, F. Pagnoni ; coordinatore: P. Grillo. Dipartimento di Studi Storici \"\"Federico Chabod\"\", 2026 Jan 30. 38. ciclo, Anno Accademico 2024/2025.\"","filename":"phd_unimi_R13793.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 05-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1119222"},"title":"IL CONTRATTO TURBATO: UNA PROSPETTIVA RIMEDIALE","internalauthor":"SPOLIDORO, AMELIA CHIARA CATERINA","type":"Tesi di dottorato","year":"2024","abstract":"The thesis introduces and illustrates contractual disturbance. A contractual disturbance occurs when surprising events reveal themselves during the execution phase of the contract, leading to doubts regarding the applicability of a specific rule, whether contractual or statutory, and the identification of a potential substitute rule. In a strong sense, disturbance does not concern all contracts, but only those that are strongly negotiated, meaning those in which the agreement is the result of a dialogue of wills.    The aim of the research is to clarify how contractual disturbance should be addressed using the tools of legal criticism.    The reasoning is not conducted according to the rules of deduction, nor according to those of inference, but rather from particular to particular, that is, as reasoning by paradigms.    Through an examination of the cases in which the legislator has averted the risk of the occurrence of a disturbance by establishing an appropriate provision to deal with the potentially disruptive effects of supervening events, the need to set up the reasoning from the bottom up, starting with remedies, is ascertained.    In the second chapter, the remedial techniques chosen by the legislator in the provisions studied in the first chapter are reviewed. This allows, on the one hand, to discern their regularity and, on the other, to highlight how their varying effectiveness is intimately linked to the context in which they are applied.    Finally, regarding the specific issue of creating a rule capable of healing disturbance in its strongest sense, the enhancement of mediatory remedies and settlement is proposed. These approaches are also examined in light of further inquiry into the legal criteria that should guide a competitive discussion between the parties, conducted with fairness and good faith.","language":"ita","citation":"IL CONTRATTO TURBATO: UNA PROSPETTIVA RIMEDIALE / A.c.c. Spolidoro ; tutor: G. Gitti ;  coordinatore: G. Ludovico. Dipartimento di Diritto Privato e Storia del Diritto, 2024 Nov 28. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13327.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1119222/2592851/phd_unimi_R13327.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1119904"},"title":"MATHEMATICAL PROGRAMMING METHODS FOR PARTIALLY UNDEFINED OPTIMIZATION MODELS","internalauthor":"MESSANA, ROSARIO","type":"Tesi di dottorato","year":"2024","abstract":"This thesis proposes novel methods for formulating and solving partially undefined mathematical programming models. By leveraging mathematical programming methods and off-the-shelf solvers, we aim to automate the process of generating compact algebraic representations for unknown components. Our approach addresses limitations of existing methods, such as lack of interpretability and control over model complexity. We explore various learning scenarios, including static and interactive settings, and consider both objective function and constraint learning. Our contributions include:      - static constraint learning – we develop methods to approximate unknown convex polyhedra from positive and negative data points, using mixed-integer linear programming and column generation;      - interactive constraint learning – we design algorithms to solve 0-1 linear programs with missing constraints and learn surrogate constraints, using an oracle-based approach inspired by active learning techniques;      - online objective learning – we propose a novel algorithm based on mixed-integer linear programming for online facility location with non-linear profit functions.  Our work advances the field of automatic mathematical programming model formulation and provides practical tools for solving complex optimization problems with incomplete information.","language":"eng","citation":"MATHEMATICAL PROGRAMMING METHODS FOR PARTIALLY UNDEFINED OPTIMIZATION MODELS / R. Messana ; tutor: A. Ceselli ; coordinatore: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2024 Dec 04. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13370.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1119904/2595786/phd_unimi_R13370.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1210380"},"title":"ENGINEERING THE COMPLEX ELECTRICAL RESPONSE OF METALLIC CLUSTER-ASSEMBLED FILMS FOR NEUROMORPHIC COMPUTING APPLICATIONS","internalauthor":"DECASTRI, DAVIDE","type":"Tesi di dottorato","year":"2026","abstract":"Mammalian brain outperforms modern computers in executing complex tasks with high energy efficiency. These capabilities rely on the processing of stimuli by a network consisting in thousand billion neurons intricately interconnected through synapses. Neurons integrate signals in a non-linear way. Synapses can modulate their effectiveness according to stimuli (synaptic plasticity), providing the basis for learning. Nontrivial responses to stimuli are due to the collective dynamics regulating the network operations along with network topology.  Neuromorphic Computing (NC) draws inspiration from the structure and operation of the brain to offer an alternative to the present Von Neumann paradigm of computation. Metallic cluster-assembled films (MCAFs) constitute a potential physical substrate for this scope due to their topological complexity, non-linear conduction properties, and plasticity.  A key role in determining MCAF conduction properties is played by their ability to undergo reversible structural modifications, thus producing changes in their electric conductivity. This phenomenon is referred as Resistive Switching (RS). Even if MCAF based devices have been already exploited in different computing tasks, we still have poor insight on the physics underlying the complex dynamics that govern RS activity. The main goal of my thesis is to exploit a novel approach relying on micro-thermography to characterize the evolution of conductivity in MCAF and gain a deeper understanding of this rich phenomenology. My analysis led to the identification of “switching sites” undergoing the structural modifications responsible of RS. This strategy also allowed to study the statistical properties of RS in space and time, unveiling the presence of non-trivial correlations in these systems. My analysis also highlighted the impact of sample geometry and dimension on the number and distribution of the switching regions. Furthermore, I probed the electrical response to different stimuli, and I observed stereotyped behaviours that emerge from the average response of the switching regions. Modelling the deterministic component of the electrical response, offers the possibility to enhance controllability of MCAF based devices, while the intrinsic stochasticity provides a natural mechanism for efficient state-space exploration, ultimately supporting efficient programmability of such systems.","language":"eng","citation":"ENGINEERING THE COMPLEX ELECTRICAL RESPONSE OF METALLIC CLUSTER-ASSEMBLED FILMS FOR NEUROMORPHIC COMPUTING APPLICATIONS / D. Decastri ; supervisore: P. Milani ; tutor: F. Borghi ; phd coordinator: A. Mennella. Dipartimento di Fisica Aldo Pontremoli, 2026 Jan 29. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13961.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1210380/3231872/phd_unimi_R13961.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1193063"},"title":"COMPARATIVE ANALYSIS OF DISSECTION TECHNIQUES IN POST-BARIATRIC ABDOMINOPLASTY","internalauthor":"AMENDOLA, FRANCESCO","type":"Tesi di dottorato","year":"2025","abstract":"Introduction  Post-bariatric abdominoplasty represents a critical reconstructive step for patients who have undergone massive weight loss. Despite its functional and aesthetic benefits, seroma remains one of the most frequent postoperative complications, often linked to tissue trauma and thermal damage during surgical dissection. Electrosurgery, while effective for hemostasis, can produce variable thermal effects depending on operating mode and contact medium. This study aimed to compare three dissection techniques—cutting mode, coagulation with dry gauze, and coagulation with saline-moistened gauze—in terms of drainage output, seroma incidence, and seroma volume after post-bariatric abdominoplasty.  Methods  A prospective observational study was conducted on 320 consecutive patients undergoing post-bariatric abdominoplasty performed by the same surgical team between 2023 and 2025. Subjects were divided into three groups according to the dissection technique: Group A (cutting mode), Group B (coagulation with dry gauze), and Group C (coagulation with saline-moistened gauze). All patients met inclusion criteria of weight stability for at least six months, BMI < 30 kg/m², and absence of major comorbidities. Data collected included postoperative drainage volume (24 h, 48 h, and total), incidence of clinically relevant seromas, and seroma volume in affected patients. Statistical analyses comprised ANOVA for continuous variables, Chi-square tests for categorical outcomes, and logistic regression to identify predictors of seroma formation.  Results  Significant differences were observed among the three groups. Group B showed the highest mean total drainage volume (210 ml) compared with Groups A (146.5 ml) and C (145 ml) (p < 0.001). The incidence of clinically relevant seromas was also greater in Group B (32%) than in Group A (20%) and Group C (11%) (p = 0.0008). Logistic regression confirmed surgical technique as an independent predictor of seroma development, while BMI, smoking, diabetes, and operative time were not statistically significant. Among patients who developed seromas, mean fluid volume was higher in Group B (58 ml) than in Groups A (41 ml) and C (45 ml). No significant differences were found regarding infection rate, wound dehiscence, or reoperation.  Conclusion  The findings demonstrate that the electrosurgical coagulation technique using dry gauze is associated with increased postoperative exudation and seroma formation, likely due to higher thermal injury and lymphatic disruption in subcutaneous tissue. Conversely, cutting mode and coagulation with saline-moistened gauze minimize heat diffusion and reduce seroma incidence. Incorporating cold saline as a contact medium represents a simple, cost-effective strategy to enhance safety and outcomes in post-bariatric abdominoplasty. Further randomized controlled trials with extended follow-up and ultrasound monitoring are warranted to validate these results and establish standardized dissection protocols.","language":"eng","citation":"COMPARATIVE ANALYSIS OF DISSECTION TECHNIQUES IN POST-BARIATRIC ABDOMINOPLASTY / F. Amendola ; tutor: E. Asti ;  co-supervisor: M. Marino coordinator: M. Del Fabbro. Università degli Studi di Milano, 2025 Dec 19. 38. ciclo, Anno Accademico 2025.","filename":"phd_unimi_R13993.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1193063/3174602/phd_unimi_R13993.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/906906"},"title":"SINGLE-CELL TRANSCRIPTIONAL LINEAGE TRACING REVEALS COMPLEXITY AND PLASTICITY OF BREAST CANCER PRO-METASTATIC PHENOTYPES","internalauthor":"RODA, NICOLO'","type":"Tesi di dottorato","year":"2022","abstract":"Breast cancer (BC) represents a major clinical hurdle, with metastatic outcome accounting for poor patient prognosis. Phenotypic intra-tumor heterogeneity inversely correlates with prognosis in BC and is considered at the basis of metastatization. Traditionally, BC poly-clonal structure was investigated through the genetic barcoding of cells followed by the tracing of the offspring. However, this analysis did not allow a solid investigation of the transcriptional profile associated to clones throughout tumor progression.   In this work, we exploited a recently published library of expressed barcodes to perform concomitant clonal and transcriptional tracing in breast cancer by single-cell RNA sequencing. We applied this technology to the triple-negative BC cell line MDA-MB-231 and the luminal B patient-derived xenograft MBC26 to study the transcriptional profile of clones during BC metastatization.   We found that clonal populations in vivo display proliferative heterogeneity, with some clones expanding more than others. Furthermore, we showed that single clones mainly activate one of two distinct transcriptional programs, either highly-proliferative or migratory/stressed/stem-like. Remarkably, we found that most times the same clones in distinct tumors display a high similarity in terms of transcriptional profile. In this scenario, however, we found that the metastatic progression of a clone is not determined by the clonal lineage, as a given clone can spread metastases in one tumor without being metastatic in another one. We found that the metastases to lungs and liver are composed of an overlapping setting of clones, with the vast majority of metastatic cells deriving from a single pro-metastatic clone. Notably, we showed that the pro-metastatic clones upregulate a set of genes that significantly distinguish them from the non-metastatic ones. These genes display a strong and significant clinical value, as they can be condensed in gene signatures predicting worse BC patient prognosis. Mechanistically, the pro-metastatic clones were shown to hyper-activate pathways involved in extracellular matrix (ECM) deposition, hypoxia response, unfolded protein response (UPR), type-I interferon (IFN) response, and migration, thereby reinforcing the role of these pathways in metastasis spreading. In line with this, we demonstrated that the knock-down of five that were upregulated by the pro-metastatic clones and involved in the above-mentioned processes (i.e., ANGPTL4, KCNQ1OT1, ITGB4, LY6E, and IFI6) significantly reduced the metastatic burden in vivo. Therefore, our work provided an unprecedented insight in the clonal phenotype that fosters metastatic progression in BC.","language":"eng","citation":"SINGLE-CELL TRANSCRIPTIONAL LINEAGE TRACING REVEALS COMPLEXITY AND PLASTICITY OF BREAST CANCER PRO-METASTATIC PHENOTYPES / N. Roda ; supervisor: P. G. Pelicci. Dipartimento di Oncologia ed Emato-Oncologia, 2022 Mar 14. 33. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12075.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/906906/1978449/phd_unimi_R12075.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1238820"},"title":"Valutare la giustizia spaziale nei processi di rigenerazione urbana. La valutazione di impatto sociale come  strumento di insorgenza (italiano)","internalauthor":"D'ANTONIO, GIULIA","type":"Tesi di dottorato","year":"2026","abstract":"Spatial justice involves the organization and management of space and the distribution of resources in an equitable way, with the goal of addressing the structural inequalities that shape urban life. Adopting a spatial justice perspective means critically questioning urban transformation processes, the power relations that underpin them, and the ways in which local communities are included, or excluded, from decision-making.  Within this framework, the Social Impact Assessment (SIA) – conceived as the process of analyzing, monitoring, and managing the social changes generated by planned interventions – emerges as a potentially transformative tool. Freed from a purely technical or functionalist use, SIA can be rethought as a situated and political practice, capable of guiding urban planning toward more just, inclusive, and participatory forms.  This research explores the potential of SIA as a tool to prevent exclusion and gentrification in urban regeneration projects. The selected case study is the Città Studi neighborhood in Milan, the site of a significant transformation project led by the University of Milan, which involves relocating its scientific departments to the former Expo area (MIND - Milan Innovation District). This intervention represents a paradigmatic example of the growing role of universities in contemporary urban processes—not only as knowledge producers, but also as political and economic actors.  The study investigates how decision-making processes in urban regeneration are structured, whether and how spatial and social impact assessments are implemented, which communities are involved or excluded, and what role planning tools play in fostering grassroots participation. Special attention is given to the ambivalent role of the university—as both a potential agent of change and a driver of urban inequality.  Adopting a feminist and decolonial perspective, the research calls for a paradigm shift toward an insurgent form of planning, where evaluation is not merely technical, but becomes a space of conflict, co-creation, and radical imagination. SIA is proposed as a situated epistemological practice rooted in the knowledge of those who inhabit and transform the city, and as a means of recognizing and confronting the power dynamics embedded in urban space.  In this context, the research asks how we, as researchers and planning professionals, can act ethically, construct genuinely just urban regeneration processes, and bridge the gap between theory and practice, between transformative visions and concrete urban realities.","language":"ita","citation":"Valutare la giustizia spaziale nei processi di rigenerazione urbana. La valutazione di impatto sociale come  strumento di insorgenza / G. D'antonio ; tutor: M. Brambilla ; cotutor: M. Boffi ; coordinator: E. Damiani. Dipartimento di Lingue, Letterature, Culture e Mediazioni, 2026 Apr 29. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14171.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1238820/3313016/phd_unimi_R14171.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/814079"},"title":"THE INVOLVEMENT OF THE NOTCH PATHWAY IN THE GNRH NEURONS DEVELOPMENT","internalauthor":"COTELLESSA, LUDOVICA","type":"Tesi di dottorato","year":"2021","abstract":"The proper development of the hypothalamic-pituitary-gonadal (HPG) axis is essential for normal  reproductive competence. Misfunctions in the axis that impairs GnRH synthesis or function result in  GnRH deficiency. Idiopathic congenital hypogonadotropic hypogonadism (CHH) is a rare  reproductive disorder, with significant heterogeneity of genetic inheritance, that is primarily caused  by gonadotropin-releasing hormone (GnRH) deficiency. Clinically, the disorder is characterized by  an absence of puberty and infertility. In approximately 50% of cases, CHH patients also suffer from  a reduced or deficient sense of smell (hyposmia or anosmia, respectively). In this case, the disorder  is termed Kallmann syndrome (KS) and results from a failure or incomplete embryonic migration of  GnRH-producing neurons. The significance to elucidate the genetic causes of CHH is related to the  relatively high percentage (about 50%) of patients that are still considered idiopathic. It is known  from the literature that Notch signaling has a role in the migration of neurons in the developing cortex  and that it is expressed in the olfactory system of many species, so we would like to understand if  Notch signaling has a role in the migration of GnRH neurons in the olfactory system. Hence, the aim  of my PhD was to understand: 1) if Notch signaling molecules are expressed along the GnRH  migratory pathway in human fetal and adult post-mortem brain sections; 2) if Notch plays a role in  the establishment of the correct GnRH migratory process or GnRH axonal targeting to the  hypothalamic regions, using zebrafish as an in vivo model; 3) to address whether patients affected by  CHH present mutations in the Notch signaling pathway; 4) to functionally validate the eventual  mutations using an immortalized GnRH cell line (GN11).  We explored by multiplex fluorescent in situ hybridization and immunohistochemical assays the  expression of both JAG1, NOTCH1 and NOTCH2 in coronal human fetal sections of the nasal  compartment and nasal/forebrain junctions in early developmental stages. These experiments  revealed that JAG1, NOTCH1 and NOTCH2 are expressed along the GnRH migratory pathway during  human fetal development, suggesting a paracrine and/or autocrine mechanism. We then used   zebrafish as in vivo model to investigate the involvement of jag1 in GnRH3 neurons development  and migration. Firstly, we have demonstrated the expression of jag1a, jag1b, notch1a and GnRH3 in  the olfactory placode of zebrafish embryos, revealing a possible collaboration between these factors  in the GnRH3 neurons development. Taking advantage of the zebrafish transgenic line  tg(GnRH3:EGFP), we demonstrated that downregulation of jag1b, but not jag1a, strongly affects the  development of the GnRH3 neurons at 48 and 72hpf. Treatment of tg(GnRH3:EGFP) embryos with  the Notch inhibitor, DAPT (γ-secretase inhibitor), phenocopied the morpholino experiments, further  supporting a role for notch1/jag1 in the development of GnRH3 neurons. Additionally, we performed  migration assay on immortalized GnRH cells, and we observe that JAG1 act as a repellent factor for  the motility of these cells.  Based on the human and zebrafish data and considering the KS-like phenotype of our jag1b  morphants, we next sought in our cohort of CHH/KS patients for possible mutation in JAG1 gene and  four rare missense variants in the JAG1 gene were identified (R117G, F206Y, Y931I, 1160N).  Overexpression of all JAG1 variants in GN11 cell line coupled with an immunofluorescence assay  revealed that only the JAG1 variant D1160N was mislocalized and retained into the cytoplasm. The  functionality was evaluated through the Luciferase assay, and D1160N variant did not activate the  transcription of the Notch Responsive Element promoter. Combining morphological analysis in vivo  (in human and zebrafish), together with genetic and pharmacological manipulation in zebrafish, and  human genetic analysis, we provide compelling evidence that Notch1/Jag1 signaling has a role in the  development of GnRH neurons/olfactory system and indicate that Notch1/Jag1 signaling  insufficiency may contribute to the pathogenesis of CHH in humans.","language":"eng","citation":"THE INVOLVEMENT OF THE NOTCH PATHWAY IN THE GNRH NEURONS DEVELOPMENT / L. Cotellessa ; tutors: L. PERSANI, P. GIACOBINI ; supervisors: M. BONOMI, V. VEZZOLI ; phd coordinator: M. LOCATI. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2021 Mar 12. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11974.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/814079/1702862/phd_unimi_R11974.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1038352"},"title":"ONLINE LEARNING METHODS FOR DIGITAL MARKETS","internalauthor":"COLOMBONI, ROBERTO","type":"Tesi di dottorato","year":"2024","abstract":"We cast several problems arising from digital markets and economics into an online learning framework, where a learner sequentially interacts with an unknown environment, trying to discover its relevant features to maximize her cumulative reward.    After an introduction to online learning in Chapter 1, we start with a study of the bilateral trade problem in Chapter 2.  Here, the learner plays the role of a broker whose goal is to increase the value of the market by sequentially interacting with pairs of sellers and buyers, facilitating trades between them.  We show how the interplay between the feedback received by the learner and the set of available trading mechanisms affects the attainable regret regimes, devising ad hoc solutions to address the exploration/exploitation dilemma in various types of environments.    In Chapter 3, we present an analysis of transparency in repeated first-price auctions.  Here, the learner participates in a sequence of first-price auctions to win objects whose exact value is revealed only when she wins the corresponding auction.  We show how the level of transparency of the auctioneer (i.e., the amount of information disclosed at the end of each auction) influences the regret rates in different types of environments.        In Chapter 4, we study the problem of adaptive optimal taxation.  Here, the learner plays the role of a policymaker whose goal is to increase social welfare (seen as a weighted sum of private utility and public revenue) by sequentially setting the tax rate in the labor market.  Interestingly, once framed in a formal online learning setting, this problem can be seen as a non-trivial generalization of the classical dynamic pricing problem.        Finally, in Chapter 5, we propose an abstract framework generalizing bandits with delayed feedback.  This framework allows us to capture scenarios arising frequently in advertising campaigns, where the feedback received comes in the form of delayed and composite income, the sources of which depend on the actions the learner took in the past, and whose exact contributions are not easily identifiable.","language":"eng","citation":"ONLINE LEARNING METHODS FOR DIGITAL MARKETS / R. Colomboni ; supervisor: N. Cesa-Bianchi ; co-supervisor: M. Pontil, T. Cesari ; coordinatore: R. Sassi. - Milano. Dipartimento di Informatica Giovanni Degli Antoni, 2024 Apr. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R12845.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1038352/2381318/phd_unimi_R12845.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/957397"},"title":"THE DIMENSIONS OF VARIABILITY MODELING OR, ON THE DESIGN OF SOFTWARE AND LANGUAGE PRODUCT LINES","internalauthor":"FAVALLI, LUCA","type":"Tesi di dottorato","year":"2023","abstract":"Modern software systems must fulfill the needs of an ever-growing customer base. Due to the innate diversity of human needs, software should be customizable and reconfigurable. During the last decades, researchers and practitioners gained interest in Software Product Lines as an engineering technique suited to manage the complexity of highly-variable software systems without resorting to the clone-and-own approach, which is empirically proven to reduce the maintainability of software assets. This dissertation discusses several design aspects of Software Product Lines, with particular attention dedicated to the topic of Language Product Lines, i.e., Software Product Lines for the creation of families of programming language compilers and interpreters. The dissertation will overview the entire life-cycle of a Language Product Line: conception, creation, development, testing, deployment and maintenance. Each phase requires the proper tools and techniques, including an evaluation framework for the assessment of the quality of the results.","language":"eng","citation":"THE DIMENSIONS OF VARIABILITY MODELING OR, ON THE DESIGN OF SOFTWARE AND LANGUAGE PRODUCT LINES / L. Favalli ; tutor: W. Cazzola ; phd school headmaster: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2023 Apr 27. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12627.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/957397/2155092/phd_unimi_R12627.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1196116"},"title":"GOVERNANCE, TRADE FINANCING AND SANCTIONS: A MULTI-LAYERED OF BANCA COMMERCIALE ITALIANA'S BRANCHES IN LONDON AND NEW YORK 1921 - 1941.","internalauthor":"CASTELLI, FEDERICO","type":"Tesi di dottorato","year":"2025","abstract":"The thesis Governance, Trade Financing, and Sanctions: A Multi-Layered Analysis of Banca Commerciale Italiana’s Branches in London and New York, 1912–1941 investigates the evolution of international banking practices through the lens of Banca Commerciale Italiana’s (Comit) operations in London and New York during a period marked by profound economic and political upheaval. Combining social network analysis with institutional and archival methodologies, the thesis explores how changing models of governance, financial intermediation, and external constraints shaped the trajectories and activities of Comit in London and New York.  The study begins by analysing the transformation of managerial élites within Comit, focusing on the careers of Carlo Lovioz and Guglielmo Reiss Romoli. Their respective experiences—Lovioz rooted in a cosmopolitan, relational banking culture, and Romoli emerging from a more technocratic, domestically trained environment—reflect broader shifts in the composition and functioning of Italian financial élites. Through a reconstruction of their professional networks, the analysis reveals how managerial roles were shaped by the interplay between traditional relational practices and the growing importance of technical expertise. This duality underscores the coexistence of overlapping governance models and the evolution of Italian elites during the interwar years. Further attention is given to the role of Comit’s foreign branches in supporting trade finance amid the volatility of the global economy, particularly in the aftermath of the 1929 crash and the 1931 Banking Crisis. By examining the operational strategies of the Bank’s New York and London offices, the research highlights how Comit adapted its international presence to shifting macroeconomic conditions and institutional environments in the two main financial hub of the period. The study traces the evolution of the bank’s business specialisations, while also addressing the internal reorganisations that followed major financial disruptions in the Bank’s U.S. network during 1930s. The final section of the thesis turns to Comit’s role in navigating the international sanctions regime imposed on Italy following the invasion of Ethiopia and enforced by the League of Nations in 1935. The analysis situates Comit within the broader landscape of financial diplomacy, examining how the bank contributed to Italy’s economic reintegration during a period of political isolation. Particular focus is placed on Comit’s activity in London, where it played an important role in re-establishing financial relations with British banks despite the constraints of the economic and financial sanctions’ framework and the new international economic governance that emerged after the devaluation of sterling. Through a detailed examination of British enforcement mechanisms, bilateral clearing systems, and Comit’s facilitative role in sustaining the Italian merchant vessel fleet, the thesis sheds light on the bank’s capacity to mediate between state interests and private financial networks.  Overall, the research provides an integrated interpretation of the interplay between managerial agency, institutional change, and international constraints in shaping the trajectory of Italian banking abroad. It offers new insights into the governance structures, operational adaptations, and the strategies that defined Comit’s international activities throughout interwar.","language":"eng","citation":"\"GOVERNANCE, TRADE FINANCING AND SANCTIONS: A MULTI-LAYERED OF BANCA COMMERCIALE ITALIANA'S BRANCHES IN LONDON AND NEW YORK 1921 - 1941 / F. Castelli ; tutor: G. Maifreda, Stefano Ugolini ; coordinatore : P. Grillo. - Milano. Dipartimento di Studi Storici \"\"Federico Chabod\"\", 2025 Nov 19. 37. ciclo\"","filename":"phd_unimi_R13254.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 14-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/976049"},"title":"LA NOZIONE DI AIUTO DI STATO E LA NECESSITÀ DI UNA NUOVA MODERNIZZAZIONE DELLA DISCIPLINA","internalauthor":"LATORRE, ESTER","type":"Tesi di dottorato","year":"2023","abstract":"The purpose of this dissertation is to analyse the notion of State aid, with the aim of understanding whether it is still adequate to respond to the new needs inherent to the European single market as a result of recent economic and political events.  The analysis starts from the examination of State aid competences, since they are the backbone of the whole system, which, as is well known, is regulated by Art. 107 et seq. TFEU. In this context, the focus is on the intersection between the primary authority of the Member States, which, at least at an initial stage, have full discretion as to the granting of a measure of advantage, and the strong powers of the European Commission, the only institution entrusted with aid control.  Having examined how the intersection between these competences constitutes a point of encounter and, in some respects, of collision in this field, this research analyses the genesis and evolution of the notion of State aid, in order to understand the path that led to its current definition contained in a 2016 Commission notice (the “Commission Notice on the notion of State aid as referred to in Article 107(1) of the Treaty on the Functioning of the European Union”), which is also discussed in detail.  Having established the foundation, the focus then shifts to the impact that two recent events have had on the State aid regulation: the Covid-19 pandemic and the Russian-Ukrainian conflict. The economic crises they generated resulted in State aid becoming one of the most widely used tools to provide relief for the real economy: in this context, the temporary frameworks issued to deal with the situation are analysed, as well as the interpretation that was given to the notion of aid.  In the same perspective of understanding how modern events may have conditioned the definition in question (and vice versa), the paper first looks at the Brexit phenomenon and the difference between the European notion of “State aid” and the international notion of “subsidy”, and then inserts a third term of comparison given by the concept of “foreign subsidies”, which is the topic of a very recent protectionist regulation issued by the EU legislator.  Finally, an extensive reflection is dedicated to the prospects of modernising the notion of State aid, where it is argued that the start of a new innovation process may be the key to the correct maintenance of level playing field.","language":"ita","citation":"LA NOZIONE DI AIUTO DI STATO E LA NECESSITÀ DI UNA NUOVA MODERNIZZAZIONE DELLA DISCIPLINA / E. Latorre ; tutor: F. Rossi Dal Pozzo; coordinatore: F. Biondi. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2023 Jul 04. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12579.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/976049/2219781/phd_unimi_R12579.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/980671"},"title":"SCREENING AND IDENTIFICATION OF NEW FOOD DERIVED PEPTIDES WITH MULTI-TARGET CHOLESTEROL-LOWERING ACTIVITY","internalauthor":"LI, JIANQIANG","type":"Tesi di dottorato","year":"2023","abstract":"In recent years, there is a significant focus on the potential health benefits of food peptides. These short and medium-size peptides are produced by the hydrolysis of food proteins and may be absorbed by the body to modulate specific metabolic pathways by binding or inhibiting targeted receptors. This modulation can lead to positive effects on metabolic diseases, making it particularly noteworthy because it aligns with the trend of many individuals seeking healthier lifestyles through dietary management rather than relying on pharmaceuticals. Additionally, bioactive peptides are typically associated with very low or non-existent toxic or adverse effects. Thus, the identification and exploration of the mechanisms behind bioactive peptides present the opportunity to develop innovative functional foods and nutraceuticals. To date, eggs, meat, fish, soybean, wheat, milk, and its derivatives have been the primary sources of bioactive peptides, as they are widely available and easily accessible. Notably, recent research has also focused on alternative sources such as lupin and hempseed, which are rich in protein and have shown promising health benefits. Lupin, a legume commonly found in Mediterranean countries, has been found to contain bioactive peptides that can lower blood pressure and improve cardiovascular health. Similarly, hempseed, derived from the industrial hemp, has been shown to have anti-inflammatory and antioxidant properties, making it a potential source of bioactive peptides that could have a range of health benefits. Based on these considerations, the aim of this PhD thesis was to screen and identify new promising peptides from lupin and hempseed protein. The identified peptides were evaluated for their ability to target hypercholesterolemia, which is a medical condition characterized by high levels of cholesterol and is a major risk factor for the development of cardiovascular disease (CVD). To achieve this objective, multidisciplinary approaches were employed, involving peptidomic techniques to profile the peptide sequences, molecular modeling methods to predict potentially bioactive peptides, and biochemical and cellular tools to evaluate the bioactivity of peptides and to explore their possible mechanism of action.  Briefly, in the present study, the peptides derived from lupin (Lupinus albus) and hempseed (Cannabis sativa) generally presented significant cholesterol-lowering activity. In detail, peptides derived from lupin showed PCSK9 inhibitory activity. Among these, the most active peptide, known as P5 (LILPHKSDAD), reduced the protein-protein interaction between PCSK9 and LDLR with an IC50 equals to 1.6 µM and showed a dual hypocholesterolemic activity, since it shows complementary inhibition of the HMGCoAR. Moreover, P5 was successfully transported by differentiated human intestinal Caco-2 cells through transcytosis, and, during transport, it was partially metabolized in a breakdown fragment (LPKHSDAD, P5-met), which retained the biological activity of the parent peptide. Based on these observations, P5 analogs, including P5-Best (LYLPKHSDRD), P5-H6A (LILPKASDAD) and P5-S7A (LILPKHADAD), were computationally designed to target both PCSK9 and HMGCoAR, displaying an improved and dual hypocholesterolemic activity evaluated by biochemical assays. In addition, hydrolysates derived from hempseed were shown to have a hypocholesterolaemia effect by dropping the activity of the HMGCoAR, showing a similar cholesterol-lowering activity of statins. Since proteins are hydrolysed during digestion, the activity may be attributed to specific peptides encrypted in the protein sequences that are released by digestion and absorbed at an intestinal level. Hence, further experiments using intestinal trans-epithelial transport revealed that among the peptides contained within hempseed hydrolysates are able to pass through the mature Caco-2 cell barrier. Particularly, peptide H3 (IGFLIIWV) possess antioxidant activity in HepG2 cells by modulating the Nrf-2 and iNOS pathways, leading to the decrease of cellular H2O2-induced ROS, NO, and lipid peroxidation levels. Meanwhile, since there is a link between inflammation and oxidative stress, the evaluation of the anti-inflammatory effect of peptide H3 in HepG2 cells was carried out. As expected, peptide H3 was shown to modulate the production of pro (IFN-γ, TNF and IL-6)- and anti (IL-10)-inflammatory cytokines and NO through regulation of the NF-κB and iNOS pathways, exerting an anti-inflammatory capacity in the HepG2 cells. Furthermore, a deeper mechanistic investigation of peptide H3 was also performed in HepG2 cells. Peptide H3 can modulate the activity of the key targets involved in cholesterol metabolism, i.e., LDLR, SREBP-2, HMGCoAR, p-AMPK (Thr 172), HNF-1α, and PCSK9, and improve the capacity of HepG2 cells treated with peptide H3 to absorb extracellular LDL cholesterol.  In conclusion, the investigation of bioactive peptides holds significant promise in developing novel molecular entities with hypocholesterolemic activity. This study provides valuable insights into the potential of lupin peptides (P5 and its derivatives) and hempseed peptide (H3) as peptide-based inhibitors targeting PCSK9 and HMGCoAR, making them viable candidates for hypocholesterolemic interventions. However, it is important to acknowledge that in cases where the condition's severity leads to significant pathology, food- or food-supplement-based interventions may not be effective. Additionally, it is crucial to recognize that the current evidence is primarily derived from in vitro studies, highlighting the need for further research to validate these findings in animal models and human clinical trials. Conducting rigorous clinical trials in the future will provide a more comprehensive understanding of the efficacy and safety of bioactive peptides, ultimately enhancing cholesterol management strategies and improving overall health outcomes. In summary, this study underscores the promise of investigating bioactive peptides for hypocholesterolemic interventions. Nevertheless, it is imperative to conduct additional research to validate these findings and consider the limitations of food- or food-supplement-based approaches in cases involving severe pathology. By addressing these knowledge gaps, we can advance our understanding of bioactive peptides, optimize cholesterol management strategies, and ultimately improve overall health outcomes.","language":"eng","citation":"SCREENING AND IDENTIFICATION OF NEW FOOD DERIVED PEPTIDES WITH MULTI-TARGET CHOLESTEROL-LOWERING ACTIVITY / J. Li ; Faculty advisor: C.  Lammi ; PhD coordinator: G. Vistoli. Università degli Studi di Milano, 2023 Jul 11. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12715.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/980671/2234163/phd_unimi_R12715.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/887953"},"title":"ENDOTHELIUM IN PETRI DISH (2D) OR ON-A-CHIP (3D): STUDIES ON ENDOTHELIAL FUNCTION / DYSFUNCTION","internalauthor":"SCRIMIERI, ROBERTA","type":"Tesi di dottorato","year":"2022","abstract":"Endothelial cells (ECs) form the inner layer of all the blood vessels and, due to this strategic localization, they constantly face oscillating blood glucose concentrations in relation to the pre- and post- prandial cycles. They do not represent a passive barrier between blood and tissues, but they play a wide variety of pivotal roles to control vascular homeostasis. Uncontrolled hyperglycaemia elicits ECs to become dysfunctional, leading to the onset of endothelial dysfunction, defined as a shift of properties of the endothelium toward a proinflammatory and prothrombotic phenotype characterised by altered release of Nitric  Oxide (NO) and overproduction of pro-inflammatory cytokines and Reactive Oxygen Species (ROS). Endothelial dysfunction is classically described in patients affected by diabetes and has a role in the pathogenesis of many cardiovascular complications associated with this pathology. In particular, diabetes is a group of life-long chronic metabolic disorders characterized by high levels of glucose in the blood and by a predisposition to premature atherosclerosis, the main reason for high morbidity and impaired life expectancy in patients. To investigate the effects of high glucose on ECs, Human Umbilical Vein Endothelial Cells (HUVEC) were cultured in the presence of either high glucose-containing medium or of blood sera collected from diabetic patients. Cells were seeded both in 2D cell culture systems on flat dishes, a method which has yielded major advances in our knowledge about endothelial pathophysiology, and in 3D microfluidic chips, which show a higher degree of structural complexity allowing perfusion, thus generating shear stress fundamental for endothelial homeostasis. In 2- and 3- D, the cells were cultured until they reach confluence to reproduce the physiological inner layer of a blood vessel as closely as possible. High glucose rapidly alters the cellular redox balance resulting in a higher production of ROS associated with a lower content of the antioxidant glutathione (GSH). ROS induce iNOS, which overproduces NO leading to endothelial hyperpermeability. In parallel, mitochondrial dysfunction occurs as a result of the imbalance in mitochondrial dynamics in favour of mitochondrial fission. This evidence is connected to the higher storage of triglycerides caused by both enhanced lipogenesis and reduced β-oxidation.  The next step was to individuate a countermeasure that might prevent the detrimental effects of high glucose on HUVEC. Numerous observational studies demonstrated that the circulating levels of Vitamin D3 (VitD) are low in patients affected by diabetes. In these experimental models, VitD is capable of blocking the increase of ROS production, thus preventing all the harmful effects caused by high glucose on HUVEC.   In summary, the results reveal that it is fundamental to keep glycaemia within the physiological range in diabetic patients, preventing hyperglycaemic peaks, and that VitD could represents a serviceable tool to control the redox equilibrium, thus re-establishing NO levels and permeability and mitochondrial fitness, to limit or at least delay the insurgence of endothelial dysfunction caused by high fasting glucose concentrations.","language":"eng","citation":"ENDOTHELIUM IN PETRI DISH (2D) OR ON-A-CHIP (3D): STUDIES ON ENDOTHELIAL FUNCTION / DYSFUNCTION / R. Scrimieri ; tutor: J.A.M. Maier ; director: N. Landsberger. Dipartimento di Scienze Biomediche e Cliniche L. Sacco, 2022 Jan 17. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12363.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/887953/1925875/phd_unimi_R12363.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/818694"},"title":"THE WEIGHTED QUANTILE SUM REGRESSION: EXTENSIONS AND APPLICATIONS","internalauthor":"RENZETTI, STEFANO","type":"Tesi di dottorato","year":"2021","abstract":"During these last few years an increasing body of scientific evidence showed that looking at the single exposure to chemicals without considering the mixture effect can cause an underestimate of the chemical exposures risk. This poses also statistical challenges on how to manage more complex datasets. Weighted Quantile Sum (WQS) regression is a new statistical model that allows to deal with this problems. It is able to test the association of the overall environmental exposures with an outcome and to find the main actors in the association between the exposure and the dependent variable.  Through this work we showed how we adapted the model to allow to fit a WQS regression in presence of binary, multinomial and count outcomes. Moreover, we implemented two more extensions: the possibility to test for an interaction between the WQS index (representing the overall exposure) and a continuous or categorical variable; and the ability of having two indices in the same model, one looking in the positive and the second in the negative direction when the mixture can have a bidirectional effect on the outcome. The first extension answers to a frequent and important line of inquiry in epidemiologic studies that is whether there is an effect modification (i.e., an interaction) between an exposure and a particular covariate of interest that can affect the association between the exposure and the outcome. The second extension allows to estimate both the protective and harmful effect of the mixture within the same regression model. Lastly, we showed how to apply this novel method in the genetic context thanks to the inclusion of the double WQS index. We then compared its results with the standard methodology used to test the effect of a gene set on a particular phenotype.  The simulation studies performed to test the new extensions showed the good performance of the methods reducing the bias and standard error of the estimates of the effect of the mixture on the outcome and correctly identifying the elements in the mixture that play a major role in the studied association. A high specificity was also observed. Through the case studies we were able to see how WQS confirmed previous major findings and providing new insights respect to previous literature. When we tested for the interaction between age or sex and the exposure to lead (Pb), cadmium (Cd), mercury (Hg), selenium (Se) and manganese (Mn) we found that the association between the forced vital capacity (FVC) and Pb and Hg was attenuated among older children, while female FVC is more susceptible to Cd and Hg compared to males. The application of the double index to test the association between 43 nutrients and obesity showed a harmful effect of moisture (from all sources), polyunsaturated fatty acids, saturated fatty acids, sodium, caffeine and cholesterol while a protective effect was found for beta-carotene, vitamin B12, vitamin B6, vitamin D, folic acid, vitamin C, folate DFE and alpha-carotene. Finally, through WQS we observed a significant role of the genes involved in cell-cycle in the risk of death for ovarian cancer which was not shown applying single sample Gene Set Enrichment Analysis.  The advantages of WQS regression and the extension that we described in this work are the ease of use and interpretation of the results; moreover, none of the other environmental mixture methods allow to consider the effect modification due to a covariate or to measure the amount of positive and negative association when the elements in the mixture show both effects. This work will be the starting point for additional future extensions, improvements and applications of the model while all these extensions will be implemented in the gWQS package of the statistical software R.","language":"eng","citation":"THE WEIGHTED QUANTILE SUM REGRESSION: EXTENSIONS AND APPLICATIONS / S. Renzetti ; tutor: M. Ferraroni, S. Calza ; coordinatore: C. La Vecchia. Dipartimento di Scienze Cliniche e di Comunità, 2021 Mar 10. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11883.pdf","fileformat":"Adobe PDF","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/818694/1715813/phd_unimi_R11883.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/931483"},"title":"TRACTABLE DEPTH-BOUNDED APPROXIMATIONS TO SOME PROPOSITIONAL LOGICS. TOWARDS MORE REALISTIC MODELS OF LOGICAL AGENTS.","internalauthor":"SOLARES ROJAS, ALEJANDRO JAVIER","type":"Tesi di dottorato","year":"2022","abstract":"The depth-bounded approach seeks to provide realistic models of reasoners. Recognizing that most useful logics are idealizations in that they are either undecidable or likely to be intractable, the approach accounts for how they can be approximated in practice by resource-bounded agents. The approach has been applied to Classical Propositional Logic (CPL), yielding a hierarchy of tractable depth-bounded approximations to that logic, which in turn has been based on a KE/KI system. This Thesis shows that the approach can be naturally extended to useful non-classical logics such as First-Degree Entailment (FDE), the Logic of Paradox (LP), Strong Kleene Logic (K3) and Intuitionistic Propositional Logic (IPL). To do this, we introduce a KE/KI-style system for each of those logics such that: is formulated via signed formulae, consist of linear operational rules and branching structural rule(s), can be used as a direct-proof and a refutation method, and is interesting independently of the approach in that it has an exponential speed-up on its tableau system counterpart. The latter given that we introduce a new class of examples which we prove to be hard for all tableau systems sharing the ∨/∧ rules with the classical one, but easy for their analogous KE-style systems. Then we focus on showing that each of our KE/KI-style systems naturally yields a hierarchy of tractable depth-bounded approximations to the respective logic, in terms of the maximum number of allowed nested applications of the branching rule(s). The rule(s) express(es) a generalized rule of bivalence, is (are) essentially cut rule(s) and govern(s) the manipulation of virtual information, which is information that an agent does not hold but she temporarily assumes as if she held it. Intuitively, the more virtual information needs to be invoked via the branching rule(s), the harder the inference is for the agent. So, the nested application of the branching rule(s) provides a sensible measure of inferential depth. We also show that each hierarchy approximating FDE, LP, and K3, admits of a 5-valued non-deterministic semantics; whereas, paving the way for a semantical characterization of the hierarchy approximating IPL, we provide a 3-valued non-deterministic semantics for the full logic that fixes the meaning of the connectives without appealing to “structural” conditions. Moreover, we show a super-polynomial lower bound for the strongest possible version of clausal tableaux on the well-known class of “truly fat” expressions (which are easy for KE), settling a problem left open in the literature. Further, we investigate a hierarchy of tractable depth-bounded approximations to CPL based only on KE. Finally, we propose a refinement of the p-simulation relation which is adequate to establish positive results about the superiority of a system over another with respect to proof-search.","language":"eng","citation":"TRACTABLE DEPTH-BOUNDED APPROXIMATIONS TO SOME PROPOSITIONAL LOGICS. TOWARDS MORE REALISTIC MODELS OF LOGICAL AGENTS / A.j. Solares Rojas ; supervisore: A. Zamansky, M. D'Agostino ; coordinatore: A. Pinotti. Dipartimento di Filosofia Piero Martinetti, 2022 Jul 15. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12279.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/931483/2043800/phd_unimi_R12279.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1204983"},"title":"HIGH-THROUGHPUT PROFILING OF INNATE IMMUNE CELLS TO UNVEIL TUMOR ESCAPE MECHANISMS IN MATCHED COLORECTAL CANCER AND LIVER METASTASES","internalauthor":"MARZANO, PAOLO","type":"Tesi di dottorato","year":"2026","abstract":"\"Colorectal cancer (CRC) represents one of the leading global health burdens, with the liver being its predominant site of distant metastasis. A significant proportion of patients with colorectal liver metastases (CRLM) are diagnosed with synchronous lesions (sCRLM), identified at or shortly after diagnosis of the primary tumor, a clinical scenario linked to aggressive disease and poor outcomes. A major clinical challenge in this setting is that the majority of CRCs with liver metastasis are microsatellite stable or low instable (MSS or MSI-L, respectively), tumor types largely unresponsive to immune checkpoint (IC) therapies. Indeed, MSS/MSI-L tumors display \"\"immune cold\"\" microenvironments dominated by immunosuppressive mechanisms, which severely constrain treatment options. This unmet clinical need highlights the importance of dissecting the immune microenvironment of sCRLM, to identify early drivers of metastatic progression and highlight immunological features with therapeutic potential, ultimately supporting a new immune-weighted stratification of patients for novel therapeutic approaches.  To this end, we combined single-cell transcriptomic with paired V(D)J profiling to generate a multi-compartmental innate immune map of synchronous CRC and matched sCRLM, together with circulating blood samples.  Our analyses revealed that Tumor-Associated Macrophages (TAMs) and Dendritic Cells (DCs) emerged as dominant players of the tumor microenvironment (TME) along divergent tumor-specific trajectories. In CRC, TAMs were enriched in inflammatory states that paradoxically supported immune activation while simultaneously laying the groundwork for metastatic dissemination. Conversely, CRLM was dominated by proliferative CTLA4high immunoregulatory TAMs, whose higher frequencies were associated with shorter disease-free survival and worse prognosis. Furthermore, we identified two CRLM-specific TAM subsets characterized by IL7R expression and a cytotoxic/NK-like signature, suggesting unconventional differentiation trajectories or functional mimicry through trogocytosis. In parallel, DCs displayed a CRLM-specific developmental program in which cDC1 subsets differentiated into immunoregulatory LAMP3+ DCs (mregDCs) enriched for IDO1 expression and immune checkpoint ligands.  Natural Killer (NK) and Innate Lymphoid Cells (ILCs) showed strikingly distinct patterns between blood and tumor tissues. Circulating NK cells followed a canonical CD56bright-to-CD56dim trajectory, which bifurcated into a conventional cytotoxic-high branch and into a disease-specific cytokine hepatic-primed one. In sharp contrast, within CRLM the CD56bright population expanded dramatically compared to circulation, and diversified into IFNG-activated, cytotoxic-enriched, and stress-adapted states, with no developmental connection to hepatic CD56dim NK cells. Importantly, CRLM-associated CD56bright NK cells displayed concurrent upregulation of effector programs and multiple inhibitory receptors, including TIGIT, CXCR4, and SIGIRR, reflecting a paradoxical state of activation restrained by layered inhibitory checkpoints.  Finally, integrative analyses resolved a highly heterogeneous γδ T cell landscape across blood, CRC, and CRLM. Vδ1 T cells predominated in all compartments, with an inversion of the expected Vδ2 dominance in circulation, indicating disease-associated remodeling. Gene co-expression analysis revealed tissue-specific functional signatures, including IFNG-driven activation programs in tumors, cytotoxic/TEMRA modules in blood, and residency/regulatory features in CRC. By integrating TCR clonotype tracking, we uncovered direct evidence of active trafficking of identical γδ T clonotypes from blood to CRLM. Crucially, these clonotypes underwent compartment-specific functional rewiring, with cytotoxic programs preserved in circulation, whereas intrahepatic counterparts with the acquisition of exhaustion and stress signatures, highlighting the liver metastatic niche as a site of immune restraint.  Altogether, these findings delineate possible mechanisms involved in the early immunological remodeling that occurs in synchronous CRLM, showing how the hepatic niche actively reprograms myeloid, NK, and γδ T cell compartments toward states of restrained activation and immune escape. By linking clonal fate mapping with transcriptional states, this work provides a mechanistic framework for characterizing early immune influences in synchronous CRLM, reframing the liver not as a passive metastatic destination but as an active architect of immune escape. Such mechanistic insights not only expand the understanding of metastatic immune biology but also point toward new opportunities for therapeutic innovation, by paving the way for novel immunotherapeutic strategies specifically targeting IC-resistant CRLM.\"","language":"eng","citation":"HIGH-THROUGHPUT PROFILING OF INNATE IMMUNE CELLS TO UNVEIL TUMOR ESCAPE MECHANISMS IN MATCHED COLORECTAL CANCER AND LIVER METASTASES / P. Marzano ; tutor: D. Mavilio ;  co-tutor: R. Piazza ; supervisor: J. Mikulak ;  director: N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2026 Jan 27. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13849.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 22-GIU-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1230495"},"title":"HOW TO REDUCE TRANSPLANT STRESS IN URBAN TREES","internalauthor":"COMIN, SEBASTIEN","type":"Tesi di dottorato","year":"2026","abstract":"Urban vegetation is nowadays recognized as a key component of the adaptation and mitigation strategies against climate change. In this context, municipalities and public services are promoting large scale tree planting programs in urban environment. However, these programs frequently experience very high rates of planting failure within the first years after planting and slow establishment, jeopardizing their ecological and socioeconomic benefits. The success of a tree planting program depends on a multidisciplinary process, involving nursery practices, site preparation, species and stock selection, irrigation, and pruning. This thesis analyses how nursery preconditioning and post planting pruning can help reduce transplant stress and improve establishment, root development, and ecosystem service provision in young urban trees. It addresses four main questions: (i) whether substrate amendment with Ascophyllum nodosum extracts can accelerate nursery production and induce persistent morpho physiological traits that increase tolerance to transplant stress; (ii) whether pruning carried out according to best management practices during establishment can reduce the severity and duration of post planting stress (PPS) under limited irrigation, and how this interacts with species’ isohydric vs near anisohydric drought strategies; (iii) how different crown pruning techniques affect auxin mediated carbon allocation, root growth and below ground biomass; and (iv) how severe pruning influences tree cooling capacity and microclimate amelioration in street conditions.   The first experiment was conducted in a forest nursery, where seedlings of woody species were grown in a substrate amended with different doses of a pure A. nodosum extract. Growth, gas exchange and early root development were monitored. High doses increased biomass, chlorophyll content and gas exchange, and improved germination in some species, but did not lead to stable modifications in root traits or root:shoot ratio that are clearly associated with better transplant tolerance.  The second experiment was carried out within a large urban planting program and tested pruning during the establishment phase under sub optimal irrigation in near isohydric and near anisohydric species. The results indicate that the intensity of PPS was not directly related to the isohydric–anisohydric behaviour, while species identity strongly influenced recovery time. Pruning caused limited changes in water status and gas exchange, and its effect on the duration of PPS remained secondary compared with species and site conditions.  The third experiment compared different crown pruning techniques on young urban trees, monitoring leaf physiology, root growth, wood anatomy and phloem auxin concentration. Both pruning treatments did not lower root growth but instead improved the total biomass of new absorbing roots. Topping altered crown architecture and auxin transport. Reduction cuts better preserved crown architecture and shows no differences in auxin downwards translocation compared to unpruned control.  The fourth experiment quantified the effects of severe pruning on microclimate and tree physiology of street trees using micrometeorological measurements, energy balance modelling and gas exchange. Severe crown reduction markedly decreased leaf area index, shading, latent heat dissipation and canopy conductance, reducing cooling capacity and thermal comfort improvement at the site, despite temporary increases in leaf level photosynthesis.  Overall, the results highlight that reducing transplant stress in urban trees requires coordinated action across the whole establishment process. Single interventions applied in isolation are unlikely to compensate for planting material with weak root systems, unsuitable sites or irregular water supply. Instead, it is necessary to integrate nursery practices, an accurate matching between species and planting sites, and early management that supports balanced shoot–root development and stable physiological functioning. The evidence provided by this thesis contributes quantitative data and mechanistic insight that can be used to refine guidelines for urban tree production and management, and to design planting programs that are more likely to achieve long term survival and delivery of ecosystem services in real urban conditions.","language":"eng","citation":"HOW TO REDUCE TRANSPLANT STRESS IN URBAN TREES / S. Comin ; tutor: A. Fini ;  co-tutor: F. Ferrini ;  coordinatore: S. R. Pilu. - Milano - Facoltà di Agraria - DiSAA. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2026 Mar 27. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13802.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1230495/3291042/phd_unimi_R13802.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1212381"},"title":"LA DIMENSIONE COSTITUZIONALE DEL DIRITTO ALL'ORIENTAMENTO SESSUALE","internalauthor":"DI GIOVANNI, SARA","type":"Tesi di dottorato","year":"2026","abstract":"The doctoral dissertation, entitled La dimensione costituzionale del diritto all’orientamento sessuale, aims to reconstruct a right to sexual orientation within the Italian constitutional framework, moving beyond the traditional heterosexual paradigm. The approach adopted relies on an evolutionary and consistent reading of the constitutional text, intending to outline a right fully embedded in the Italian constitutional architecture.  The first chapter retraces the history of homosexuality, highlighting how it has been perceived and regulated over the centuries. From Ancient Greece to the present day, homosexuality has been subjected to repression and silence, through alternating phases of tolerance, freedom, persecution, and marginalization. This trajectory was initially shaped by Christian morality, which established the heterosexuality/homosexuality dichotomy and relegated the latter to the realm of sin, and later, in the nineteenth century, by the process of pathologization, whose effects have had a lasting impact on the social and legal perception of homosexuality and on the configuration of LGBTQ+ rights.  The second chapter examines the constitutional foundations of the protection of sexual orientation, focusing on the fundamental principles of the Italian Constitution, such as the primacy of the individual, equality, and non-discrimination. The aim is to demonstrate how these principles can provide a solid basis for the recognition of the right to sexual orientation, not as a newly created right, but as an implicit one that may emerge from the constitutional order. The chapter also considers the role of dialogue with supranational sources – most notably the European Convention on Human Rights – in affirming legal protection for sexual orientation.  The third chapter investigates the individual dimension of the right to sexual orientation, addressing crucial issues such as the right to health, freedom of expression, and the right to asylum for LGBTQ+ persons facing persecution. Despite legal and normative advances, the research highlights the persistence of discrimination, stigmatization, and marginalization, still influenced by the legacy of pathologization.  The following chapter addresses the relational dimension of the right to sexual orientation, focusing on the rights to marriage and parenthood for same-sex couples. While certain jurisprudential developments and limited legislative progress can be observed, the heterosexual paradigm continues to prevail, perpetuating inequalities and limiting the recognition of same-sex and rainbow families. The fifth chapter turns to the collective dimension of sexual orientation, centering on the representation of the LGBTQ+ community in the public and legal spheres. The community should not be regarded as a “traditional” minority, but rather as a vulnerable group which, while characterized by a plurality of identities and orientations, shares a common history of oppression and discrimination. The research analyzes the forms of social and legal representation of the LGBTQ+ community, highlighting the fundamental role of legal and political language in processes of recognition.  Ultimately, the dissertation demonstrates that the full protection of the right to sexual orientation constitutes an essential component of the constitutional project of a society committed to guaranteeing the development of personality and the dignity of every individual. The failure to recognize the rights of LGBTQ+ persons not only violates the principle of equality but also signals a broader deterioration of democracy and of the State’s capacity to ensure the inclusion of all its citizens.","language":"ita","citation":"LA DIMENSIONE COSTITUZIONALE DEL DIRITTO ALL'ORIENTAMENTO SESSUALE / S. Di Giovanni ; tutor: M. E. D'Amico ; co-tutor: B. Liberali ; coordinatrice: F. Biondi. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2026 Feb 02. 38. ciclo","filename":"phd_unimi_R13680.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 23-LUG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1215475"},"title":"DEMOGRAPHIC DECLINE IN ITALIAN MUNICIPALITIES: EMPIRICAL EVIDENCE AND EXPLORING NEW FORMS OF HORIZONTAL AND VERTICAL COORDINATION TO COUNTERACT DEPOPULATION","internalauthor":"RAUTI, ANTONIO WALTER","type":"Tesi di dottorato","year":"2026","abstract":"Italy’s demographic decline represents today the most evident reflection of a profound institutional crisis. Depopulation is not a purely demographic or economic phenomenon, but the result of a structural fragility within the governance system, unable to coherently coordinate the different levels of government, resources, and public policy instruments. The research proposes a systemic interpretation of this interdependence, showing how the capacity of local institutions to respond to decline depends on the degree of vertical and horizontal coordination and on the strategic use of digitalization. On these foundations, two original instruments have been theorized: the Municipal Fragility Index (MFI) and the Digital Fragility Index (DFI), designed to measure the demographic, administrative, and technological vulnerability of Italian municipalities. The study shows that institutional fragmentation, exacerbated by the 2014 Delrio Reform, has widened the gap between dynamic and peripheral areas, reducing planning capacity and the overall cohesion of the system. The weakness of the intermediate level of government has increased territorial inequality and made the relationship between citizens and institutions more fragile. From this diagnosis emerges a proposal based on multilevel governance as the key to demographic resilience. Vertical coordination among the State, Regions, and Municipalities, horizontal cooperation among local administrations, and inclusive digitalization constitute the pillars of a new architecture for territorial development. Integrating within this perspective the objectives of the National Recovery and Resilience Plan and the 2030 Agenda means transforming decline from a threat into an opportunity, from a symptom of backwardness into a driver of institutional innovation and community renewal. Population is not merely a variable to be managed, but the very measure of democratic vitality and of the collective capacity to build a shared future.","language":"eng","citation":"DEMOGRAPHIC DECLINE IN ITALIAN MUNICIPALITIES: EMPIRICAL EVIDENCE AND EXPLORING NEW FORMS OF HORIZONTAL AND VERTICAL COORDINATION TO COUNTERACT DEPOPULATION / A.w. Rauti ; tutor: R. Ruffini ;  coordinatore: E. Damiani ;  co-tutor: L.Violini, G. Nasi. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2026. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14032.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open from 13-FEB-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1203335"},"title":"GENETIC DISSECTION OF PLANT ARCHITECTURE TRAITS IN HORDEUM VULGARE (BARLEY)","internalauthor":"GIPLI, VALERIO","type":"Tesi di dottorato","year":"2025","abstract":"Lodging is one of the major threats that affect barley (Hordeum vulgare spp. vulgare) production by causing the fall of the plant under external forces such as rain and wind or the weight of the plant itself. Since the Green Revolution, breeders minimized the load of those forces by reducing the plant center of gravity developing semidwarf varieties. However, this approach has reached its maximum potential. Enhancing culm strength through the manipulation of culm morphology traits has been proposed as a new alternative strategy to develop resistant varieties, yet the genetic mechanisms underlying these traits remain elusive. In this context, this PhD project aimed to make a step forward to fill this gap by applying three different approaches.  Firstly, a forward genetic approach has been conducted to discover candidate genes associated with culm diameter in a 6-row big culm TILLMore mutant line (TM3325) previously discovered by our group. To prevent any pleiotropic effects due to row-type spike morphology this TM3325 line has been crossed with its background Morex and a 6-row near isogenic line of Bowman (BW898) and whole genome sequencing (WGS) data has been collected for all three parental genotypes. A WGS-based bulk segregant analysis (BSA) approach has been conducted by preparing and sequencing three contrasting pairs of DNA bulks considering second internode outer diameter, as well as plant height and spike length as these traits were also significantly divergent in the TILLING line but not strongly correlated in the F2 segregating population.  In addition, a pair of bulks contrasting for outer diameter was also analysed for the BW898 F2 population. Comparison of BSA results between the two populations suggest the presence of a candidate gene responsible for all traits in chromosome 2H while additional signals have been detected in chromosomes 4H and 5H for outer diameter, 6H for spike length and 4H for plant height. In mutant line TM3325 only the gene HORVU.MOREX.r3.2HG0180320 has been detected as harboring a potentially damaging mutation (premature STOP codon) in chromosome 2H. This is an orthologue of the Arabidopsis AtCLASP gene which encodes a microtubule associated protein involved in organ shape and size. A haplotype analysis conducted on a spring malting barley germplasm panel previously studied by Bretani et al. (2022) further showed a natural allelic variant of this gene had a significant effect on the outer diameter in 6-row cultivars.   Complementing this work, a reverse genetic approach has been applied to characterize the barley orthologue of SMOS1, a rice gene that was previously shown to regulate culm morphology traits and used in breeding lodging resistant lines. Four TILLING lines were identified from the HorTILLUS population characterized under greenhouse conditions, and a haplotype analysis was conducted considering the same population mentioned above. Although results obtained so far did not confirm the involvement of the gene in barley culm traits, the identification of four independent mutations in the gene provides a starting point for further analyses to clarify its biological role.   Finally, datasets for the diversity panel analysed by Bretani et. al (2022) were leveraged to explore the feasibility of using genomic selection to predict the section modulus trait, which indicate the strength of the culm considering only its morphology. Various alternative models were tested considering population structure caused by row-type, different marker densities and the effect of integration as fixed effect of GWAS peaks marker detected by Bretani et. al (2022). The highest predictive ability obtained was 0.82 considering together both row-type cultivars, GWAS peak markers and 100 genome-wide SNPs only. Interestingly, exclusion of 6-row varieties from the training set caused a drop of predictive ability  to 0.54 considering 5000 SNPs which may indicate an effect caused by population structure. Including 6-row cultivars in the training dataset enhanced prediction of 2-row cultivars to 0.59 indicating a beneficial effect of their inclusion.","language":"eng","citation":"GENETIC DISSECTION OF PLANT ARCHITECTURE TRAITS IN HORDEUM VULGARE (BARLEY) / V. Gipli ; tutor: L. Rossini ; co-tutor: C. da Silva Linge ; coordinatore: R. Pilu. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2025 Dec 15. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13968.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 16-GIU-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1212941"},"title":"THE PLURALISM OF MODES OF EXISTENCE: ONTOLOGY AND GENEALOGY","internalauthor":"FRIGERIO, CHRISTIAN","type":"Tesi di dottorato","year":"2026","abstract":"This thesis has two objectives: to reconstruct the genealogy of the concept of “mode of existence,” which occupies a central position in contemporary philosophical debate, both continental and analytical; and to discuss the conceptions of modes of existence developed by different authors. The first part outlines an approach called “existential ontology,” proposed as a replacement for Husserl's formal ontology once the residues of univocity are renounced and the multifariousness of being is accepted, which should allow for a comparison of the concepts of “mode of existence” proposed by the authors examined. The second part provides a general framework for interpreting the genealogy of these concepts, based on the distinction between three traditions that have conceptualized the question of modes of existence: the analytical tradition (born out of the debate between Meinong and Russell); the phenomenological tradition (originating from Husserl); and the speculative tradition (whose origin can be traced back to the early 1900s debate between William James and F.H. Bradley).The third part of the thesis follows this latter tradition, examining its developments in French philosophy, with chapters devoted to Étienne Souriau, Gilbert Simondon, and Bruno Latour, as well as Gilles Deleuze, examined as the “nemesis” of speculative philosophies of modes of existence as the major speculative proponent of the univocity of being. The conclusion summarizes the positive proposal on how to understand the concept of “mode of existence” that has emerged from these analyses, completing the formal framework that should pave the way for discussion on particular modes of existence.","language":"eng","citation":"THE PLURALISM OF MODES OF EXISTENCE: ONTOLOGY AND GENEALOGY / C. Frigerio ; tutor: R. Fabbrichesi, M. Geuna ; coordinatore: S. Allovio. Dipartimento di Filosofia Piero Martinetti, 2026 Feb 23. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13994.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 09-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1133057"},"title":"TRAYECTORIAS DEL EXILIO: LA IDENTIDAD CULTURAL REPUBLICANA EN LA LITERATURA DE MAX AUB Y DE MARÍA TERESA LEÓN","internalauthor":"BIFFI, GAIA","type":"Tesi di dottorato","year":"2025","abstract":"Within the heterogeneous panorama of the Spanish republican exile of 1939, Max Aub and María Teresa León turn out to be two significant figures. Their commitment to the republican cultural memory converges in an intellectual production that aims at reaffirming the historical legitimacy of a democratic society project based on social justice and equality, and on international antifascist values. According to this perspective and considering the transnational development of diasporic itineraries and the historical interactions between the vicissitudes of the republican collective and the main conflicts of the 20th century, the literature of Aub and Teresa León acquires an aura of political exemplarity that reflects a counter-hegemonic meaning of global interest.   So, the main objective of this work is to examine the literary work of the two writers with a focus on the ways in which they represent the conflicts between the dominant cultural identity and subaltern identities in the context of the Spain's social field resulting from the Civil War and from the Francoist dictatorship. This focus is also to be understood as functional to examine the ways through which the literature of these authors shows up the contradictions of their historical era and the related network of supranational connections.  This thesis has been structured in six chapters. The first two are focused on the biographies and on the intellectual productions of Aub and Teresa León before the beginning of their exiles: the purpose is to study the origins of their involvement into the collective political and cultural project of republican Spain, as well as the first phases of the convulsive trajectories of their migration routes. For both writers, France will be the first place of destination, but, in the case Aub, he will be indelibly marked by his experience in the French prisons and concentration camps.  Continuing with the chronological development, Chapter III aims to explain the essential features of the political and social commitment of the Spanish intellectuals of the 1939 diaspora, and to describe the social and cultural context of Mexico and Argentina, the countries where Aub and Teresa León respectively settled. Starting from these theoretical and conceptual foundations, the following sections of the thesis are structured on the basis of two turning points that conditioned the creative practices of Max Aub and María Teresa León both in terms of communicative necessity and factual limitations: firstly, the end of the Second World War –with the triumph of the Western liberal democracies–; subsequently, the year 1955, when Francoist Spain officially became a member of the United Nations, in the polarised scenario of the Cold War. In order to provide a rigorous and detailed view of their intellectual evolution, the works of both Aub and Teresa León has been categorised as follows: works published during the Second World War –Chapter IV–, works published during the transitional phase between the Second World War and the Cold War –chapter V– and, finally, works edited while the United States of America and Franco's Spain were building a closer relationship –chapter VI–, up to the entry of Franco's dictatorship into the United Nations. Furthermore, a brief sub-chapter has been devoted, as an epilogue, to analyse the two writers' stance on the process of stabilisation of the Franco regime within the so-called Western Bloc and on the prospects for dialogue with future generations regarding the value of political and cultural exemplarity of republican memory.","language":"spa","citation":"TRAYECTORIAS DEL EXILIO: LA IDENTIDAD CULTURAL REPUBLICANA EN LA LITERATURA DE MAX AUB Y DE MARÍA TERESA LEÓN / G. Biffi ; tutor: S. Cattaneo, J. Sánchez Zapatero ; coordinator: L. Pinnavaia, J. A. B. Hernandez. - Università degli Studi di Milano. Dipartimento di Lingue, Letterature, Culture e Mediazioni, 2024 Jan 24. 37. ciclo","filename":"phd_unimi_R13209.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1133057/2629938/phd_unimi_R13209.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/932668"},"title":"ENTRE MARGES ET IMAGES. TRAJECTOIRES MALLARMÉENNES DANS LA CRITIQUE LITTÉRAIRE DE SARTRE ET DERRIDA","internalauthor":"TESTA, GIORGIA","type":"Tesi di dottorato","year":"2022","abstract":"\"In this thesis we aim to study how the model of Mallarmé's work has structured and oriented the literary criticism of Jean-Paul Sartre and Jacques Derrida. If the two philosophers have devoted specific studies to the Symbolist poet – Sartre's Mallarmé. La lucidité et sa face d'ombre and Derrida's “La double séance” –, the importance of Mallarmé and his poetic and metaphysical revolution cannot be limited to these texts. Through a rereading of the critical works of Sartre and Derrida, preceded by a contextualisation of the aesthetic work within a broader theory of Being, it was noted how Mallarmé pervades the entire critical path of the philosophers.  In fact, reading the texts dedicated to Jean Genet (Saint Genet and Glas), Ponge (L'Homme et les choses and Signéponge), as well as the works on Flaubert, Artaud and Baudelaire, shows that Mallarmé's model operates as a hidden intertext, influencing the two intellectuals' critical positions on the authors in question. Through his radical poetic experience, Mallarmé becomes for Sartre the model of the committed poet, un poète engagé; this paradoxical aesthetic posture will be inapplicable to writers who have failed to complete, as Mallarmé did, a path of historical disengagement and aesthetic silence.  For Derrida, Mallarmé is the figure-symbol of the metaphysical crisis that runs through the 20th century: Derrida's analyses of the \"\"cas Mallarmé\"\" reveal how the poet heralded deconstruction, and consequently all the disseminated readings produced by the deconstructive method. The result of these bundles of cross-readings, which complement historicist criticism with deconstructionist criticism, will be to bring out the universally valid side of Mallarmé's poetics: Mallarmé's aesthetic revolution has so conditioned the history of literature and philosophy as to become an archetype for the most diverse theoretical approaches.\"","language":"fre","citation":"ENTRE MARGES ET IMAGES. TRAJECTOIRES MALLARMÉENNES DANS LA CRITIQUE LITTÉRAIRE DE SARTRE ET DERRIDA / G. Testa ; tutor: Eleonora Sparvoli, J.-F. Louette ; coordinatrice: M. V. Calvi. Università degli Studi di Milano, 2022 May 30. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12150.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/932668/2047976/phd_unimi_R12150.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1222075"},"title":"DIRITTI SOCIALI IN TRANSIZIONE. LA SFIDA DELL¿EFFETTIVITÀ NELL¿ORDINAMENTO COSTITUZIONALE MULTILIVELLO.","internalauthor":"CASILLI, GIULIO","type":"Tesi di dottorato","year":"2026","abstract":"This doctoral dissertation aims to examine the social dimension from the perspective of constitutional law, identifying three main areas of inquiry. The first concerns the impact of this dimension on the configuration of the form of State; the second addresses the dogmatic construction of social rights; the third focuses on their close interrelation with the democratic principle and on the mechanisms ensuring their effective protection within the multilevel constitutional order.    Social rights are framed within the broader context of the realization of that real freedom implicit in the constitutional design of human emancipation and full personal development – and, in particular, of the homme situé – which finds fulfilment, in conjunction with civil and political rights, through the pursuit of the objective of substantive equality enshrined in the Republican Constitution.    Starting from the theoretical interconnection among liberty, equality, and solidarity, the research investigates social rights in their manifestation as concrete practices, rooted in the historical, social, and economic conditions in which their exercise takes shape. Special attention is devoted to the complex issue of the effectiveness of such rights, examined within the framework of a multilevel system where the protection of social rights interacts with European and regional policies, the transformation of the welfare systems, and the constraints and limits imposed by economic and financial sustainability.    Finally, the analysis focuses on the constitutional function of the Essential Levels of Services (Livelli Essenziali delle Prestazioni), as provided for in Article 117(2)(m) of the Italian Constitution. These are conceived as instruments ensuring a uniform guarantee of social rights within an articulated and interconnected system, in which the State, the European Union, and the Regions jointly pursue the common aim of safeguarding human dignity and equality, thereby reinforcing the overall coherence, integrity, and vitality of the democratic order.","language":"ita","citation":"Diritti sociali in transizione. La sfida dell'effettività nell'ordinamento costituzionale multilivello / G. Casilli ; tutor: L. Violini; co-tutor: R. Ruffini; coordinatore: E. Damiani. Università degli Studi di Milano, 2026. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14102.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 04-SET-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/985071"},"title":"¿ROLE OF ENDOTHELIAL DYSFUNCTION IN THE PATHOGENESIS OF UNPROVOKED VENOUS THROMBOEMBOLISM¿","internalauthor":"CANCELLARA, ASSUNTA","type":"Tesi di dottorato","year":"2023","abstract":"Background and Aim  Venous thromboembolism (VTE) is a multifactorial disease that includes deep vein thrombosis (DVT) and pulmonary embolism (PE). VTE patients can be classified on the basis of the risk factor(s) that trigger the thromboembolic event. Indeed, up to 50% of VTE events occur in absence of predisposing conditions and are therefore classified as unprovoked VTE (uVTE). Being uVTE pathogenesis still unknown, uVTE patients are characterised by a high risk of recurrence, and the therapeutic management of these patients to prevent VTE recurrence is still controversial. A better comprehension of uVTE pathogenesis and the identification of the molecular mechanisms underlying VTE triggering in these patients are needed to guide patient treatment through the definition of new clinicopathological entities and the definition of molecular targets for the development of novel therapeutic strategies. Endothelial dysfunction (ED) plays a crucial role in promoting thrombus formation, yet its presence in uVTE patients has been poorly investigated, so far. Therefore, in this study we investigated ED in uVTE, using patient-derived endothelial colony-forming cells (ECFCs) that represent an optimal non-invasive model to assess the functionality of the endothelial compartment. In particular, in this project we aimed to:  • set-up and optimize ECFC-based functional assays aimed at assessing thrombogenic endothelial properties;  • investigate the presence of constitutive ED in uVTE patients and the involved underlying molecular mechanisms;   • investigate whether ED in uVTE patients is further promoted by pro-inflammatory stimuli;  • evaluate whether ED contribute to VTE recurrence risk in uVTE patients;  • assess whether ECFC features of ED are restricted to uVTE or shared with secondary VTE.  Methods  Optimization of functional assays. ECFC-based TGA and thrombogenesis assay were preliminarily set up on commercially-available human umbilical venous endothelial cells (HUVECs), then tested on ECFCs isolated and expanded from 8 healthy donors (HDs). ECFCs were used at passages 4-6, in basal conditions or after TNF\uf061-stimulated activation. TNF\uf061\uf02dinduced EC activation was assessed as upregulation of the adhesion molecule VCAM-1 and the pro-coagulant molecule Tissue Factor (TF) by flow cytometry. EC function was assessed by analyzing: a) thrombin generation assessed by TGA on ECs - a modification of Hemker’s method; b) platelet deposition and fibrin formation under flow conditions, assessed in thrombogenesis assay.  Assessment of ED role in uVTE pathogenesis. 78 VTE patients and 27 HDs were enrolled in the study. VTE patients were classified as: i) provoked VTE (pVTE) (n=28) when the VTE event was associated with major risk factors, ii) weakly provoked VTE (wpVTE) (n=28) when the VTE event was associated with minor risk factors; iii) unprovoked VTE (uVTE) (n=22) when the VTE event occurred in the absence of any provoking risk factors. A peripheral blood sample was collected at a single timepoint from all the enrolled subjects for ECFC isolation and plasma collection. In VTE patients, blood withdrawal was executed 3 months after the index VTE event, along with simultaneous assessment of validated predictors of VTE recurrence (namely, post thrombotic syndrome, D-dimer levels, and presence of residual venous obstruction). To investigate the presence of constitutive ED, ECFCs obtained from the different subgroups of VTE patients and HDs were characterized by assessing: i) their immunophenotype; ii) their ability to promote thrombosis in ECFC-based TGA and thrombogenesis assay; iii) their secretion of soluble ED markers (soluble adhesion molecules including the soluble forms of ICAM-1, VCAM-1, PECAM-1 and E-Selectin) in culture supernatants; to assess the in vivo relevance of these markers, they were also measured in the plasma of the same patients; iv) their transcriptomic profile assessed by RNA sequencing to investigate possible molecular pathways underlying ED in uVTE. To investigate whether ED in uVTE patients is further promoted by pro-inflammatory stimuli, the phenotype and functionality of TNF\uf061-treated ECFCs were assessed by using the same functional assays used to study constitutive ED. To investigate the role of ED in VTE recurrence, ECFC features of ED were analyzed in patients stratified according to their recurrence risk.  Results  Optimization of functional assays. TGA and the thrombogenesis assay were optimized to the use of ECs as a substrate. Both assays demonstrated the ability to discriminate between unstimulated and activated ECs, either HUVECs or ECFCs, whose activation was confirmed by the upregulation of VCAM-1 and TF expression. In particular, TNF\uf061-activated HUVECs and ECFCs were similarly characterized by significantly higher thrombin generation, platelet deposition and fibrin formation compared with their unstimulated counterparts. Based on these results, both ECFC-based functional assays were used for subsequent experiments addressing ED in uVTE, using patient-specific ECFCs.  Assessment of ED role in uVTE pathogenesis. ECFCs were isolated from the three subgroups of VTE patients with a similar efficiency as HDs, but they were characterized by increased early senescence. The presence of constitutive ED was observed only in uVTE patients, as assessed as: a) a faster and higher peak of thrombin generation observed in TGA; b) increased platelet deposition observed in the thrombogenesis assay, in uVTE patients compared with HDs. Relevant to the increased platelet deposition, higher levels of soluble ICAM-1 and PECAM-1 were detected in the culture supernatants of ECFCs obtained from uVTE patients, the in vivo relevance of this finding being suggested by the observation of increased levels of soluble ICAM-1 also in the plasma of the same patients. Based on the preliminary analysis of the transcriptomic ECFC profiling, the upregulation of these adhesion molecules in uVTE patients may be supported by a downregulated gene expression of GSTM1 and PTGIR that were downregulated in uVTE ECFCs compared with ECFCs obtained from both HDs and patients with secondary VTE.  A higher propensity of ECFCs obtained from uVTE patients to promote thrombus formation was also confirmed in inflammatory conditions, as only TNF\uf061-stimulated ECFCs from these patients showed a shorter lag time in TGA and higher platelet deposition in the thrombogenesis assay, compared with HDs. Notably, ECFC treatment with TNF\uf061 increased the amount of thrombin generated in TGA only in HDs but not in uVTE, wpVTE or pVTE patients, likely related to direct oral anticoagulants (DOACs) taken by the vast majority of VTE patients at the time of blood collection.  Finally, by stratifying patients according to their risk to develop VTE recurrences based on the presence of residual venous obstruction, we showed that several ECFC features of ED were broadly higher in uVTE and wpVTE patients with a high risk of recurrence compared with low-risk patients, thus suggesting that ED may also play a role in VTE recurrence in these patients.  Conclusions  In this study, we validated the use of ECFCs for assessing endothelial functions relevant to the study of human thromboembolic diseases. By applying properly optimized assays, we performed a functional characterization of patient-derived ECFCs, demonstrating that uVTE patients have endothelial prothrombotic alterations that may play a relevant role in the pathogenesis of the disease and in the risk of VTE recurrence. By extending the ECFC characterization on a larger cohort of patients, deepening the molecular characterization of ED, and by addressing the impact of anticoagulation on ED and VTE recurrence, this experimental approach has the potential to further dissect the molecular pathways underlying ED in uVTE patients, with the final aim to identify molecular targets for the development of novel therapeutic strategies aimed at preventing VTE recurrences in these patients.","language":"eng","citation":"¿ROLE OF ENDOTHELIAL DYSFUNCTION IN THE PATHOGENESIS OF UNPROVOKED VENOUS THROMBOEMBOLISM¿ / A. Cancellara ; tutor: S. Della Bella ; supervisore: F. Calcaterra ; phd course coordinator: N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2023 Jul 25. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12743.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/985071/2246013/phd_unimi_R12743.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/846870"},"title":"SEARCHING FOR NOVEL MOLECULAR TARGETS IN ASTROCYTES FOR THE TREATMENT OF RETT SYNDROME","internalauthor":"ALBIZZATI, ELENA","type":"Tesi di dottorato","year":"2021","abstract":"Rett syndrome (RTT) is a rare devastating neurodevelopmental disorder that with an incidence of ~ 1:10,000 represents the most common genetic cause of severe intellectual disability in girls. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been reported in over 95% cases of classical forms of RTT. Although initial studies supported a role for MeCP2 exclusively in neurons, recent data indicate a function also in astrocytes, which emerged as critical players involved in RTT pathogenesis through non-cell autonomous effects. Nevertheless, many aspects of RTT astrocyte dysfunctions remain unknown. With this PhD project, we wanted to use different in vivo and in vitro approaches that could help fill this gap of knowledge, in particular as regards to the effects that RTT astrocytes exert on neuronal health, and the involved molecular mechanisms.   We herein demonstrate that astrocytes in the Mecp2 null mouse brain show progressive and area-specific alterations in morphology, with cortical areas exhibiting the most affected phenotype compared to the hippocampal cells; no phenotype, instead, is observed in cerebellar astrocytes, at least at early time points. These data, that have been reinforced by in vitro studies, represent the first evidence in the RTT field of the importance of considering astrocyte regionality. Considering the link between astrocyte morphogenesis and synaptogenesis, we have further investigated the effects of KO astrocytes on synaptic phenotypes. Our studies highlight a clear defect in synaptic maturation particularly in the Mecp2 null motor cortex. However, our in vivo exploration of synaptic terminals have not permit to find a stringent correlation between astrocyte morphology and synaptic defects probably due to the use of a globally null mouse model. Conversely, by using in vitro co-cultures, we have demonstrated for the first time that the lack of Mecp2 in astrocytes dramatically influences the synaptogenesis of WT neurons, by affecting both pre- and post-synaptic terminals by the release of one or more thermo-labile neurotoxic factors. To identify the involved molecular mechanisms, we have used RNAseq profiling which molecular pathways are activated in wild-type neurons by the paracrine effects triggered by KO astrocytes. Bioinformatic analyses have confirmed that KO astrocytes influence neuronal pathways mainly associated with the pre- and post-synaptic compartments, the mitochondrial functionality and inflammatory responses, therefore suggesting the possibility of an aberrant release of pro-inflammatory molecules. Collectively, the data presented in this thesis advance our understanding on the pathophysiology of RTT and point astrocytes and their paracrine factors as active players for the synaptic defects observed in RTT. We believe that the identification of the involved factors might reveal novel therapeutic approaches for the treatment of RTT.","language":"eng","citation":"SEARCHING FOR NOVEL MOLECULAR TARGETS IN ASTROCYTES FOR THE TREATMENT OF RETT SYNDROME / E. Albizzati ; tutor: N. Landsberger ; supervisor: A. Frasca ; coordinatore: M. Locati. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2021 Jun 11. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11955.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/846870/1811136/phd_unimi_R11955.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1211978"},"title":"LA ¿CIVILIZZAZIONE¿ DELL¿ISTRUTTORIA DEL PROCESSO AMMINISTRATIVO DI LEGITTIMITÀ: ITALIA E GERMANIA A CONFRONTO","internalauthor":"DURANTI, FABIO SERGIO","type":"Tesi di dottorato","year":"2026","abstract":"This dissertation aims to examine the issue of investigation in the administrative process on legitimacy, highlighting the legal problems that have always been linked to its structure. The analysis is conducted in order to propose de jure condendo solutions that could make the investigation more rational, taking in to account the judicial review on public powers which characterizes administrative process on legitimacy.  The discussion begins with an excursus on the legislation from an evolutionary perspective in order to better understand the reasons that led the legislator to decide that the investigation should’ve been managed by the judge. The study then takes into account the developments in case law at the end of the last century and their subsequent codification in the “Codice del processo amministrativo” of 2010. The norms governing investigations in the new administrative process owe much both to historical developments and to the numerous doctrinal and jurisprudential theories that extracted guiding principles from the sparse previously in force norms.  The Code of Administrative Procedure has, at least in part, abandoned the structure of the “sistema dispositivo con metodo acquisitivo”, transferring some investigative powers to the parties, following the principles found in Article 111 of the Italian Constitution. In doing so, the legislator decided to take distance from the reasons which justified the assignment of investigative powers only to the judge, redistributing these powers in a not so consistent way.  The paper also proposes a comparative study of the rules and principles governing investigation in the administrative process in Germany. This analysis appears to be interesting since the German provisions require the judge to investigate ex officio; legal doctrine has recognized that this system, established in 1960 and still in force today, was designed to avoid that administrative court judgments could be based on inaccurate factual grounds. Nevertheless, German scholars and jurisprudence have long been in favour of expanding the parties’ powers regarding the investigation, which are not provided for by law, with the result that in Germany, too, there has been an interpretative and applicative effort to “civilize” the investigation in the administrative process.  Finally, the research proposes a comparison between the rules and principles in force in the two legal systems examined in order to extract useful guidelines to better understand the needs that led to the restriction of the judge’s ex officio investigative powers. Through such an analysis, an attempt will be made to justify the recovery of the judge’s authority over investigation in the administrative process on legitimacy.","language":"ita","citation":"\"LA \"\"CIVILIZZAZIONE\"\" DELL'ISTRUTTORIA DEL PROCESSO AMMINISTRATIVO DI LEGITTIMITÀ: ITALIA E GERMANIA A CONFRONTO / F.s. Duranti ; tutor: M. Ramajoli, L. Bertonazzi ; coordinatrice F. Biondi. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2026 Feb 02. 38. ciclo, Anno Accademico 2024/2025.\"","filename":"phd_unimi_R13677.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1211978/3238565/phd_unimi_R13677.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/920022"},"title":"NOVEL STRATEGIES TO IMPLEMENT EXTRACORPOREAL LIFE SUPPORT TECHNIQUES","internalauthor":"VIVONA, LUIGI","type":"Tesi di dottorato","year":"2022","abstract":"Extracorporeal techniques are the ultimate resources for critically ill patients with life threating respiratory or cardiac failure, maintaining tissue oxygenation for days to weeks by supporting the lungs, the heart, or both. We focused our interest on novel strategies to implement this technology in order to guarantee safer and more efficient extracorporeal life support.   The first approach was a novel regional anticoagulation strategy based on ion-exchange resins, which aimed at avoiding the risks related to systemic anticoagulation. In this experiment, conducted on a swine model, we were able to reduce the concentration of ionized calcium in the extracorporeal circuit, thus inhibiting its coagulation activity, while having an extracorporeal blood flow of 500mL/min. On the other hand, by re-infusing calcium in the systemic circulation, we were able to maintain a normal coagulation function in our in vivo model.  Secondly, we devised a thermodilution technique to quantify recirculation flow in a membrane lung, a step needed in order to reduce the amount of oxygenated blood flowing back into the extracorporeal circuit. We built an in vitro setup mimicking a patient undergoing veno-venous ExtraCorporeal Membrane Oxygenation (vv-ECMO) to measure the recirculation fraction, which was computed as the ratio between the areas under the curve of temperature traces recorded on the drainage line and at reinfusion line. We found that our thermodilution technique provided a punctual measurement of the fraction of oxygenated blood recirculating into the membrane lung.  Thirdly, we tested sodium hydroxide (NaOH) as an alternative medium to clear carbon dioxyde (CO2) in a membrane lung, comparing its efficacy and efficiency against those of various fresh gas flows. Despite its limitations for clinical practice, this strategy shows that NaOH solutions have a high CO2 absorbing capacity. The partial pressure of CO2 (pCO2) of the alkaline sweep fluid was persistently very close to 0 mmHg, as the added CO2 was instantly hydrated and dissociated to bicarbonate and carbonate. This optimized the transmembrane pCO2 gradient, increasing the efficiency of extracorporeal CO2 removal.  The last experiment of this cycle aimed at understanding the relevance of haematocrit (HCT) during extracorporeal CO2 removal. In our in vitro study, we kept inlet pCO2 stable, blood flow at membrane lung at 250 mL/min, and sweep gas flow at 5 L/min according with membrane lung characteristics. We showed that variations in HCT corresponded to variations in the amount of removed CO2 (V̇CO2). Specifically, in our study, an increase of HCT by 20% determined a rise in V̇CO2 of 15% compared to treatment baseline.  Overall, starting from physiology, we tackled some open issues of extracorporeal life support. Our results are promising and expand the fund of knowledge on extracorporeal techniques. The next steps will require further studies in order to take our findings from the bench to the bedside.","language":"eng","citation":"NOVEL STRATEGIES TO IMPLEMENT EXTRACORPOREAL LIFE SUPPORT TECHNIQUES / L. Vivona ; tutors: A. Pesenti, G. Grasselli ; phd coordinator: C. Sforza. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2022 Apr 21. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12215.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/920022/2013280/phd_unimi_R12215.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/824035"},"title":"THE ROLE OF THE M6A METHYLTRANSFERASE METTL3 IN AN IN VITRO MODEL OF ANTIGEN-SELECTED GERMINAL CENTER B CELLS","internalauthor":"GRECO, FEDERICA","type":"Tesi di dottorato","year":"2021","abstract":"N6-methyladenosine (m6A) represents the most abundant modification introduced into messenger RNA. In mammals, m6A regulates gene expression by controlling different facets of mRNA metabolism including splicing, translation and stability. Emerging evidences have assigned to m6A a critical role in the regulation of cellular and humoral immunity.   To date, the function of m6A in mature B cells, especially those recruited into T-cell dependent immune responses, remains unexplored. Here, we show that the Mettl3 gene, encoding for the catalytic subunit of the m6A methyltransferase complex, is expressed at relatively stable levels throughout B-cell development and increases in mature B cells activated in response to the engagement of the CD40 receptor. Given the crucial role played during a T-cell dependent immune response by CD40 signaling in sustaining the transient expansion of antigen-selected B cells in the light zone of the germinal center (GC) and, together with Interleukin-21 (IL-21), their terminal differentiation into antibody-secreting plasma cells (PCs), we asked to which extent these processes are under m6A methylation control. To answer these questions, we disrupted by CRISPR/Cas9 technology the Mettl3 gene in primary in vitro-induced germinal center-like B (iGB) cells, which were stimulated for 8-to-13 days with membrane-bound CD40-ligand (mCD40L). Efficient targeting of the Mettl3 gene in iGB cells exerted distinct phenotypes on CD40-activated B cells starting from the fourth day of the culture, when IL-4 was replaced with IL-21 in the culture medium. Using two independent sgRNAs to disrupt the Mettl3 gene, we observed a consistent significant growth delay of Mettl3-mutant iGB cells, which was restricted to the first 48 hours of mCD40L + IL-21 stimulation. The proliferation defect of Mettl3-mutant iGB cells caused their rapid counter selection when placed in competition with Mettl3-proficient counterparts.   The growth impairment of CD40-activated Mettl3-mutant iGB cells was associated with limited upregulation of c-MYC expression, a defect in cell-cycle progression at the G1-to-S transition, due to reduced expression of E2F family members, and defective activation of the nutrient-sensitive mTORC1 signaling pathway. During the first 48 hours of mCD40L + IL-21 stimulation, Mettl3-mutant cultures suffered also from a significant defect in the transcriptional activation of genes encoding for master regulators of PC differentiation, including Irf4, Blimp1, Pou2af1 and Xbp1. The growth and developmental defects of Mettl3-mutant iGB cultures were normalized in the following 48 hours, due to the exhaustion of the proliferative burst of control B cells, while mutant ones completed the missing cell divisions, prior to undergoing terminal differentiation and/or senescence.   Sequencing of the Mettl3 gene, retrieved from day-8 Mettl3-mutant iGB cultures, indicated a strong counter selection of iGB cells carrying loss-of-function alleles. This result was confirmed in terminally differentiated CD138+ plasmablasts isolated from day-13 in Mettl3-mutant iGB cultures, which displayed METTL3 protein levels comparable to those of wild-type cells. Altogether, these results establish for the first time a strict requirement for a full complement of METTL3 molecules, for optimal mitogenic B cell response to CD40 engagement, for initiating PC differentiation and for PCs persistence. In light of these results, our work assigns to METTL3 a crucial supportive function in B cells for the processes of clonal selection and antibody affinity maturation occurring in the GC during T-cell dependent immune responses.   To shed further light on the importance of METTL3 function in developmental decision-making processes, we employed an in vitro model of reversible immortalization of multipotent murine hematopoietic progenitor cells (HPCs), by expression of an estradiol-inducible form of the HoxB8 (H8) transcription factor. Application of CRISPR/Cas9 technology to H8-HPCs ensured efficient Mettl3 gene targeting in these cells. We could show that interference with Mettl3 expression led to the counter selection of highly proliferating Mettl3-mutant H8-HPCs. Moreover, Mettl3-targeted H8-HPCs expressed prematurely the myeloid-associated marker CD11b and displayed accelerated myeloid differentiation upon estradiol withdrawal from the culture medium. Altogether, these results support a view whereby METTL3 sustains self-renewal of multipotent HPCs and prevents inappropriate and premature differentiation of these cells into the myeloid lineage.","language":"eng","citation":"THE ROLE OF THE M6A METHYLTRANSFERASE METTL3 IN AN IN VITRO MODEL OF ANTIGEN-SELECTED GERMINAL CENTER B CELLS / F. Greco ; tutor: S. Casola ; phd coordinator: G. Viale. Dipartimento di Oncologia ed Emato-Oncologia, 2021 Mar 30. 32. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11751.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/824035/1734000/phd_unimi_R11751.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1228075"},"title":"THE SCOPE OF THE LAW APPLICABLE TO COMPANIES IN THE EU.","internalauthor":"RICIFARI, REBECCA","type":"Tesi di dottorato","year":"2026","abstract":"Despite the crucial role of corporate mobility in ensuring the proper functioning of the internal market, and although Articles 49 and 54 of the Treaty on the Functioning of the European Union expressly recognize the freedom of establishment for certain – albeit not all – legal persons, the European Union still lacks a coherent, explicit, and comprehensive regime governing the law applicable to such entities. While recent legislative developments – most notably Directive (EU) 2019/2121 – have improved coordination among Member States’ legal systems, they fail to address, at least expressly and holistically, the problem of the law applicable to companies and other bodies.    As a result, the matter remains, at least formally, governed by national private international law provisions and techniques, with the undesirable consequences this entails. Member States, in fact, not only rely on different connecting factors to determine the law applicable to companies and other entities but also disagree on which institutions fall within the scope of “company law” and should therefore be governed by choice-of-law rules on companies. All this often results in the non-recognition of companies and other entities incorporated under the law of a Member State and having their registered office, central administration, or principal place of business therein and in the impossibility for such entities to transfer their seat to another Member State, thereby significantly hindering cross-border corporate mobility and, hence, the effective exercise of the freedom of establishment.    Nevertheless, the very nature of the European Union legal order, along with the complex interaction between Union and national sources of law, makes it mandatory to use the adverb “formally” when affirming that the regulation of the law applicable to companies is left to national legal systems. Multiple sources of EU law directly affect – and prevail over – national law. First, the Court of Justice of the European Union has assigned to Article 54 of the Treaty on the Functioning of the European Union a meaning that exceeds well beyond its literal function of identifying the legal persons entitled to exercise the freedom of establishment. The provision, in fact, requires Member States to recognize companies that are validly incorporated in another Member State and have their registered office, central administration, or principal place of business within the Union and to permit operations resulting in a modification of the law applicable to the entity. Secondly, the EU legislator has enacted a range of secondary law instruments that, in different ways, exert an influence over domestic conflict-of-law regimes. Indeed, on the one hand, when these instruments harmonize substantive law, they render – at least to some extent – immaterial the lingering divergences among national conflict rules. On the other hand, where they harmonize private international law in fields adjacent to company law, they define and redefine the institutions ascribable to the lex societatis.    Building on these premises, this research reconstructs the current legal framework governing the law applicable to companies within the European Union by identifying and analyzing the impact of EU law on national choice-of-law provisions concerning the law applicable to companies and other entities. Hence, first, the present study analyzes how, when, and to what extent European Union law supersedes national private international law rules and mechanisms governing the law applicable to companies. This inquiry demonstrates that, although formally, matters related to the law applicable to companies remain unharmonized, the pervasive influence of EU law considerably limits national regulatory autonomy and mitigates the impact of the consequences arising from the formal differences that still persist in Member States’ private international law regimes. This, in turn, supports the claim that a European private international law regime on the matter, to a large extent, already, de facto, exists. Secondly, the study critically assesses whether the current EU regulatory framework in this field is consistent with, and adequate to serve, the objectives of the European Union established by Treaties. Building on this latter analysis, the present study advocates for the adoption of a regulation on the law applicable to companies and other entities and examines its possible content.","language":"eng","citation":"THE SCOPE OF THE LAW APPLICABLE TO COMPANIES IN THE EU / R. Ricifari ; tutor: S. Bariatti, J. Meeusen ;  Coordinatrice: F. Biondi. - milano. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2026 Mar 19. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13261.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 23-SET-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1032276"},"title":"INTEGRATIVE GENOMICS UNVEILS TRANSCRIPTION FACTOR ROLES IN CELLULAR FATEAND SPATIALLY RESOLVED TRIPLE-NEGATIVE BREAST CANCER IMMUNITY CAPACITY","internalauthor":"SLOVIN, SHAKED","type":"Tesi di dottorato","year":"2024","abstract":"In this thesis, we explore integrative genomics through advanced sequencing to understand biological systems and processes, focusing on two main projects. The first investigates transcription factors (TFs) in cellular differentiation, addressing the inefficiency in current cellular conversion strategies due to the complex TF regulatory landscape. We developed a comprehensive screening of 130 developmental TFs, comparing their dosages in a single experiment to identify novel pioneer factors crucial for cellular identity. This approach aims to enhance our understanding of cell fate decisions. The second project examines triple-negative breast cancer (TNBC), characterized by its aggressiveness and treatment challenges due to tumor heterogeneity. We propose a novel clinical workflow combining spatial transcriptomics, RNA sequencing, and Immunohistochemistry to analyze TNBC, focusing on PD-L1 status. This method revealed sub-tumoral variations and identified LY6D as a new diagnostic marker, highlighting the potential of spatial transcriptomics in personalized medicine for TNBC. Overall, this dissertation contributes to the fields of cellular reprogramming and cancer diagnostics by integrating various genomic data and technologies to uncover complex molecular mechanisms and identify new therapeutic targets.","language":"eng","citation":"INTEGRATIVE GENOMICS UNVEILS TRANSCRIPTION FACTOR ROLES IN CELLULAR FATEAND SPATIALLY RESOLVED TRIPLE-NEGATIVE BREAST CANCER IMMUNITY CAPACITY / S. Slovin ; supervisor:  D. Cacchiarelli ; internal advisor: G. Gambardella ; external advisor: P. Carninci. - English. Dipartimento di Oncologia ed Emato-Oncologia, 2024 Apr 22. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12713.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1032276/2368469/phd_unimi_R12713.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/820854"},"title":"EVOLUTION EQUATIONS WITH APPLICATIONS TO POPULATION DYNAMICS","internalauthor":"AFFILI, ELISA","type":"Tesi di dottorato","year":"2021","abstract":"The main topic of this thesis is the analysis of evolution equations reflecting issues in ecology and population dynamics. In mathematical modelling, the impact of environmental elements and the interaction between species is read into the role of heterogeneity in equations and interactions in coupled systems. In this direction, we investigate three separate problems, each corresponding to a chapter of this thesis. The first problem addresses the evolution of a single population living in a periodic medium with a fast diffusion line; this corresponds to the study of a reaction-diffusion system with equations in different dimensions. We derive results on asymptotic behaviour through the study of some generalised principal eigenvalues. We find that the road has no impact on the survival chances of the population, despite the deleterious effect expected from fragmentation. The second investigation regards a model describing the competition between two populations in a situation of asymmetrically aggressive interactions; this consists of a system of two ODEs. The evolution progresses through two possible scenarios, where only one population survives. Then, the interpretation of one of the parameters as the aggressiveness of the attacker population naturally raises questions of controllability. We characterise the set of initial conditions leading to the victory of the attacker through a suitable (possibly time-dependant) strategy. The third and last part of this thesis analyses the time decay of some evolution equations with classical and fractional time derivatives. Depending on the type of derivative and some degree of non-degeneracy of the spatial operator, quantitative polynomial or exponential estimates are entailed.","language":"eng","citation":"EVOLUTION EQUATIONS WITH APPLICATIONS TO POPULATION DYNAMICS / E. Affili ; tutor: E. Valdinoci, L. Rossi ( Sorbonne Universite'). Università degli Studi di Milano, 2021 Mar 11. 33. ciclo, Anno Accademico 2020. [10.13130/affili-elisa_phd2021-03-11].","filename":"phd_unimi_R12038.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/820854/1723235/phd_unimi_R12038.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/852006"},"title":"LA LEGITTIMA DIFESA NEL DOMICILIO (ART. 52 C. 2-4 C.P.) UN¿INDAGINE TRA STORIA, COMPARAZIONE, TEORIA E PRASSI","internalauthor":"ROSSI, LUCREZIA SILVANA","type":"Tesi di dottorato","year":"2021","abstract":"\"The thesis deals with the delicate issue of self defence exercised in the home, which has been the subject of two reforms in the last fifteen years – first in 2006, then in 2019 –, arousing widespread criticism and conflicting opinions regarding its exact scope.  The great public attention for the institute and the two legislative interventions have stimulated the interest and the desire to investigate the origin, the ratio and the evolution of the justification regulated by art. 52 c.p. The purpose of this survey is twofold: on the one hand, an attempt has been made to understand the needs underlying the reforms and, more generally, the foundation of the need so well rooted in contemporary society for a differentiation of treatment for attacks perpetrated inside the house; on the other hand, starting from the study of the discipline currently in force and the concrete application of the same by jurisprudence, an attempt has been made to find a more satisfactory balance between the widespread needs and compliance with the Constitutional Charter and the European Convention of human rights, in short a \"\"sustainable counter-reform\"\".  The thesis is divided into three parts, of which the first is dedicated to the historical-comparative analysis of the justification. In particular, the study traces the origins of the institute starting from Roman law up to the present day, trying to highlight the historical precedents capable of explaining the current predisposition of a special figure of self defence in favour of anyone who is attacked in private places, where individuals boasts an ius excludendi alios against the aggressor. The historical research is accompanied by a comparative survey, also set in a historical perspective, which broadens the gaze to the choices made on the subject by the main European systems – notably the French and English ones –, as well as by the US federal system.  The second part of the thesis concerns the internal law in force; in particular, the paper first deals with law no. 59 of 13 February 2006 and then the law n. 36 of 26 April 2019, i.e. the reforms that have given prominence to the special figure of home self defence. To this end, both the criminal political context that marked its origin and the content of the reforms in the light of the jurisprudence of legitimacy are considered; in fact, a study was carried out on all the rulings issued by the Court of Cassation regarding home self defence from 1 January 2000 until 1 January 2021. Thanks to this research, it emerged on the one hand how the first reform is substantially devoid of concrete repercussions and, on the other hand, how the second legislative intervention, if not subjected to a corrective interpretation in the light of constitutional and conventional guidelines, is dangerous for system tightness. Along this line, the investigation focuses in particular on the role that the requirement of necessity and the normative presumptions of legitimacy of the reaction should assume. With reference to the case of excess, then, are presented the criteria for detecting the serious disturbance and the conditions of impaired defence to which excuse effects are linked.  Finally, the third and last part of the paper deals with the institution from a de iure condendo perspective; specifically, starting from the results achieved through the survey carried out, an attempt was made to put forward a proposal for reorganization of the justification which is divided into three steps, ideally connected to each other. According to this working hypothesis, art. 52 c.p. would gain rationality and effectiveness if, first of all, the paragraphs governing home self defence currently in force were eliminated; furthermore, beside the provision referred to art. 52 c. 1 c.p., there should be an excuse linked to the state of emotional disturbance experienced by the attacked, applicable in cases of excess and error in self defence; finally, an iuris tantum presumption of current danger could be envisaged for the sole safety of those present in the event of aggression perpetrated within the home and business.  The coexistence of these amending proposals would seem capable of giving a renewed balance to the justification, first of all giving voice and recognition to the widespread requests, furthermore respecting the principles and values of which the Constitution and the European Convention of human rights are an expression, and lastly still giving a push contrary to the current anti-statist tendency, if not even anti-constitutional, of which the two recent reforms on the subject have become spokesmen.\"","language":"ita","citation":"LA LEGITTIMA DIFESA NEL DOMICILIO (ART. 52 C. 2-4 C.P.) UN¿INDAGINE TRA STORIA, COMPARAZIONE, TEORIA E PRASSI / L.s. Rossi ; tutor: G. L. Gatta ; coordinator: C. Luzzati. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2021 Jun 24. 33. ciclo, Anno Accademico 2020. [10.13130/rossi-lucrezia-silvana_phd2021-06-24].","filename":"phd_unimi_R11900.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/852006/1825689/phd_unimi_R11900.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/814967"},"title":"NONLINEAR WAVES EXCITATION AND INTERACTION IN PURE ELECTRON PLASMAS","internalauthor":"PANZERI, NICOLA","type":"Tesi di dottorato","year":"2021","abstract":"Nonneutral plasmas are excellent subjects for well controlled studies on basic physics problems and industrial research over a wide range of parameters. For the long-time confinement, merger and recombination of antimatter, the method of choice is some variant of the Penning-Malmberg trap, and many of the techniques for the manipulation of charged particles, such as cooling, compression, transfer, and ultimately a stable confinement in a quiescent state, are based on methods first developed by the nonneutral plasma community using electron plasmas. Another fascinating properties of nonneutral plasmas is the fluid analogy: in a cold, magnetized, nonneutral plasma, the 2D transverse dynamics equations are isomorphic to the Euler equations for an ideal 2D fluid. Hence, a pure electron plasma in a Penning-Malmberg trap evolves as an inviscid, incompressible bidimensional fluid.  The study and control of the various waves and instabilities is of great interest in physics, and it is often intertwined with non-linearity and turbulence. Experiments aimed at unveiling hidden dependencies between parameters or improve the control over non-equilibrium, unstable configurations can lead to the discover of new phenomena, and a more thorough understanding of basic plasma physics, like the excitation and interaction of different plasma modes in pure electron plasmas, is likely to be a useful tool for a range of applications.  In this thesis work, we present the results of the experiments made on two different Penning-Malmberg traps on the excitation and interaction of nonlinear waves in pure electron plasmas. On the Eltrap device, located at the University of Milan, Italy, we perform experiments on the excitation and control of high order diocotron modes via the rotating electric field technique. On the CamV device, located at the University of California, San Diego, we investigate the newly discovered phenomenon of TG waves splitting due to the interaction with a diocotron mode.","language":"eng","citation":"NONLINEAR WAVES EXCITATION AND INTERACTION IN PURE ELECTRON PLASMAS / N. Panzeri ; tutor:  M. ROME' ; coordinatore:  M. PARIS. Dipartimento di Fisica Aldo Pontremoli, 2021 Jan 27. 33. ciclo, Anno Accademico 2020. [10.13130/panzeri-nicola_phd2021-01-27].","filename":"phd_unimi_R11965.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/814967/1705144/phd_unimi_R11965.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1025742"},"title":"NEUTRALIZING ACTIVITY AGAINST SARS-COV-2 OF HUMAN BREAST MILK FROM COVID-19 POSITIVE AND NEGATIVE LACTATING MOTHERS","internalauthor":"MORNIROLI, DANIELA","type":"Tesi di dottorato","year":"2024","abstract":"Nutrition plays a fundamental role in human health, even more so for the paediatric and neonatal populations. Breast milk is undoubtedly the best food for newborns, both for the benefits due to its nutritional content and for the presence of numerous functional and bioactive substances. The bioactive substances present in breast milk perform several functions that promote the short- and long-term health of the newborn. Among the important functional properties of human milk, its marked antimicrobial and, in particular, antiviral activity has a paramount role. The SARS-CoV-2 pandemic, the pathogen behind COVID-19, in its dramatic nature, was the cue for global scientific research to rediscover and test compounds with presumed, or proven, antiviral activity. The presence of a considerable amount of these antiviral compounds in breast milk would explain its non- specific antiviral activity against many viruses, including SARS-CoV-2. Given these premises, a study was conducted to investigate the non-specific antiviral activity of breast milk, thus independent of the presence of antibodies, against SARS-CoV-2. Breast milk samples were collected from mothers with a positive nasopharyngeal swab for the presence of the virus (group A) and from mothers with a negative nasopharyngeal swab, not vaccinated against the virus and with a negative history of COVID-19 infection. Samples were collected at the following timepoints: 2 days postpartum (T0, colostrum), 7 days postpartum (T1, transitional milk), and 20 days postpartum (T2, mature milk). The collected samples were then analysed to assess NT50 microneutralization according to the Reed and Muench method. The neutralisation assay analysed the cytopathic effect caused by viral  replication in a population of VERO cells placed in culture, incubated with breast milk samples, and infected with SARS-CoV-2. To assess the presence of antibody activity possibly responsible for the neutralisation, samples from both groups A and B were tested with ELISA kits for antibodies directed against SARS-CoV-2.  The results confirmed the ability of samples from positive mothers (group A) to neutralise the virus, with a decreasing effect from T0 to T2. ELISA tests on these samples showed a direct correlation between the antibody titre present in the sample and the neutralising capacity of the sample. As for group B, mothers seronegative for the virus, samples also showed neutralising activity, decreasing at time points, without a direct correlation between neutralising capacity and antibody titre in the sample. The presence of a certain antibody titre also in the samples of group B mothers is primarily attributable to the presence of secretory immunoglobulin A with cross-reactivity against SARS-CoV-2, a finding already described in the literature, but without a correlation between titre and neutralising capacity. The results of this study therefore demonstrate that breast milk possesses compounds, other than antibodies, capable of neutralising the SARS-CoV-2 virus, with the effect being more pronounced in colostrum and less evident in mature milk. Preliminary tests were also conducted on the same samples to assess the nature of the compounds responsible for this effect. Preliminary results showed a direct correlation between the neutralising capacity of the sample and the amount of eicosatrienoic acid (20:3 ω-9), the possible antiviral effect of which has not yet been described in the literature. In addition, pilot tests following the study showed an increasing neutralising effect of increasing concentrations of oligosaccharides in    breast milk (from 0.12 mg/dL to 0.5 mg/dL), which are more represented in colostrum than in mature milk.  In conclusion, breast milk has an innate antiviral capacity, exerted independently of the specific antibodies. Future studies are needed to understand which compound, or synergy of compounds, may be responsible for this effect.","language":"eng","citation":"NEUTRALIZING ACTIVITY AGAINST SARS-COV-2 OF HUMAN BREAST MILK FROM COVID-19 POSITIVE AND NEGATIVE LACTATING MOTHERS / D. Morniroli ; tutor: M.L. Giannì, F. Mosca ; coordinatore: L. Pinotti. Dipartimento di Scienze Cliniche e di Comunità, 2024 Feb 08. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R12903.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1025742/2350529/phd_unimi_R12903.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1051408"},"title":"THE EFFECT OF INDOOR TOTAL SUSPENDED PARTICLES (TSP) ON THE HUMAN UPPER RESPIRATORY SYSTEM: FROM THE MICROBIOME TO HERV METHYLATION","internalauthor":"SOLAZZO, GIULIA","type":"Tesi di dottorato","year":"2024","abstract":"Air pollution is well known for its adverse effects on human health. Among all air contaminants, particulate matter is one of the most studied because of its effect on the cardiovascular and respiratory system. Almost the entire global population is exposed daily to an unhealthy level of these contaminants and most of the exposure comes from the indoor setting where we spend a large portion of our daily time. The link between particulate matter exposure and human disease is still not fully understood, although inflammation is commonly observed after exposure to particulate matter. For that reason, investigating how the upper respiratory microbiome responds to particulate matter exposure is critical. These microorganisms that inhabit our upper airways play a crucial role in the homeostasis of the immune system and defend against external environmental stimuli. Furthermore, inflammation is also correlated with the activation of human endogenous retroviral elements integrated in our genome, the HERV genes. These genes regulate essential processes, and their dysregulation is associated with various inflammatory and immune-related diseases.  The aim of this project is to investigate the effects of indoor Total Suspended Particles (TSP) on the upper respiratory microbiome and the methylation levels of HERV genes. Additionally, this study aims to examine whether the microbiome can influence the effect that indoor TSP has on HERV methylation. To achieve this aim, we recruited 34 healthy office workers from the University of Milan and the University of Como. We monitored them and their workplaces for six weeks total, three weeks during the winter and three weeks during the summer. At the end of every week, we collected both environmental and biological samples. The TSP samples were collected using an active filter-based technique. The biological samples included anterior nares and nasopharynx swabs to evaluate the upper respiratory microbiome, and buccal brushes to measure the HERV methylation.   The first part of the project analyzed the environmental samples collected in the two seasons. The indoor and outdoor TSP concentrations were calculated gravimetrically. Then, we used the DNA extracted from the TSP collected on cellulose ester filters to characterize the TSP microbiome through whole genome shotgun (WGS) sequencing. We observed differences between the outdoor and the indoor TSP in both concentration and microbiome composition. The differences in microbiome composition we observed were probably influenced by the presence of plants, animals, and human activity in the environment.   The second part of the project characterized the anterior nares microbiome in healthy subjects and described the seasonal variation in this microbiome using both 16S rRNA and whole genome shotgun (WGS) sequencing. Specifically, we compared the anterior nares microbiome with the nasopharynx microbiome, and we analyzed how the indoor TSP exposure affected them. We observed significant differences between the two seasons in both microbiome diversity and composition in the anterior nares samples. The winter samples were enriched in Moraxella species (Moraxella catarrhalis and Moraxella nonliquefaciens) and the diversity was lower. The microbiome of the anterior nares was similar in taxa composition to the nasopharynx microbiome. They were both mostly dominated by gram-positive bacteria. However, the nasopharynx microbiome reported a higher diversity, and enrichment in Staphylococcus aureus, while the anterior nares microbiome had a high abundance of Corynebacterium, Cutibacterium acnes, and Staphylococcus epidermidis. In both microbiomes, we observed that the indoor TSP exposure affects commensal gram-positive bacteria such as Corynebacterium accolens and Streptococcus pneumoniae. Consistent with in vitro studies, an increase in Staphylococcus aureus relative abundance was identified in response to TSP exposure. Finally, we observed positive correlations in the abundance of some respiratory bacteria found in both TSP and human samples.  The third part of the project examined the impact of indoor TSP exposure and the microbiome on HERV methylation, investigating whether the upper respiratory microbiome can modulate the effect of this pollutant on HERV genes. Indoor TSP exposure alone did not affect the DNA methylation of the HERV genes studied. However, the upper respiratory microbiome was associated with changes in methylation of HERV-K. Furthermore, in our analysis of the interaction between indoor TSP exposure and the microbiome on HERV methylation, we identified that at low abundance of Cutibacterium acnes and Actinomyces naeslundii, indoor TSP exposure is associated with increased methylation of HERV-W. This HERV sequence was previously found to be hypermethylated in response to air pollution exposure.   In conclusion, this evidence indicates that indoor TSP exposure directly affects the respiratory microbiome, and consequentially the methylation of HERV-K and HERV-W.","language":"eng","citation":"THE EFFECT OF INDOOR TOTAL SUSPENDED PARTICLES (TSP) ON THE HUMAN UPPER RESPIRATORY SYSTEM: FROM THE MICROBIOME TO HERV METHYLATION / G. Solazzo ; tutor: V. Bollati ; coordinatrice: M. Guarino. Dipartimento di Scienze Cliniche e di Comunità, 2024 May 30. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R13105.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1051408/2413953/phd_unimi_R13105.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/971654"},"title":"NEW PERSPECTIVES IN LIVESTOCK NUTRITION TO IMPROVE HEALTH AND PERFORMANCE","internalauthor":"SANDRINI, SILVIA","type":"Tesi di dottorato","year":"2023","abstract":"In the last years the livestock and poultry farming are dealing with important changing, characterized by an increase in animal product demand, which must be associated with greater sustainability of animal production sector. In these light different measures are under investigation, involving biosecurity, genetics, health care, farm management, animal welfare and nutrition, to prevent diseases and promote animal health. The main objectives of this thesis were to investigate 1) the effects of yeasts (Chapter 3, 4 and 5) and nucleotides (Chapter 6) supplementation as feed additives to improve animals’ performance and gut health, and 2) the in vivo and in vitro efficacy of an essential oil-based compound (EOC) to inhibit sporulation and thus to prevent oocysts from becoming infectious in Holstein dairy calves (Chapter 7). Therefore, the beneficial effects of yeasts and yeast derived products in horse nutrition have been firstly reviewed (Chapter 3). Then an in vivo trial (Chapter 4) was performed to investigate the effects of Saccharomyces cerevisiae supplementation in mature horses’ diet, in a crossover experimental design, considering changes in body weight and feed consumption of treated animals together with a focus on the apparent digestibility of dietary fibrous fractions using Acid Insoluble Ash as marker in the faeces. The obtained results outlined no significant changes in body weight and feed intake in yeast-fed horses, while apparent digestibility was improved for dry and organic matter, neutral detergent fibre, acid detergent fibre, hemicellulose, and cellulose in treated animals. The administration of live yeast to mature horses showed positive effects of the digestibility of the fibrous fractions of a high frorage:concentrate ratio diet. A second study (Chapter 5) was aimed to investigate the effects of a combination of three different yeasts strain supplementation to weaning piglets, on animal performance and gut health. The obtained results did not show a significant improvement of growing performance, but differences in faecal consistency depending on the experimental week. Yeast-fed piglets showed improved ileum morphological and histochemical parameters, as 16S rRNA sequencing for faecal microbial community outlined decreased abundance of potential pathogens bacteria and increased presence of beneficial bacteria. The administration of a compound containing a combination of three yeasts in weaned piglet showed to improve the gut health on treated animals.  In the third study (Chapter 6) nucleotides’ administration in broiler was tested when provided in drinking water during critical phases of the production cycle. Growth and slaughter performance, and the incidence of footpad lesions were investigated in a 42-days trial. No significant effect of nucleotides supplementation on broilers’ performance and footpad lesions were evidenced during the trial. The observed lack of effectiveness for nucleotides supplementation can be partially attributed to the mitigation effect of the optimal rearing conditions provided in the experimental farm during the trial. The last study (Chapter 7) was aimed to assess whether the administration of an essential oil-based compound was able to reduce the excretion of oocysts of Eimeria spp., in vitro and in vivo with the aim to improve animal health and performance. The in vitro study showed no effectiveness of the product to inhibit the Eimeria oocysts sporulation, stating that the product was unable to prevent the acquisition of infection.  The in vivo study performed on Holstein dairy calves between the 21st and the 120th day of life did not evidenced significant differences on growing performance and faecal score and the supplementation of the essential oil-based compound did not affect the number of oocysts eliminated in the feces, although a significant reduction in the number of oocysts per gram of feces (OPG) emitted over time in both groups was observed. Overall, these results contributed to the investigation of nutritional strategies to improve the animal health and growth performance. Nevertheless, further investigations are suggested to improve our knowledge about the gaps that have been observed.","language":"eng","citation":"NEW PERSPECTIVES IN LIVESTOCK NUTRITION TO IMPROVE HEALTH AND PERFORMANCE / S. Sandrini ; tutor: A. Agazzi; coordinatore: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2023 Jun 05. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12735.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/971654/2206817/phd_unimi_R12735.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1019636"},"title":"DEGENERATIONS OF AUTOMORPHISMS ON IRREDUCIBLE HOLOMORPHIC SYMPLECTIC VARIETIES","internalauthor":"LI BASSI, LUCAS","type":"Tesi di dottorato","year":"2023","abstract":"The aim of this thesis is to study the degeneration of special automorphisms (termed non-symplectic) on certain families of irreducible holomorphic symplectic varieties (IHS varieties).\\newline\\newline  In fact, the moduli space of smooth cubic threefolds is isomorphic to a moduli space $\\mathcal{N}^{\\rho, \\zeta}_{\\langle 6\\rangle}$ of IHS varieties equipped with a special order 3 non-symplectic automorphism. This is a result by Boissière--Camere--Sarti, \\cite{BCS}. In the same paper, the authors extended the result to the general case with a so-called nodal singularity. Extending this map primarily means studying the limit of a one-parameter degeneration whose central point is the period of a nodal cubic threefold. What happens is that if we consider a one-parameter family in $\\mathcal{N}^{\\rho, \\zeta}_{\\langle 6\\rangle}$ that has a nodal period as its limit, it turns out that at the limit the family degenerates into a family of IHS varieties with an order 3 non-symplectic automorphism with a larger invariant. In this sense, we say the automorphism \\emph{degenerates}. Secondly, it means providing a map (which in this case is birational) between the nodal locus and a suitable moduli space of IHS varieties possessing a non-symplectic order 3 automorphism, with precisely a larger invariant.\\newline\\newline  The first part of the thesis is dedicated to finding a similar result for non-generic nodal cubics. In particular, by going to increasingly higher codimension, a birational map is found between the subspaces of the nodal locus whose generic element is a cubic with a single singularity $A_i$ for $i=2,3,4$, and a moduli space of IHS varieties of type $K3^{[2]}$ with a non-symplectic $\\rho_i$ automorphism of order 3. To achieve this, we employ techniques developed by Boissière, Camere, and Sarti to arrive at a bijective restriction of the period map.\\newline\\newline  The second part, in collaboration with Boissière and Comparin, is dedicated to a detailed study of the geometry of the limit which can in fact be expressed as the symplectic resolution of the Fano variety of lines lying on the cyclic cubic fourfold, that is, a cyclic 3-to-1 cover of $\\mathbb{P}^4$ branching over a cubic threefold which in this case has isolated singularities of type $A_i$ for $i=2,3,4$.","language":"eng","citation":"DEGENERATIONS OF AUTOMORPHISMS ON IRREDUCIBLE HOLOMORPHIC SYMPLECTIC VARIETIES / L. Li Bassi ; tutor: C. Camere, A. Sarti ; coordinatore: D. Bambusi. Dipartimento di Matematica Federigo Enriques, 2023 Dec 07. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13189.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1019636/2331420/phd_unimi_R13189.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1204993"},"title":"DEVELOPMENT OF APTAMER-BASED ENTRY INHIBITORS TARGETING CONSERVED HOST RECEPTORS OF RESPIRATORY VIRUSES","internalauthor":"DELLAVEDOVA, JESSICA","type":"Tesi di dottorato","year":"2025","abstract":"Respiratory viruses represent a significant public health challenge, with both seasonal and emerging pathogens capable of causing severe disease, especially in vulnerable populations. Among these, Human Rhinoviruses (HRVs) and Coronaviruses (CoVs) are notable for their ability to exploit conserved host protein receptors to mediate cellular entry—a feature that presents an attractive target for therapeutic intervention.   This thesis focuses on the preclinical development of Aptamer 6 (Apt6), a nucleic acid ligand previously identified in our laboratory for its ability to inhibit coronavirus infection by binding to the human angiotensin-converting enzyme 2 (ACE2) receptor (Villa et al., 2022). To translate Apt6 into a viable therapeutic candidate, we implemented a comprehensive optimization strategy, including metabolic stabilization through chemical modifications and PEGylation, as well as sequence minimization guided by structural modelling. Functional evaluation was carried out using advanced in vitro systems, particularly air–liquid interface (ALI) cultures of human airway epithelium, to assess antiviral efficacy under physiologically relevant conditions.   A second aim of the thesis is to validate the aptamer selection pipeline and demonstrate its broader applicability to other conserved viral entry mechanisms. To this end, we initiated a de novo aptamer selection procedure targeting the intercellular adhesion molecule 1 (ICAM1)—the primary receptor for the major group of HRV serotypes. Since ICAM-1 is a conserved entry receptor utilized by a large number of HRVs, its blockade offers a strategic point of intervention. Using an optimized in-house SELEX (Systematic Evolution of Ligands by EXponential enrichment) protocol, we selected and characterized novel aptamers capable of binding ICAM-1 and interfering with HRV entry.   Together, these efforts advance the development of aptamer-based antivirals targeting host-virus interactions and highlight the potential of this platform for broader therapeutic applications.","language":"eng","citation":"DEVELOPMENT OF APTAMER-BASED ENTRY INHIBITORS TARGETING CONSERVED HOST RECEPTORS OF RESPIRATORY VIRUSES / J. Dellavedova ; tutor: P. Ciana ;  coordinatore: G. Norata. Dipartimento di Scienze della Salute, 2025 Dec. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13820.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 22-GIU-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1119759"},"title":"CALABI-YAU MANIFOLDS OF TYPE A AND THE CONE CONJECTURE FOR HYPERELLIPTIC VARIETIES","internalauthor":"MONTI, MARTINA","type":"Tesi di dottorato","year":"2024","abstract":"A Calabi-Yau n-fold Y is a compact, complex, Kähler n-fold with trivial canonical bundle and h^{i,0}(Y)=0 for 0<1 and Oguiso and Sakurai classified them in dimension 3. In this thesis we provide higher dimensional examples that ensure the existence of Calabi-Yau manifolds of type A in all odd dimension.  After that, we study the geometry of Calabi-Yau 3-folds of type A.   Thanks to Oguiso and Sakurai, we know that there exist only two families F^A_G of Calabi-Yau 3-folds A/G of type A and each of them corresponds uniquely to a group G which acts freely on A and does not contain any translations. More in details, the family F^A_{D_4} is constructed by Catanese and Demleitner and the family F^A_{(Z/2Z)^2}  is constructed here.   In particular, these families are irreducible and each X in F^A_G admits a finite étale cover A which splits into the product of three elliptic curves.  Our main results include the full classification of the automorphisms group and the possible quotients of manifolds in F^A_G for both choices of G. We prove that Aut(X) is finite for X in F^A_G.  Furthermore, if X in F^A_{D_4} then X/U is birational to a Calabi-Yau 3-folds for every U in Aut(X), while  if X in F^A_{(Z/2Z)^2} then X/\\U is birational either to a Calabi-Yau 3-fold or to a 3-fold with negative Kodaira dimension or to a 3-fold Y with trivial Kodaira dimension and K_Y is not 0. In particular,   we compute the Hodge numbers and the fundamental groups of Calabi-Yau 3-folds Y birational to the quotient X/U where X in F^A_G and U in Aut(X).    In the second part, we establish the Morrison-Kawamata cone conjecture for hyperelliptic varieties. The cone conjecture, an open problem in birational geometry, predicts that the nef and movable cones, of  projective varieties Y with K_Y numerically trivial, admit a rational polyhedral structure under the action of automorphism and birational automorphism groups, respectively. The conjecture provides insights into both the geometry and birational geometry of varieties, specially from the point of view of Minimal Model Program. To prove the conjecture for hyperelliptic varieties, we generalize the techniques established by Prendergast-Smith for abelian varieties. Additionally, we investigate whether  hyperelliptic varieties  A/G have a rational polyhedral nef cones. We obtain a result in relation to the representation of G, in particular we deduce that all the Calabi-Yau manifolds of type A studied in this thesis have rational polyhedral nef cones. Finally, we study the extremal rays of the nef cones of these latter manifolds. We prove that the extremal rays are semi-ample divisors, by generalizing a proof of Oguiso and Sakurai. Thereby, we deduce that all nef divisors are semi-ample divisors.","language":"eng","citation":"CALABI-YAU MANIFOLDS OF TYPE A AND THE CONE CONJECTURE FOR HYPERELLIPTIC VARIETIES / M. Monti ; tutor: A. Garbagnati, A. Sarti ; coordinatore: D. P. Bambusi, B. Psquier. Dipartimento di Matematica Federigo Enriques, 2024 Dec 05. 37. ciclo","filename":"phd_unimi_R13228.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1119759/2709160/phd_unimi_R13228.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1211555"},"title":"MONITORING PHONON DYNAMICS IN QUANTUM MATERIALS BY TIME-RESOLVED SPONTANEOUS RAMAN SCATTERING","internalauthor":"FINARDI, ALICE MARGHERITA","type":"Tesi di dottorato","year":"2026","abstract":"This thesis collects the results of my work as doctoral student of the Ph.D. School in Physics, Astrophysics and Applied Physics at Università degli Studi di Milano, that has been carried out since October 2022 at the Istituto Officina dei Materiali of the Consiglio Nazionale delle Ricerche (IOM-CNR) and within the framework of Nanoscale Foundries and Fine Analysis (NFFA) facility.  My research activity has been devoted to the study of phonon dynamics in photoexcited quantum materials, employing time-resolved spontaneous Raman spectroscopy (TRRS) as the primary experimental approach. Among ultrafast spectroscopies, TRRS provides unique access to phonons and other low-energy excitations in systems impulsively  driven into transient non-equilibrium states, allowing mode-specific monitoring of their population dynamics. This makes TRRS particularly powerful for investigating electron-phonon and phonon-phonon couplings, as well as the evolution of crystal symmetries after photoexcitation. Motivated by the broad span of applications of this  technique and by its complementarity with other ultrafast spectroscopies targeting electronic, lattice or spin degrees of freedom, a dedicated TRRS setup was developed at the NFFA-SPRINT laboratory, hosted in the premises of the FERMI@Elettra facility (Elettra-Sincrotrone Trieste).  This booklet thus summarizes my work for the commissioning and characterization of the new setup, and presents the results from three case studies addressing the properties of semiconductors, 2D chalcogenides and a strong correlated oxide. In a first experiment, the phonon relaxation dynamics of silicon is investigated. The possibility of tuning the phonon-phonon anharmonic interaction is explored by varying the external temperature and the excitation density. Furthermore, the photodoping dynamics is directly monitored via a Fano interference effect between electronic and phononic Raman scattering. A second experiment, targeting bulk and single-layer MoS2, reveals a photodoping-induced phonon frequency renormalization and a long-lived excitation anisotropy in the phonon subsystem, dictated by mode symmetries and inaccessible under equilibrium conditions. In a third experiment, TRRS is employed to monitor the evolution of the lattice symmetry of magnetite and the phonon-specific energy flow while triggering a photoinduced Verwey phase transition.","language":"eng","citation":"MONITORING PHONON DYNAMICS IN QUANTUM MATERIALS BY TIME-RESOLVED RAMAN SCATTERING / A.m. Finardi ; supervisor:  G. Rossi ;  co-supervisor: R. Cucini ; director of the school: A. Mennella. Dipartimento di Fisica Aldo Pontremoli, 2026 Jan 23. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13971.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1211555/3236818/phd_unimi_R13971.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/824047"},"title":"ROLE OF LSD1 IN AGING- AND STRESS- DEPENDENT EPIGENETIC DRIFT LEADING TO DEPRESSION AND ANXIETY DISORDERS","internalauthor":"FORASTIERI, CHIARA","type":"Tesi di dottorato","year":"2021","abstract":"The current understanding of the pathophysiologic processes underlying neuropsychiatric disorders remains dramatically limited, despite their epidemic diffusion and tremendous impact on patients’ health and society. Mounting evidence suggests that the disruption of stress-coping mechanisms might be coupled to maladaptive forms of plasticity underlying stress-vulnerability, fostering mood disorders such as anxiety and major depressive disorder (MDD). The correct tuning of the relative ratio between the epigenetic enzyme Lysine-Specific Demethylase 1 (LSD1) and its neuronal-specific dominant negative isoform neuroLSD1 is crucial to guarantee homeostatic adaptive plasticity in response to environmental stimuli, in the frame of a stress-resiliency instrumental pathway. Another homeostatic regulator of excitatory neurons playing a fundamental part in environmental stress-response is the neuronal-enriched splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) that is heavily implicated in the onset of several neurological disorders, such as autism and epilepsy, and has been recently listed among the few genetic loci associated to MDD.  During my PhD, I dissected a higher primates-restricted functional interaction between RBFOX1 and LSD1. Specifically, RBFOX1, thanks to a single nucleotide variation present only in higher primates and humans and generating a new acceptor splice site, acquires the ability to regulate splicing inclusion of a novel LSD1 cryptic exon, that we named exon E8b. This alternative spliced exon not only negatively regulates LSD1 levels by Nonsense-mediated mRNA decay, but also modulates brain-restricted expression of neuroLSD1, affecting LSD1 and neuroLSD1 ratio. Notably, we further demonstrated the involvement of LSD1/neuroLSD1 ratio modulation in physiological brain aging and psychiatric drift in humans. If on the one hand the evolution-driven acquisition of LSD1 as RBFOX1-regulated target could contribute to increase the complexity of stress response and environmental adaptation, on the other hand it likely represents a novel vulnerability harbor multiplying susceptibility substrates for stress-related neuropsychiatric disorder.  In parallel, always with the idea to identify neurobiological mechanisms associated with stress susceptibility, I evaluated the involvement of specific LSD1 genetic variants able to set different levels of LSD1/neuroLSD1 ratio and potentially impacting stress susceptibility in humans.","language":"eng","citation":"ROLE OF LSD1 IN AGING- AND STRESS- DEPENDENT EPIGENETIC DRIFT LEADING TO DEPRESSION AND ANXIETY DISORDERS / C. Forastieri ; tutor: E. BATTAGLIOLI ; supervisor: F. RUSCONI ; phd coordinator: M. LOCATI, N. LANDSBERGER. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2021 Mar 25. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12097.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/824047/1734032/phd_unimi_R12097.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/959397"},"title":"DISSECTING THE ROLE OF Β-CATENIN AND MYC IN GASTRIC TUMOR FORMATION","internalauthor":"MULE', PATRIZIA","type":"Tesi di dottorato","year":"2023","abstract":"Tissue development, homeostasis and regeneration are remarkable processes that require the concerted activation and restriction of distinct gene-expression programs. The Wnt signaling pathway plays a prominent role in regulating the homeostasis of gastrointestinal epithelium by promoting stem cell maintenance, proliferation and cell fate specification.   Aberrant activation of the Wnt/β-catenin signaling pathway occurs in the vast majority of human gastrointestinal tumors. Despite it is well known that deregulation of Wnt signaling pathway is a clear genetic event driving the onset of intestinal tumors, its role in gastric tumorigenesis remains elusive. Here, using conditional transgenic mouse models, we show that Wnt constitutive activation does not have any oncogenic effect in the gastric epithelium and cooperates with MYC in driving gastric tumorigenesis. By integrating transcriptomic and epigenomic analysis with organoid models, we provide phenotypic and mechanistic insights about how MYC and β-catenin integrate their activities in regulating stem cell function and tumor formation. Mechanistically, we reveal that MYC enhances β-catenin chromatin occupancy and Wnt-transcriptional program activation. By dissecting the MYC-dependent transcriptional program both in gastric stem cells and mouse-derived organoids, we uncover that MYC represses a large number of autophagy-related genes, resulting in the suppression of the autophagic degradation pathway. Finally, we highlight that the impairment of Epithelial Cell Adhesion Molecule (EpCAM) autophagic degradation promotes β-catenin chromatin accumulation and activation of oncogenic Wnt transcriptional program. Our work reveals an unprecedented signaling framework relevant for Wnt/Myc driven-gastrointestinal tumor development.","language":"eng","citation":"DISSECTING THE ROLE OF Β-CATENIN AND MYC IN GASTRIC TUMOR FORMATION / P. Mule' ; supervisor: D. Pasini ; coordinator: S. Minucci. Dipartimento di Scienze della Salute, 2023 Apr 13. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12411.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/959397/2162289/phd_unimi_R12411.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/984889"},"title":"BASIC SCIENCE FOR TISSUE ENGINEERING IN VETERINARY ORTHOPAEDIC RESEARCH","internalauthor":"HERRERA MILLAR, VALENTINA RAFAELA","type":"Tesi di dottorato","year":"2023","abstract":"The complex micro- and macro-structure of the meniscus requires a multidisciplinary approach to increase the knowledge currently available about the biology that characterizes its development. In the tissue of adult animals, it is possible to distinguish three zones according to the vascularisation, to the biochemical composition and to the regenerative abilities: 1) an outer zone, completely vascularised, with a fibrous-like matrix and capable of regenerating itself; 2) an intermediate zone with transitional characteristics; 3) an inner zone, non-vascularized, with a cartilaginous-like matrix and with poor repair capacity. Therefore, the meniscal tissue engineering, linking the structure and function of the tissues under normal conditions, seeks to develop a compound able to repair injuries of the inner zone, restoring the physiological characteristics to the tissue and avoiding degenerative phenomena. In particular, the aim of this PhD project was to analyse selected endogenous and exogenous factors that can influence the differentiation of meniscal cells. To do this, the project was divided into four parts: 1) role of hypoxia on chondrogenic differentiation of immature meniscal cells; 2) role of hypoxia on vascular factors involved in meniscus maturation; 3) role of endostatin on the chondrogenic differentiation of meniscus cells in a three-dimensional construct; and 4) characterization and validation of micro-computed tomography for the visualization of complex micro-structures such as the meniscal vascular network. Data were obtained through morphological, biochemical, biomechanical, molecular analyses and high-resolution imaging techniques.","language":"eng","citation":"BASIC SCIENCE FOR TISSUE ENGINEERING IN VETERINARY ORTHOPAEDIC RESEARCH / V.r. Herrera Millar ; tutor: A. Di Giancamillo ; coordinatore: F. Ceciliani. Dipartimento di Scienze Biomediche per la Salute, 2023 Jul 13. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12546.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/984889/2245554/phd_unimi_R12546.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1018328"},"title":"DEVELOPMENT OF A BIOINFORMATIC SUITE TO IMPROVE THE CLINICAL IMPLEMENTATION OF NEXT GENERATION SEQUENCING IN PRECISION MEDICINE FOR ONCOLOGY","internalauthor":"VOZZA, GIANLUCA","type":"Tesi di dottorato","year":"2023","abstract":"The identification of clinically relevant variants has been moving through a data-driven path, and a large number of projects have been launched with the aim of favoring the implementation of NGS-based molecular profiling, particularly to define diagnostic, prognostic, and therapeutic pathways for cancer patients. It would be particularly useful to map the country-level mutational prevalence in CPGs in both the affected population and their relatives to assess the degree of heritability of specific mutations predisposing to different types of solid tumors such as breast, ovarian, and colon cancers. Additionally, a comprehensive profiling of the tumor genome of patients is needed to detect variants that may indicate a potential therapeutic response to new drug treatments. In order to do that, action is required within a structured network composed of the main oncology institutions across the country, through collaborative efforts as ACC, and the implementation of a centralized system for the storage, analysis, and interpretation of large volumes of data. For the purpose of centralized analysis and interpretation, we have developed multiple bioinformatic tools to:    i) Perform rigorous QC on the reads used in the clinical setting to detect any coverage biases in clinically relevant regions.    ii) Perform benchmarking and standardization of variant calling pipelines through the development of a software that simplifies fine-tuning and reduces the time required for the curation of potential FNs. This software should also harmonize the various variant notations in VCF files from major variant callers in a precise and reproducible manner.    iii) Interpret and report variants based on ACMG guidelines (2015 for germline variants and 2017 for somatic variants) and develop ML-based algorithms for assessing the pathogenicity of variants with uncertain significance.    This work converged into the development of multiple bioinformatic tools:    i) Covdetect for detecting coverage biases in relevant genomic regions as where VOIs lie; ii) RecallME to harmonize different variant notation formats and to benchmark VC pipelines on a set of expected variants; iii) MolProBoard to visualize and interpret reported VOIs iv) RENOVO to assess the pathogenicity level of VUS.    These tools were then bundled into a single suite for implementing NGS-derived data within the clinical settings, as presented in this thesis.","language":"eng","citation":"DEVELOPMENT OF A BIOINFORMATIC SUITE TO IMPROVE THE CLINICAL IMPLEMENTATION OF NEXT GENERATION SEQUENCING IN PRECISION MEDICINE FOR ONCOLOGY / G. Vozza ; added-supervisor: A. Magi ; internal advisor: S. Gandini ; tutor: L. Mazzarella ; co-tutor: P. G. Pelicci ; phd coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2023 Dec 12. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12747.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1018328/2327483/phd_unimi_R12747.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/893211"},"title":"STRUCTURE-BASED DESIGN OF GLYCOMIMETIC LIGANDS FOR THE N-TERMINAL DOMAIN OF BC2L-C LECTIN","internalauthor":"LAL, KANHAYA","type":"Tesi di dottorato","year":"2021","abstract":"The prevalence of drug-resistant infections has challenged the existing treatment regimen using antibiotics. There is a need to discover and employ alternative and complementary therapies to counteract these life threatening infections. In fast few decades, the use of anti-adhesion molecules targeting virulence factors such as lectins has been proven an attractive approach to counteract the infections by disarming the pathogens. This thesis work aimed to design glycomimetic antagonists of the N-terminal domain of the BC2L-C lectin (BC2L-C-nt) from the drug-resistant pathogen known as B. cenocepacia. We employed a fragment-based approach to design glycomimetic antagonists of the target protein (BC2L-C-nt). The initial studies were focused towards the binding site prediction and target evaluation by computational tools which identified additional druggable regions near the fucoside binding site in BC2L-C-nt.  These additional regions have been explored further to evaluate the druggability by employing virtual screening of a small fragment library. This identified an interesting region (region ‘X’) that could host the drug-like fragments by establishing some key interactions. These interactions with the lectin have been confirmed using a group of biophysical techniques, including X-ray crystallography. Remarkably, the binding mode of one of the fragment (KL3) has been validated by X-ray crystallography at high resolution confirming the ability of site X to host drug-like fragments. Further, the fragments have been chemically connected to the fucose core to obtain high-affinity bifunctional glycomimetic ligands. Interestingly, the crystal complexes of BC2L-C-nt with two bifunctional glycomimetic ligands again confirmed the druggability of the identified site, thus also validated the computational predictions. Hence, the first generation of glycomimetic ligands with binding affinities in micromolar range have been successfully designed. These glycomimetics provide further opportunities to design high-affinity ligands. Future studies based on structure-based approaches and robust synthetic routes to synthesize glycomimetics can lead towards the high-affinity ligands as anti-adhesive agents against B. cenocepacia.","language":"eng","citation":"STRUCTURE-BASED DESIGN OF GLYCOMIMETIC LIGANDS FOR THE N-TERMINAL DOMAIN OF BC2L-C LECTIN / K. Lal ; tutor: A. Bernardi, L. Belvisi, A. Imberty, A. Varrot ; coordinatore: E. Licandro. Dipartimento di Chimica, 2021 Dec 15. 33. ciclo, Anno Accademico 2020. [10.13130/lal-kanhaya_phd2021-12-15].","filename":"phd_unimi_R12139.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/893211/1941382/phd_unimi_R12139.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1135895"},"title":"NON - RELIGIOUS DISCOURSES AND THE SECULARIZATION OF THE SECULAR: A COMPUTATIONAL STUDY OF ORGANIZED NON - RELIGION IN THE UNITED STATES AND THE UNITED KINGDOM (1881-2019).","internalauthor":"BALAZKA, DOMINIK","type":"Tesi di dottorato","year":"2025","abstract":"Despite the growth of Non-Religion Studies in recent years, historical changes within secularity remain underexplored and there is a shortage of extensive longitudinal studies dealing with the phenomenon. This shortcoming arguably stems, on one side, from the lack of sufficient granularity in the commonly used longitudinal survey data and, on the other, from a chronic indifference of secularization theory toward the changes occurring within secularity itself. It was argued that secularization is a process of broader (non-)religious change, and that secularization theory can and should be extended to the analysis of non-religion. This thesis employs a series of computational methods, ranging from Topic Modeling to Sentiment Analysis and Dynamic Word Embedding, to explore a large collection of magazines published by two American and two British non-religious organizations between 1881 and 2019. The analysis reveals that the historical fluctuations in the relevance attributed to religion by militant non-religious organizations closely follows fluctuations in the public visibility of religion. Furthermore, in line with the theoretical expectations, the relevance of these topics is consistently higher among groups with a more radical orientation (i.e., among atheists rather than humanists) and in contexts characterized by a lower degree of secularization (i.e., in the US rather than the UK). On the contrary, the demand for positive non-religious identities remained prevalently stable over time showing signs of a descending trend only throughout the latest decades. Sentiment Analysis, in combination with linear regression, confirmed that the proportion of negative sentiment in religion-related topics is positively associated with the perceived relevance of religion. Finally, Dynamic Word Embedding revealed two prevalent shifts. On one side, the critique of religion progressively moved away from an ideological confrontation of religious others and towards a more moderate focus on pragmatic concerns. Second, the conceptualizations of atheism and humanism increasingly converged, emphasizing a positive non-religious identity, political activism, and the organizational aspects of the secular movement.","language":"eng","citation":"NON-RELIGIOUS DISCOURSES AND THE SECULARIZATION OF THE SECULAR: A COMPUTATIONAL STUDY OF ORGANIZED NON-RELIGION IN THE UNITED STATES AND THE UNITED KINGDOM (1881-2019) / D. Balazka ; supervisor: F. Biolcati Rinaldi, D. Houtman ; co-supervisor: A. Ferrara, G. Watts ; coordinatore: P. Rebughini. - Milano. Università degli Studi di Milano, 2025 Feb 03. 36. ciclo","filename":"phd_unimi_R13009.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1135895/2636849/phd_unimi_R13009.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/914143"},"title":"ASTROMETRY TECHNIQUES FOR THE CALIBRATION OF THE ASTRI TELESCOPE WITH THE VARIANCE METHOD","internalauthor":"IOVENITTI, SIMONE","type":"Tesi di dottorato","year":"2022","abstract":"In the study of Very High-Energy (VHE) astrophysical phenomena the next generation of Imaging Atmospheric Cherenkov Telescopes (IACT) will play a key role thanks to specific ground-based astronomical observations. In this context, the ASTRI project developed a novel instrument endowed with a Schwarzschild-Couder dual-mirror optical configuration (that has never been adopted before in gamma-ray astronomy) and a dedicated Cherenkov camera entirely designed by the Istituto Nazionale di Astrofisica (INAF) based on SiPM sensors. The prototype telescope ASTRI– Horn is located in Italy and carried out successfully in 2019 the techno- logy validation phase, paving the way for the realization of the MiniAr- ray: 9 identical telescopes working in stereoscopic mode to be installed in Tenerife (Canary Islands) within the next three years. However, several issues related to the pointing performances emerged during operations with ASTRI–Horn. Actually, the pointing calibration is generally a critical aspect for Cherenkov telescopes, as their cameras are designed for the detection of nanosecond atmospheric flashes rather than for imaging the starfield and, consequently, it is impossible to use the standard astrometry of the focal plane. Furthermore, in the case of ASTRI, the compactness of the mechanical structure prevents from installing an auxiliary monitoring camera sharing the same optical system of the telescope. Despite these difficulties, the optimization of the pointing performances is crucial for ensuring the scientific accuracy of the whole system.  The present PhD thesis aims at the development and validation of new astrometric techniques for the pointing calibration of the ASTRI telescope exploiting the so-called Variance method, a statistical algorithm implemented in the Cherenkov camera electronic board. Thanks to the Variance, the AS- TRI telescope is endowed with an ancillary output owning the potentiality to image the stellar component of the night sky background in the Field of View (FoV), with a quite coarse angular resolution (~11°, corresponding to the pixel size of the Cherenkov camera), but a relatively good sensitivity for an IACT (visual magnitude limit ~7). As we discuss in this document the Variance constitutes a unique opportunity for enhancing the pointing performances of the telescope, and we demonstrate that our procedures offer a chance to reach the critical accuracy level required for achieving the scientific objectives of the ASTRI project.  Unfortunately, in this period the COVID-19 pandemic and other accidental events, heavily delayed the maintenance operations on the ASTRI– Horn telescope, and up to now it is still impossible to make new observations dedicated to the validation of our procedures, hence only data taken in previous months were used. As in any other experimental activity, new data taken on purpose would have considerably facilitated our work, but due to the present situation, we focused our attention on Variance data available in the ASTRI archive that has never been explored before. The resulting work represents the first complete and detailed analysis of the Variance method together with its numerous unexplored applications. Our custom astrometry techniques allowed us to reveal that ASTRI–Horn was affected by two kinds of systematic errors, that we characterized and measured for the first time. The experience gained with archive data allowed us to understand how to apply our routines for calibrating the incoming ASTRI MiniArray, indicating an effective strategy to match the crucial requirement for the pointing accuracy. The resulting procedure has already been inserted into the calibration plan of the MiniArray and its Online Observation Quality System (OOQS).  The structure of the present document is articulated in eight chapters and three appendices, whose content can be summarized as follows.  Chapter 1 presents the status of the art in VHE astrophysics, focusing on the observational features of cosmic rays and gamma rays, together with a description of the main open questions in this research field.  Chapter 2 is dedicated to IACTs, presenting their history and operating principles, and introducing the major examples of instruments currently in activity worldwide.  Chapter 3 focuses on the ASTRI project, presenting both the prototype telescope ASTRI–Horn and the incoming observatory of the MiniArray. In particular, it is reported a detailed description of the most relevant sub-systems for this thesis: the camera, the optical scheme, and the pointing strategy.  Chapter 4 goes into the details of the Variance method. A technical description of its functioning at the electronic level is provided at first, while the core of the chapter is dedicated to our routines for the production of sky images and their calibration.  Chapter 5 reports specific tools and procedures that we developed for the analysis of Variance images: the astrometric calibration, the de-convolution of the star signal, and the transformation function to correct the artifacts introduced by the geometric arrangement of the pixels.  Chapter 6 describes the algorithm to assess the alignment of the Cherenkov camera to the optical axis of the telescope exploiting the apparent rotation of the FoV during long observing runs in tracking mode.  Chapter 7 shows a custom procedure for the star identification developed on purpose for Variance images (as it is impossible to adopt the standard astrometry software for their analysis) allowing to monitor in real-time the actual pointing direction of the telescope.  Chapter 8 contains the concluding remarks. It summarizes the main results achieved in this thesis, highlighting their importance but also some limitations and suggesting further improvements. Future perspectives of this work are briefly presented at last, with particular attention to its implementation on the incoming ASTRI MiniArray.  At the end of this document, three appendices report additional/complementary material concerning respectively metrological techniques for the inspection of shape and reflectivity of primary mirror segments (A), more details about the software developed for this thesis and the access to it (B), and the massive activity of outreach and education carried out during the doctoral period in the field of Cherenkov astronomy (C).","language":"eng","citation":"ASTROMETRY TECHNIQUES FOR THE CALIBRATION OF THE ASTRI TELESCOPE WITH THE VARIANCE METHOD / S. Iovenitti ; supervisor: M. Potenza ; co-supervisor: G.Sironi, G. Pareschi. Università degli Studi di Milano, 2022 Mar 22. 34. ciclo, Anno Accademico 2021. [10.13130/iovenitti-simone_phd2022-03-22].","filename":"phd_unimi_R12351.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/914143/1996260/phd_unimi_R12351.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1149636"},"title":"GREEN SENSORS AND SMART SERVICES FOR THE OPTIMIZATION OF AGRI-FOOD SUPPLY CHAINS IN A VIEW OF INDUSTRY 4.0: GREATER SUSTAINABILITY OF PRODUCTION, BUSINESS COMPETITIVENESS AND REDUCTION OF FOOD WASTE","internalauthor":"VIGNATI, SARA","type":"Tesi di dottorato","year":"2025","abstract":"The 12th Sustainable Development Goal (SDG) focuses on the concept of sustainable consumption and production, with a particular focus on reducing food loss and waste (Goal 12.3) by 2030. In order to achieve this in the fresh-cut chain, it is necessary to implement systemic improvements, including advanced agronomic practices, optimised harvest timing, effective post-harvest storage and innovative packaging. Green technologies such as optical sensing have the potential to enhance quality, extend shelf life and reduce environmental impact. However, their high costs present a significant barrier to adoption, as multiple devices are often required to address the complexities of supply chains. Research is addressing this challenge by developing compact, and low-cost imaging solutions for both pre- and post-harvest monitoring.  This doctoral research project concerns the application of non-destructive imaging techniques to assess the quality of some fresh and fresh-cut products, in terms of freshness and shelf life. Additionally, it involves the development of customized optical devices in a view of Industry 4.0, with the objective of enhancing the sustainability of the supply chain and reducing food loss and food waste. Two distinct measurement configurations were employed at laboratory scale, each with a different application objective. The first configuration concerned a cost-effective IoT hyperspectral prototype, that has been designed and successfully tested. The prototype operated within the spectral range of 400 nm to 1000 nm and has been developed using commercial equipment and a 3D-printer. It has reached satisfactory results for the current stage of technology development, which is estimated to be at a TRL (Technology Readiness Level) of 2. The prototype exhibited the capacity to differentiate between healthy and damaged tissue and to be sensible to variations in leafy vegetables over time, thereby demonstrating the capability to detect changes in the product as it undergoes decay. The prototype was designed for future integration at critical points in the production chain. Instead, the second configuration was proposed with the aim of monitoring the quality level of packaged products, thereby improving their management at the sales point and providing consumers with information on the true quality level of the products. This study demonstrated the potential of multispectral imaging for non-destructive monitoring of fresh-cut lettuce deterioration through packaging. The application of chemometric methods enabled effective identification and classification of fresh samples. However, the classification accuracy for subsequent days was found to be variable due to differences in decay rates between sample groups and light reflections from packaging.   In conclusion, this PhD project has demonstrated the benefits and potential of imaging systems as an effective and sophisticated tool for quality assessment in the food industry throughout the production chain, as well as one of the key tools for reducing food loss and waste. However, continued research and development is essential to refine these technologies and make them accessible and adaptable for wider applications. By integrating these tools into sustainable practices, the agri-food sector can make significant progress towards achieving global sustainability goals.      Keywords: Green technology, food quality, imaging, industry 4.0, sensor design, cost-effective, chemometrics.","language":"eng","citation":"GREEN SENSORS AND SMART SERVICES FOR THE OPTIMIZATION OF AGRI-FOOD SUPPLY CHAINS IN A VIEW OF INDUSTRY 4.0: GREATER SUSTAINABILITY OF PRODUCTION, BUSINESS COMPETITIVENESS AND REDUCTION OF FOOD WASTE / S. Vignati ; tutor: R. Guidetti ; co-tutor: R. Beghi ; coordinatore: D. Mora. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2025 Mar 04. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13616_3.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1149636/2693483/phd_unimi_R13616_3.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/913457"},"title":"POTENTIAL AND PITFALLS OF CELLULOSE NANOCRYSTALS IN ADVANCED PACKAGING MATERIALS: THEIR ROLE IN FOOD SAFETY","internalauthor":"AKGUN, BEGUM","type":"Tesi di dottorato","year":"2022","abstract":"In this thesis, the studies of the 3-year doctoral thesis carried out at the PhD School in Food Systems of the University of Milan between 2018-2021 are presented. The thesis consists of 6 main chapters and each chapter is presented in the form of an article.  The main purpose of the project was to investigate the safety of cellulose nanocrystals (CNCs) in detail when used as a food contact material, and to contribute to their safety assessments to take advantage of their use to increase the functionalities of packaging films without using petroleum-based plastic materials.  First, a review (Chapter 1) was written to get better insight into what the engineered nanomaterials (ENMs) are and what the detection methods are to test them better. After a broad literature review, CNCs were taken as a specific case of ENMs and all the techniques for their characterization and the pros and cons of this material were discussed. A roadmap about the CNCs characterization was created based on recent guidelines published by EFSA. Then, CNCs were evaluated in-depth to define their physicochemical characteristics and morphological feature in Chapter 2 to be used as reference material for further studies.  Additionally, the suspicion of the existence of CNCs in some products that are prone to human consumption sheds light on our work on this subject. Even if CNCs are not intentionally added to the food products we consume, they may have the potential to enter our bodies through the consumption of certain food products. For this reason, different kinds of microcrystalline cellulose (MCC) sources were chosen to represent a sort of approved cellulosic additive source. Due to their similar production ways which generally consist of a chemical acidic hydrolysis, possibly followed by ultrasonication, it was reasonable to search for the presence of CNCs in different MCCs. If the existence of CNC can be proven in MCC, safety concerns must change the direction. For this purpose, different sources of MCCs have been investigated to trace the possible presence of CNCs in Chapters 3 and 4 to support EFSA requirements for the safety of nanoparticles in the food chain.  After the comprehensive characterization and detection of CNCs in different food additive sources, they were integrated into polymeric matrices in two different ways: as coating on polyethylene terephthalate (PET) films and as a reinforcement material in polylactic acid (PLA). Investigations to observe the migration and/or release of nano-sized matter from these polymeric combinations were done. Since the risk assessment of CNCs, in this case, requires new methodologies for their physicochemical characterization, a combination of advanced techniques that differ from traditional analytical techniques was used to study the migration. Therefore, in Chapters 5 and 6, the characteristics of the reference CNCs defined in previous chapters were used to investigate and define the nano-sized matter released/migrated from the polymeric matrices to the food simulants after the incubation period.","language":"eng","citation":"POTENTIAL AND PITFALLS OF CELLULOSE NANOCRYSTALS IN ADVANCED PACKAGING MATERIALS: THEIR ROLE IN FOOD SAFETY / B. Akgun ; supervisor: S. Limbo ; coordinator: D. Mora. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2022 Mar 01. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12232.pdf","fileformat":"Unknown","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/913457/1994344/phd_unimi_R12232.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1035708"},"title":"NF-YA ISOFORMS ROLES IN CLAUDIN LOW CANCERS","internalauthor":"LONDERO, MICHELA","type":"Tesi di dottorato","year":"2024","abstract":"NF-Y is a pioneer transcription factor that regulates the expression of genes involved in cell cycle progression and metabolism. It is composed of: NF-YA, NF-YB and NF- YC subunits. NF-YA recognizes and binds to the CCAAT box, a DNA element found enriched in the promoters of cancer-specific genes in several tumor gene expression profiles analyzed, including those of breast, colon, thyroid, prostate, and leukemia cancers. NF-YA is present in two major isoforms called NF-YAl (long), and NF-YAs (short), which alternative splice exon 3. NF-YAl/NF-YAs ratio changes in different tissues, cell lines and differentiational stages. A robust increase in mRNA levels of NF- YA has been observed in different tumors of epithelial origin, among which BRCA and STAD. In human breast and gastric cancers and cell lines, NF-YAs isoform is highly expressed in all subtypes except in Claudinlow in which NF-YAl isoform is predominant. Recently it has been identified a 158 genes signature defining Claudinlow tumor subclass common to BRCA and STAD, correlating with high NF-YAl/NF-YAs ratio.  For the first part of my PhD project, I worked with two different BRCA Claudinlow cell lines that mainly express NF-YAl. Through CRISPR/Cas9n genome-editing I obtained homozygous exon 3 deleted clones (NF-YAl-KO). NF-YAl-KO clones had an impaired ability to form compact aggregates, their migration, extravasation, invasion, and metastasis formation abilities were significantly impaired both in vitro and in vivo compared to negative controls. RNA-seq data underlined pathways downregulated in all NF-YAl-KO clones, among which EMT and angiogenesis, corroborating in vitro and in vivo data.  In parallel, I have investigated the role of different RNA-binding proteins in driving NF-YA alternative splicing, among which RBFOX2, QKI and CELF2 both in BRCA and in STAD cell lines. Through transient overexpression, I validated RBFOX2 as splicing factor promoting the maturation of NF-YAl.  Finally, through a frameshift mutation in NF-YA gene, I have investigated the effect of NF-YA alternative translation initiation sites (TISs) usage in HeLa cells and its impact at cellular and molecular levels.","language":"eng","citation":"NF-YA ISOFORMS ROLES IN CLAUDIN LOW CANCERS / M. Londero ; tutor: R. Mantovani. Dipartimento di Bioscienze, 2024 Mar 08. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13018_2.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1035708/2376230/phd_unimi_R13018_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/974209"},"title":"L'ORGANIZZAZIONE CRIMINALE NIGERIANA IN ITALIA: MODELLI DI INTERAZIONE CON LE MAFIE AUTOCTONE TRA DIMENSIONI LOCALI E TRAFFICI INTERNAZIONALI","internalauthor":"FEDERICO, ALIDA","type":"Tesi di dottorato","year":"2023","abstract":"Nigerian secret cults, that developed in Nigerian universities in the 20th century, have become one of the main characters of the international organized crime scene. Their presence in Italy, a territory with a traditional mafia settlement, has prompted me to explore the dynamics of interaction between them and local mafia groups, taking into consideration both the dimensions of power syndicate and enterprise syndicate (Block, 1980). Starting from the assumption that the control of the territory by a mafia group implies that no activity in a certain area can take place without the group’s approval (Santino, 1995), the hypothesis of this study is that the presence of Nigerian organized crime in mafia-controlled areas depends on the types of interaction established with the local mafia organization. Interactions which, in turn, are determined both by the dynamics of the local mafia group (concerning both the control of the territory and the management of illegal activities) and by the possible adaptation processes of foreign criminal groups to the indigenous mafia’s rules.  The empirical context selected to test the hypothesis has involved both areas with traditional mafia settlements (Palermo and the Domitio coast) and some of mafia expanded settlements (Piedmont/Turin, Emilia Romagna, Lazio/Rome) where the secret cults have settled. Nevertheless, the research has focused mainly on Palermo. The field research I carried out has relied on qualitative research techniques, for which I collected 42 semi-structured interviews with observers and witnesses. The 'mafia group-entrepreneurs' model of Sciarrone (2009), duly adapted to the object and purposes of the study, has been implemented to analyze the data collected. Moreover, Ruggiero's 'legal-illegal continuum' model, which aims to identify the crimes of the powerful (2015), was used. Both these analytical tools have been employed to identify the criminal nature of secret cults – can they be defined as mafia groups, or simply as criminal organizations?  My research has corroborated this hypothesis. Patterns of interaction between local mafia groups and Nigerian secret cults are mainly represented by 'subordination' (when Nigerian organized crime is directly influenced by the Cosa nostra) and 'autonomy' (if the two criminal groups are completely independent). In some instances, but far less frequently, I have also identified a 'co-participation' model between the groups (that happens when the two criminal organizations have a series of deals in place to manage illicit activities together). While the 'full' autonomy model prevails in the regions of expansion of mafia groups, because of the minor territorial control established by mafia organizations there, in the areas with traditional mafia settlements the model of subordination coexists with that of 'relative' autonomy. These dynamics, therefore, make the presence of Nigerian crime more insidious in areas of expansion of mafia groups, as it is less contested.","language":"ita","citation":"L'ORGANIZZAZIONE CRIMINALE NIGERIANA IN ITALIA: MODELLI DI INTERAZIONE CON LE MAFIE AUTOCTONE TRA DIMENSIONI LOCALI E TRAFFICI INTERNAZIONALI / A. Federico ; Tutor: A. Dino, M. Massari ; Coordinatore: F. Basile. Dipartimento di Studi Internazionali, Giuridici e Storico - Politici, 2023 Jun 26. 35. ciclo","filename":"phd_unimi_R12552.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/974209/2214862/phd_unimi_R12552.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1047995"},"title":"FROM SYNTHESIS TO APPLICATION:PORPHYRINS AS VERSATILE COMPOUNDS IN ENERGY, SENSING, AND CATALYSIS","internalauthor":"ALBANESE, CECILIA","type":"Tesi di dottorato","year":"2024","abstract":"Porphyrins, belonging to the class of heterocyclic tetrapyrrolic organic compounds, exhibit notable prevalence in nature. Structurally, these compounds feature a planar arrangement of four interconnected pyrrolic units, forming a flat macrocycle with an extensive conjugated system comprising 18 π-electrons. Their central cavity readily accommodates metal cations, forming stable complexes with transition metal ions. This PhD Thesis delves into the synthesis, characterization, and varied applications of porphyrins.   The distinctive colour spectrum of porphyrins, spanning from red to green, originates from robust absorption within the visible spectrum. UV-VIS absorption spectroscopy plays a crucial role in examining their light-harvesting properties. When coupled with electrochemical methods and theoretical calculations, it provides insights into the involved molecular orbitals. Tailoring the chemical structure enables the precise adjustment of the HOMO-LUMO energy gap, resulting in a macrocycle with distinctive absorption and redox properties. This versatility makes it suitable for a wide range of applications, including disease treatment, sensor technology, catalysis, nonlinear optics, and molecular photovoltaics.  The synthesis of porphyrins involves conventional approaches such as the Adler-Longo process and Lindsey's one-flask two-step methodology. Challenges in this process include the generation of by-products. Subsequent modifications, including metal coordination and the introduction of functional groups, further refine the porphyrinic core for specific applications.  This PhD Thesis presents a comprehensive three-year research project, elucidating the synthesis, characterization, and applications of porphyrins. The exploration encompasses various applications such as Dye-Sensitized Photo-Electrochemical Cells (DSPEC), chemiresistive gas sensors, CO2 reduction catalysis, and second-order Nonlinear Optics (NLO). Each section explores design strategies, synthetic optimization, and performance evaluation, providing an in-depth understanding of the versatile realm of porphyrins.","language":"eng","citation":"FROM SYNTHESIS TO APPLICATION: PORPHYRINS AS VERSATILE COMPOUNDS IN ENERGY, SENSING, AND CATALYSIS / C. Albanese ; tutor: F. Tessore ; cotutor: G. Di Carlo ; director of the school: D. Passarella. Dipartimento di Chimica, 2024 May 15. 36. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13119.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1047995/2405723/phd_unimi_R13119.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/816791"},"title":"INVESTIGATION ON PHARMACOLOGICAL AND AGE-INDUCED MODULATIONS OF CARDIAC PEACEMAKING AND ELECTROPHYSIOLOGICAL CHARACTERIZATION OF A COMPOUND MUTATION IN THE CARDIAC SODIUM CHANNEL","internalauthor":"MOLLA, DAVID","type":"Tesi di dottorato","year":"2021","abstract":"Abstract:    During my Ph.D. internship at the ‘PaceLab’, I have been involved in several scientific projects that, although involving different experimental models and with different aims, share the common background of cardiac pacemaker modulation and ion channels activity. In this sec-tion are briefly described the three main research lines in which I took part; a more complete discussion of the data will be presented later in this thesis. Notably, by the time I am writing this proposition, two of these studies have been submitted to scientific journals.       - Identification of the bradycardic molecule contained in the traditional Chinese medi-cine drug Tongmai Yangxin:  The identification of new bradycardic agents able to specifically bind HCN channels, rises great interest in the scientific community since a decreased cardiac pacemaker cur-rent would lead to an general heart rate lowering without side-effects. To date, despite a long and intensive investigation, only one pure bradycardic agent (Ivabradine)1-3 is used in the clinical setting. Ivabradine is considered virtually free of negative side-effects even though, in some rare cases, it can elicit minor optical limitations.   A few years ago, our research group started a collaboration with a traditional Chinese medicine (TMC) drug producer (Le Ren Tang Pharmaceutical Factory, Tianjin, China) with the aim of unravelling the molecular mechanism of one of their products: Tongmai Yangxin (TMYX). This drug is currently used in China for the treatment of several car-diac diseases like coronary artery disease, palpitation, heart failure and angina4 and, like other TCM compounds, it is a mixture of botanical and animal products. Remarkably, recent investigations highlighted its ability to reduce cardiac metabolic disorders, oxida-tive stress and inflammation on stable angina patients4-6.   Our previous studies explored the bradycardic action of this drug; in particular, its ef-fects were evaluated on freshly isolated rabbit SAN myocytes. TMYX displayed a dose dependent and fully reversible rate slowing of the spontaneous action potential (AP) ac-tivity, specifically acting on the pacemaker current by shifting the activation curve of HCN channels towards more negative potentials; furthermore, its efficacy appeared to be strictly correlated to the intracellular cAMP concentration. Detailed analysis demon-strate that this drug acts as a functional cAMP surmountable competitive antagonist, competing for the CNBD of f-channels according to a mode of action never observed before for the regulation of this current. Still, the nature of the bio-active molecule is un-known.   With the aim of identify this principle, TMYX was divided into 4 fractions (F1-4) by our Chinese colleagues at the Pharmaceutical Informatics Institute of Zhejiang University (Hangzhou, China) according to the solubility of its components, and the ability of each preparation to modulate spontaneous rate and the If current was evaluated by patch-clamp experiments in rabbit SAN myocytes. Data clearly demonstrate that only the most hydrophilic fraction (F1) displayed features similar to the total drug, decreasing the AP rate up to ~20% specifically acting on the pacemaker current.  To further narrow down the number of molecules to examine, F1 was subsequently di-vided into 4 sub-fractions (F1.1-1.4) and, as for the previous preparations, their effects were examined on rabbit SAN myocytes. The results pointed out the presence of the target molecule both in F1.1 and F1.2 since they were able to reduce the spontaneous AP firing by ~25 and ~20%, respectively, with a specific action on If  current.   Eventually, HPLC data revealed the presence of uridine in both these sub-fraction, sug-gesting that this molecule (or one of its derivates) could be involved in the bradycardic process. Therefore, a preliminary experiment was carried out to analyze its possible car-diac rate regulation properties on rabbit SAN myocytes. Surprisingly, the perfusion of uridine (1 μM) generated a small increase in the AP rate (+3.45%) but a decrease in the pacemaker current at -65mV. Additional experiment are requested in order to shed more light on the properties of this molecule, however, given that uridine, and in partic-ular its cyclic nuclidic form (cUMP), have been reported to interact with some isoforms of the HCN channels family7-9, it appears to be a good starting point for the identifica-tion of the active principle of TMYX.      - Age-related changes in cardiac autonomic modulation and heart rate variability in mice:  The incidence of mortality caused by age-associated cardiovascular diseases is increas-ing dramatically and it will represent a serious clinical issue in the next decades10,11.  In humans, the natural process of aging is associated with progressive changes in cardi-ac autonomic nervous system (ANS) regulation that may predispose to higher cardiac risks. Animal models of aging are needed to gain insights into the relation between the aging of the ANS and cardiac pathophysiology. Specifically, the aim of this study is to verify the translational relevance of mouse models for further in-depth evaluation of the link between cardiac ANS regulation and increased arrhythmic risk with advancing age.  Therefore, heart rate and time- and frequency-domain indexes of HRV were calculated from ECG recordings in two groups of conscious C57BL6/J male mice of different ages (4- and 19-months-old) during daily undisturbed conditions following peripheral β‐adrenergic (atenolol), muscarinic (methylscopolamine), and β‐adrenergic + muscarinic blockades and β‐adrenergic (isoprenaline) stimulation. Eventually, vulnerability to ar-rhythmias was evaluated during daily, undisturbed conditions and following β‐adrenergic stimulation.  HRV analysis and heart rate responses to autonomic blockades revealed that 19-month-old mice had a lower vagal modulation of cardiac function compared with 4-month-old mice. This age-related autonomic effect did not however affect basal heart rate, since it compensated for the lower intrinsic heart rate observed in 19-month-old compared with 4-month-old mice. Both time- and frequency-domain indexes of HRV were reduced fol-lowing muscarinic, but not β‐adrenergic, blockade, suggesting that HRV is largely modulated by vagal tone in mice. Finally, 19-month-old mice showed a larger vulnera-bility to both spontaneous and isoprenaline-induced arrhythmias.  These results reveal the presence of a reduced cardiac vagal modulation and HRV asso-ciated with an increased vulnerability to cardiac arrhythmias in older mice, which is consistent with the human condition. Given their short life span, mice could be further exploited as an aged model for studying the trajectory of vagal decline with advancing age using HRV measures, and the mechanisms underlying its association with proarrhythmic remodeling of the senescent heart.      - Electrophysiological characterization of a SCN5A compound mutation (K1578N-G1866fs) discovered in a young patient affected by sinus node disfunction, atrial flut-ters and drug-induced long QT syndrome:  Given its high relevance in the generation of the cardiac AP event, alterations in the ge-netic sequence encoding for NaV1.5 channel (SCN5A) are often related to severe dis-function in the heart function12.   In this situation, a compound mutation (K1578N/G1866fs) has been reported in a child affected by severe bradycardia, atrial flutter and drug-induced QT prolongation. Nota-bly, the parents, who present a heterozygous mutation each, did not suffer of any cardi-ac problem and their ECG signals were unremarkable. Following clinical examinations, the diagnosis was sinus node disfunction and the patient was implanted with a pace-maker13.  With this study we intended to characterize the electrical properties of the Na+ current carried by the mutated NaV1.5 channels in order to better understand the impact of these alteration and explore whether the patient will benefit from a specific pharmaco-logical treatment.  According to the literature14,15, SCN5A gene can undergo a series of alternative splicing events, among which the inclusion of different exon 6 sequences that identify the neona-tal and the adult NaV1.5 isoform. Consequently, the electrical difference between these two isoforms was assessed by patch-clamp experiments on HEK-293 cells transfected with a vector containing their genetic sequence. The results displayed no differences in the current density compared to the adult isoform (HP: -120 mV) while a positive shift of both activation and inactivation curves were detected (5.1 mV and 8.8 mV, respec-tively).  The impacts of the mutations on the Na+ current were then evaluated on the same mod-el both in the patient (compound mutation K1578N/G1866fs in the neonatal isoform) and in the parents (heterozygous expression in the adult isoform) conditions. For what concerns the parents, the data collected are reasonably in agreement with the clinical in-vestigation indicating no pathologic conditions. On the other hand, the transfection of both the mutations in the neonatal SCN5A isoform caused a dramatic reduction in the current density associated to a rightward shift of the activation curve (6.5 mV), com-pared to the corresponding WT isoform.  In addition, since the time at which the neonatal to adult isoform switch occurs has still not been clearly identify, the compound mutation was also inserted in the WT adult vector. However, no changes were detected in the current density while a leftward shift of the activation curve (7.5 mV), which can be ascribed to the isoform change, suggested that the alterations have a similar effect on the activation kinetics regarding of the iso-form in which are expressed.   Eventually, no changes in the recovery from inactivation process were found between all the conditions investigated.  All in all, these data show an important loss-of-function of NaV1.5 channels in the pa-tient’s condition, suggesting that the two mutations (K1578N–G1866fs), when ex-pressed together, generate a far worst phenotype than their single heterozygous expres-sion. Furthermore, even when incorporated in the adult SCN5A isoform, the effects caused by the alterations did not change suggesting that the neonatal to adult isoform switch will probably grant no benefits for the patient.","language":"eng","citation":"INVESTIGATION ON PHARMACOLOGICAL AND AGE-INDUCED MODULATIONS OF CARDIAC PEACEMAKING AND ELECTROPHYSIOLOGICAL CHARACTERIZATION OF A COMPOUND MUTATION IN THE CARDIAC SODIUM CHANNEL / D. Molla ; tutor: M. Baruscotti ; coordinatore: C. Sforza. Dipartimento di Bioscienze, 2021 Feb 23. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12111.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/816791/1710446/phd_unimi_R12111.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1130675"},"title":"UNRAVELING THE EFFECTS OF NEUROREHABILITATION IN PERSONS WITH NEUROLOGICAL DISORDERS: RECOVERY VERSUS COMPENSATION","internalauthor":"MESTANZA MATTOS, FABIOLA GIOVANNA","type":"Tesi di dottorato","year":"2025","abstract":"This thesis investigates the mechanisms behind motor improvements in people with multiple sclerosis (PwMS), focusing on the concepts of recovery and compensation as outlined in Levin’s theoretical framework. This framework identifies three levels of motor recovery and compensation: functional, motor performance, and neural. Distinguishing between recovery and compensation is crucial for understanding the factors that contribute to rehabilitation advancements. Throughout this PhD program, we applied this theoretical framework to examine gait function in PwMS, aiming to address three critical gaps in the existing literature through three cross-sectional studies. The first gap involves a limited understanding of how physical therapists decide between restitution and compensation for patients, along with the factors that influence this choice. Therefore, the first study identified the factors affecting therapists' decisions to choose restorative approaches (focused on regaining normal gait) versus compensatory approaches (aimed at developing alternative strategies). The study revealed that physical therapists often favor a restorative approach when treating patients perceived to have a higher potential for recovery. This preference was influenced by clinical factors such as the severity of motor impairment and the expected outcomes.  The second gap arises from the lack of a standardized index to quantify motor performance quality, which restricts the exploration of relationships among the functional, performance, and neural levels of recovery and compensation. Thus, the second study established a summary index for assessing gait quality, condensing multiple kinematic measures into a single metric that effectively captures movement quality alterations in MS patients. The findings indicated significant alterations in gait, particularly in the knee and ankle joints during the gait cycle, underscoring the necessity of focusing on these areas in clinical evaluations. Lastly, the third gap derives from an inadequate knowledge regarding the interactions between neural integrity, motor performance, and functional gait levels in PwMS. Consequently, the final study examined the relationship between gait function, gait quality, and the integrity of sensorimotor tracts, hypothesizing that sensorimotor network integrity would show a stronger correlation with movement quality than traditional functional measures. The results confirmed this hypothesis, revealing that sensorimotor network integrity is indeed more closely linked to movement quality than functional measures. These findings highlight the importance of considering neural integrity and movement quality in therapeutic decision-making and suggest that integrating data from neural, motor performance, and functional levels could enhance the understanding of compensation mechanisms in MS.","language":"eng","citation":"UNRAVELING THE EFFECTS OF NEUROREHABILITATION IN PERSONS WITH NEUROLOGICAL DISORDERS: RECOVERY VERSUS COMPENSATION / F.g. Mestanza Mattos ; tutor: M. Clerici co-tutor:  D. Cattaneo coordinatore: C. Sforza. - Aula V2, Via Venezian 15 - Milano. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2025 Jan 24. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13202.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1130675/2623253/phd_unimi_R13202.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1259798"},"title":"PER UN WELFARE COLLABORATIVO E SUSSIDIARIO. ORIGINI, SVILUPPI E PROSPETTIVE DI UN MODELLO COSTITUZIONALE","internalauthor":"GALLI, ALBERTO AMBROGIO","type":"Tesi di dottorato","year":"2026","abstract":"This research analyses, from a historical, systematic and constitutional perspective, the evolution of the Italian welfare model in light of the progressive legal and constitutional recognition of the Third Sector. It examines whether this process has affected not only the organisation of social services, but also the very configuration of the general interest and social rights within the Italian constitutional order.     The underlying hypothesis is that the ongoing transformation cannot be explained solely by the financial crisis of the twentieth-century welfare state, but reflects a deeper redefinition of the relationship between the State and society. Whereas, within the state centred paradigm of the post-war period, the general interest largely coincided with direct intervention by the public authorities, in the contemporary constitutional framework it increasingly tends to emerge as the outcome of a collaborative process in which public institutions and social organisations contribute to the achievement of substantive equality.     The study reconstructs the historical roots of Italy’s solidarity-based pluralism, from nineteenth-century mutual aid movements to the post-war expansion of social security, and subsequently to the crisis of the state-centred model and the reform of the Third Sector introduced by Legislative Decree No. 117 of 2017. Particular attention is devoted to the principle of horizontal subsidiarity under Article 118, fourth paragraph, of the Constitution, interpreted in conjunction with Articles 2 and 3 as a principle governing relations between public administrations and Third Sector organisations.     The analysis of constitutional case law, beginning with Judgment No. 131 of 2020 and continuing with the subsequent decisions, reveals the emergence of a collaborative welfare model grounded in subsidiarity, in which organised solidarity acquires constitutional significance. From this perspective, the involvement of the Third Sector extends beyond a merely organisational dimension and contributes to reshaping the structure of social rights and redefining the general interest as the outcome of a collaborative process in which the State and civil society share responsibility for promoting substantive equality.     This development must also be situated within a broader European framework, characterised by the progressive recognition of the social economy as a structural component of European Union policies. The European Action Plan for the Social Economy and the 2023 Council Recommendation demonstrate the gradual integration of the competition-based approach with a paradigm that places greater emphasis on solidarity, cooperation and the distinctive characteristics of social economy organisations, thereby guiding the legal order towards the recognition of such organisations as essential actors in promoting social cohesion and sustainable development.","language":"ita","citation":"PER UN WELFARE COLLABORATIVO E SUSSIDIARIO. ORIGINI, SVILUPPI E PROSPETTIVE DI UN MODELLO COSTITUZIONALE / A.a. Galli ; tutor: G. Ragone ;  co-tutor: L. Violini ; coordinatore: E. Damiani. - Università degli Studi di Milano. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2026 Jul 13. 38. ciclo","filename":"phd_unimi_R14036.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 13-GEN-28"}
,{"handle":{"url":"https://hdl.handle.net/2434/1189518"},"title":"LA PARTITA DEGLI SPALTI. RELAZIONI TRA TIFOSERIE E CRIMINALITA' ORGANIZZATA NEL CALCIO MODERNO.","internalauthor":"SORGENTE, LORENZO","type":"Tesi di dottorato","year":"2025","abstract":"The thesis takes a sociological approach to the sensitive issue of contacts between football fans and criminal organizations. The relationship between fan clubs and organized crime does not exhaust the range of topics covered in the thesis, which attempts a complex analysis of the world of stadiums, fans, and organized groups in the stands, the interconnections between these actors and  social phenomena, and the broader urban context in which sporting events and fan activities take place.","language":"ita","citation":"LA PARTITA DEGLI SPALTI. RELAZIONI TRA TIFOSERIE E CRIMINALITA' ORGANIZZATA NEL CALCIO MODERNO / L. Sorgente ; tutor: M. Massari ;  co-tutor: V. Martone ;  coordinatore del dottorato: F. Basile. - Milano. Dipartimento di Studi Internazionali, Giuridici e Storico - Politici, 2025 Oct 30. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13304.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 22-APR-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1056208"},"title":"CONTRAST-ENHANCED MAMMOGRAPHY: THE EMERGENT CONTRAST-ENHANCED BREAST IMAGING MODALITY","internalauthor":"MAGNI, VERONICA","type":"Tesi di dottorato","year":"2024","abstract":"Purpose: To evaluate if background parenchymal enhancement (BPE) on contrast-enhanced mammography (CEM), graded according to 2022 CEM-dedicated Breast Imaging Reporting and Data System (BI-RADS) lexicon, is associated with breast density, menstrual status, and age.  Methods: This bi-centric retrospective analysis included CEM examinations performed for second-level assessment of suspicious mammographic findings. Three readers independently and blindly evaluated BPE on recombined CEM images and breast density on low-energy CEM images. Inter-reader reliability was estimated using Fleiss κ. Multivariable binary logistic regression was performed, dichotomising breast density and BPE as low (a/b BI-RADS categories, minimal/mild BPE) and high (c/d BI-RADS categories, moderate/marked BPE).  Results: A total of 200 women (median age 56.8 years, interquartile range 50.5−65.6, 140/200 in menopause) were included. Breast density was classified as a in 27/200 patients (13.5%), as b in 110/200 (55.0%), as c in 52/200 (26.0%), and as d in 11/200 (5.5%), with moderate inter-reader reliability (κ=0.536; 95% confidence interval [CI] 0.482–0.590). BPE was minimal in 95/200 patients (47.5%), mild in 64/200 (32.0%), moderate in 25/200 (12.5%), marked in 16/200 (8.0%), with substantial inter-reader reliability (κ=0.634; 95% CI 0.581–0.686). At multivariable logistic regression, pre-menopausal status and breast density were significant positive predictors of high BPE, with adjusted odds ratios of 6.120 (95% CI 1.847–20.281, p=0.003) and 2.416 (95% CI 1.095–5.332, p=0.029) respectively.  Conclusion: BPE on CEM is associated with well-established breast cancer risk factors, being higher in women with higher breast density and pre-menopausal status.","language":"eng","citation":"CONTRAST-ENHANCED MAMMOGRAPHY: THE EMERGENT CONTRAST-ENHANCED BREAST IMAGING MODALITY / V. Magni ; tutor:  F. Sardanelli ; phd coordinator: C. Sforza. Universita' degli Studi di MILANO, 2024 Jun 04. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12841.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1056208/2425632/phd_unimi_R12841.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/818160"},"title":"INVESTIGATING THE IMMEDIATE CONSEQUENCES OF NORMAL AND MUTANT HTT LOSS IN HD-HESC THROUGH THE DTAG SYSTEM.","internalauthor":"CERNIGOJ, MANUEL","type":"Tesi di dottorato","year":"2021","abstract":"Huntington’s Disease (HD) is a neurodegenerative disorder cause by a dominant CAG triplet repeat  expansion (poly-glutamine(Q) in the protein) in the first exon of the Huntingtin gene (HTT). In the  healthy population, the number of CAG repeats range between 9 and 35, while an expansion above  36 CAG repeats causes the manifestation of the pathology later in life. Numerous studies indicate  that the pathological CAG length causes the poly-Q expanded protein to acquire a toxic function  which ultimately kills the neurons1–10. Other studies show that several disfunctions associated with  the presence of the mutant protein can be phenocopied in cells and mice deleted of the healthy  gene, suggesting that a loss of function mechanism may also contributes to HD11–13. Thus the  disease seems to be the result of a two-component pathological mechanism; first a loss-of-function  (LOF) due to reduced normal HTT physiological activity, and second a gain-of-function (GOF) due  to mutant HTT toxic effects14. Being able to discriminate between LOF and GOF phenotypes is  especially relevant when considering the ongoing gene silencing clinical studies aiming at reducing  HTT level either in an allele-specific or non-allele-specific manner15–17. On top of that, transcriptional  alterations have been reported both in HD patients and HD mouse models18, and several evidence  have linked HTT to gene expression1,19–27. However, these data refer to situations in which a  transcriptional balance has already been established following the genetic perturbation. No data is  available regarding the mechanisms acutely implemented by the cell immediately after perturbation  to re-establish transcriptional balance in response to those changes. For these reasons, in this  project we aimed at generating a human embryonic stem cell (hESC) HD model in which normal or  mutant HTT can be rapidly and efficiently removed upon exposure to a small molecule. This is made  possible by a degradation tag (dTAG)28 that, when fused to HTT, induces a proteosome-mediated  degradation upon exposure to a cell permeable ligand. Accordingly, the first part of the project  consists in the generation of two dTAG-hESC-HD lines in which either the normal or the mutant  allele were targeted by Cas9-assisted genome editing followed by the assessment of the efficiency  and degradation kinetic of tagged HTT in both cell lines. These experiments revealed complete  tagged HTT loss between one and two hours of treatment with a ligand concentration of 10-7 M.  Moreover, no difference was observed when comparing degradation kinetics of normal and mutant  HTT in self-renewing dTAG-hESC lines. We aim to use these lines to study the immediate  transcriptomic changes and the potential compensatory mechanisms established by the cells in  response to normal or mutant HTT protein depletion. Therefore, a first RNA-seq experiment was  performed to investigate over time transcriptional changes during dTAG-HTT degradation. This  experiment revealed no substantial transcriptomic changes between normal and the HTT-depleted  state of self-renewing dTAG-hESC HD lines. We are now looking into the transcriptional changes  driven by HTT degradation in hESC in vitro derived neurons that can provide useful information on  the biosafety of the ongoing HTT-lowering approaches for HD treatment.","language":"eng","citation":"INVESTIGATING THE IMMEDIATE CONSEQUENCES OF NORMAL AND MUTANT HTT LOSS IN HD-HESC THROUGH THE DTAG SYSTEM / M. Cernigoj ; scientific tutor: E. CATTANEO ; coordinator: D. BESUSSO. Dipartimento di Bioscienze, 2021 Mar 22. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12034.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/818160/1714294/phd_unimi_R12034.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/818623"},"title":"\"L'EFFICACIA DEL GIUDICATO PENALE IN \"\"ALTRI\"\" GIUDIZI CIVILI EX ART. 654 C.P.P. PREMESSE PER UNO STUDIO.\"","internalauthor":"CASI, MICHELE","type":"Tesi di dottorato","year":"2021","abstract":"1. – The title of the final dissertation is The limits of the res judicata effect of criminal judgments in “other” civil proceedings according to art. 654 c.p.p. Methodological foundations for a subsequent study.     2. – The research carried out during the doctoral cycle takes its roots in the discipline dedicated to the res judicata effect of the criminal judgement in “other” civil proceedings, as per art. 654 of the Italian code of criminal procedure [hereinafter “c.p.p.”]. The analysis of the law and of the doctrine has led to detect some critical interpretations, in particular in relation to its scope and to the subjective and objective limitations to the res judicata effect of the  criminal judgement in subsequent civil proceedings. In addition, the analysis of the edited jurisprudence in relation to the rule in question has led to observe an incoherent application of the said discipline. The analysis of the most relevant doctrine and jurisprudence confirms the numerous interpretative perplexities that involve the discipline set in art. 654 c.p.p., in particular with regard to its divergence from the principles that govern the res judicata  according to the traditional doctrine in civil procedural law. The same notes were also the subject of the recent XXXII National Conference of the Italian Association of Civil Procedural Law Scholars on The Statute of the Judge and the Assessment of Facts (Messina, 27-28 September 2019).    3. – At a methodological level, the research has been carried out by elaborating a complete bibliography on each of the main topics dealt with. The essays, the articles and the most relevant jurisprudence have been examined with scientific method in order to obtain a more complete vision of the topics covered by the dissertation. Specific consideration was given to the contribution ZUMPANO, Rapporti tra processo penale e processo civile, Turin, 2000, on the relationship between criminal and civil proceedings. Each issue developed in the dissertation has been addressed with the conceptual and dogmatic instruments of civil procedural law science; they have also been applied to the analysis of issues belonging to criminal procedural law. According to this, the author often found a difficulty in the translation, both terminological and conceptual, of the basic institutions between the two procedural law  sciences.    4. – The primary result of the research was to redefine the object of the final work. It regards the logical and legal premises necessary for an analysis of art. 654 c.p.p., to be carried out later in time. In this way, the structure of the final report is divided into three chapters. (1) The introductory premises on the res judicata effect of the criminal judgement in other criminal judgements having the same object (artt. 648 and 649 c.p.p.). (2) The hypothesis of  a positive and binding effect of the criminal res judicata in subsequent criminal judgements having a different object. (3) The res judicata effect of the criminal judgement in civil tort and damage judgements (artt. 651-652 c.p.p.) and the relative premises: (i) the right to compensation relating to crimes (art. 185 of the criminal code) and (ii) the damage claim in the criminal proceedings (artt. 74 ff. c.p.p.) and in the civil proceedings.    5. – Considering all the elements, the dissertation deals with some issues that constitute the leitmotiv of the work. They are, first, the typical object of a criminal judgement as a fact. Second, the classification of the notion of crime as a prejudicial element in a technical sense. Third, the definition of the right to compensation for damages related to a crime. Fourth, the scope of application of the discipline dedicated to the damage claim related to a crime. Fifth,  the peculiarities of the discipline of the res judicata effect of criminal judgement in civil proceedings in relation to its scope of application and its subjective limitation.","language":"ita","citation":"\"L'EFFICACIA DEL GIUDICATO PENALE IN \"\"ALTRI\"\" GIUDIZI CIVILI EX ART. 654 C.P.P. PREMESSE PER UNO STUDIO / M. Casi ; tutor: E. Merlin; coordinatore: M.T. Carinci. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2021 Mar 05. 33. ciclo, Anno Accademico 2020.\"","filename":"phd_unimi_R11843.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/818623/1715630/phd_unimi_R11843.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1272580"},"title":"INSIGHT INTO THE FORMATION OF SPODUMENE-RICH PEGMATITES: THE ARAÇUAÍ PEGMATITE DISTRICT, BRAZIL","internalauthor":"DE LEO, ALESSANDRO","type":"Tesi di dottorato","year":"2026","abstract":"Spodumene-rich pegmatites are among the most important sources of lithium, but the processes controlling their formation remain debated. In particular, the origin of Li-enriched pegmatitic melts may involve extreme fractional crystallization of granitic magmas, direct crustal anatexis, source pre-enrichment, or multi-stage enrichment processes. Once emplaced, this primary record may be further modified by internal pegmatite differentiation, country-rock interaction, and late- to post-magmatic pro-cesses. This thesis investigates these issues through the study of the Outro Lado spod-umene-rich pegmatite and associated Li-barren pegmatites and two-mica granite from the Itinga Pegmatite Field, Araçuaí Pegmatite District, Minas Gerais, Brazil.  The study combines field and drill-core observations, petrography, major- and trace-element mineral chemistry, and U-Pb geochronology of apatite, cassiterite, monazite and zircon. The sampling strategy was designed to compare mineralized and non-mineralized pegmatitic bodies within the same geological setting, with particular fo-cus on the mineralogical expression of Li enrichment, internal variability of the spod-umene-rich pegmatite, and its chronological relationship with local granitic magma-tism.  The Outro Lado SRP is simply zoned and consists of a volumetrically limited, spodu-mene-free border zone and a volumetrically dominant internal zone characterized by a relatively stable spodumene-bearing assemblage. Spodumene is the main Li-bearing mineral, whereas petalite and lepidolite are rare or accessory. Together with the lim-ited development of F-rich Li minerals in the associated Li-barren pegmatites and two-mica granite, this assemblage indicates a generally F-poor pegmatite-granite associa-tion, in which the SRP represents the spodumene-dominated Li-mineralized end mem-ber. Although the studied lithologies share an overall LCT affinity, muscovite chemis-try distinguishes the spodumene-rich pegmatite from Li-barren pegmatites and the two-mica granite, with SRP muscovite enriched in Cs, B, Sn, Rb and locally Li, and depleted in Ti, Zr and Mg. Internal muscovite variability does not define a continuous margin-to-centre differentiation trend. Instead, the strongest deviations are concentrat-ed in samples and local domains in contact, or proximal, with country-rock schist. The SRP-schist contact records early bidirectional metasomatism: tourmalinization of the schist indicates outward transfer of pegmatitic components, whereas Ba-Mg-Sr-Eu-Na2O-Pb enrichment in border-zone SRP muscovite indicates inward transfer of com-ponents from the country rock. This exchange occurred during emplacement or before the onset of border-zone crystallization, suggesting very early fluid saturation and/or fluid-assisted diffusion at the pegmatite-country rock interface.  U-Pb geochronology defines two main chronological stages. Monazite and zircon from the Teixeirinha two-mica granite yield overlapping crystallization ages of 527 ± 9 Ma and 526 ± 11 Ma, respectively, whereas monazite from one Li-barren pegmatite gives an indistinguishable age of 524 ± 10 Ma. Cassiterite from the spodumene-rich pegma-tite yields a younger age of 496 ± 13 Ma, interpreted as recording crystallization of the Li-mineralized body. Apatite ages across the studied lithologies define a coherent age population with a weighted mean of 487 ± 11 Ma, interpreted as cooling in the granite and at least part of the Li-barren pegmatite system, and as crystallization in the spod-umene-rich pegmatite.  These results indicate that Li mineralization in the studied system is associated with a younger cassiterite-apatite age interval of 476-509 Ma, interpreted as the uncertainty envelope of SRP crystallization and closely related thermal evolution, rather than with the older monazite-zircon crystallization interval of 514-537 Ma recorded by the dated two-mica granite and one Li-barren pegmatite. This age offset makes the dated Teixeirinha Granite unlikely to represent the immediate parental source of the SRP-forming melt. At the same time, the shared LCT affinity of the studied pegmatite-granite association indicates that the older Teixeirinha Granite and Li-barren pegma-tite represent an LCT-affiliated but non-mineralized stage, rather than a chemically unrelated system.  Petrographic and mineral-chemical constraints further indicate that the studied Li de-posit likely formed from a melt already sufficiently enriched in Li to saturate spodu-mene, rather than through strong internal differentiation within the exposed pegmatite body. The source of this Li-rich melt remains unresolved, but the timing of SRP crys-tallization places Li mineralization within a late post-collisional magmatic-thermal in-terval during which the Araçuaí-West Congo Orogen was still cooling through inter-mediate-temperature conditions of ~425-550 °C and was affected by widespread re-gional hydrothermal circulation. In this framework, the data are compatible with a younger Li-enriched melt derived either from an unexposed evolved granite or from renewed melting/reworking of previously Li-enriched crustal material, potentially linked to the older G4 granitic-pegmatitic stage.","language":"eng","citation":"INSIGHT INTO THE FORMATION OF SPODUMENE-RICH PEGMATITES: THE ARAÇUAÍ PEGMATITE DISTRICT, BRAZIL / A. De Leo ; tutor: F. Farina ; co-tutor: M. Tiepolo ; coordinatore: G. Muttoni. Dipartimento di Scienze della Terra Ardito Desio, 2026 Sep 18. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13903.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1272580/3404680/phd_unimi_R13903.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1230736"},"title":"NEW GO- AND RGO-BASED MORALS AND CARBENE-FUNCTIONALIZED GOLD NANOPARTICLES FOR HETEROGENEOUSLY CATALYZED REDUCTIONS","internalauthor":"FORMENTI, MATTEO","type":"Tesi di dottorato","year":"2026","abstract":"This work aims to develop and study new materials for catalytic uses, with a specific focus on reducing aromatic nitrocompounds.  The work focuses on two main classes of materials. The first one is MORALs, an acronym for   Metal-ORganic ALloys, a class of materials composed of organic molecules embedded in metal particles. In previous studies, this class of materials has been reported to exhibit improved catalytic properties compared to the single metal or organic molecule that constitutes it. In this work, the chosen organic molecule is graphene oxide, combined with two different metals, palladium and nickel. The resulting materials can also be further modified by reducing graphene oxide to reduced graphene oxide. All materials were analyzed using various analytical techniques and evaluated for their ability to reduce nitrobenzene.  This work focuses on two main classes of materials that have recently attracted growing interest in the field of heterogeneous catalysis. The first class comprises the so-called MORALs, an acronym for Metal ORganic ALloys. These hybrid systems consist of organic molecules embedded within metallic particles. Previous studies have shown that MORALs can display catalytic properties superior to those of either the pure metal or the isolated organic molecule, suggesting the emergence of synergistic effects arising from their intimate combination. Graphene oxide (GO) was selected as the organic component due to its high specific area and ability to interact strongly with metal species. GO was combined with two different metals, palladium and nickel, chosen for their well established catalytic roles in reduction reactions. The resulting MORALs were further diversified by subjecting graphene oxide to chemical reduction, yielding reduced graphene oxide (RGO) and enabling a direct comparison between the two different modifications. All synthesized materials were thoroughly characterized using a variety of analytical techniques aimed at elucidating their structural and chemical composition. Their catalytic performance was then evaluated in the reduction of nitrobenzene, a model reaction of both academic and industrial relevance.  The second class of materials investigated consists of N heterocyclic carbene (NHC)-functionalized gold nanoparticles. Gold nanoparticles (AuNPs) are widely recognized for their unique optical, electronic, and catalytic properties, which have enabled applications ranging from sensing and biomedicine to fine chemical synthesis. However, the performance and stability of AuNPs are strongly influenced by the nature of the ligands that cap their surface. In recent years, NHCs have emerged as a powerful alternative to traditional thiol based ligands, offering stronger metal-ligand bonds, enhanced robustness under reaction conditions, and the possibility of fine tuning the electronic environment of the metal surface. Two iso TT derivative were selected as the NHC precursors. This choice was motivated by the opportunity to explore the applicability of a novel ligand scaffold and to assess how its structural features influence the stabilization and reactivity of gold nanoparticles. The synthesis of the NHC functionalized AuNPs was followed by a comprehensive characterization aimed at elucidating the properties of both the organic ligand and the resulting hybrid nanomaterials. Particular attention was dedicated to understanding the interaction between the NHC and the gold surface. To evaluate their practical relevance, the supported gold nanoparticles were tested in the reduction of nitrobenzene. This reaction served as a benchmark to assess the robustness, activity, and potential advantages of the different functionalized materials.  Functionalization with N heterocyclic carbenes has also been explored as a strategy to modify catalytic materials for the study of the hydrogen spillover phenomenon, a process in which activated hydrogen atoms migrate from a metal surface onto an adjacent support. Understanding and controlling spillover is of considerable interest, as it can influence reaction pathways, extend the effective catalytic surface, and enhance the performance of supported metal catalysts in hydrogenation reactions. In collaboration with Professor Bert Chandler and his research group, NHC ligands were employed to functionalize Au/rutile catalysts. This system provides an ideal platform for investigating spillover, as gold nanoparticles can activate hydrogen under specific conditions, while rutile offers well defined surface sites capable of participating in hydrogen migration. By introducing NHCs , the study aimed to probe how ligand functionalization affects the hydrogen activation step. A comprehensive set of measurements was carried out using in situ FT IR spectroscopy, enabling real time monitoring of surface species. Kinetic analyses, including Arrhenius plots and reaction order determination, were performed to highlight differences between the unfunctionalized and NHC functionalized catalysts. These experiments provided insight into how the presence of the organic ligand modifies the mechanism of hydrogen transfer across the metal–oxide interface. Finally, the materials were evaluated in the reduction of p nitrophenol. Comparing the catalytic behavior of the functionalized and unfunctionalized systems allowed for a deeper understanding of the role of NHCs in modulating hydrogen mobility and reactivity.","language":"eng","citation":"NEW GO- AND RGO-BASED MORALS AND CARBENE-FUNCTIONALIZED GOLD NANOPARTICLES FOR HETEROGENEOUSLY CATALYZED REDUCTIONS / M. Formenti ; tutor: C. Della Pina ;  co-tutor: M. Pagliaro ;  coordinatore: L. Prati. Dipartimento di Chimica, 2026 Mar 31. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13687.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1230736/3291546/phd_unimi_R13687.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1176700"},"title":"EXPLORING THE ROLE OF METAL VARIABILITY IN MOFS USING SYNCHROTRON RADIATION TECHNIQUES","internalauthor":"VANDONE, MARCO","type":"Tesi di dottorato","year":"2025","abstract":"Metal-Organic Frameworks (MOFs) are a unique class of hybrid materials that combine high porosity, crystallinity, and modularity, making them promising candidates for applications ranging from gas storage to catalysis. This thesis explores the intricate relationship between MOF structure, metal composition, and functional properties, with a particular focus on multi-metal systems and their tunability. In detail, a set of coupled techniques, leveraging the capabilities of synchrotron-based diffraction and spectroscopic techniques, is employed and thoroughly described in each chapter, in order to deeply characterize the multi-metal character of the synthesized systems and to understand its impact over the properties of the system. Significant emphasis is placed on the impact of crystallite size on MOF defectivity, particularly in the prototypical HKUST-1 framework. Using a variety of analytical tech- niques, including in situ ambient pressure near-edge soft X-ray absorption fine structure spectroscopy (AP-NEXAFS) and in situ CO-dosed IR spectroscopy, the role of crystal size in determining the distribution of Cu(I) / Cu(II) species and the kinetics of defect formation under thermal activation is investigated. In following chapters, the presented work shifts toward catalytic applications of MOFs, with a focus on the direct methane-to-methanol (MTM) conversion using molecular oxygen as an oxidant. The performance of MIL-100(Fe) as an heterogeneous catalyst for this process is investigated using advanced operando X-ray-based techniques including XRD, XAS, XES, and RIXS. Together, these techniques confirmed the formation of Fe(II) active sites at elevated temperatures, facilitating MTM conversion. Catalyst deactivation is attributed to CH3• escape, leading to the formation of Fe3O(OMe) and Fe3O(OH) units. Despite this limitation, the system demonstrates catalytic activity over multiple reaction cycles using O2 as oxidant. As a natural continuation of the work on MIL-100(Fe), subsequent work is focused on the synthesis and the structural and spectroscopic characterization of multimetal FeM- PCN-250 (M: Cr(III), Mn(II), Ni(II)) MOFs. The incorporation of secondary metals into the trimeric [Fe3O] cluster is examined using coupled XAS and HR-PXRD. Thanks to the coupled experiments performed using in situ and operando set-ups, it was possible to confirm the robustness of the framework when exposed to reaction conditions and reveal how the metal tuning deeply affects the electronic structure, as well as the catalytic ac- tivity of these MOFs in terms of methane oxidation. Lastly a series of heterobimetallic MOFs, M3−xM’x(OH)2(btca)2 (M: Zn(II), M’: Co(II), x: 0, 1, 1.5, 3), were synthesized to investigate how controlled variations in metal content influence the flexibility of the frameworks and their adsorption behavior, particularly for CO2. The discussion centers on the adaptability of MOFs, citing notable examples from the existing literature, and how changes in the composition of the metal within SBUs affect the dynamics of the framework upon guest adsorption. In particular the adjustment of Zn(II) and Co(II) ion levels at two coordination sites within M(btca) MOFs was found to affect the CO2 ad- sorption behavior of the framework effectively illustrating that the structural response depends on the metal composition. To conclude, the work presented in this PhD thesis offers significant insight into the design principles of multimetal MOFs, illustrating how aspects such as structural flexibility, defect formation, and metal substitution play pivotal roles in dictating their reactivity. The results add to the comprehensive understanding of MOF-based catalysis and establish a foundation for the systematic development of advanced materials aiming at improved performance in future applications.","language":"eng","citation":"EXPLORING THE ROLE OF METAL VARIABILITY IN MOFS USING SYNCHROTRON RADIATION TECHNIQUES / M. Vandone ; tutor: V. Colombo. Dipartimento di Chimica, 2025 Jul 24. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13532.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1176700/3114509/phd_unimi_R13532.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1194318"},"title":"ENDOCYTIC CONTROL OF CELL-AUTONOMOUS AND NON-CELL-AUTONOMOUS FUNCTIONS OF P53","internalauthor":"CACCIATORE, ROBERTA","type":"Tesi di dottorato","year":"2025","abstract":"NUMB is a multifunctional adaptor protein historically recognized for its role in determining cell fate decisions through inhibition of NOTCH signaling, a process achieved via endocytic trafficking. Subsequently, NUMB has emerged as a significant tumor suppressor, particularly in the context of breast cancer, where it stabilizes the critical tumor suppressor protein p53 by inhibiting its targeting to proteasomal degradation by the E3 ubiquitin ligase MDM2. This role of NUMB is isoform-specific, mediated by alternatively spliced variants containing a short insert encoded by exon 3 (Ex3) – NUMB-1 and NUMB-2. Loss of expression of these NUMB isoforms, but not of isoforms lacking Ex3 (NUMB-3 and NUMB-4), is a frequent alteration in breast cancer that correlates with reduced p53 activity, increased chemoresistance, and poor clinical outcomes.   Despite the importance of isoform-specific functions of NUMB to cancer, little is known about their differential biological roles in physiological or pathological contexts. To bridge this gap, we identified the interactomes of the four major mammalian NUMB isoforms using an affinity purification-mass spectrometry approach. Among these interactomes, the endocytic adaptor protein Sorting Nexin 9 (SNX9) was found to be the most abundant specific interactor of NUMB-1 and NUMB-2. We validated this interaction through in vitro binding, GST-pulldown and co-immunoprecipitation assays, which revealed that NUMB-1/2 and SNX9 participate in tripartite complex with p53. We conducted a systematic analysis of the molecular determinants mediating the formation of the NUMB-SNX9-p53 complex by in vitro binding assays with a series of recombinant full-length proteins and domain-specific fragments, alongside in vivo co-immunoprecipitation experiments with wild-type (WT) and mutant versions of the proteins. Our results revealed that formation of the NUMB-SNX9-p53 complex critically depends on the interaction of both NUMB-1/2 and SNX9 with acidic phospholipids (primarily PIP2) enriched in the plasma membrane. The polybasic Ex3-encoded sequence of NUMB-1/2 is critical for mediating this protein-phospholipid interaction, while Ex3-lacking isoforms (NUMB-3/4) are defective in this binding. In SNX9, its PX domain serves as the crucial lipid binding surface, and this interaction likely induces a conformational change unmasking a p53 binding site. Membrane tethered SNX9 and NUMB-1/2 can bind through a bidentate interaction involving distinct binding sites in SNX9’s low complexity (LC) domain and NUMB’s phosphotyrosine-binding (PTB) domain, specifically the PTB-binding groove and Ex3 insert.   Through this interaction, SNX9 recruits p53 to the complex, serving as an intermediary scaffold bridging or facilitating the interaction between p53 and NUMB-1/2 at the plasma membrane.  The biological role of the NUMB-SNX9-p53 complex is to mediate vesicular trafficking of p53 via the exosome pathway. By characterizing the molecular composition of purified EVs derived from various normal-like and cancer cell lines, in which the complex proteins or exosome biogenesis pathways were inhibited (genetically or pharmacologically), we demonstrated that the sorting of p53 into intraluminal vesicles (ILVs), intermediates in exosome biogenesis, was critically dependent on both SNX9 and NUMB-1/2. The exosomal secretion of p53 has biological consequences for both the donor and recipient cells. In the donor cell, exosomal export of p53 significantly diminishes the intracellular pool under basal conditions, suggesting that this mechanism could function alongside the well-established p53 regulatory mechanisms based on post-translational modifications and protein-protein interactions, to control p53 homeostasis in a cell-autonomous manner. In the recipient cells, p53 delivered by exosomes remains functionally active, capable of mediating classical p53-dependent responses to DNA damage, including activation of transcriptional targets and growth arrest. This finding points to a previously unrecognized role of vesicular p53 trafficking in mediating non-cell-autonomous paracrine-like tumor suppressive signaling to the surrounding microenvironment, with implications for both tissue homeostasis and cancer development.   Given that the Ex3-encoded sequence is also critical for mediating NUMB’s interaction with MDM2 and p53 in a tripartite complex that leads p53 stabilization, we explored the relationship between this complex and the NUMB-SNX9-p53 complex in regulating p53. Through in vitro binding assays, size-exclusion chromatography analysis, liposome binding assays, and in vivo immunofluorescence and co-immunoprecipitation assays, we established that the formation of these two Ex3-dependent complexes is mutually exclusive, with MDM2 and SNX9/PIP2 competing for binding to NUMB’s Ex3-encoded sequence. The result of this competition at the cellular level is the formation of two spatially restricted NUMB-p53 complexes that have opposing effects on p53: NUMB-MDM2-p53 stabilizes p53 leading to an increase in intracellular levels while NUMB-SNX9-p53 traffics p53 to exosomal export thereby reducing the intracellular pool. These findings reveal an additional layer of complexity in the regulation of p53’s tumor suppressor function, where endocytic trafficking complements canonical p53 regulatory mechanisms to maintain p53 homeostasis.  In summary, this thesis describes for the first time the regulation of WT p53 through vesicular trafficking to the surrounding microenvironment, via a mechanism that is dependent on two endocytic proteins, SNX9 and NUMB. It establishes NUMB-1 and NUMB-2 as central players in both the intracellular stabilization and extracellular dissemination of p53 and define a mechanistic basis for NUMB’s isoform-specific tumor suppressor role. These findings represent a paradigm shift in our understanding of non-cell-autonomous tumor suppression and the maintenance of tissue homeostasis. The deregulation of this process is likely to play a critical role in tumor development and progression, opening new avenues in the development of anti-cancer therapies.","language":"eng","citation":"ENDOCYTIC CONTROL OF CELL-AUTONOMOUS AND NON-CELL-AUTONOMOUS FUNCTIONS OF P53 / R. Cacciatore ; added supervisor: I. Colaluca; internal advisor: S. Minucci; external advisor: G. Melino ; tutor: P. Di Fiore. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Jul 28. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13465.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 07-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1128038"},"title":"FUNCTIONAL STUDY OF THE NONCODING REGULOME OF THE NUCLEAR FACTOR Y IN HUMAN CANCER","internalauthor":"PAGANI, GIULIA","type":"Tesi di dottorato","year":"2025","abstract":"Backgroud. Noncoding RNAs (ncRNAs) are key regulators of several biological processes, and their altered expression and function are associated with tumorigenesis. In this work, we focused on antisense RNAs (asRNAs), which play a critical role in gene expression regulation. Generally thought to modulate their sense genes in cis through sequence complementarity or through the act of transcription, asRNAs can also regulate different molecular targets in trans, in the nucleus or in the cytoplasm. We also explored the role of the alternative polyadenylation (APA) of mRNAs in sustaining tumor aggressive features. Indeed, shortening of the 3’ untranslated region (3’UTR) leads to oncogene activation by microRNA binding site elimination with consequent relief from their repression in cancer cells. We focused on the nuclear transcription factor Y (NF-Y), a master regulator of proliferation in normal and tumor cells. Since its physiological role and involvement in cancer are well-documented, we aimed to study the ncRNA-mediated regulation of NF-Y activity in the development and progression of human cancers.    Aims. We aimed to explore the noncoding regulome of the NF-Y transcription factor in human cancer. Specifically, we studied the asRNA NFYC Antisense 1 (NFYC-AS1) and investigated APA of NFYA, which encodes for the regulatory subunit of NF-Y.    Results. On the one hand, we molecularly characterized NFYC-AS1 by assessing its expression, transcript structure, and biological function. Moreover, we dissected its mechanism of action by employing different loss-of-function strategies, including Gapmer antisense oligonucleotides (ASOs) and CRISPR/Cas9-mediated deletion of the transcription start site. We reported NFYC-AS1 as a cell cycle-regulating asRNA with a dual mode of action in cis and in trans, exploiting both its transcription- and RNA-dependent functions. On the other hand, we functionally characterized NFYA APA by annotating the 3’UTR isoforms and studying their biological effects on transcript stability, cellular localization, translation efficiency, and microRNA-mediated regulation. Additionally, we manipulated NFYA APA by using both CRISPR/Cas9-mediated deletion of the most used polyadenylation signal (PAS) and ASOs masking the different PASs of NFYA 3’UTR. We demonstrated that APA appeared to be a relevant post-transcriptional mechanism that controls NF-YA activity in cancer.    Conclusions. We functionally characterized two distinct noncoding RNA-mediated mechanisms important for the regulation of NF-Y expression and activity. Notably, the emerging application of ASOs in the clinics opens the possibility to target pathogenic asRNAs or mask PASs of deregulated genes in cancer to therapeutically manipulate their protumorigenic activity.","language":"eng","citation":"FUNCTIONAL STUDY OF THE NONCODING REGULOME OF THE NUCLEAR FACTOR Y IN HUMAN CANCER / G. Pagani ; supervisor: P. Gandellini. - Università degli studi di Milano, Milano, Italia. Dipartimento di Bioscienze, 2025 Jan 09. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13459_2.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1128038/2617394/phd_unimi_R13459_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1119700"},"title":"CUSTOMIZING IMMERSIVE SPATIAL AUDIO: FROM INDIVIDUALIZED BINAURAL RENDERING TO REAL-VIRTUAL ACOUSTIC BLENDING","internalauthor":"FANTINI, DAVIDE","type":"Tesi di dottorato","year":"2024","abstract":"The accurate simulation of spatial sound is essential for creating immersive audio experiences, with applications spanning virtual and augmented reality, hearing aids, teleconferencing, and gaming. This thesis discusses several contributions to the field of immersive spatial audio with a focus on customized listening. The topics addressed by these contributions are twofold: individualizing binaural rendering and real-virtual acoustic blending.  In the domain of binaural rendering, the thesis discusses some approaches to replicate the acoustic interaction between sounds and the pinna, which has a unique shape. This is needed to obtain spatial audio simulations that closely mimic real sound sources. In this regard, a method for personalizing head-related transfer functions (HRTFs) based on pinna anthropometric parameters is presented. The thesis also presents novel pinna parameters to better characterize the pinna anatomy, thus improving HRTF individualization. Furthermore, it presents a method to estimate the personal acoustic coupling between the pinna and headphones based on pinna anthropometry. The objective is to provide personalized compensation for headphones responses to ensure their transparency.   With regard to real-virtual acoustic blending, the thesis presents a method to automatically match artificial reverberation to a target room impulse response (RIR). This enables the reverberation of arbitrary virtual sound sources to match the acoustical properties of an existing environment. The method was evaluated in an experiment assessing the co-immersion of virtual sound sources within an audio augmented virtuality framework.   Finally, the thesis proposes tools and datasets relevant to spatial audio research. Specifically, an artificial reverberator from the class of scattering delay networks (SDN) is presented. Moreover, a couple of datasets for the simulation of ecologically-valid virtual auditory environments are discussed, including an RIR dataset and a speech dataset for the generation of turn-taking conversations.","language":"eng","citation":"CUSTOMIZING IMMERSIVE SPATIAL AUDIO: FROM INDIVIDUALIZED BINAURAL RENDERING TO REAL-VIRTUAL ACOUSTIC BLENDING / D. Fantini ; supervisor: F. Avanzini ; co-supervisor: S. Ntalampiras ; PhD coordinator: R. Sassi. - Milano. Dipartimento di Informatica Giovanni Degli Antoni, 2024 Dec 04. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13393.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1119700/2594895/phd_unimi_R13393.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/827287"},"title":"TERNARY OXIDE SEMICONDUCTOR PHOTOANODES FOR SOLAR ENERGY CONVERSION","internalauthor":"POLO, ANNALISA","type":"Tesi di dottorato","year":"2021","abstract":"Solar energy conversion and storage into hydrogen is a valuable approach to capture the energy that is freely available from sunlight and to turn it into a clean fuel. Photoelectrochemical (PEC) water splitting through the dual-absorber tandem cell technology has emerged as a promising strategy to this aim. The work conducted in the frame of this PhD thesis aimed at playing a part in the development and optimization of efficient oxide-based semiconductor photoanodes for water oxidation, which is the kinetic bottleneck of the overall PEC water splitting process.   Photoanodes based on films of absorbing materials were successfully synthesized with a high optical transparency as important requirement for maximizing the solar energy conversion efficiency of the final tandem cell device. Subsequently, their intrinsic properties as single photoabsorber photoanodes were largely improved, on the basis of the results obtained through comprehensive PEC studies in parallel with thorough structural, morphological, and spectroscopic investigations.  The attention was focused on three different classes of promising ternary metal oxides, able to absorb a large portion of the solar spectrum, namely i) BiVO4 (bandgap Eg = 2.4 eV), known for its excellent solar light to hydrogen conversion efficiency, ii) the copper tungstate-based materials CuWO4 (Eg = 2.3 eV) and CuW(1-x)Mo(x)O4 (Eg = 2.0 eV), ideal to be employed as visible-light active alternative to WO3, and iii) ZnFe2O4 (Eg = 2.0 eV) belonging to the spinel ferrites class, possessing excellent photothermal and chemical stability.   Specifically, BiVO4 was studied either as a visible light sensitizer towards TiO2 or as a single photoanode material to focus on the identification and improvement of its intrinsically poor electron transport and interfacial transfer properties. In the first case, the TiO2/BiVO4 heterojunction system was proved to be effective in producing highly reductive electrons, suitable for overall water splitting, through TiO2 sensitization towards visible light. This, together with the counterintuitive mechanism at the basis of the observed impressive functionality, was effectively disclosed through combined PEC and photocatalytic reduction test studies. The multifaceted role of Mo6+ doping onto both the bulk and surface properties of BiVO4 films was also revealed through an in-depth PEC and impedance spectroscopy study. By improving either the bulk conductivity or the interfacial charge transfer of optimized Mo6+ doped BiVO4 photoanodes a conspicuous enhancement was attained of their photoactivity towards water oxidation with respect to the pure material.   The presence of intra-gap states in CuWO4, acting as electron traps and thus being responsible for a severe internal charge recombination, was verified by means of the first ultrafast transient absorption study performed with this material, in combination with both an electrochemical and a photochromic characterization. This issue, which strongly limits the PEC performance of CuWO4 photoanodes, was addressed by adopting a 50% Mo for W substitution resulting in CuW0.5Mo0.5O4 photoanodes, exhibiting not only a greatly extended visible light-induced photoactivity compared to the pure material, as a result of enhanced absorption, but also a considerably improved charge separation. All these factors contributed to the much better PEC performance attained with respect to CuWO4 electrodes. This study was finalized by the identification of a suitable hole scavenger species for copper tungstate-based materials, able to ensure enhanced photocurrent generation compared to pure water oxidation while minimizing dark currents.  Finally, in the frame of my seven months stage in Prof. Sivula’s group at the EPFL in Lausanne, a thorough study was performed on the impact that several parameters, such as the annealing temperature, the film thickness and the creation of oxygen vacancies through a reductive treatment in hydrogen atmosphere, have on the PEC performance of ZnFe2O4 photoanodes. The verified synergism between the higher crystallinity of the films subjected to a high-temperature annealing treatment and the hydrogenation efficiency, which proved effective in optimizing charge separation in the thicker photoactive layers, allowed one to maximize the performance of ZnFe2O4 electrodes for water oxidation. This study also shed light onto the strict correlation occurring between structural parameters, i.e. the film crystallinity and the spinel inversion degree, and the resulting PEC performance, which proved to be in turn controlled by the film morphology.","language":"eng","citation":"TERNARY OXIDE SEMICONDUCTOR PHOTOANODES FOR SOLAR ENERGY CONVERSION / A. Polo ; tutor: M. V. Dozzi ; co-tutor: E. Selli ; coordinatore: E. Licandro. Dipartimento di Chimica, 2021 Mar 24. 33. ciclo, Anno Accademico 2020. [10.13130/polo-annalisa_phd2021-03-24].","filename":"phd_unimi_R11851.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/827287/1744730/phd_unimi_R11851.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/820923"},"title":"EVALUATION OF ARTHROCENTESIS WITH HYALURONIC ACID INJECTIONS FOR MANAGEMENT OF TEMPOROMANDIBULAR DISORDERS","internalauthor":"GOKER, FUNDA","type":"Tesi di dottorato","year":"2021","abstract":"Objectives: Although, arthrocentesis is an accepted safe treatment modality used for the management of TMD patients with pain, the benefit of hyaluronic acid (HA) injections remains uncertain. The aim of this study was to investigate whether intra-articular injections of hyaluronic acid as an adjunct therapy with arthrocentesis can be more effective than other medications for the improvement of symptoms associated with temporomandibular disorders.   Materials and methods: For this purpose, an electronic search of Medline, Scopus and Cochrane databases was performed up to September 2020. No language, and publication date limitation was set. The following search terms were used: “arthrocentesis”, “hyaluronic acid”, “intra-articular injections”, “viscosupplementation”, with “temporomandibular disorders”. Inclusion criteria was prospective or retrospective studies, case reports, and randomized clinical trials that reported the application of HA injections compared to other intra-articular drugs for the treatment of temporomandibular disorders. Exclusion criteria included systemic reviews, animal studies. Additionally, a retrospective clinical study was performed on 12 TMD cases for evaluation of changes before and after arthrocentesis with hyaluronic acid (HA) injections in quality of life (QoL) of these patients.  Results: In the systemic review, the initial screening included 1327 articles. After a more detailed evaluation of the titles, abstracts, and full texts; a total of 29 studies were selected (26 randomized studies, 2 controlled clinical trials, 1 retrospective report). In the clinical study 12 patients were included.  According to the results, intra-articular injections of HA and other medications together with arthrocentesis seemed to be beneficial for improvement of functional symptoms of TMD and pain. The case series also supported support the efficacy of HA injections with a significant improvement of QoL of these patients. However, after the evaluation of the reports in literature, it was impossible to identify an optimum drug or a protocol in improving the pain and/or functional symptoms of temporomandibular problems due to diversity of treatment modalities and conflicting results.   Conclusion: As a conclusion, there was no consensus in the studies that HA injections showed better results in comparison with other treatment modalities.  According to the results of this systematic review and clinical study HA injections with/without arthrocentesis seems to be beneficial in terms of clinical symptoms and QoL of the patients.","language":"eng","citation":"EVALUATION OF ARTHROCENTESIS WITH HYALURONIC ACID INJECTIONS FOR MANAGEMENT OF TEMPOROMANDIBULAR DISORDERS / F. Goker ; tutor: M. Del Fabbro ; coordinator: M. Del Fabbro. Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, 2021 Mar 01. 33. ciclo, Anno Accademico 2020. [10.13130/goker-funda_phd2021-03-01].","filename":"phd_unimi_R11884.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/820923/1723455/phd_unimi_R11884.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/889925"},"title":"GEOGRAPHICAL MOBILITY AND OCCUPATIONAL OUTCOMES IN WESTERN EUROPE. A COMPARISON BETWEEN ITALY, UK AND GERMANY","internalauthor":"MATAJ, IRA","type":"Tesi di dottorato","year":"2021","abstract":"The aim of my research is to study internal geographical mobility and its association with social mobility in a comparative perspective for selected countries in Europe, namely Italy, UK and Germany using longitudinal data. The first part of my thesis focuses on the selection process that takes place in the movements of the population. What are the characteristics of individuals who move? How are they different from the non-movers in terms of education, social origin, civil status?  The second part will analyze how geographic mobility affects labour market outcomes. Are individuals who move more likely to have an upward occupational mobility? Since geographic mobility affects men and women differently, a dedicated section will focus on gender differences in these trajectories. To test the research hypothesis I use random-effect and fixed-effect probability models with panel data. The results show differences between the countries in term of selection processes and social mobility. The empirical results also confirm that women gain less from migration in terms of occupational outcomes compared to men.","language":"eng","citation":"GEOGRAPHICAL MOBILITY AND OCCUPATIONAL OUTCOMES IN WESTERN EUROPE. A COMPARISON BETWEEN ITALY, UK AND GERMANY / I. Mataj ; tutor: G. Ballarino ; co-tutor: N. Panichella. Dipartimento di Scienze Sociali e Politiche, 2021 Dec 17. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11970.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/889925/1931979/phd_unimi_R11970.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/972695"},"title":"ORGANIZZAZIONE, POTERE E VIOLENZA NELLA STORIA DELLA `NDRANGHETA: IL CASO DI VIBO VALENTIA","internalauthor":"MASCARO, LAURA","type":"Tesi di dottorato","year":"2023","abstract":"This thesis aims to study the 'ndrangheta phenomenon in the province of Vibo Valentia, with two main objectives. Firstly, it aims to reconstruct the dynamics of the mafia families operating in the area by analysing their organisational structure, their connections and their territorial projections beyond the provincial borders. Secondly, it seeks to trace a detailed genealogical tree of the Mancuso family in order to identify the leadership styles of the various bosses and to understand the mechanisms through which they construct their authority and credibility.  The sources used for this research include investigative and procedural documents, newspaper articles, academic publications and popular works. The methodology employed is characterised by a variety of research methods and techniques, including document analysis, case studies and comparative analysis.  The contribution of this thesis to the field of research is evident on several levels. First, it highlights the existence of multiple centres of mafia power within the province, which respond in different ways to the dynamics of the 'ndrangheta leadership in Reggio Calabria. Second, it sheds light on how different bosses with different leadership styles emerge within a mafia family, influencing the organisation's adaptive responses to the evolving criminal environment. Finally, it proposes a reversal of traditional interpretations that identify a single historical leader for a period of time, recognising instead the complexity and nuance of leadership dynamics within the Mancuso family. Through a rigorous and in-depth examination, this research contributes to a more  understanding of the structure and functioning of the 'ndrangheta in the province of Vibo Valentia, providing fresh interpretative insights into the power dynamics and relationships that characterize the mafia organization.","language":"ita","citation":"ORGANIZZAZIONE, POTERE E VIOLENZA NELLA STORIA DELLA `NDRANGHETA: IL CASO DI VIBO VALENTIA / L. Mascaro ; tutor: C. Castellano ; cotutor: M. Massari ; coordinatore: F. Basile. Dipartimento di Studi Internazionali, Giuridici e Storico - Politici, 2023 Jun 26. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12475.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/972695/2210086/phd_unimi_R12475.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/890342"},"title":"CELL PENETRATING PEPTIDE-CONJUGATED MORPHOLINO: A NOVEL COMPOUND TO RESCUE SMA IN A SYMPTOMATIC PHASE","internalauthor":"BERSANI, MARGHERITA","type":"Tesi di dottorato","year":"2022","abstract":"Cell Penetrating peptide-conjugated Morpholino: a novel compound to rescue SMA in a symptomatic phase  Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality. Recently approved SMA therapies have transformed a deadly disease into a survivable one, but these compounds show an effective rescue only if administered in the early stages of the disease. Basing on these evidence is clear that safe, symptomatic-suitable, non-invasive treatments with high clinical impact across different phenotypes are urgently needed. To address these issues, we conjugated antisense oligonucleotides with Morpholino (MO) chemistry, that has shown to increase SMN protein levels, to cell-penetrating peptides (CPPs) for better cellular distribution. Systemically administered MOs linked to r6 and (RXRRBR)2XB peptides crossed the blood-brain barrier and increased SMN protein levels remarkably, causing striking improvement of survival, neuromuscular function, and neuropathology, even in symptomatic SMA animals. This thesis demonstrates that MO-CPP conjugates can significantly expand the therapeutic window through minimally invasive systemic administration, opening the path for clinical applications of this strategy.","language":"eng","citation":"CELL PENETRATING PEPTIDE-CONJUGATED MORPHOLINO: A NOVEL COMPOUND TO RESCUE SMA IN A SYMPTOMATIC PHASE / M. Bersani ; tutor: S. Corti ; supervisor: M. Nizzardo ; coordinatrice: C. Sforza. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2022 Jan 18. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12329.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/890342/1933382/phd_unimi_R12329.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/914584"},"title":"SINDROME DELLE APNEE OSTRUTTIVE DEL SONNO: ANALISI DELL'ACCURATEZZA DELLA PROGRAMMAZIONE DIGITALE SPLINTLESS NELL'AVANZAMENTO MAXILLO-MANDIBOLARE'","internalauthor":"BASERGA, CAMILLA","type":"Tesi di dottorato","year":"2022","abstract":"Many different clinical presentations are described by the Sleep-Disordered Breathing (SDB). They gradually go from Simple Snoring to the Upper Airway Resistance Syndrome (UARS) up to the Obstructive Sleep Apnea Syndrome (OSAS) with an increased severity.  Clinical presentations of the Sleep-Disordered Breathing are several, but they have in common the following features: snoring, morning headaches, daily sleepiness and a general worsening of the cognitive performances.  Symptoms are directly proportional to the type of sleeping disorder and to the severity of respiratory obstruction. It needs to be remembered that, eventually, sleeping disorders can evolve into cardiovascular and cerebrovascular complications. OSAS is a clinical condition that, with a multisystemic involvement, could negatively affect life in terms of length and quality.  OSAS is certainly the most common SDB, affecting the 1-4% of population. Recent epidemiological studies have showed the high prevalence of the disorder with high rates of delayed or missed diagnosis. The risk factors associated to this clinical condition are high BMI, excessive alcohol consumption, smoking, nasal congestion, menopause and reduced estrogens levels and some medications (eg benzodiazepines). Data in literature show that the risk factor mainly involved in theappearance and progression of OSAS is a BMI >25.  It is nowadays known that the treatment of this condition has to be multidisciplinary, both medical and surgical. The maxillo-mandibular advancement (MMA) has been widely confirmed to be a treatment with a success rate of the 90 to 100%, totally comparable to CPAP.  The surgical technique of MMA was inherited by orthognathic surgery. The mandible-first approach is demonstrated that it is more beneficial when an anticlockwise rotation and a posterior downgrafting of the maxilla are needed as in OSAS surgery. Moreover, in the last decade, the virtual surgical planning has become a useful tool on a daily basis in orthognathic and OSAS surgery with both CAD-CAM wafers and, more recently, plates and cutting guides.  The aim of this prospectivel clinical study is to analyze the accuracy of the virtual planning of MMA in OSAS patients with splintless technique.","language":"ita","citation":"SINDROME DELLE APNEE OSTRUTTIVE DEL SONNO: ANALISI DELL'ACCURATEZZA DELLA PROGRAMMAZIONE DIGITALE SPLINTLESS NELL'AVANZAMENTO MAXILLO-MANDIBOLARE' / C. Baserga ; tutor: A. B. Giannì ; coordinatore del corso: M. Del Fabbro. Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, 2022 Mar 16. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12304.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/914584/1997707/phd_unimi_R12304.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1119009"},"title":"LA GIUSTIZIA ALGORITMICA ALLA PROVA DELLE GARANZIE COSTITUZIONALI","internalauthor":"VALSECCHI, ANDREA","type":"Tesi di dottorato","year":"2024","abstract":"Algorithmic justice, understood as the application of algorithms and artificial intelligence within judicial systems, has already raised numerous concerns regarding constitutional safeguards. While in European legal systems, including the Italian context, it remains confined to experimental initiatives without yet achieving widespread structural implementation, certain foreign experiences, particularly that of the United States, have underscored the urgency of examining the phenomenon from a constitutional law perspective. Following an introductory chapter that delineates the scope of the inquiry and outlines the methodology employed, the first part of this work, utilizing an empirical and inductive approach, is devoted to an analysis of the current state of algorithmic justice, with particular emphasis on the U.S. experience concerning the use of risk assessment tools in criminal proceedings and the experiments with so-called predictive justice in European legal systems.      The second part of the study focuses on the regulatory frameworks governing artificial intelligence and algorithmic justice in both the United States and Europe, with special attention to recent developments in Europe such as the Artificial Intelligence Act (European Union) and the Framework Convention on Artificial Intelligence (Council of Europe).  Having outlined the current state of art and the applicable regulatory frameworks, the third part of the thesis reflects on the impact of algorithmic tools on judicial decision-making and their implications for constitutional guarantees, particularly those related to the right to a fair trial within the framework of European constitutional law. Drawing on the extensive U.S. jurisprudence on the compatibility of algorithms in judicial proceedings with judicial discretion and due process of law, the analysis centers on those constitutional guarantees that appear most challenged by the use of algorithms in judicial decision- making. These include judicial independence and impartiality, the right to defense, equality of arms, and the right to an effective remedy. Finally, acknowledging the issues at stake, the concluding part of the work, also in light of recent regulatory solutions adopted in Europe, seeks to reflect on the concept of algorithmic fair trial, considering both the limitations and opportunities of algorithmic justice and the guarantees necessary to accompany such a profound transformation.","language":"ita","citation":"LA GIUSTIZIA ALGORITMICA ALLA PROVA DELLE GARANZIE COSTITUZIONALI / A. Valsecchi ; tutor: B. Randazzo ; coordinatrice: F. Biondi. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2024 Dec 18. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13277.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1119009/2591747/phd_unimi_R13277.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1153298"},"title":"OPTIMIZATION ALGORITHMS FOR THE SYMMETRIC AND ASYMMETRIC ELECTRIC TRAVELING SALESMAN PROBLEM","internalauthor":"ONDEI, CRISTINA","type":"Tesi di dottorato","year":"2025","abstract":"The Electric Traveling Salesman Problem (ETSP) is a variant of the traditional TSP in which the vehicle is assumed to be equipped with limited battery. Therefore, the vehicle needs to be recharged along the route, and, for this purpose, a set of recharge stations is provided. The aim is to visit all the customers once, minimizing the overall cost of recharged energy. We consider both the symmetric and asymmetric versions of the problem. We propose an extended formulation for the symmetric problem and a column generation algorithm to solve it, where columns correspond to station-to-station paths. When dealing with the asymmetric version, we consider the possibility of negative cost arcs in the underlying graph. This corresponds to traveling along downhill roads with vehicles that can recharge their batteries. We propose an adaptation of the previous extended formulation, with its branch-and-price algorithm, and a compact formulation, solved with a branch-and-cut algorithm. The last part of the thesis is focused on a data-driven approach for the feasibility of the Resource Constrained Shortest Path Problem (RCSPP).","language":"eng","citation":"OPTIMIZATION ALGORITHMS FOR THE SYMMETRIC AND ASYMMETRIC ELECTRIC TRAVELING SALESMAN PROBLEM / C. Ondei ; supervisor: G. Righini ; cosupervisor: A. Ceselli ; coordinator: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2025 Mar 11. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13565.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1153298/2711129/phd_unimi_R13565.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1177470"},"title":"ANALYSING TEACHERS' RELATIONSHIPS TO INVESTIGATE TERTIARY EFFECT AND WORK-RELATED OUTCOMES","internalauthor":"ZANGA, GIULIETTA","type":"Tesi di dottorato","year":"2025","abstract":"The aim of this dissertation is to investigate the influence of teachers' social networks on various aspects of their professional and personal attitudes. In particular, it focuses on teachers' stereotypes and biases, which may represent antecedents of the so-called tertiary effects of social origin on educational inequalities—namely, the often unconscious ways in which schools and their agents contribute to the reproduction of these inequalities. The use of Social Network Analysis (SNA) offers an innovative contribution to this field by exploring how stereotypes and biases are shaped and reinforced through interpersonal relationships, depending on both the characteristics of the individuals within the network and the structural features of the network itself.  The dissertation begins with a theoretical overview of tertiary effects and teacher biases, followed by two empirical chapters based on original data collections that address the role of teachers’ social networks. The first study draws on the tradition, relatively underexplored in Italy, of network research among teachers, and investigates how collegial interactions influence job satisfaction and self- efficacy. The second study, which bridges the SNA approach and the literature on tertiary effects, examines how teachers’ networks impact the development and persistence of stereotypes related to educational inequality.  The main contribution of this work lies in proposing a relational perspective for analysing teacher biases, offering a novel implementation of Social Network Analysis within this context. The findings     highlight the importance of considering teachers’ social networks in the analysis of both their professional outcomes and their role in perpetuating educational inequalities.","language":"eng","citation":"ANALYSING TEACHERS' RELATIONSHIPS TO INVESTIGATE TERTIARY EFFECT AND WORK-RELATED OUTCOMES / G. Zanga ; supervisor: G. Ballarino ; co-supervisor: R. Vacca ; coordinatore: M. Guerci. Dipartimento di Economia, Management e Metodi Quantitativi, 2025 Sep 25. 37. ciclo","filename":"phd_unimi_R13273.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1177470/3117925/phd_unimi_R13273.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/922848"},"title":"SEDIMENTOLOGY AND STRATIGRAPHY OF TURBIDITE SYSTEMS WITH CONTRASTING ARCHITECTURES: EXAMPLES FROM THE TERTIARY PIEDMONT BASIN (NW ITALY) AND THE TAZA-GUERCIF BASIN (NE MOROCCO)","internalauthor":"REGUZZI, SIMONE","type":"Tesi di dottorato","year":"2022","abstract":"Architectures of submarine fans and turbidite systems are endowed by a high grade of complexity, inherited by the large variability of depositional flows characterising them. This complexity is reflected upon the superimposition of depositional elements (e.g., channels, levées, splays, etc.) giving rise to contrasting sedimentary facies and geometries at different scales. Thus, the understanding and prediction of their heterogeneity over space is essential to obtain reliable depositional models, which can be applied in the field of natural resources exploration.  Despite heterogeneities of facies and architectures in turbidite deposits are largely studied, several questions regarding evolutionary controls still remain open due to the intricate interplay between autocyclic and allocyclic factors and the lack of roboust chronostratigraphic (i.e., time-related) constraints to be applied to turbidite systems evolution.  This doctoral work focuses on two turbidite units, different for facies, architectures, age, and depositional setting. The work pursues the goal of complementing sedimentological data (collected with cm-scale resolution) with bio-chronostratigraphic data (both novel and collected from the literature) in order to provide a trustworthy estimation of the geological time in turbidite systems depositional models.  In the first two chapters an overview on sediment gravity flows and their evolutionary models is provided, emphasising classical facies and depositional geometries.  In chapter three, the sedimentary architecture and the controls on the evolution of a channel-levée complex from the Tachrift Turbidite System (Upper Miocene, Melloulou Fm., TazaGuercif Basin, NE Morocco) is addressed. The studied complex is spectacularly well exposed and then suitable for detailed sedimentological logging with cm-scale resolution.  Results show a tripartite stratigraphic organisation of the complex, including: (i) a lowermost mud-prone interval with relatively small (a few hundred of metres across and metre-thick) and vertically stacked channels fills, (ii) a middle interval (ca. 4 m-thick and >1 km-wide) made of dominantly amalgamated sandstones with eastward-directed lateral accretion packages (LAPs), and (iii) an uppermost interval made of vertically aggraded channel fills with variously directed LAPs and well-developed levées. This organisation suggests that, after a relatively short phase of inception (lowermost interval), the channel underwent a prolonged lateral migration, prior to become aggradational (uppermost interval). Proportions of turbidite vs. hemipelagic deposits suggest that the migrational and aggradational phases straddle a lapse of reduced turbidite input to the studied section of the slope. It is suggested that the observed architectural style turnaround reflects the feedback of channel morphodynamics, sediment input, and along-dip channel depth profile.  In chapter four, the Rupelian Monastero Fm. turbidite system (Tertiary Piedmont Basin, NW Italy) is addressed. This 1100 m-thick turbidite system was deposited adjacent to a coeval and heteropic fan delta system (i.e., the Savignone Conglomerates), upon a south-eastward dipping clastic ramp, and consists of an apparently monotonous succession of thin-bedded sandstone-mudstone couplets intercalated by erosive-based amalgamated bedsets made of sandstones and conglomerates. The unit was studied along the best exposed and most continuous section (Val di Grue-San Gaudenzio section) by cm-scale resolution sedimentological logging. Thesedimentological data were subsequently complemented with bio-magnetostratigraphic data (novel and from the literature) to refine the depositional model. In addition, seismic lines interpretation (in professional partnership with Eni S.p.A.) was used to constrain the Monastero Fm. depositional setting in the host basin.  Results provide information about facies and architecture of the Monastero Fm. and insights for analogue systems: (i) the investigated stratigraphy is dominated for the 60% of section thickness by a muddy heterolithic background (with a density of 3 beds/m on average) alternated with conglomeratic channel fills and sandy lobes, (ii) the 65% of the studied section is composed of sedimentary bed repetitions interpreted as hyperpycnites, (iii) these repetitions cohexist with ‘classical’ turbidite facies indicating that the latter may represent the transformation of the former, (iv) bio-magnetostratigraphic data suggest an average accumulation rate of 400 m/Ma for the Monastero Fm., with an estimated return period of sedimentary gravity flows lower than a few thousand years, (v) seismic interpretations confirm the confined nature of the Monastero Fm. turbidite system.  In conclusion, the new results of this doctoral work suggest that the use of magneto-biochronology can provide useful constraints for depositional age models, thus contributing to enhance our understanding of the time-scale and control factors of changes in sediment delivery to deep-water.","language":"eng","citation":"SEDIMENTOLOGY AND STRATIGRAPHY OF TURBIDITE SYSTEMS WITH CONTRASTING ARCHITECTURES: EXAMPLES FROM THE TERTIARY PIEDMONT BASIN (NW ITALY) AND THE TAZA-GUERCIF BASIN (NE MOROCCO) / S. Reguzzi ; tutor: M. Marini ; co-tutor: F. B. Felletti, M. Rossi ; coordinatore: F. Camara Artigas, M. I. Spalla. Dipartimento di Scienze della Terra Ardito Desio, 2022 May 06. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12189.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/922848/2020892/phd_unimi_R12189.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1132376"},"title":"INVESTIGATING THE ROLE OF THE E3 UBIQUITIN LIGASE HECW IN AUTOPHAGY AND STRESS RESPONSE","internalauthor":"CESARE, GIULIANA","type":"Tesi di dottorato","year":"2025","abstract":"As neurodegenerative diseases continue to rise in prevalence among the aging population,  understanding the underlying molecular mechanisms becomes imperative. Autophagy plays a crucial  role in maintaining cellular homeostasis by degrading aggregated proteins and damaged organelles.  However, the mechanisms regulating autophagy during aging remain poorly understood.  Ubiquitination has emerged as a critical mechanism in controlling autophagy. Hecw, the Drosophila  melanogaster ortholog of HECW1/2, encodes a E3 ubiquitin implicated in ribonucleoparticles (RNPs)  dynamics and neuroprotection. Hecw mutations in flies determine the onset of neurodegenerativelike phenotypes that resemble those of well-characterized autophagy mutants. Yet, the role of Hecw  in autophagy remains unexplored. This study aimed to investigate whether Hecw is involved in the  regulation of autophagy and how its loss contributes to the onset of neurodegenerative-like  phenotypes and stress susceptibility.  Our in vivo findings demonstrate that Hecw mutations cause age-related brain atrophy, emergence of  locomotor deficits as well as reduction of the levels of ref(2)P, the Drosophila homolog of autophagy  cargo receptor p62. Notably, we find that Hecw is essential in the aging brain for induction of  autophagy, rather than for autophagosome maturation or cargo clearance. Additionally, investigations  in the larval fat body and adult ovaries revealed that Hecw mutants show impaired autophagy  induction in response to amino acid restriction, underscoring a disruption in autophagy regulation.  Furthermore, we found that Hecw mutants are more susceptible to oxidative stress. Loss of Hecw in  Atg7 mutants exacerbates their vulnerability to oxidative stress, indicating that Hecw and Atg7  operate in parallel pathways regulating autophagy. Using RNAi experiments, we showed that  depletion of Atg1 or Atg7 in a Hecw mutant background exposed to thermal stress leads to  accumulation of ref(2)P and of the autophagy protein Atg8a, suggesting that loss of Hecw further  reduces the autophagic flux when initiation or maturation are compromised.  To elucidate how Hecw controls ref(2)P levels, we examined its mRNA expression. We discovered  that Hecw mutants display an early reduction in ref(2)P transcription in pre-symptomatic flies,  indicating that Hecw supports ref(2)P expression from an early age. Consistent with this, we observed  that restoring ref(2)P levels throughout development partially mitigated neurodegeneration in Hecw  mutants. Additionally, we showed that Hecw influences the level of Mitf (fly TFEB, a transcription  factor essential for autophagy induction), and observed that Hecw mutants experience a decline in  Mitf protein levels that correlates with reduced mTORC1 activity. Notably, reduced Mitf in Hecw  mutants correlates with reduced expression of its transcriptional targets during aging, a decline that  can be reversed by increasing ref(2)P. Our findings indicate that Hecw plays a critical role in sustaining ref(2)P levels and modulating  autophagy, particularly during aging. The decline in ref(2)P expression in Hecw mutants appears to  be linked to lowered transcriptional regulation by Mitf and by the oxidative stress modulator  CncC/NRF2, suggesting a complex interplay between these pathways. The relationship between  ref(2)P regulation, the mTORC1-Mitf axis and CncC signaling remains unclear. However, recent  studies on SMURF1, a E3 ligase of the NEDD4 subfamily, imply that such regulation may stem from  the ability of NEDD4 family members to modulate phase separation. Our observations of ectopic  formation of ref(2)P-positive bodies upon Hecw overexpression further support this idea, suggesting  the involvement of Hecw in regulating protein aggregation during the autophagic response.  Overall, this work furthers our understanding of Hecw, the least characterized member of the NEDD4  subfamily of E3 ligases, in supporting neuronal health during aging and upon stress response.  Considering that HECW1 has been implicated in humans in the onset of familial Amyotrophic Lateral  Sclerosis (ALS), our results related to p62/ref(2)P regulation may pave the way for new therapeutic  strategies to treat neurodegenerative disorders associated with the accumulation of protein and RNA  aggregates.","language":"eng","citation":"INVESTIGATING THE ROLE OF THE E3 UBIQUITIN LIGASE HECW IN AUTOPHAGY AND STRESS RESPONSE / G. Cesare ; tutor: T. Vaccari ;  coordinatore: S. Ricagno. Dipartimento di Bioscienze, 2025 Jan 23. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13349.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1132376/2628010/phd_unimi_R13349.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1126195"},"title":"MIR-181A/B INHIBITION AS A NEW STRATEGY FOR MITOCHONDRIAL DISEASE TREATMENT","internalauthor":"VOLPE, MARIAGRAZIA","type":"Tesi di dottorato","year":"2024","abstract":"Mitochondrial diseases (MDs) are a group of rare inherited disorders caused by defective oxidative phosphorylation (OXPHOS) and defined by a wide range of clinical phenotypes. MDs show extreme genetic heterogeneity, which makes the development of efficient treatments particularly difficult. Indeed, despite recent progress, no effective therapies are currently available. Gene/mutation-independent approaches targeting downstream affected pathways are highly needed, considering their genetic heterogeneity.  In this context, microRNAs (miRNAs) emerge as promising therapeutic agents due to their ability to simultaneously regulate different pathways. In particular, miR-181a and miR-181b (collectively referred to as miR-181a/b) are two miRNAs involved in mitochondrial processes, and their downregulation has recently been demonstrated to exert a protective action on different MD models associated with neuronal degeneration.   This study further investigates the effects of miR-181a/b inhibition in MD contexts and evaluates the feasibility of translating this approach into clinical applications by testing a therapeutic technology to achieve long-term miR-181a/b downregulation in vivo. We assessed the efficacy of our therapeutic approach in different MD models: the Ndufs4 knockout (KO) mouse, which serves as a Leber’s Hereditary Optic Neuropathy (LHON) and Leigh syndrome (LS) model, two of the most prevalent MDs, and the rotenone-induced mouse model, an additional in vivo model of LHON. Notably, our results demonstrate that the downregulation of miR-181a/b consistently ameliorates various phenotypes across all tested conditions. Furthermore, the therapeutic strategy targeting miR-181a/b in vivo exhibited a highly safe and specific profile, paving the way for clinical application.","language":"eng","citation":"MIR-181A/B INHIBITION AS A NEW STRATEGY FOR MITOCHONDRIAL DISEASE TREATMENT / M. Volpe ; supervisor: A. Indrieri ; internal advisor: I. Trapani ; external advisor: E. Rugarli ; internal examiner: P. Piccolo ; external examiner: C. Viscomi. Dipartimento di Oncologia ed Emato-Oncologia, 2024 Dec 19. 36. ciclo","filename":"phd_unimi_R13143.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 21-DIC-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1229335"},"title":"THE BIOGEOCHEMISTRY OF BODY CONCEALMENT: FROM HYPOGEAL CDI TO FORENSIC TAPHONOMY","internalauthor":"TAGLIABUE, GIULIA","type":"Tesi di dottorato","year":"2026","abstract":"The present PhD project provides an integrated and methodologically exploratory investigation of the processes governing cadaver decomposition in clandestine burials, here conceptualized as the Hypogeal Cadaver Decomposition Island (HCDI). Conducted at Ticino-LEAFs (Ticino Park–LABANOF facility for Environmental Analysis in Forensic Sciences), the research brings together taphonomic observation, soil biogeochemistry, and macro- and microanalytical approaches, offering a broad perspective on how cadaver decomposition may interact with the surrounding environment. The study also considers the influence of concealment methods on these dynamics, as well as the potential for the hypogeal environment to preserve time-dependent information that may be relevant to forensic investigations.  Twenty-one piglets that had died of natural causes, completely independent of this research, were selected as human analogues and assigned to different burial treatments, including textile wrapping, quicklime application, and the simulation of gunshot traumas. They were subsequently exhumed at predetermined, progressively increasing PBIs. To support standardization and comparability between specimens, pre-burial radiographs were taken, weight matching within groups was carried out, and fixed burial positions were maintained. This controlled framework helped identify subtle shifts in both decomposition-derived anomalies and soil-mediated processes.  A multi-proxy analytical workflow was employed to characterize the HCDI. Soil texture, Total Organic Carbon (TOC), pH, Dissolved Organic Matter (DOM), Volatile Fatty Acids (VFA) and other organic acids, and soil magnetic properties were monitored throughout the experiment. DOM appeared to be one of the more sensitive markers of hypogeal decomposition: its concentrations increased during intermediate post-burial intervals, likely reflecting the release of soluble organic compounds during active decay, and decreased once decomposition processes slowed. FT-IR spectrometry contributed substantially to the interpretation of DOM composition, revealing functional groups associated with proteins (potentially useful for monitoring decomposition-related proteolysis), lipids (which may indicate the presence of adipocere), and other biomolecules. In trauma-bearing subjects, the soil surrounding gunshot wounds showed molecular signatures that may be linked to blood infiltration, suggesting that DOM can sometimes retain information not only on decomposition intensity but also on lesion-induced biochemical inputs.  Where multiple concealment methods were introduced, soil responses diverged considerably. Indeed, quicklime, rather than accelerating decay, preserved tissues and promoted adipocere formation. FT-IR spectrometry captured the sequential hydration and carbonation of lime, while DOM concentrations peaked abruptly before declining, suggesting that this analysis may help detect decomposition-linked anomalies in soil even when tissues remain preserved. Clothing also influenced the system by absorbing putrefactive fluids and altering soil-microbe interactions, at times affecting chemical anomalies that might otherwise help differentiate decomposition phases. Taken together, these observations indicate that concealment methods can function as active taphonomic agents and should therefore be considered when interpreting biogeochemical evidence from burial environments.  pH measurements complemented these observations and generally appeared to reflect increases associated with the release of alkaline decomposition products, namely NH4+. However, the presence of lime or textile seemed to modify these trends, implying that pH may serve as a reliable first-line indicator only when soil-cadaver exchange is unimpeded. Similarly, VFA profiles obtained through HPLC were informative but inconsistent across groups, highlighting the value of multi-proxy interpretation rather than reliance on a single biomarker.  A novel aspect of the project was the exploratory application of magnetic susceptibility and hysteresis analyses to hypogeal decomposition. Although decomposition products apparently do not directly alter magnetic signatures, burial disturbance and the redox processes associated with organic-matter degradation appeared to produce measurable differences between control soils and HCDI samples. The latter tended to show more homogeneous magnetic behavior, with grain-size distributions that may indicate transformations of iron-bearing minerals under reducing conditions. These observations suggest that magnetic methods have potential as complementary laboratory tools for detecting or characterizing burial contexts, particularly in settings where traditional biochemical indicators may be altered, such as in the presence of clothing.  From a taphonomic perspective, decomposition progressed across post-burial intervals but showed substantial heterogeneity influenced by concealment methods. Indeed, quicklime appeared to cause extensive desiccation in early PBIs and later to induce mummification, whereas clothing absorbed decomposition fluids and reduced visible soft-tissue breakdown, ultimately contributing to humid mummification. These modifications resulted in inconsistent Total Body Score (TBS) values among subjects within the same interval and increasingly widened inter-group variability as decomposition advanced. Consequently, the application of standard PMI-estimation methods, particularly the Accumulated Degree Days (ADD) method and Vass’s universal formula for buried bodies, proved challenging. ADD tended to underestimate PMI for much of the experiment, while Vass’s formula tended to overestimate it, suggesting that neither method is currently calibrated for buried remains exposed to heterogeneous taphonomic conditions.  In parallel, the study examined gunshot-related lesions on piglet remains, integrating taphonomic assessment with SEM–EDX microanalysis. While soft-tissue evidence degraded rapidly, bone appeared to retain key ballistic features even in advanced stages of decay, despite inherent limitations in their diagnosis. The analysis of Inorganic Gunshot Residue (IGSR) may help address some of these challenges. Firearm-related particles persisted, although in altered forms, reflecting environmental leaching and mineralogical interactions. Because particles considered characteristic of and consistent with IGSR tended to reduce with increasing burial time, the study suggests broadening diagnostic criteria when examining remains subjected to prolonged hypogeal conditions. This highlights the potential value of interdisciplinary approaches, indicating how anthropological and chemical analyses may be combined to support trauma reconstruction when soft tissues have been substantially altered by decomposition.  Overall, this research considers the burial environment as a responsive, multifactorial system shaped by cadaveric decay, soil chemistry, microbial activity, and anthropogenic disturbance. Even in coarse, rapidly draining soils such as those characterizing the experimental area, the HCDI appeared to preserve detectable anomalies in pH, DOM quantification and characterization, and magnetic signatures. At the same time, the experiment highlights the challenges involved in developing universal PMI or PBI estimation methods, given the strong influence of soil properties and concealment strategies on decomposition trajectories. By integrating taphonomic, biogeochemical, magnetic, and microanalytical approaches, this thesis proposes a holistic framework for interpreting clandestine burials. It suggests that multidisciplinary analysis may offer a more comprehensive understanding of the multifaceted interactions governing hypogeal decomposition, thereby potentially improving the accuracy, reliability, and contextual relevance of forensic interpretations.","language":"eng","citation":"THE BIOGEOCHEMISTRY OF BODY CONCEALMENT: FROM HYPOGEAL CDI TO FORENSIC TAPHONOMY / G. Tagliabue ; tutor: L. Trombino ;  co-tutor: C. Cattaneo ;  coordinatore: G. Muttoni. - Milano. Dipartimento di Scienze Biomediche per la Salute, 2026 Apr 02. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13855.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1229335/3286314/phd_unimi_R13855.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/886066"},"title":"QUANTITATIVE LIPIDOMICS AND PROTEOMICS IN MEDICINAL CHEMISTRY","internalauthor":"RADREZZA, SILVIA","type":"Tesi di dottorato","year":"2022","abstract":"The ‘omics sciences are currently in development offering a new and combined perspective of cellular and organismal environment. Among these, genomics and proteomics are among the most developed while lipidomics is still an emergent field. The importance to provide a strong methodological approach paired to a rigorous data interpretation is explained by the recent discovery of the lipids’ key role not only as structural components and energetic source but also in many biological processes (i.e., second messengers, regulators of inter-cellular interactions and of surface charge, involvement in metabolic diseases, cancer etc.).   Thanks to the recent significant advances, mass spectrometry is the most suitable analytical method in many of ‘omics sciences despite their integration is still at the beginning and a careful optimization of protocols is needed. Nevertheless, considering the molecular complexity, only a multi-omics vision can give a complete picture of intra- and extra-cellular processes in physiological and pathological conditions as well as in response to an environmental or chemical exposure to finally contribute to the field of precision medicine.  So, the work herein aims to provide proteomics and lipidomics perspectives, both as single and integrated approaches, to different research questions by high-resolution mass spectrometry.   At first, the investigation on skin hairless mice proteome allowed me to show how an endogenous peptide, β-alanil-L-histidine (a.k.a. carnosine), is acting in defense of UV-A damages. Indeed, several major protein systems shown an alteration by UV-A treatment including calcium signaling, mitochondrial function or sirtuin expression, which were all restored by a preventive treatment of the skins by a topical application of carnosine. These proteomics alterations could result (at least in part) from ROS generated by UV-A, or/and the generation of lipid oxidation products (HNE, acrolein) resulting from the peroxidation of polyunsaturated fatty acids in the irradiated skins. The implication of such agents is emphasized by the potent efficacy of carnosine in restoring a normal proteomic profile of UV-A-treated skins, in accordance with its ability to neutralize the formation of adducts on proteins and their subsequent modification, thereby restoring their function.  Moving to lipidomics, the biological importance recently demonstrated by fatty acid esters of hydroxy fatty acids (FAHFAs) asked for a tailored method optimization for their identification and quantification in human matrix. In fact, increasing evidence on the physiological roles of FAHFAs, including anti-inflammatory, anti-diabetic and immunomodulatory ones, motivates a more extensive characterization of these lipids as possible biomarkers and therapeutic targets for pathological conditions such as diabetes or obesity. Nevertheless, the low concentration in human tissues, the large structure heterogeneity and that the major amount of FAHFAs in cells is incorporated into triacylglycerols challenge current analytical methods for their accurate identification and quantification. The achieved samples’ preparation and instrumental method optimization successfully enabled to isolate, detect, and quantify endogenous FAHFAs for the first time on human adipose tissue revealing significant alterations based on metabolic status (obese insulin sensitive or resistant vs lean subjects) and adipose tissue portions (visceral vs subcutaneous). These results will be useful to better understand the biological potentiality of this bioactive lipids in metabolic pathologies.  Then, the two multi-omics studies herein conducted were aimed to evaluate molecular effects of low-molecular-weight hyaluronic acid (LMW-HA) in proteome and lipidome of normal human dermal fibroblasts and to analyze lipidome and proteome profile changes induced by γ-Oryzanol (Orz) prevention treatment in obese-induced rats, respectively.   LMW-HA showed an impact both on proteome and lipidome profile, mainly at 0.50 % of concentration. The proteomics results were not only confirmed but also corroborated by lipidomics and integratomics ones. Indeed, mitochondria functionality, cells maturation and lipids metabolism were concordantly demonstrated. About lipidome changes, we saw a particular increasing of ceramides, triacylglycerols and cholesterol esters involved in the skin moisturizing and epidermis renewal and so supporting the beneficial role of low-molecular weight as cosmetic ingredient. Nevertheless, the correct balance between their synthesis and degradation is essential for the skin wellness and further studies are necessary for the deepening of these dynamics.  The Orz’s effects assessment, instead, provided only marginal significant alterations both in plasma’s proteome and lipidome probably due to the weakness of the animal model. Further thoughts and experiments are needed to confirm the biological relevance of Orz mainly showed in biological tests so far.    To conclude, although a lot of questions related to these research topics are still unanswered and other omics should be included in an integrative vision (metabolomics for example), during this multidisciplinary PhD journey I appreciated the complexity and the value of omics sciences in deepening our knowledge about several research fields approaching more and more the precision medicine goal.","language":"eng","citation":"QUANTITATIVE LIPIDOMICS AND PROTEOMICS IN MEDICINAL CHEMISTRY / S. Radrezza ; tutor: M. Carini, A. D'Amato ; supervisore esterno: M. Fedorova ; coordinatore: G. Aldini. Dipartimento di Scienze Farmaceutiche, 2022 Jan 13. 34. ciclo, Anno Accademico 2021. [10.13130/radrezza-silvia_phd2022-01-13].","filename":"phd_unimi_R12190.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/886066/1920830/phd_unimi_R12190.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1201457"},"title":"THE IMPACT OF VASCULAR SMOOTH MUSCLE CELL SENESCENCE ON MITOCHONDRIA DYSFUNCTION AND ANGIOGENESIS","internalauthor":"ROSSI, CLARA","type":"Tesi di dottorato","year":"2025","abstract":"INTRODUCTION: Atherosclerosis, the principal underlying cause of most cardiovascular diseases, progresses from early fatty streaks to advanced unstable plaques that, if ruptured, cause life-threatening events. A hallmark of plaque instability is intraplaque angiogenesis, the formation of neovessels. These neovessels are often immature and leaky, facilitating intraplaque haemorrhage, which exacerbates inflammation, promotes plaque growth, and culminates in rupture and thrombotic complications. While hypoxia is a critical driver of this process, additional pro-angiogenic mechanisms within the plaque microenvironment remain incompletely defined. Atherosclerosis is also an age-associated disease characterized by the accumulation of senescent cells, particularly vascular smooth muscle cells (VSMCs), which remain metabolically active but exhibit significant morphological changes, mitochondrial dysfunction and adopt a senescence-associated secretory phenotype (SASP). Despite growing recognition of senescent VSMCs’ detrimental roles in atherosclerosis, like sustained local inflammation, matrix degradation, and tissue remodelling, their potential contribution to intraplaque angiogenesis through pro-angiogenic SASP has not yet been elucidated.   Moreover, while statin therapy, the most widely used drugs for the prevention and treatment of atherosclerosis, plays a crucial role in managing atherosclerosis by reducing cholesterol levels and promoting plaque stability, its impact on mitochondrial dysfunction and SASP in senescent VSMCs remains largely unexplored.     AIM: This study aimed to investigate the interplay between VSMC senescence, mitochondrial dysfunction, SASP, and angiogenesis, and to evaluate the effect of simvastatin on these processes, and to test whether targeting specific SASP-related pathways (VEGF/VEGFR2 and NF-κB) may represent more effective therapeutic strategies.     RESULTS: We demonstrated, using both single-cell RNA sequencing datasets and immunohistochemistry, that senescent VSMCs are significantly more abundant in human unstable carotid atherosclerotic plaques than in stable ones. Consequently, based on these premises and in order to study senescent VSMCs more thoroughly, we developed and characterized two in vitro models of VSMC senescence: replicative (or old cells) and doxorubicin-induced mimicking stress-induced premature senescence, by assessing key senescence features such as cell morphology, cell cycle arrest, SASP, and mitochondrial dysfunction. Interestingly, both senescent models displayed an accumulation of dysfunctional mitochondria characterized by reduced mitochondrial membrane potential (MMP) and respiration, accumulation of reactive oxygen species (ROS), and an altered mitochondria morphology when compared to their young cells control. Moreover, TFAM and TOM70 expression was found to be downregulated only in old cells suggesting a reduction of mitochondrial biogenesis. In addition, both models of senescent VSMCs showed a significant increase in the gene expression and protein production of pro-inflammatory cytokines, including IL-1β, IL-6, and IL-8, thereby validating the SASP profile.  Next, we investigated whether simvastatin could ameliorate age-associated phenotypes in senescent VSMCs. Simvastatin (0.1 μM) improved mitochondrial respiration and reduced ROS production and the inflammatory SASP in both doxorubicin-induced and old VSMCs.  Notably, when mevalonic acid, a downstream product of the HMG-CoA reductase pathway, was added, these beneficial effects of simvastatin on mitochondrial function and the SASP were no longer observed. This indicates that simvastatin's impact on mitochondrial respiration and SASP is specifically mediated through the inhibition of HMG-CoA reductase, the enzyme targeted by statins in the cholesterol biosynthesis pathway.  Multiplex analysis of the inflammatory SASP in the cell culture medium of the senescent VSMCs confirmed the appropriateness of our in vitro models as doxorubicin-treated and old cells produced significantly more pro-inflammatory proteins such as IL-1β, IFN-γ and TNF-α compared to young cells, as already reported in the literature. Surprisingly, we also found that doxorubicin and old VSMCs produced significantly more pro-angiogenic molecules like Angiopoietin 1 and 2, IL-6, IL-8 and VEGFa, compared to young control cells. Interestingly, VEGFa showed a 4-fold increased concentration in doxorubicin and old cells when compared to young control cells.  We next investigated the paracrine effect of the SASP derived from both our senescent VSMC models on angiogenesis, by exposing Human Umbilical Vein Endothelial Cells (HUVECs) to senescent VSMC-conditioned media. HUVECs treated with conditioned media from senescent cells showed enhanced endothelial cell proliferation, migration, and tube formation when compared the their control treated with conditioned medium from young cells.   Notably, simvastatin-treated senescent VSMCs secreted significantly lower levels of pro-angiogenic factors, especially VEGFa, compared to their untreated control. Consistently, conditioned media from simvastatin-treated senescent VSMCs led to a significant reduction in HUVECs proliferation, migration, and tube formation compared to untreated media from senescent VSMCs.   As VEGF stood out as the main pro-angiogenic factor in our multiplex analysis, we supplemented the conditioned media from senescent VSMCs with rivoceranib, a selective VEGFR2 inhibitor, and assessed its impact on angiogenesis. Interestingly, VEGFR2 inhibition completely abolished SASP induced HUVEC proliferation, migration, and tube formation, confirming the central role of VEGF and its receptor VEGFR2 in mediating the paracrine pro-angiogenic effects of the SASP produced by senescent VSMCs.   Since NF-κB is a well-known regulator of the SASP, we pharmacologically inhibited NF-κB activity and we found a significant reduction in VEGF production in senescent VSMCs, suggesting that targeting this pathway could reduce the angiogenic potential of senescent VSMCs.     CONCLUSIONS: Overall, our findings underscore the multifaceted role of VSMC senescence in promoting atherosclerotic plaque progression and vulnerability. By integrating transcriptomic, histological, and functional analyses, we identify cellular senescence not only as a passive hallmark of vascular aging but as an active driver of plaque destabilization, particularly through mitochondrial dysfunction and the pro-angiogenic secretory phenotype.","language":"eng","citation":"THE IMPACT OF VASCULAR SMOOTH MUSCLE CELL SENESCENCE ON MITOCHONDRIA DYSFUNCTION AND ANGIOGENESIS / C. Rossi ; tutor: A. Corsini ; co-tutor: S. Bellosta ; coordinatore: G.D. Norata. - Milano. Dipartimento di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti, 2025 Dec 16. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13829_2.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1201457/3200993/phd_unimi_R13829_2.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/885232"},"title":"ENVIRONMENTAL ASSESSMENT OF UNDERCURRENT AGRICULTURAL TECHNOLOGIES TOWARDS CIRCULAR NUTRIENT MANAGEMENT","internalauthor":"HERRERA MORENO, AXEL MAURICIO","type":"Tesi di dottorato","year":"2021","abstract":"Circular Economy consists of re-designing effective processes that allow the subsequent recovery of wastes for new production methods, avoiding using new resources. However, an emerging holistic approach requires evidence of its systemic capacities to transition from unsustainable linear practices that had led our planet to face significant environmental problems such as climate change and alteration of biochemical flows. This study aimed to assess technologies that have proven to close C, N, and P loops regarding their overall environmental impact from two study cases; a) Microalgae production by using nutrient and water recovered streams; and b) Integrated anaerobic digestion system with precision agriculture, and bioenergy production. Results showed that the re-use of end-products is critical for positive environmental impacts due to avoided emissions from production, transport, and use of mineral sources, satisfying the aim of supporting a closed-loop integrated system. Nutrient recovery practices reduced GHG emissions, protected and enhanced soil carbon stocks, improved ground- and surface-water quality.","language":"eng","citation":"ENVIRONMENTAL ASSESSMENT OF UNDERCURRENT AGRICULTURAL TECHNOLOGIES TOWARDS CIRCULAR NUTRIENT MANAGEMENT / A.m. Herrera Moreno ; tutor: F. Adani ; coordinatore: D. Bassi. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2021 Dec 16. 34. ciclo, Anno Accademico 2021. [10.13130/herrera-moreno-axel-mauricio_phd2021-12-16].","filename":"phd_unimi_R12257.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/885232/1918573/phd_unimi_R12257.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1046296"},"title":"EN PITHO TEN KERAMEIAN. ANALISI TIPOLOGICA, TECNOLOGICA E FUNZIONALE DEL PITHOS NELLA PEUCEZIA PREROMANA: IL CASO DI JAZZO FORNASIELLO (GRAVINA IN PUGLIA - BA)","internalauthor":"LOJACONO, AGNESE","type":"Tesi di dottorato","year":"2024","abstract":"The cultural importance of the pithos, the large container for foodstuffs, is emphasized both in written sources and in iconographic documents where it appears in scenes of daily life, sacred rituals, as well as in relation to mythical episodes. However, the most significant evidence of its importance is provided by the study of material culture. For this reason, in the present study, the preferred area of investigation is pre-Roman Peucetia, a region with a significant agricultural vocation, where numerous pithoi are attested from different excavation sites.  In this paper, we consider the case study of the large containers from the Peucetian site of Jazzo Fornasiello (Gravina in Puglia). This site has been excavated by a team from the University of Milan since 2009, under the scientific direction of Professors Marina Castoldi and Claudia Lambrugo. The large containers remained in use for centuries, sometimes passed down through generations, being dismissed only when the dwelling, understood as a social unit, was deconstructed and abandoned. The pithos, due to the technical difficulties of production, is a valuable artifact that is repaired for a long time rather than replaced, and due to its considerable size, it is often unmovable. It is also important to note that, for its function as a container for foodstuffs, this ceramic artifact quickly became a symbol of family wealth.  In an attempt to accurately understand how the large containers of Jazzo Fornasiello were used, Professor Silvia Bruni and her team from the Department of Chemistry at the University of Milan conducted specific investigations on traces of organic substances. The results, particularly from the analysis of wine markers, demonstrated that alcoholic beverages were definitely stored inside the pithoi at Jazzo Fornasiello.  All diagnostic fragments, found in the excavations of Jazzo Fornasiello until the 2019 campaign, were carefully recorded. Comparing the catalogued fragments with published findings from other Apulian and Enotrian excavations, it was possible to obtain a typological classification of the pithoi attested in the site.  Within the current research, wide space was dedicated to archaeometric analyses, conducted in close collaboration with Professor Giacomo Eramo from the Department of Earth and Environmental Sciences at the University of Bari “Aldo Moro”. The analyses were performed on a large sample of vases in order to fully reconstruct the production chain underlying the making of the pithoi. The present research, which included a study of the large containers for foodstuffs from all perspectives, clearly highlighted the fundamental cultural significance that this ceramic form must have had within the Apulian communities, and within the agricultural-pastoral community settled at Jazzo Fornasiello between the 6th  and 3rd centuries BCE, in particular. Indeed, as a symbol of family wealth, it becomes a vehicle for family memory and a tool used in domestic rituals associated with the celebration of ancestor worship.","language":"ita","citation":"EN PITHO TEN KERAMEIAN. ANALISI TIPOLOGICA, TECNOLOGICA E FUNZIONALE DEL PITHOS NELLA PEUCEZIA PREROMANA: IL CASO DI JAZZO FORNASIELLO (GRAVINA IN PUGLIA - BA) / A. Lojacono ; tutor: C. Lambrugo ; coordinatore: F. Slavazzi. Università degli Studi di Milano, 2024 Jun 19. 36. ciclo","filename":"phd_unimi_R12848.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1046296/2401049/phd_unimi_R12848.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1121854"},"title":"NATURAL SOURCES OF ELLAGITANNINS TO COUNTERACT H. PYLORI INFECTION","internalauthor":"MARTINELLI, GIULIA","type":"Tesi di dottorato","year":"2024","abstract":"Helicobacter pylori colonises the gastric mucosa of at least 50 % of the world’s human population, causing a variety of gastric diseases, including chronic gastritis, peptic ulcer, and gastric cancer. Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide. It is estimated that approximately 90 % of gastric cancers can be attributed to infection with H. pylori. The ability of the bacterium to colonise and to induce inflammation and immune cell recruitment, is achieved through a combination of virulence factors.  Firstly, the present study undertook an in-depth investigation of the host response to two distinct H. pylori strains, the cagA-positive 26695 strain and a cagA-negative clinical one, in non-tumoral human gastric epithelial cells (GES-1) in comparison with the widely used AGS cells derived from a stomach tumour. The expression of several pro-inflammatory genes, the release of major inflammatory mediators (IL-8 and IL-6), and the involvement of the transcription factor NF-kB induced in both gastric epithelial cells by H. pylori were studied, underlying the dissimilar inflammatory response in both cell lines due to the different virulence of the bacteria. Along with an analysis of transcriptome, GES-1 cell line appeared to be a more responsive cellular model for gastric inflammation, and the study provided new insights into the molecular pathways modulated by H. pylori in GES-1 cells, thereby identifying promising new targets for the pharmacological therapy.  Beside the conventional pharmacological treatment of H. pylori infection based on bacterial eradication, natural compounds, including ellagitannins (ETs), could function as an adjuvant to existing therapies, potentially mitigating the consequences of H. pylori infection by impairing bacterial adhesion and subsequent gastric inflammation. This approach may limit the antibiotic resistance and minimize the side effects associated with the therapy.  Secondly, this study considers novel strategies for the control of H. pylori-related gastritis based on natural products. Therefore, extracts containing ETs from the Genus Castanea, Punica, and Fragaria, along with their pure ETs, including castalagin, vescalagin, agrimoniin, casuarictin, punicalagin, and punicalin, exhibited anti-inflammatory properties during H. pylori infection. They all inhibited the release of IL-8 by infected GES-1 cells (IC50 inhibition range of 10-50 μg/mL and around 10 μM for extracts and ETs, respectively), at least in part due to the impairment of NF-κB signalling. Moreover, they exhibited antibacterial activity (MIC value approximately 100 μg/mL and 25 μM for the extracts and ETs, respectively). Based on these results, castalagin, which exhibited comparable activities to the other pure ETs, was selected as a reference for further investigation to gain insight into the activity of this class of molecule in H. pylori context. At the transcriptional level, the selected ellagitannin, castalagin, was observed to downregulate genes involved in inflammatory pathways (e.g. NF-κB and AP-1), thereby confirming the anti-inflammatory properties of this compound during H. pylori infection. The anti-bacterial and the anti-inflammatory properties of the Castanea sativa Mill. leaf extract (100 μg/mL) and castalagin (25 μM), were also confirmed in an innovative H. pylori-murine gastric organoids model, which most closely mimics the physiology of entire organ. Both extract and molecule  inhibited genes involved in NF-κB pathway, including CXCL1, CXCL10, and CCL2. Furthermore, the extract (500 mg/kg, and 100 mg/kg) and castalagin (25 mg/kg) were observed to strongly inhibit H. pylori colonization and inflammation in mice, and to impact immune cells, especially monocytes and neutrophils, induced by the activation of NF-κB pathway during infection.  The results of this project contribute to the existing body of knowledge regarding the diverse outcomes of H. pylori infection and suggest the potential for new pharmacological natural products in the prevention and/or treatment of gastritis induced by H. pylori.","language":"eng","citation":"NATURAL SOURCES OF ELLAGITANNINS TO COUNTERACT H. PYLORI INFECTION / G. Martinelli ; tutor: M. Dell'Agli ; co-tutor:  P. Sperandeo ; coordinatore: G. D. Norata. - Dipartimento di Scienze Farmacologiche e Biomolecolari. Dip. di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti, 2024 Dec 19. 37. ciclo","filename":"phd_unimi_R13253.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open from 04-DIC-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/841241"},"title":"CHARACTERIZATION OF TLS POLYMERASE ETA FUNCTION UNDER REPLICATION STRESS INDUCED BY LOW DNTP POOLS","internalauthor":"NAVA, GIULIA MARIA","type":"Tesi di dottorato","year":"2021","abstract":"RNA:DNA hybrids are transient physiological intermediates that arise during several cellular processes such as DNA replication. Although these structures have physiological relevance, their stable accumulation perturbs DNA replication, inducing replication stress and genome instability. Cells possess two enzymes that process these structures restoring the correct DNA:DNA sequence: RNase H1, which just handles stretches of multiple rNMPs, and RNase H2 that processes either single or multiple ribonucleotides hybridized with DNA. Mutations in the human RNase H2 lead to carcinogenesis and a severe auto-inflammatory disease known as Aicardi-Goutières syndrome. S.cerevisiae yeast cells lacking RNases H enzymes (rnh1Δ rnh201Δ) accumulate ribonucleotides in their genome, becoming sensitive to different replication-stress inducing agents such as hydroxyurea (HU), a compound that decreases the dNTP pools, stalling replication forks. Unexpectedly, we found that this HU-sensitivity is completely suppressed by removing the RAD30 gene, coding for the translesion DNA polymerase η.  In this study, I characterized this novel activity for the yeast Pol η under HU-induced replication stress, and the toxicity observed in RNase H depleted-cells, also focusing on possible regulatory mechanisms. Our data indicate that Pol η acts at HU-stressed replication forks, with recruitment that seems to depend on PCNA mono-Ub, and might also be regulated by the Pol η-SUMOylation levels. We proved that the catalytic reaction performed by Pol η is detrimental for RNase H deficient cells, causing DNA damage checkpoint activation and G2/M arrest. These harmful effects arise during the first replication cycle in HU and seem to be due to the incorporation of stretches of ribonucleotides promoted by Pol η. In agreement, a Pol η mutant allele with enhanced ribonucleotide incorporation further exacerbates the sensitivity to HU of cells lacking RNases H enzymes.  All these data are compatible with a model in which Pol η promotes DNA replication from stalled replication forks, inducing the formation or stabilization of RNA:DNA hybrids. These hybrids could result from either direct incorporation of rNMPs into DNA or incorrect Okazaki fragments maturation or R-loops stabilization. However, in a scenario where RNase H activity fails to restore DNA, these hybrids become toxic for cells. Finally, performing an SGA screening, I identified some negative interactors of RAD30 that might compensate for the role played by the polymerase at HU-stalled replication forks.","language":"eng","citation":"CHARACTERIZATION OF TLS POLYMERASE ETA FUNCTION UNDER REPLICATION STRESS INDUCED BY LOW DNTP POOLS / G.m. Nava ; supervisiore: F. Lazzaro. Dipartimento di Bioscienze, 2021 May 21. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12003.pdf","fileformat":"Adobe PDF","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/841241/1793359/phd_unimi_R12003.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/975933"},"title":"ROLE OF THE ALOG GENE FAMILY IN THE INFLORESCENCE DEVELOPMENT OF ORYZA SATIVA AND ARABIDOPSIS THALIANA","internalauthor":"BERETTA, VERONICA MARIA","type":"Tesi di dottorato","year":"2023","abstract":"Human population growth makes it of primary importance to find new ways to sustainably increase agricultural crop production to meet the increasing food demand. In this context, inflorescence architecture is one of the key agronomical traits which determines grain yield; thus, it has been a major target for crop domestication and improvement. For example, in rice an increased number of branches allows the panicle to bear more seeds, leading to a higher yield.  To study the molecular genetic processes that lead to inflorescence architecture establishment, we used two model plant species: Oryza sativa, model plant for monocotyledons, and Arabidopsis thaliana, model plant for dicotyledons. In both Arabidopsis and rice, inflorescence architecture development depends on a complex gene regulatory network that controls the identity and activity of the reproductive meristems.  A substantial number of genes involved in the pathways that lead to inflorescence architecture development have been identified, however, this complex developmental process is still far from understood. To identify new players involved in panicle development, reproductive meristems of Arabidopsis and rice were isolated by laser microdissection at different stages of development and used for RNA-seq analysis. The analysis of differentially expressed genes between the various stages of meristem development showed that several members of the ALOG (Arabidopsis LIGHT-DEPENDENT SHORT HYPOCOTYL 1 and Oryza G1) gene family showed the same expression pattern in meristematic tissues, suggesting a possible role in the determination of inflorescence architecture. These genes are OsG1L1, OsG1L2 and TAW1/OsG1L5 of rice; and AtLSH1, AtLSH3 and AtLSH4 of Arabidopsis.  One member of the rice ALOG gene family, TAW1/OsG1L5, was already shown to be a fundamental regulator of inflorescence development in rice (Yoshida et al., 2013), further suggesting an important role for the ALOG gene family in reproductive development.  My Ph.D. research project was focused on elucidating the role of the ALOG genes in inflorescence development in both Arabidopsis and rice.  We generated single and multiple mutants in both species using CRISPR-Cas9. The molecular and morphological analysis of the mutants revealed that the knock-out of these genes determined defects in plant inflorescence architecture linked to the process of identity acquisition of the reproductive meristems.","language":"eng","citation":"ROLE OF THE ALOG GENE FAMILY IN THE INFLORESCENCE DEVELOPMENT OF ORYZA SATIVA AND ARABIDOPSIS THALIANA / V.m. Beretta ; tutor : M. Kater ; supervisore: V. Gregis. Dipartimento di Bioscienze, 2023 Jun 26. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12493.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/975933/2219388/phd_unimi_R12493.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/858928"},"title":"NUTRITIONAL STRATEGIES FOR IMPROVING THE GUT HEALTH OF MONOGASTRIC ANIMALS","internalauthor":"GIORGI, SILVIA","type":"Tesi di dottorato","year":"2021","abstract":"Optimal gastrointestinal functionality and health is essential for sustainable animal production, especially considering that nowadays, the challenge in livestock sector is to maintain a high productivity and food security in a sustainable way, reducing the use of antimicrobials. Nutritional strategies that aim to improve animals’ performance preserving their intestinal health, are essential for achieving these goals. Therefore, in the present thesis, various nutritional interventions were evaluated, using short and medium chain fatty acids in particular, on the growth and intestinal well-being of pigs. The purpose of this thesis was to: 1) evaluate the effects of an innovative form of a medium chain fatty acid, lauric acid saponified with calcium, supplemented in post-weaning piglet diet on their growth and gut health and as a possible alternative to reduce the use of antibiotics; 2) asses the effectiveness of the combination of a short chain fatty acid (tributyrin) and a medium chain fatty acid (monolaurin) in post-weaning piglet diet on their growth performance and some gut health parameters; 3) evaluate the effects of lauric acid saponified with calcium administered to sows diet starting from the last 3 weeks of gestation, on sows productivity and on the growth performance and health of their offspring; 4) to assess the effect of fatty acids and different milk fractions on porcine IPEC-J2 cell line proliferation and viability. The results presented in this thesis highlight how short and medium chain fatty acids are effective candidates for improving animal health, reducing the use of antibiotics. This may contribute to the development of a more sustainable livestock production system based on the respect of animal health and the reduction of antimicrobials, as recommended by the “One Health” approach. However, further investigations are necessary to better understand the mechanisms of action, the dosage and the best forms of administration of short and medium chain fatty acids (alone or synergistically) integrated in pigs’ diets, in particular during weaning, to further improve their growth performance and gut health.","language":"eng","citation":"NUTRITIONAL STRATEGIES FOR IMPROVING THE GUT HEALTH OF MONOGASTRIC ANIMALS / S. Giorgi ; advisor: V. Bontempo, M. Lessard, M. Blais ; phd course coordinator: V. Grieco. Dipartimento di Scienze Veterinarie per la Salute, la Produzione Animale e la Sicurezza Alimentare, 2021 Jul 21. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11902.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/858928/1844153/phd_unimi_R11902.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/816797"},"title":"LA RETORICA DEL PRIMORDIALISMO NEL DISCORSO NAZIONALISTA DI SUZUKI TAKAO E WATANABE SHŌICHI. ANALISI DI TRE SAGGI DI NIHONJINRON","internalauthor":"VITALI, ELISA","type":"Tesi di dottorato","year":"2021","abstract":"After fifty years since the boom of the Theories on Japanese culture (Nihonbunkaron) and in conjunction with the rise of Japan as a cultural superpower in the world, the official ideology of the establishment still keeps alive the stereotypes, clichés and myths connected to the particularistic paradigm of ‘Japanese nation’ which was popular since the postwar period among Japanese intelligentsia especially in the form of the amatorial essay. Far from being weakened, the Nihonjinron nationalist discourse persists and proliferates through theories, opinions, discussions dealing with Japaneseness in the form of essays, articles, academic seminars, public discussions. Re-interpreting the primordialist perspective in the field of Nationalism Studies as a category of social practice (Coakley 2017), it is especially the belief in the primordiality of Japanese nation that is recently re-assessed with renewed strength by some ideologized and influential intellectuals as Suzuki Takao and Watanabe Shōichi. Echoing the philosophical ideas of German organicism on the nation embodied by Herder and Fichte, the textual and rhetorical analysis of Suzuki’s (2016, 2017) and Watanabe’s (2008) essays offers an interesting tool to bring on the surface the ideological mechanisms underlying Nihonjinron and its ideological core, primordialism.","language":"ita","citation":"LA RETORICA DEL PRIMORDIALISMO NEL DISCORSO NAZIONALISTA DI SUZUKI TAKAO E WATANABE SHŌICHI. ANALISI DI TRE SAGGI DI NIHONJINRON / E. Vitali ; tutor: V. Sica ;  coordinatore: M. V. Calvi. Università degli Studi di Milano, 2021 Feb 25. 33. ciclo, Anno Accademico 2020. [10.13130/vitali-elisa_phd2021-02-25].","filename":"phd_unimi_R11867.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/816797/1710462/phd_unimi_R11867.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1132395"},"title":"METAL COMPLEXES AND THEIR BIOLOGICAL ACTIVITY IN VIVO","internalauthor":"PECORARO, TANIA","type":"Tesi di dottorato","year":"2025","abstract":"Luminescent transition metal complexes (TMCs) represent a class of compounds with remarkable photophysical and electrochemical properties, arising from their unique electronic structures. Complexes containing Pt(II), Ir(III), Ru(II), Cu(I) for example are characterized by the presence of partially filled d-orbitals, exhibit a range of fascinating phenomena including phosphorescence, long-lived excited states, and tuneable emission wavelengths. These features, in conjunction with their chemical versatility and stability, have rendered TMCs indispensable in numerous fields, spanning optoelectronics, sensing, and bioimaging. Within this diverse landscape of TMCs, platinum complexes have garnered particular attention owing to their exceptional luminescence properties and the pivotal role of supramolecular self-assembly in dictating their behaviour. Thanks to the square planar geometry, when the Pt(II) ion is coordinated to conjugated ligands self-assembly can occur leading to the creation of supramolecular structures. These complexes in the assemblies can exhibit strong metal-metal interactions that engender unique photophysical characteristics, including intense phosphorescence and long-lived excited states [8,9]. The self-assembly of these complexes is strongly medium dependent and can further modulates their electrochemical properties and modify their reactivities enabling the creation of stimuli-responsive materials and sophisticated functional systems.   In Professor De Cola's research group, the behaviour of self-assembling platinum complexes has been extensively studied. The possibility of using water-soluble, self-assembling platinum complexes makes them ideal candidates for in vivo imaging applications. It is known that one of the major problems of classic luminescent markers is the presence of oxygen in biological systems, as this is a known quencher of long-lived luminescent states. However, self-assembled structures would protect the metal centre, thus preventing oxygen access. Although the self-assembly process has been extensively studied to evaluate its spectroscopic effects, its potential for modulation at the biological level has never been thoroughly investigated  While many Pt(II) complexes are toxic and several anticancer drugs have been developed taking advantage of their toxicity, there is a wide variety of transition metals, in biological systems that play crucial roles in enzymatic function, protein transport and storage, oxygen transport, and photosynthesis. Deficiencies in metals can lead to various of diseases in humans, such as anemia, growth retardation, and heart disease in infants due to iron, zinc, and copper deficiencies. Amongst the enzyme that play an important role in maintaining the cell metabolism and healthy our body superoxide dismutase (SODs), which utilize copper and zinc to neutralize reactive oxygen species, and catalase, which employs manganese to decompose hydrogen peroxide are very relevant. The significance of these metalloenzymes has spurred intensive research in recent years, with a particular focus on the synthesis of artificial metalloenzymes that mimic the catalytic processes of their natural counterparts.  To achieve the goal of mimicking enzymatic activity, it is crucial to simulate an environment that closely resembles the natural enzymatic task. One promising strategy involves confining these artificial metalloenzymes within nanostructures, thereby creating a controlled and restricted system. This approach aims to replicate the spatial constraints and microenvironment found within enzyme active sites, potentially enhancing the catalytic efficiency and selectivity of the artificial metalloenzymes. A promising approach for enhancing the stability of transition metal complexes (TMCs) in biological environments is the utilization of soft or hard porous nanomaterials as confinement systems. Nanotechnology has experienced a remarkable surge in research and development across various sectors, including medicine. Nanomaterials, owing to their nanoscale dimensions, exhibit unique properties that differ significantly from their bulk counterparts, making them attractive for biomedical applications. The potential of nanomaterials as drug delivery vehicles stems from their ability to protect drugs from degradation, facilitate targeted delivery, enable relatively straightforward manufacturing processes, demonstrate biocompatibility, and accommodate diverse drug types. Consequently, employing nanomaterials for the transport and protection of catalytic TMCs complexes offers a promising strategy to overcome the challenges associated with their instability in biological systems. In this field, transition metal complexes represent a valuable resource for therapeutic and diagnostic applications in modern medicine. Their diverse chemical interactions, encompassing redox processes and coordination chemistry, allow for the development of tailored approaches to disease treatment. Ongoing research endeavours to discover and optimize novel metal complexes, enhancing their efficacy, safety, and specificity for various medical applications. As such, transition metal complexes are poised to play an increasingly pivotal role in the future of pharmacology and therapeutic interventions.  The aim of my research is to develop transition metal complexes able to self-assembly to achieve new functions or simple catalysis-mimic compounds. To enhance their stability in biological media, I have investigated soft and hard porous structures creating hybrid nanosystems. The first objective of my research focused on Pt(II) complexes, containing conjugated ligands, exploiting the high tendency of such square planar compounds, to self-assembly in supramolecular structures. The synthesized water-soluble Pt(II) complexes have been investigated to assess their assembly tendency and in a very complex media such as living organisms. The obtained results suggest that the self-assembly of the complexes, and in particular of a positively charged compound, modulate their photophysical properties, and, very interestingly, trigger important biological effects, suggesting a kind of antioxidant activity. For this reason, in the second objective I have designed and synthesized metallic complexes as mimic for the natural enzymes, containing Cu and Zn as metals. Artificial metalloenzymes have become increasingly important in the last decades as a promising approach to combine homogeneous catalysis and biocatalysis for therapeutical applications. In cell systems, the enzymes superoxide dismutase (SOD), catalase (CAT), oxidase (OXD) and peroxidase (POD) are involved in redox homeostasis. Therefore, artificial systems able to function as antioxidant under few pathological situations associated with an enhanced oxidative stress, such as diabetes, cancers, inflammatory bowel and neurodegenerative diseases are the basis of my ongoing research. In the last part, the third objective of my work, I have focused on the development of soft, non-lipid-based vesicle, i.e. Qs (QS), eventually covered with silica, and hard porous nanosystems such as organosilicates. The porous nanoparticles have been employed for the encapsulation of some of the complexes in order to confer water compatibility and to enhance their stability.  In conclusion, this PhD research has yielded significant advancements in two key areas: i) understanding self-assembly in vivo and in particular the biological impact of redox active assemblies; ii) SOD mimic systems that can be used in biological samples due to the enhanced stability dictated by a nanocage and the water miscibility again promoted by the scaffold. These findings can open new venue on the design of systems in which the modulation of the redox activity can be tuned by molecule-molecule interaction as well as the novel way to protect unstable species.","language":"ita","citation":"METAL COMPLEXES AND THEIR BIOLOGICAL ACTIVITY IN VIVO / T. Pecoraro ; tutor: L. De Cola ;  co-tutor: I. S. Rimoldi. - Dipartimento di Scienze Farmaceutiche  UNIMI -Milano. Dipartimento di Scienze Farmaceutiche, 2025 Jan 29. 37. ciclo","filename":"phd_unimi_R13336.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1132395/3086286/phd_unimi_R13336.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1155318"},"title":"GENOMICS FOR WILD AND MEDICINAL PLANT DIVERSITY STUDIES","internalauthor":"PALENI, CHIARA","type":"Tesi di dottorato","year":"2025","abstract":"Genomic resources are a fundamental asset in investigating genetic diversity, evolutionary history and adaptive potential of populations. During this doctorate, we aimed at developing genomic resources for non-model, medicinal plant species in order to facilitate research in biodiversity genomics, flower development, and genetic improvement, focusing on two plant species: Salvia pratensis and Althaea officinalis. In one part of the project, a good quality, annotated genome assembly was obtained for Salvia pratensis. The genome was used to study flower development related genes of the MADS-box family of transcription factors and as a reference to perform species delimitation between S. pratensis and three closely related taxa which are endemic to Italy or have an otherwise restricted range. A phylogeny for Italian Salvia species was also obtained. Genetic variation data was obtained with Genotyping-By-Sequencing (GBS). In the second part of the project, in collaboration with Aboca S.p.A. Società Agricola, we set the basis for future studies aimed at improving Aboca’s collection of Althaea officinalis, a medicinal plant used for many natural products, to increase activity of its root extracts. Experimental fields were set up in Aboca and Milan to obtain plants for genome size estimation and to test the viability of self-pollinated seeds. Finally, a protocol was set up in Aboca to efficiently obtain root extracts from individual plants, in order to have a measure of the desired phenotype. This is essential to verify how much variation is present in the collection and in the future link it to the plant’s genotype. The results from this project set the stage for improving the ex situ collection of the Salvia genus in the Botanical Garden of Brera, give support to delimitation of endemic Italian species, and set the stage for genetic improvement of Aboca’s collection, potentially with integration of wild genotypes.","language":"eng","citation":"GENOMICS FOR WILD AND MEDICINAL PLANT DIVERSITY STUDIES / C. Paleni ; tutor: M. Kater. Dipartimento di Bioscienze, 2025 Mar 31. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13553.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1155318/2720034/phd_unimi_R13553.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1138655"},"title":"HYDROGELS FOR GROWTH OF LIVING MICRO-ORGANISMS","internalauthor":"KANG, HUIXUAN","type":"Tesi di dottorato","year":"2025","abstract":"In this work, I successfully achieved the goals of my PhD project on culturing diatoms, structural colored bacteria, and microalgae in different hydrogels, as well as co-culture bacterial and microalgal cells in the same hydrogel system.   In our first project, we developed an innovative approach to study diatoms embedded in hydrogels with controlled conditions, resulting in a straightforward technique to investigate species-specific photo-regulation of benthic diatoms. This work opens an opportunity for further research to better understand how individual diatom species respond to different light conditions and the mechanisms that regulate their endogenic rhythms.   In the second project, we have synthesized and characterized various hydrogels with different morphologies as matrices to grow three structural colored bacterial strains. By changing hydrogel compositions and studying their mechanical and physical properties, we successfully developed several methods for the bacteria to form bacterial biofilm with structural color, both in 2D and in 3D hydrogel matrix, which may contribute to further production of sustainable living pigmentations. The co-culture of microalgae and bacteria suggested the microalgal cells can contribute to bacterial growth thanks to the oxygen they produce from photosynthesis.  In our last projects, we developed two advanced methods to culture microalgal cells. Microalgal growth in 3D granular hydrogels provides a possible solution for cell aggregation problem in bulk hydrogels. The granular hydrogels are made of fully degradable and highly biocompatible polymers with a facile synthesis method. Due to the interconnected microporous structure, microalgae are able to migrate and proliferate within the hydrogels, enabling faster cell growth, higher photosynthetic efficiency, and less self-shading effect. We also embedded nutrients-encapsulated silica nano-capsules into GelMA hydrogels and used them to culture microalgae, higher cell density and biomass production were achieved by using this culture method, suggesting a potential application to use silica nano-capsules to provide essential nutrients for microalgal cultivation. This work has provided a promising technique for harvesting renewable microalgal bio-resources and have potential applications in both laboratory and industry.","language":"eng","citation":"HYDROGELS FOR GROWTH OF LIVING MICRO-ORGANISMS / H. Kang ; tutor: L. De Cola ; phd coordinator: G. Vistoli. - Via Mangiagalli, 25, Milano. Dipartimento di Scienze Farmaceutiche, 2025 Jan 29. 37. ciclo, Anno Accademico 2024. [10.17605/OSF.IO/WQDU6].","filename":"phd_unimi_R13296_2.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1138655/2645582/phd_unimi_R13296_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/833926"},"title":"LE VERSIONI OMERICHE DI MELCHIORRE CESAROTTI: INTRODUZIONE, ANALISI E COMMENTO","internalauthor":"LA ROSA, MADDALENA","type":"Tesi di dottorato","year":"2021","abstract":"\"My dissertation, entitled \"\"Le versioni omeriche di Melchiorre Cesarotti: introduzione, analisi e commento\"\", aims to present an overall picture of the Homeric studies carried out by Melchiorre Cesarotti during his career as a professor in Padua and, specifically, to offer a study of the editorial, critical and translation work done by him on the Iliad in the two editions published in Padua, the first between 1786 and 1794 (at the Penada publisher) and the second between 1798 and 1802 (at the publisher Brandolese). The thesis is divided into two parts: on the one hand, the first traces the long period of Cesarotti’s Homeric criticism starting from his modernist turn of 1762, on the other it reconstructs the translation studies that he deepens in the years of his academic chair; the second part presents a textual analysis of his translations of the Iliad and a synthesis of the peculiarities of the poetic translation, aimed at carrying out both a poetic and moral reform of the Homeric poem.\"","language":"ita","citation":"LE VERSIONI OMERICHE DI MELCHIORRE CESAROTTI: INTRODUZIONE, ANALISI E COMMENTO / M. La Rosa ; tutor: M. Mari ; coordinatore: P. Piacentini. Università degli Studi di Milano, 2021 Apr 15. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11913.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/833926/1768602/phd_unimi_R11913.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/920907"},"title":"DESIGN AND SYNTHESIS OF NEW PET RADIOTRACERS IN DRUG DISCOVERY","internalauthor":"MASPERO, MARCO","type":"Tesi di dottorato","year":"2022","abstract":"In this manuscript, the scientific work of the PhD of Dr Marco Maspero is described. This is focused on the development of PET radiotracers, for their application as imaging probes for the detection of diseases and as valuable tools in drug discovery. Two main approaches are applied:  - A monomodal approach for the preparation of 18F and 11C radiolabeled small molecules targeting the fibrotic process;  - A multimodal approach for the development of peptide-based dually labelled compounds suited for optical and PET (68Ga) imaging.  The manuscript describes the synthetic approaches and the chemical characterizations of the novel compounds, as well as the results of their in vitro analysis. From this work, novel potential radiotracers for the fibrotic process have been identified, and it was also confirmed and expanded the described charge-cell binding correlation for peptide-based hybrid multimodal imaging agents.  The project was developed at the University of Milan, Italy, under the supervision of Prof. Clelia Dallanoce, and in collaboration with the Nuclear Medicine Unit of the San Raffaele Hospital, Milan, Italy, and the University of Heidelberg, Germany.","language":"eng","citation":"DESIGN AND SYNTHESIS OF NEW PET RADIOTRACERS IN DRUG DISCOVERY / M. Maspero ; tutor: C. Dallanoce ; coordinatore: G. Aldini. Dipartimento di Scienze Farmaceutiche, 2022 Apr 04. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12263.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/920907/2015668/phd_unimi_R12263.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1136155"},"title":"SEDIMENTARY ARCHITECTURE AND INTERNAL HETEROGENEITY OF TURBIDITE CHANNEL-LEVEE DEPOSITS: THE TACHRIFT TURBIDITE SYSTEM (LATE TORTONIAN, TAZA-GUERCIF BASIN, NE MOROCCO)","internalauthor":"INVERNIZZI, DANIELE","type":"Tesi di dottorato","year":"2025","abstract":"Turbidite channel-levee deposits have been studied for over fifty years, both in modern and ancient deep-water systems. Recent advances in 3D seismic imaging have improved our understanding of these systems, yet the internal facies complexity remains elusive. Studying well-exposed outcrops is essential to fill this gap, offering detailed insights into sedimentary heterogeneity. This knowledge is not only crucial for scientific research but also for hydrocarbon exploration and groundwater management, and carbon capture industry as these systems serve as significant reservoirs.   Despite recent advancements, understanding the detailed internal structure and evolution of turbidite channel-levee deposits is limited due to the low resolution of subsurface data. The lack of continuous outcrop exposures showing the relationship between channel-fills and levee deposits further complicates model calibration. This thesis aims to address these gaps through detailed documentation of well-exposed ancient channel-levee deposits.  The study area is located in the Taza-Guercif Basin, northeastern Morocco and was part of the Rifian Corridor, a key marine connection between the paleo-Mediterranean Sea and the Atlantic Ocean during the Late Miocene. The basin preserves a series of late Tortonian to early Messinian turbidite systems, including the Tachrift Turbidite System, which features multiple channel-levee deposits.  This PhD work is part of a larger project called the 'Tachrift Project’, which focuses on the sedimentary characterization of the nine superimposed channel-levee deposits within the Tachrift Turbidite System (late Tortonian to early Messinian) in the Taza-Guercif Basin, NE Morocco. As part of this broad research project involving numerous researchers from different universities, the thesis focuses on Complexes 5 and 7, two of the nine superimposed channel-levee deposits within the Tachrift Turbidite System.  The exceptional outcrop quality offers valuable data on channel-fill and levee deposits, providing a rare opportunity to study these features at a sub-seismic resolution. This research contributes to refining models of sedimentary heterogeneity and improving our understanding of similar subsurface analogs.  A classical sedimentological approach was applied, including geological mapping, facies analysis, and physical stratigraphic correlation. Over 130 stratigraphic logs were collected across multiple outcrops oriented along strike and along dip and covering both lateral and vertical facies variability. Key sedimentary parameters were used to assess sedimentary heterogeneity. These data provide a basis for reconstructing the evolution, architecture and sedimentary heterogeneity of channel-levee deposits.  This detailed study, integrated with previous research conducted within the turbidite system, has enabled the identification of two main depositional styles of channel-levee deposits, each characterized by different architectural elements and facies associations. The first depositional style, termed 'Erosional channel-fills,' is characterized by a symmetrical distribution of facies relative to the channel axis and is the product of high-energy flows that incise and progressively fill conduits that range from straight to low-sinuosity. The second style refers to 'Laterally accreting channels,' which exhibit high sinuosity with asymmetrical facies distributions and geometries, along with lateral migration, reflecting lower energy conditions.  Both studied Complexes 5 and 7 displayed a similar depositional evolution, beginning with the deposition of highly sinuous, ephemeral, and small-scale channels, followed by phases of progressively increasing flow energy and magnitude, leading first to the development of distributary channels with significant lateral expansion and low aggradation (Laterally accreting elements), and later to straighter, more incisional channels (Erosional channel-fills). During the deposition of each channel-levee complex, these conditions of lateral expansion versus aggradation can alternate, creating a highly complex stacking pattern. The deactivation of both complexes is abrupt and marked by the presence of thick marlstone intervals.   This thesis, which also involved the quantification of key sedimentological variables such as bed thickness, grain size, and net-to-gross ratios, contributes to a deeper understanding of turbidite channel-levee complexity and offers important analogues for subsurface exploration and resource management.","language":"eng","citation":"SEDIMENTARY ARCHITECTURE AND INTERNAL HETEROGENEITY OF TURBIDITE CHANNEL-LEVEE DEPOSITS: THE TACHRIFT TURBIDITE SYSTEM (LATE TORTONIAN, TAZA-GUERCIF BASIN, NE MOROCCO) / D. Invernizzi ; advisor: F. Felletti ;                                                                                   co-advisor: M. Marini, G. Pantopoulos, A. McArthur ;  phd coordinator: M. I. Spalla. Dipartimento di Scienze della Terra Ardito Desio, 2025 Jan 27. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13355.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1136155/2637770/phd_unimi_R13355.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/923222"},"title":"SELECTIVE ASSEMBLY, PHASE TRANSITIONS AND MOLECULAR KINETICS OF DNA OLIGOMERS.","internalauthor":"DI LEO, SIMONE","type":"Tesi di dottorato","year":"2022","abstract":"In the last few years it has been shown  that the spontaneous self-assembly process of short DNA and RNA duplexes into liquid crystal ordering is a likely potential route that led to the formation of first nucleic acids able to support biological activities. In particular, it has been experimentally  demonstrated that liquid crystal domains behave as suitable micro-reactors to trigger polymerization between the stacked and not initially chemically linked short nucleic acids.  Even paired mononucleotides at high enough concentration exhibit liquid crystal ordering, unveiling the crucial role of Watson-Crick selectivity and stacking attractive interactions among base pairs. In such a possible prebiotic context, DNA sequences with both random nucleobases sequence and length are likely to be formed. Surprisingly, it has been shown that even random DNA sequence of fixed length can support liquid crystal ordering at high concentration.   The aim of this PhD thesis is to extend the knowledge of DNA liquid crystals self-assembly in the following four directions.  First, I explored the selectivity of interaction in nucleic acids solutions of random-sequence DNA oligomers of different length L. The combination of experimental results and a suitable developed theoretical model revealed a not negligible percentage of perfect duplexes.  Second, I investigated the process that leads to the onset of the nematic liquid crystal phase in aqueous solutions of DNA duplexes. The combination of static light scattering experiments and computer simulations made possible the study of both aggregation and local ordering of DNA duplexes in the isotropic phase, where no positional order is developed, and in proximity of the isotropic-nematic phase boundary.  This study gives an insight of the role on the development of local orientational order among DNA duplexes both far and in proximity of the isotropic-nematic phase boundary.  Third, I studied the diffusion of short DNA duplexes with attractive and repulsive interactions in the isotropic phase as a function of temperature. I found that the temperature dependence of diffusion coefficients reflects via an Arrhenius law the interduplex attractive interactions, whereas diffusion of repulsive duplexes is partially well described in terms of repulsive hard spheres.  Fourth, I investigated phase diagrams of mixtures of DNA single strands and duplexes with various polycations that show liquid-liquid phase separations. This phenomena leads to the onset of a concentrated but still liquid phase of polyelectrolytes, called   coacervate, in a bulk phase where polyelectrolytes are diluted. The most surprising result I found, it is the insurgence of liquid crystals in coacervates with 12 nucleobases long random DNA oligomers and  polylysine at different ionic strengths.  I believe that this PhD thesis adds important pieces to the self-assembly of nucleic acids puzzle, and in particular it shows how randomness of nucleic acids is not an impasse to both hybridization of defectless duplexes and liquid crystal ordering.","language":"eng","citation":"SELECTIVE ASSEMBLY, PHASE TRANSITIONS AND MOLECULAR KINETICS OF DNA OLIGOMERS / S. Di Leo ; supervisor: T. Bellini ; co-supervisor: T. Fraccia. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2022 May 10. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12267_02.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/923222/2021762/phd_unimi_R12267_02.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1157816"},"title":"HONEY BEES, BIODIVERSITY AND CLIMATE CHANGE","internalauthor":"DE IORIO, MARIA GRAZIA","type":"Tesi di dottorato","year":"2025","abstract":"Honey bees (Apis mellifera) are vital pollinators for both natural ecosystems and agricultural productivity. However, their populations are threatened by factors such as habitat loss, pathogens, climate change, and the genetic risks associated with selective breeding. This thesis explores the genetic and microbial dimensions of honey bee health and productivity within a closed breeding population selected since 2015 for docility, hygienic behavior, and honey production, as part of the Beenomix project in northern Italy.  The first study investigates the allelic diversity of the complementary sex determiner (csd) gene, crucial for sex determination in honey bees. Using whole genome sequencing of 100 colonies, 47 distinct csd alleles were identified, including three novel variants, demonstrating that high genetic diversity can be preserved even under selective breeding. These findings underscore the need to include csd diversity as a criterion in breeding programs to prevent the production of sterile diploid males and support colony viability.  The second study examines the seasonal dynamics of the gut microbiota and its relationship with key traits such as docility and honey production. Despite seasonal shifts in bacterial abundance driven by dietary changes, a stable core microbiome was consistently observed. Notably, colonies with higher microbial α-diversity, particularly during early summer, were associated with increased honey yield, highlighting a potential link between microbial richness and colony performance.  The third study explores the influence of host genetics on gut microbiota composition. Although time of sampling was the predominant factor shaping microbiota structure (β-diversity), differences in microbial richness (α-diversity) among genetic lines were significant. One particular line exhibited both lower microbial diversity and reduced honey production, suggesting a genetic component influencing both microbiota and economically important traits.    Together, these studies illustrate the interdependence of genetic and microbial diversity in shaping honey bee health and performance. By integrating csd gene analysis, microbiota profiling, and phenotypic data, this research provides novel insights for developing sustainable and resilient breeding strategies in apiculture. Maintaining biodiversity at both genetic and microbial levels is crucial not only for honey bee survival, but also for securing ecosystem services and agricultural productivity in the context of global environmental change.","language":"eng","citation":"HONEY BEES, BIODIVERSITY AND CLIMATE CHANGE / M.g. De Iorio ; tutor: G. Minozzi. - Dipartimento di Medicina Veterinaria e Scienze, Università degli Studi di Milano, 26900 Lodi, Italia. Dipartimento di Medicina Veterinaria e Scienze Animali, 2025 Apr 17. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13611.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1157816/2776680/phd_unimi_R13611.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1167356"},"title":"IDEATIONAL POWER IN THE COMMON AGRICULTURAL POLICY REFORMS:A DISCOURSE NETWORK ANALYSIS OF INTEREST GROUPS' POLICY NARRATIVES","internalauthor":"BORDIN, ELISA","type":"Tesi di dottorato","year":"2025","abstract":"\"This thesis explores the challenges of achieving a sustainable transition in European agriculture, focusing on the resistance to reform within the Common Agricultural Policy (CAP). Despite increasing demands for sustainability, driven by external crises, political pressures, and changes in EU decision-making, the CAP has only partially integrated environmental concerns. While new actors and ideas have entered the debate, the core of the CAP remains dominated by long-standing power structures and traditional agricultural interests, making meaningful reform difficult.  The study addresses the puzzle of the CAP reform trajectory, showing increasingly multifunctional objectives alongside an exceptionalist core. It investigates how entrenched power structures endure despite increasing criticism. Building on the CAP ideational literature, the thesis explores how policy actors deploy dominant discourses to maintain or change power structures.   Using a Discursive Institutionalist lens, this study expands Carstensen and Schmidt's (2016) conceptualization of ideational power by integrating it with the Narrative Policy Framework (NPF). It proposes a theoretical model to explain how different forms of ideational power (through, over, and in) interact to shape reform outcomes.  Empirically, the research uses Discourse Network Analysis to analyze position papers and public statements from interest groups involved in the 2017-2021 CAP reform. Findings reveal that core actors, particularly established farmers’ organizations, exercise \"\"power over ideas\"\" to control policy venues and marginalize transformative proposals. In contrast, marginal actors attempt to gain influence by aligning their narratives with dominant discourses (\"\"power through ideas\"\"). However, the deep institutionalization of power in ideas within the CAP’s exceptionalist paradigm constrains narrative options, compelling all actors to frame proposals in terms acceptable to traditional agricultural community.  The thesis concludes that a combination of ideational, structural, and coercive power sustains the CAP’s resistance to change, creating self-reinforcing dynamics that hinder transformation. Yet, it also identifies reform potential: by strategically using dominant discourses, actors may broaden stakeholder participation and open new venues for change. The study contributes to CAP and Discursive Institutionalism scholarship by clarifying how narrative strategies shape both policy stability and reform, shedding light on pathways to break entrenched policy paradigms.\"","language":"eng","citation":"IDEATIONAL POWER IN THE COMMON AGRICULTURAL POLICY REFORMS:A DISCOURSE NETWORK ANALYSIS OF INTEREST GROUPS' POLICY NARRATIVES / E. Bordin ; supervisore: P. Mattei ; co-supervisore: C. Daugbjerg ; phd coordinator: F. Franchino, M. Jessoula. Dipartimento di Scienze Sociali e Politiche, 2025 Jun 16. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13246.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1167356/3084815/phd_unimi_R13246.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1170055"},"title":"GREEN ENERGY VIA ELECTROCHEMICAL PROCESSES (GEEP)","internalauthor":"MINELLI, SIMONE","type":"Tesi di dottorato","year":"2025","abstract":"This PhD three years project is centred on the world energy policy that would like to achieve the carbon neutrality by reducing the use of fossil fuel to produce energy and substitute it with renewable sources of energy. First, the energy policy of European Union and United State are presented to understand which are the two most important occidental energetic policy. And it is understood that both two main actors have the policy to reduce greenhouse gas emission and achieve the net zero emission in 2050. Different technologies permit to achieve the net zero emission depending on the sector in which the fossil fuel need to be replaced from the renewable energy.  The main thing is how it is possible to store the energy coming from renewable sources. Because for all the renewable sources of energy, apart from the nuclear energy, the main problem is connected to their nature. They are not constant in time, and they are not equally distributed on the territory. But the energy coming from fossil fuel is disponible every time and everywhere there is an engine and a tank of fuel.   In the last year some different technologies are investigated and enveloped to store energy. These technologies could store energy via mechanical processes or via electrical processes or via biological processes or via electrochemical processes or via chemical processes and all these technologies could be efficiently used to decarbonize one ore different energy sectors.  In this PhD project titled “Green Energy via Electrochemical Processes” are investigated obviously different electrochemical processes to store energy. It is decided to study the electrochemical processes that permit to split the water into H2 using renewable source of energy. And from these large number of electrochemical processes are selected the polymer exchange membrane processes the more stable Proton Exchange Membrane Water Electrolyzer (PEMWE) and the promising Anion Exchange Membrane Water Electrolyser (AEMWE).  It is decided to investigate the green hydrogen production in correlation to the European union energy policy that has the scope to decarbonize, the industrial production, mainly steel, cement and chemicals industry and heavy and long transport made by route or ship, the air transport and the heating sectors by the production of green hydrogen.   The main part of that project is centred on the AEMWE, that is one of the most promising technologies for the future implementation of green hydrogen production. It is decided to focus the attention on the cathodic side of the electrolysers, because the Hydrogen Evolution Reaction (HER) in alkaline environment is one of the key points of that technologies because to have a good efficiency it is necessary to use a large quantity of noble metal catalysts, mainly Pt based catalysts. And it is an important voice of the CAPEX cost of these devices. Then it is investigated a new composite electrocatalyst material, made by an oxophilic component in strict interaction of a noble metal because some scientific paper evidenced that the presence of an oxophilic material in synergistic interaction with the noble metal rise the catalyst mass activity for the HER in alkaline environment. And connected to the necessity to reduce the amount of noble metal used to produce an AEMWE the Ion Beam Sputtering Deposition (IBSD) technique is selected to be investigated as synthetic method that permit to synthetized and deposited a thin composite catalysts layer on a generic substrate. This technique is selected because is easily scalable and produce a compact, reproducible  thin durable thin layer start from a metal composite target.  Zr has been selected as oxophilic element and as noble metal Pd and Pt. It is verified the synergistic interaction between the two catalysts component in the obtained thin layer electrode on FTO substrate and it is decided to verify which is the best thickness between 200, 100, 50 and 25 nm of the composite catalysts layer made by IBSD on FTO. Many samples are made by IBSD on FTO to be characterized electrochemically and physically and it is evidenced that all the sample made by IBSD show a synergistic interaction between the two composite catalyst components. The IBSD permits to obtain reproducible thin layer samples in term of composition, roughness and electrochemical properties. And for both the Pt@ZrO2 and Pd@ZrO2 on FTO substrate the best thin layer thickness is 50 nm in term of HER.  Finally, to demonstrate that IBSD is a promising technique for Membrane Electrode Assembly (MEA) manufacturing it is made a 50 nm Pt@ZrO2 catalysts layer on a commercial Anion Exchange Membrane with an active area of 50 cm2. And this MEA is assembled into the industrial partner (Claind) AEMWE device to be characterized as electrochemical hydrogen generator. The results obtained are promising for possible future implementation after an optimization of the production processes.  In parallel, due to Claind exigence, is made the envelopment of the manual hot pressing spray deposition process to produce a Membrane Electrode Assembly for the PEMWE Claind device. The aim of that part of the project is  addressed to solve a Claind production problem centred on the final purity of the H2 that need to be highly pure because Claind H2 generators are used for analytical applications.  Another parallel work is made in correlation to the PEMWE topic. Electrodeposited Iridium oxide film is characterized by Electrochemical Impedance Spectroscopy, to obtain the proton diffusion coefficient at different overpotential near to the OER. With the aim of verify which is the difference in term of proton diffusion coefficient between a highly hydrated Iridium oxide films and a sputtered or low hydrated films. Because the proton diffusion in the catalyst films influenced the Oxygen Evolution Reaction that in acidic environments it the most sluggish reaction. Due to that EIS permit to characterize a deposited IrO2 film and by know the thickness of the deposited film obtain the proton diffusion coefficient that is a key point to evaluate this type of catalysts for the OER in acidic environment. And respect to other spectroscopic investigation is more rapid, less expensive and easier to make.  As consequence of the large bibliographic research on the topics connected to the green H2 production and conversion in alkaline environment a review is made on the topic of Oxygen Reduction Reaction (ORR) Pt based nanostructured electrocatalysts material. This is connected to the exigence of some application to have a device that can work as H2 generators to store energy and  burn the produced H2 to make energy when energy is required. And in the case of a device in which the reduction occurs always in the same chamber in both situations the HER and the ORR electrocatalysts need to be the same.  And finally, another parallel work is made on an experimental setup that use EIS instrument to generate a AC current signal and by measure the potential difference permit to evaluate semiconductors conductive type. This method is enveloped due to the large experience made on EIS instrumentation during this three years PhD project. This is a good method for an easy and rapid evaluation of different semiconductor.","language":"eng","citation":"GREEN ENERGY VIA ELECTROCHEMICAL PROCESSES (GEEP) / S. Minelli ; tutor: A. Vertova ; co-tutor: A. Minguzzi ; coordinatore: D. Passarella. - MILANO. Dipartimento di Chimica, 2025 Jun 17. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13591.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 09-DIC-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1211795"},"title":"OXYGEN DELIVERY AND CONSUMPTION DURING HYPOTHERMIC OXYGENATED MACHINE PERFUSION AND THEIR IMPACT ON POST-LIVER TRANSPLANT OUTCOME.","internalauthor":"DEL PRETE, LUCA","type":"Tesi di dottorato","year":"2026","abstract":"Background  While authors recommend maintaining pO2 >600 mmHg(80KPa) for sufficient oxygenation during liver hypothermic oxygenated machine perfusion (HOPE), recent studies have underscored the adverse relationship between increased carbon dioxide(CO2) production and graft damage. This study aims to investigate the dynamic  relationship between oxygen delivery(DO2) and consumption(VO2) during HOPE and assess their impact on post-transplant(LT) outcomes.    Methods  DHOPE cases performed at our Foundation were selected and divided according to perfusate pO2 >600 mmHg(H-DO2) and <600 mmHg(L-DO2). PO2<600 mmHg was obtained by titration of post-liver pO2(>120 mmHg). DO2 and VO2 were calculated using the modified Fick equation.    Results  Twentyseven transplanted livers underwent DHOPE, comprising 12 from brain-dead and 15 from cardiac-dead donors. Among these cases, 13(48.1%) were classified in the L-DO2 group, while 14(51.9%) were in the H-DO2 group. In L-DO2 grafts, DO2 measured 1.46±1.07ml/min(pO2 233±89 mmHg), with VO2 at 0.82±0.44ml/min. In HDO2 grafts, DO2 was >5.06±1.95ml/min(pO2>600 mmHg), and VO2 was  >0.56±1.14ml/min. The increase in DO2 was directly correlated with VO2(r=0.56;p=0.046) and both showed associations with portal flow(r=0.81,p=0.001;r=0.58;p=0.047), but portal flow was not different in the two study groups(p=0.214). Importantly, early allograft dysfunction was observed in grafts with a  higher DO2(p=0.021), but not VO2(p=0.451). Grafts with steatosis ≤30% exhibited higher VO2(0.933±0.216 ml/min) than those with steatosis >30%(0.594±0.233 ml/min) (p=0.038).    Conclusion  During DHOPE, elevated DO2 may impact graft function post-LT, while steatosis may affect graft metabolic activation during HOPE. Consequently, titrating pO2 to achieve lower DO2, especially in grafts with high portal flow, should be considered.","language":"eng","citation":"OXYGEN DELIVERY AND CONSUMPTION DURING HYPOTHERMIC OXYGENATED MACHINE PERFUSION AND THEIR IMPACT ON POST-LIVER TRANSPLANT OUTCOME / L. Del Prete ; tutor: A. Zanella ; co-tutor: D. Dondossola ; coordinatore: M. Clerici. - Milano. Università degli Studi di Milano, 2026 Jan 22. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13877.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1211795/3237879/phd_unimi_R13877.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1135896"},"title":"IL GROOVE COME 'TECNOLOGIA' E LE TECNOLOGIE DEL GROOVE","internalauthor":"BOTTIN, GUGLIELMO","type":"Tesi di dottorato","year":"2025","abstract":"\"Groove is one of the most important features in many styles of popular music and an aesthetic goal for musicians and producers. I begin by formulating a model of groove as a Gestalt, describing the constituent syntactic components and the ways in which they coalesce. Next, I will examine theories of groove based on performance nuances, attempting to show how (in light of empirical studies) they fail to account for groove in programmed electronic music and sampled loops. I will then address the \"\"phenomenology\"\" of groove as a set of interdependent rhythmic elements and how this perception is actively shaped by the listener and accompanied by a quality that leads to the description in terms of a specific and embodied rhythmic feel.  In the second part, which deals with the progressive mechanization of rhythm in groove music (beginning with funk and disco music of the 1970s and ending with electronic popular music of the late twentieth century), I present the main developments of “technologies of groove”  and examine some of the devices used to automatically design/program and execute rhythmic patterns.   Finally, I interview professional producers who have been active for some time. Some began their music careers in the 1970s, before the advent of drum machines and sequencers. They told me how their approach to ” groove composition\"\" changed as music technologies evolved. Other producers started directly with electronic devices and digital audio workstations, and explained their practices for creating effective grooves with such tools.\"","language":"ita","citation":"IL GROOVE COME 'TECNOLOGIA' E LE TECNOLOGIE DEL GROOVE / G. Bottin ; tutor: M. Corbella ; coordinatore: F. Slavazzi. Dipartimento di Beni Culturali e Ambientali, 2025 Mar 07. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13310.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1135896/2636853/phd_unimi_R13310.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1165855"},"title":"POLITICAL BELIEF SYSTEMS AS NETWORKS OF ATTITUDES: CONCEPTUALIZATIONS AND IMPLICATIONS","internalauthor":"BERTERO, ARTURO","type":"Tesi di dottorato","year":"2025","abstract":"This thesis advances the study of political belief systems by integrating network-based approaches from political science, sociology, and psychometrics. The research is grounded in Philip Converse’s seminal work, which conceptualized political belief systems as interconnected networks of attitudes. Despite the foundational importance of this framework, the field has been slow to empirically embrace this networked perspective. This thesis seeks to fill this gap by employing innovative methods to study belief systems. The research is centered around two core questions: First, how can political attitudes be conceptualized as a belief system? This involves refining the construct of a belief system and investigating the implications deriving from considering attitudes as parts of a broader cognitive structure. Second, how can existing network methodologies be integrated to study belief systems? By combining Belief Network Analysis (BNA), Correlational Class Analysis (CCA), and Pairwise Markov Random Fields (PMRFs)—previously isolated within distinct research domains—the thesis promotes cross-fertilization between disciplines. Chapter 2 presents the theoretical and methodological foundations of the belief system literature. Following Converse, I define political belief systems as networks of causally interacting political attitudes. I then discuss why the dominant view on measurement in social   sciences — the latent variable model— is limited in studying these constructs. Next, I motivate why network approaches can provide new insights in this field. Finally, I conduct a scoping review of all papers adopting these approaches to study socio-political attitudes. Chapters 3, 4, and 5 present three empirical analyses. Chapter 3 contributes to the growing literature on subjective inequality by applying CCA and Exploratory Graph Analysis (EGA) to survey data from the U.S. and the Netherlands (n = 2,501 and 1,618). These methods uncover distinct cognitive structures in both countries, with CCA identifying groups sharing similar   construals and EGA modeling these as belief systems. The analysis shows that the two belief systems of each country have distinct sociodemographic correlates and that attitudes toward inequality are more socially patterned in the U.S. Moreover, we show that belief systems might represent independent factors in determining different levels of support for redistribution. These findings highlight that ignoring the structural organization of attitudes limits our understanding of public opinions on inequality and redistributive policies. Chapter 4 extends the inquiry by examining how multiple political attitudes coalesce to form a political belief system. Using original data from the 2022 Italian general election, this chapter applies three network models to explore variations in belief system structures across different social groups. The results show that political interest increases the interdependence of attitudes, leading to tighter belief systems, while education levels do not have a similar effect. Interestingly, despite ideological differences, voters from Italy’s two main coalitions (left and right) organize their attitudes similarly, whereas Movimento 5 Stelle voters display   significantly different belief structures. This chapter addresses a significant gap by showing how distinct political groups organize their support for parties and issues. Chapter 5 introduces a novel approach to Propensity to Vote (PTV) data, conceptualizing PTV as behavioral intentions embedded in a belief system regarding vote choice. Rather than using traditional data reduction techniques, this chapter models PTV data as networks, where items are connected by weighted edges representing their unique shared variance. Using data from   the European Election Studies (1989–2019; 28 countries, n = 121,959), this chapter shows that national political contexts influence the structure of PTV networks. Higher levels of party institutionalization are linked to higher network connectivity, while higher affective polarization correlates with the negativity of PTV belief systems (i.e., the higher ratio of negative to positive edges). Furthermore, increased negativity in these networks is associated with higher voter turnout in both EU and national elections, suggesting that PTV belief systems might have important downstream effects on political behavior.   In conclusion, this thesis offers both conceptual and methodological dvancements in the study of political belief systems. By integrating network-based approaches, it provides new tools to understand how political attitudes are organized and how they vary across different sociopolitical contexts and sociodemographic segments. The findings underscore the importance of accounting for the structural features of belief systems and highlight the need for further research into their causal dynamics.","language":"eng","citation":"POLITICAL BELIEF SYSTEMS AS NETWORKS OF ATTITUDES: CONCEPTUALIZATIONS AND IMPLICATIONS / A. Bertero ; supervisor: C. Vezzoni, co-supervisor: R. Vacca ; co-authors (Chapter 3): G. Franetovic, J. J. B. Mijs  Co-Authors (Chapter 5): M. J. Brandt ; coordinator: M. Jessoula. Dipartimento di Scienze Sociali e Politiche, 2025 May 23. 37. ciclo","filename":"phd_unimi_R13221_03.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1165855/3075278/phd_unimi_R13221_03.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1241820"},"title":"IMPACT OF ACLY GENE SILENCING ON HEPATIC LIPID METABOLISM","internalauthor":"RODA, SILVIA","type":"Tesi di dottorato","year":"2026","abstract":"Introduction and Aim: ATP citrate lyase (ACLY) is a key enzyme in lipid metabolism, responsible for the generation of cytosolic acetyl-CoA from mitochondrial citrate. The acetyl-CoA produced represents an essential precursor both for de novo fatty acid synthesis, through its conversion to malonyl-CoA mediated by acetyl-CoA carboxylase (ACC), and for sterol biosynthesis via the mevalonate pathway, regulated by HMG-CoA reductase (HMGR). Given its central role in the regulation of lipogenesis and cholesterol synthesis, ACLY has emerged as an important pharmacological target. In this context, bempedoic acid, a first-in-class ACLY inhibitor approved for clinical use, is currently employed in the treatment of hypercholesterolemia in statin-intolerant patients to reduce cardiovascular risk.  The aim of this project was to investigate the impact of ACLY gene silencing on hepatic metabolism, with particular emphasis on the regulation of lipid metabolism in a model of diet-induced obesity and atherosclerosis.  Methods: Wild-type mice and Ldlr⁻/⁻ mice were treated with intraperitoneal injections of GalNAc-conjugated siRNAs, specifically a negative control siRNA (GalNAc-siCtrl) or an siRNA targeting ACLY (GalNAc-siACLY). Animals were maintained for 18 weeks on a high-cholesterol Western-type diet (WTD) to induce lipid metabolic alterations. At the end of the treatment, major metabolic parameters and molecular mechanisms associated with the modulation of ACLY activity were analysed, with particular focus on plasma and hepatic lipid profiles.   To assess the extra-hepatic and systemic safety and toxicity of GalNAc-siACLY, Asgr1⁻/⁻ mice were subjected to the same therapeutic and dietary regimen. These animals lack the hepatic ASGR1 receptor, which is responsible for selective liver uptake of GalNAc-conjugated molecules. In this group, key metabolic and immuno-inflammatory parameters were also evaluated.  In parallel, the molecular effects of ACLY inhibition were investigated in in vitro models of hepatic steatosis using the HepG2 cell line. Cells were treated with free fatty acids, namely palmitate (200 µM), oleate (400 µM), or a combination of palmitate and oleate at a 2:1 ratio, to mimic intracellular lipid accumulation typical of hepatic steatosis. This approach allowed the evaluation of cellular and molecular mechanisms involved in the regulation of lipid metabolism in response to ACLY modulation.  Results: After 18 weeks of diet, ACLY gene silencing in wild-type mice led to a significant reduction in plasma cholesterol and triglyceride levels, specifically lowering LDL-associated lipids. The improvement in the circulating lipid profile was driven by an initial increase in hepatic expression of the low-density lipoprotein receptor (LDLR). Consistently, these metabolic effects were absent in Ldlr⁻/⁻ mice, indicating a functional dependence on LDLR. Wild-type ACLY knockdown mice, despite showing similar levels of hepatic steatosis, are characterised by greater macrosteatosis formation with lower microsteatosis, and consequently prevalence of larger lipid droplets. These droplets were enriched in polar lipids, particularly phospholipid precursors, at the expense of neutral lipids such as triglycerides and cholesteryl esters. Moreover, hepatic ACLY gene silencing resulted in reduced mitochondrial energy metabolism and downregulation of major transcription factors involved in metabolic control.  In vitro studies revealed that, at early stages, ACLY inhibition induces an increase in both anabolic and catabolic fatty acid pathways, particularly promoting β-oxidation and lipid droplet mobilization. With prolonged exposure to fatty acids, a progressive remodelling of hepatocellular metabolism was observed, characterized by reduced mitochondrial activity and the activation of alternative compensatory mechanisms.  In the Asgr1⁻/⁻ model, the absence of ACLY silencing in both liver and spleen was confirmed, excluding nonspecific GalNAc uptake in these tissues. However, metabolic analyses revealed increased basal plasma glucose levels and a consequent shift in energy substrate preference, suggesting impact of GalNAc-siACLY over pancreatic functions.  Conclusion: Overall, these results indicate that, under conditions of metabolic syndrome, ACLY gene silencing improves the circulating lipid profile in an LDLR-dependent manner and independently of de novo cholesterol synthesis. At the hepatic level, ACLY knockdown dos does not improve liver steatosis burden, but induces profound remodelling of the lipidome and cellular metabolism, highlighting how ACLY inhibition affects not only lipid homeostasis but also energy balance and adaptive responses in hepatocytes.","language":"eng","citation":"IMPACT OF ACLY GENE SILENCING ON HEPATIC LIPID METABOLISM / S. Roda ; tutor: G. D. Norata ;  co-tutor: F. Bonacina ;  coordinatore: G. D. Norata. - Dipartimento di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti. Dipartimento di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti, 2026 May 14. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14175.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 07-NOV-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/984128"},"title":"MILANO E IL MERCATO DELL¿ARTE NELLA SECONDA METÀ DELL¿OTTOCENTO.IL RUOLO DEGLI ANTIQUARI","internalauthor":"COLOMBI, MARTINA","type":"Tesi di dottorato","year":"2023","abstract":"The correspondence of the Grandi family company (1851-1927) provides an unpublished source of information for the study of the Milanese art market in the second half of the 19th century, observed from an as yet unexplored perspective: the one of art dealers. The investigation of the archive materials - almost six hundred documents, including letters, drafts, invoices and dispatch notes - has revealed not only the professional history of Antonio Grandi (1810-1877) and his sons Carlo (1842-1914) and Antonio (1857-1923), but also the company's international contacts and commercial strategies. Particular attention has been dedicated to the business relationship with the printseller Marseille Middleton Holloway (1809-1897) from London, that has given an in-depth insight into the European market of reproductive engravings, in which the Grandi company had a true specialisation. The documents also encouraged further research on Giuseppe Baslini (1817-1887), the most important dealer of paintings and art objects operating in Milan in the second half of the 19th century.","language":"ita","citation":"MILANO E IL MERCATO DELL¿ARTE NELLA SECONDA METÀ DELL¿OTTOCENTO.IL RUOLO DEGLI ANTIQUARI / M. Colombi ; tutor: J. Stoppa ; coordinatore: F. Slavazzi. Dipartimento di Beni Culturali e Ambientali, 2023 Jul 17. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12478.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/984128/2244130/phd_unimi_R12478.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1221455"},"title":"REGENERATIVE MEDICINE STRATEGIES FOR ENDOMETRITIS IN REPRODUCTIVE MARES:IN VITRO AND IN VIVO STUDIES","internalauthor":"GASPARI, GIULIA","type":"Tesi di dottorato","year":"2026","abstract":"Endometritis is a fertility-impairing pathology frequent in reproductive mares. Persistent post-breeding induced endometritis (PPBIE) is caused by a uterine inflammatory imbalance, while chronic degenerative endometritis (CDE) involves endometrial fibrotic alterations and has been associated with advanced age. Causing a considerate alteration of uterine environment, endometritis is believed also to impair fetal-maternal communication. Since conventional therapies often fail to achieve a resolutive endometrial regeneration, this project aimed at identifying novel alternative approaches based on the employment of secretome (conditioned medium: CM) and extracellular vesicles (EVs) derived from mesenchymal stromal/stem cells (MSCs) isolated extra-foetal adnexa as sources of regenerative medicine. Platelet rich plasma (PRP) was also examined as further alternative approach.  The initial phase of research involved in vitro studies:  1) Wharton’s jelly-derived conditioned medium (WJ-CM) and PRP were investigated in counteracting in vitro LPS-induced inflammation on equine endometrial cells (ECs). Unexpectedly, PRP did not exert an anti-inflammatory effect on stressed ECs, causing cytotoxicity and increasing ROS levels. Contrarily, WJ-CM showed a significant decrease in PGE-2 release after 24 hours of incubation, confirming its anti-inflammatory activity.   Both these regenerative products contain soluble factors and EVs. Therefore, the attention of this thesis was directed on EVs, but specifically those obtained from amniotic mesenchymal stromal/stem cells (AMCs), which are isolated from another extra-foetal tissue, namely the amniotic membrane.   2) The literature provide evidence for the anti-inflammatory and pro-regenerative properties of amniotic-derived extracellular vesicles (AMC-EVs), even in reproductive disorders. However, the mechanism of interaction between AMC-EVs and recipient ECs and the modality of EV-uptake remain to be fully elucidated. Therefore, in vitro analyses were performed to characterize the glycoprofile of ECs and AMC-EVs using a panel of FITC-conjugated lectins. Results show that ECs and AMC-EVs express fucosylated and sialylated glycans on their surface, which are actively involved in the internalization of AMC-EVs by ECs.   3) Given the potential future application of AMCs and EVs in regenerative medicine, a comparative proteomic analysis was conducted to assess the specific functional features of AMCs and their EVs. The results show that AMCs and EVs are characterized by a distinct proteomic profile, showing the expression of different sets of proteins involved in regenerative processes and thus diversified therapeutic properties. Proteins promoting anti-inflammatory activity, oxidative stress resistance and angiogenesis exhibited increased expression levels in AMCs, while ECM organization and deposition are predominantly upregulated in EVs. This emphasizes their important complementary roles in the fine regulation of the main processes involved in tissue regeneration, proposing AMCs and EVs as a dynamic and effective “couple” rather than separated actors with similar effects. Consequently, to date, we are still unable to definitively elect cells over EVs (or vice versa) as better therapeutic candidate.  4) Extracellular vesicles are internalized by ECs and exerted a functional effect in a mare treated via intrauterine infusion, which resulted in a successful pregnancy. But which bioactive molecules are transferred from EVs to target cells? The miRNA cargo of AMCs and their EVs was previously characterized by the research group under which the present project was conducted. However, most of the intercellular communication is likely mediated also by the proteomic cargo of these vesicles. In this context, the proteins involved in AMC-EV effects were evaluated in vitro assessing the effect of their incorporation into equine ECs challenged with LPS to induce inflammation. Treatment with AMC-EVs resulted in the upregulation of several proteins implicated in the modulation of the inflammatory response, components of the extracellular matrix, antioxidant enzymes and mediators, as well as various transcription factors and regulatory molecules. In contrast, a subset of pro-inflammatory mediators—including specific cytokines, oxidative stress-related factors, and inhibitors of matrix metalloproteinases—were found to be downregulated. These findings indicate that AMC-EVs may exert anti-inflammatory effects on LPS-stimulated endothelial cells through a multifaceted mechanism involving cytokine modulation, enhancement of antioxidant defenses, regulation of gene transcription, remodeling of the extracellular matrix, and modulation of key signaling pathways associated with inflammation, confirming the regenerative properties of AMC-EVs and their possible employment as cell-free therapy.  Alongside the in vitro experiments, also in vivo studies were performed.  5) Previous studies showed that AMC-EVs decrease pro-inflammatory cytokine levels and improve endometrial cell proliferation in vitro. Moreover, also the in vitro studies performed during this PhD reinforce the potential role of AMC-EVs for endometrial regeneration. Therefore, mare reproductive diseases were approached, including two kinds of endometritis.   Among the various forms of endometritis that negatively impact fertility, PPBIE represents a major cause of subfertility in mares. In the present project, stallion semen was supplemented with AMC-EVs at the time of insemination in the attempt of preventing or limiting the development of PPBIE after artificial insemination. Before administration in mares, the effect of AMC-EVs on sperm mobility parameters was assessed to exclude sperm toxicity. Sixteen susceptible mares were enrolled and inseminated with semen (n = 8; control group) or with semen supplemented with AMC-EVs (n = 8; EV group). The supplementation of AMC-EVs to the inseminating dose resulted in a reduction in polymorphonuclear neutrophil infiltration as well as intrauterine fluid accumulation. Intrauterine levels of IL-6 were significantly decreased, while anti-inflammatory IL-10 was up-regulated, suggesting successful modulation of the post-insemination inflammatory response and possible future use of this procedure in mares susceptible to PPBIE.  6) Considering the efficacy of AMC-EVs in preventing the onset of PPBIE, an additional in vivo study evaluated AMC-EV treatment in mares affected by CDE.   The aim of this project was to attempt restoring embryo-maternal communication and improving endometrial histological conditions by intrauterine administrations of AMC-EVs in twelve mares. These animals were divided into Group 1 (n=7), receiving a single treatment cycle (two administrations), and Group 2 (n=5) receiving two treatment cycles (four administrations). Each administration consisted of 2×10¹⁰ AMC-EVs diluted in 50 ml of sterile saline solution. Eleven mares were able to conceive after the treatment with AMC-EVs without significant difference in pregnancy outcomes between one or two treatment cycles. However, no improvement in endometrial histology was observed, suggesting that under the adopted therapeutical protocol AMC-EVs did not induce a complete tissue regeneration, but likely contributed to restoring functional paracrine interaction between embryo and maternal tissues.","language":"eng","citation":"REGENERATIVE MEDICINE STRATEGIES FOR ENDOMETRITIS IN REPRODUCTIVE MARES: IN VITRO AND IN VIVO STUDIES / G. Gaspari ; supervisor: A. Lange Consiglio ; co-supervisor: F. Cremonesi ; PhD coordinator: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2026 Feb 25. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13916_2.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 04-SET-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/957724"},"title":"COLLABORATIVE APPROACHES FOR SENSOR-BASED HUMAN ACTIVITY RECOGNITION IN DATA SCARCITY SCENARIOS","internalauthor":"PRESOTTO, RICCARDO","type":"Tesi di dottorato","year":"2023","abstract":"One of the most important goals of Human Activity Recognition (HAR) is to automatically obtain information on the behaviors of the users to proactively assist them with their tasks. In the literature, the majority of physical activity recognition approaches rely on fully- supervised techniques to collaboratively train a recognition model over the data collected from a large number of users. However, these solutions usually suffer from numerous issues like scalability, privacy, poor personalization, and scarcity of labeled training data. In this thesis, we will focus on analyzing in deep those problems, with the scope of proposing novel methodologies to tackle them. First of all, we consider the labeled data scarcity issue. Indeed, obtaining human-annotated activity examples is costly, intrusive, time-consuming, and hence unpractical on a large scale. Semi-supervised approaches have been suggested to reduce the size of the training set required to initialize the model, but their effectiveness revealed not satisfactory for those activities that involve similar body movements (e.g., standing and taking the elevator).  In order to mitigate this problem, we propose a novel hybrid semi-supervised and knowledge-based framework that uses the context that surrounds users (e.g. semantic location, speed, weather) to enable a machine learning model trained with a limited number of labeled data to classify a wide set of context-dependent activities. Then, we consider the scalability and privacy issues that arise in collaboratively training a recognition model with the data coming from a large number of different users. Federated Learning (FL) showed to be a promising paradigm to address these problems. However, most of the FL-based solutions for HAR proposed in the literature assume that users can always obtain labeled data to train the recognition model, hence inheriting the limitation related to human annotation that we mentioned before. Moreover, generating a single global model for all the users may not be as effective as expected. Indeed, different subjects could perform activities in different ways depending on their physical traits and habits. In order to tackle these problems, we introduce innovative hybrid semi-supervised and FL-based solutions that enable personalized, privacy-aware, and scalable activity recognition. In conclusion, we analyze the possible information leakage of FL for HAR, with the aim of obtaining hints to guide the future development of specific privacy-preserving techniques.","language":"eng","citation":"COLLABORATIVE APPROACHES FOR SENSOR-BASED HUMAN ACTIVITY RECOGNITION IN DATA SCARCITY SCENARIOS / R. Presotto ; advisor: C. BETTINI ; co-advisor: G. CIVITARESE ; school director: R. SASSI. Dipartimento di Informatica Giovanni Degli Antoni, 2023 Apr 27. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12529.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/957724/2157229/phd_unimi_R12529.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1048908"},"title":"ZEBRAFISH (DANIO RERIO) AS A MODEL SYSTEM FOR THE FUNCTIONALVALIDATION OF CANDIDATE GENES FOR HUMAN DISEASES","internalauthor":"BRIX, ALESSIA MARICA","type":"Tesi di dottorato","year":"2024","abstract":"In recent years, zebrafish (Danio rerio) has become increasingly utilized as a model for studying human gene functions and associated diseases. This has been possible due to the very high conservation of genes and of organs and systems which are fully functional within the very first days of embryonic development. The easy and efficient genetic manipulation, the large number of offspring, and the rapid and external development of the embryos make zebrafish ideal for the generation of disease models and for the conduction of large-scale drug screenings. Thus, zebrafish represents a valuable tool to be used as a support, or in particular cases as a substitute, for other animal models in preclinical research. This PhD project aimed precisely at utilizing zebrafish to generate models of human diseases whose pathogenesis is currently poorly understood and for which effective treatments are not yet available.  The main research line focused on the zebrafish model for adenosine deaminase 2 deficiency (DADA2), an auto-inflammatory disease caused by loss-of-function mutations in the ADA2 (also termed CECR1) gene and involving the hematological and vascular compartments. Advances in the comprehension of the molecular mechanisms underlying DADA2 and in the development of effective therapies are hampered by the lack of in-vivo models, due to the lack of an ADA2 orthologue in rodents. We generated a zebrafish DADA2 model with loss-of-function of the cecr1b gene, the functionally conserved ADA2 orthologue. We utilized the CRISPR-Cas9 genome editing approach to target cecr1b and generated a transient mutant model. We combined several techniques, imaging tools, and transgenic lines to characterize in detail the hematological, inflammatory, and vascular defects of cecr1b deficient embryos. We found that they recapitulated the main clinical phenotypes of patients and that they effectively responded to currently used pharmacological therapies. We identified an impairment in adenosine-mediated signaling, which we corrected resulting in a significant improvement in hematological and inflammatory defects. We have therefore developed a valuable zebrafish model for studying the physiological function of ADA2 and the pathogenetic mechanisms of DADA2 and for testing new possible therapeutic strategies. In parallel, we have deepened our knowledge of the possible pathogenesis of this disorder, laying the foundations for new potential correction methods.  6  A further line of this PhD work was dedicated to the generation of a zebrafish model of MicroCephaly Primary Hereditary 17 (MCPH17), a neurodevelopmental disorder characterized by microcephaly and mental retardation. Mutations in the CIT gene have been identified as causative for MCPH17. However, the CIT physiological function and the pathogenesis of MCPH17 are still unclear, and there is currently no curative option. To support and implement the data collected on the murine models and to further investigate the neurodevelopmental mechanisms of MCPH17, which are crucial given the congenital nature of the disorder, we generated a zebrafish model with cita deficiency. We induced cita-loss-of-function through a morpholino-mediated knockdown approach, which resulted in a significant reduction in head size, behavioral alterations, and impairment of neuronal cell populations. In parallel with the characterization of the cita morphants phenotypes, we conducted N-acetylcysteine treatments, which resulted beneficial in treating both the microcephalic condition and the behavioral alterations, as in mice. We demonstrated the potential of the zebrafish in supporting mice models for the comprehension of altered neurodevelopmental processes in MCPH17 and in providing a platform for rapid drug screenings.  A further line of research, as yet unfinished, focuses on the study of the pathogenicity of a mutation in a gene of unknown function, named GENE-X in the present thesis. GENE-X was identified as possibly responsible for a complex inflammatory/vascular/metabolic syndrome exhibited by a case report. This section of the PhD project aims to characterize the functional role of GENE-X and the pathogenicity of the mutation identified in the case report using zebrafish as a model system. We have set up and validated a gene-x morpholino-mediated knock-down strategy and started the characterization of the resulting phenotypes. Preliminary analyses, currently extended to the inflammatory and vascular phenotypes only, suggest a significative similarity to the symptoms displayed by the patient under investigation. Once completed the characterization of the model, rescue experiments with the wild-type and mutated GENE-X transcripts will be carried out to evaluate, indirectly, the pathogenicity of the disease and investigate its effects.  The last line of research included in this PhD project concerns the generation of a zebrafish model for triadin knock-out syndrome (TKOS). TKOS is a rare, inherited arrhythmogenic cardiac disorder, possibly leading to exercise-induced cardiac arrest in early childhood. Homozygous mutations in the triadin (TRDN) gene, encoding for a  7  muscular protein essential for the structural integrity of the calcium release complex and for the regulation of calcium release during excitation–contraction coupling. However, the precise role of trdn and the mechanism responsible for sudden cardiac events in children suffering from TKOS are not entirely clear, and current anti-arrhythmogenic treatments are often not effective. Hence, there is a need for an in vivo TKOS model to further study the function of TRDN and to perform drug screening to rapidly identify new compounds efficient in restoring proper cardiac function. We identified zebrafish as a possible model system for this objective. We generated a trdn-deficient zebrafish model by exploiting the morpholino-mediated knockdown. Through morphological and functional analyses, we excluded significant alterations in the structure and function of skeletal musculature and the heart, but identified a dysregulation of cardiac rhythm, as occurs in TKOS patients. We have also demonstrated how our model responds effectively to the modulation of heart rhythm by currently used drugs in human therapies, strengthening the potential of our model in the study of TKOS-related mechanisms and in the identification of possible new therapeutic targets.","language":"eng","citation":"ZEBRAFISH (DANIO RERIO) AS A MODEL SYSTEM FOR THE FUNCTIONALVALIDATION OF CANDIDATE GENES FOR HUMAN DISEASES / A.m. Brix ; tutor: A. Pistocchi ; director: N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2024 May 20. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12846.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1048908/2408129/phd_unimi_R12846.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1123376"},"title":"ORGANOIDS AS TOOLS TO STUDY BRAIN DEVELOPMENT AND DISEASE","internalauthor":"FEDELE, GIORGIA","type":"Tesi di dottorato","year":"2025","abstract":"Human brain organoids (ORG) are a widely used in vitro model that contribute to our knowledge about the biology and pathophysiology of the nervous central system (CNS). They are 3D multicellular clusters that mimic the cytoarchitecture and the developmental pathways that occur in vivo. The most debated limitation of ORG is the lack of the endothelial component. Thus, at first we have developed a co-culture in vitro system composed by the Blood Brain Barrier (BBB) and ORG. The in vitro BBB is composed by human brain microvascular endothelial cells (HBMEC) and human astrocytes (HA). ORG are generated from induced pluripotent stem cells (iPSCs) cultured with different differentiation media for 36 days, and then co-cultured with the in vitro generated BBB.  To evaluate the strength of our model, organoids in the absence (ORG) or in the presence (BBB-ORG) of the BBB were compared for their maturation stage and BDNF levels. In addition, the effects of magnesium (Mg) were investigated with a focus on excitotoxicity and neurodevelopment. Indeed, Mg is known to play crucial role in the CNS. It protects the CNS from inflammation, from excitotoxicity driven by NMDA-R over-activation, it has positive effects on the BBB integrity and it is involved in brain development. However, the mechanisms of action are still poorly understood and studied.  To shed light on the Magnesium (Mg)-driven mechanisms involved in brain development and protection, an inorganic and an organic Mg salt (Mg sulphate, MgSO4, and Mg pidolate, MgPid, respectively) were added to the culture media to reach the extracellular concentrations of 1, the physiological extracellular Mg concentration, or 5 mM, to mimic Mg supplementation. After the treatment, the possible modulation of molecules involved in excitotoxicity and neurodevelopment was investigated by qRT-PCR, western blot or ELISA. In particular, we analysed the modulation of NMDA-R, GABA-R and their neurotransmitters glutamate and GABA, neurotrophic factors, dopamine and its receptors and the Mg channels TRPM6 and TRPM7. The maturation stage and the cortical layer organization were assessed by immunofluorescence using CTIP2, TBR2 and SOX2 antibodies to detect the cortical, the subcortical neurons and the neural progenitor cells, respectively. Toluidine blue staining and ultrastructural analysis using transmission electron microscopy were performed to further confirm the results.  6  Our data demonstrate that BDNF levels are higher in the BBB-ORG model because of the presence of the endothelial component, which is the main responsible for its secretion. Moreover, the cortical layer is more organized in the presence of the BBB than in its absence, underlying its importance.  High concentrations of Mg salts lowers the levels of NMDA-R and increases GABA-Rs levels only in the presence of the BBB, thus suggesting a role in Mg in counteracting excitotoxicity. These results suggest that Mg supplementation might ameliorates the outcome of patients when administered as adjunctive therapy. Particularly, MgPid performs better than MgSO4. Interestingly, high concentration of Mg salts concentration results in a higher maturation stage of the BBB-ORG. The increased levels of released and intra-org BDNF detected in the presence of 5 mM MgPid could explain the faster maturation of the ORG.  This study confirms that the BBB-ORG is a useful tool to study the crosstalk between BBB and brain in both physiological and pathological conditions, and emphasises the importance of the continuous search for a model that closely resembles the in vivo context. Moreover, although further analyses are needed, these studies unveil the role of Mg in brain development and in modulating the release of BDNF from the BBB.  In addition, preliminary studies on the neuroinvasiveness of SARS-Cov-2 were conducted on ORG compared to BBB-ORG, and also on HBMEC and HA alone. Our results reveal once again that the presence of the BBB is fundamental for in vitro studies. Indeed, the in vitro generated BBB is crucial in protecting the organoids from viral infection, with HA being more susceptible than HBMEC to viral infection.  In conclusion, the BBB-ORG model might be useful to disclose physiological and pathophysiological events in the CNS.","language":"eng","citation":"ORGANOIDS AS TOOLS TO STUDY BRAIN DEVELOPMENT AND DISEASE / G. Fedele ; coordinatore di dottorato: N. Landsberger ; tutor: S. Castiglioni ; external advisor: F. Rios. Dipartimento di Scienze Biomediche e Cliniche, 2025 Jan 21. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13412.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1123376/2605113/phd_unimi_R13412.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1273778"},"title":"UNRAVELING THE DUAL ROLE OF MULTIPLE MYELOMA EXTRACELLULAR VESICLES IN THERAPEUTIC SIRNA DELIVERY AND IMMUNE MODULATION","internalauthor":"ABAZARI, NAZANIN","type":"Tesi di dottorato","year":"2026","abstract":"Multiple myeloma (MM) is a plasma cell malignancy that develops within a supportive, immunosuppressive bone marrow microenvironment (BMM). Progression from precursor stages, such as monoclonal gammopathy of undetermined significance (MGUS), to overt MM depends on this microenvironment, which provides critical growth and survival signals to malignant plasma cells. Among the mediators of intercellular communication, extracellular vesicles (EVs) have emerged as important carriers of biological information, transferring proteins, nucleic acids, and lipids to surrounding cells and influencing their phenotype and function. Due to their natural biocompatibility and tumor tropism, MM-derived EVs (MM-EVs) are of interest both as contributors to disease progression and as potential therapeutic delivery vehicles. This thesis represents a multidisciplinary effort to investigate a shared property of MM-EVs: their capacity to interact with recipient cells, be internalized, and deliver biologically active molecular cargo.  In the first part of this work, this intrinsic delivery competence was explored in a controlled and deliberate engineered setting. Biodistribution studies demonstrated that MM-derived EVs preferentially accumulate in myeloma lesions in vivo, supporting their capacity to reach malignant plasma cells. Based on this observation, EVs were engineered to carry siRNA/miRNA cargo, and their ability to deliver functional RNA to MM cells was validated through measurable gene silencing. These findings demonstrate that MM-derived EVs can be artificially exploited as efficient and biologically competent delivery vehicles.   In the second part of the thesis, the delivery properties of MM-EVs were investigated from a different perspective, focusing on their naturally occurring biological function. Rather than being externally engineered, EVs were studied in the context of their physiological interactions with immune cells, providing insight into how MM-derived EVs naturally mediate intercellular communication within the immune microenvironment. Exposure of peripheral blood mononuclear cells to MM-EVs was associated with reduced viability in specific immune subsets, including NK cells CD8⁺ and CD4⁺ T cells, as well as functional alterations in surviving CD8⁺ T cells characterized by reduced cytokine production and increased inhibitory receptor markers. These findings indicate that EV-mediated transfer of bioactive components can modulate immune cell function. Proteomic profiling of MM-EVs provides contextual insight into these observations. The EV cargo included proteins associated with signaling pathways involved in immune regulation, including components linked to Notch signaling.  Taken together, this work supports the concept that MM-EVs can act as biologically active carriers capable of modulating recipient cell responses. Their ability to transfer complex molecular cargo may contribute to immune dysregulation in MM. Further studies dissecting the molecular determinants of EV uptake and downstream signaling will be required to clarify the mechanisms underlying these effects and to evaluate their relevance for therapeutic targeting or exploitation.","language":"eng","citation":"UNRAVELING THE DUAL ROLE OF MULTIPLE MYELOMA EXTRACELLULAR VESICLES IN THERAPEUTIC SIRNA DELIVERY AND IMMUNE MODULATION / N. Abazari ; TUTOR: R. Chiaramonte ; CO-TUTOR: H. Harb ; COORDINATORE DEL DOTTORATO: E. Damiani. Dipartimento di Scienze della Salute, 2026 Oct 05. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14027.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 01-APR-28"}
,{"handle":{"url":"https://hdl.handle.net/2434/1161657"},"title":"EVALUATION OF PHARMACEUTICAL AND COSMETIC USE OF EXCIPIENTS OBTAINED FROM CITRUS PROCESSING WASTE PRODUCTS","internalauthor":"VOLONTE', PAOLA","type":"Tesi di dottorato","year":"2025","abstract":"Depletion of natural resources and pollution are pushing society towards the development of models based on sustainability and recycling. In recent years, the use of food industry waste as new materials in pharmaceuticals and cosmetics has attracted increasing interest. In this circular economy perspective, bergamot peel waste is an established source of high-value components such as essential oils, flavonoids, pectin, and ascorbic acid. After the extraction of such phytochemicals, the remaining biomasses can be further used to recover residual lipid traces that have not been investigated so far. This doctoral thesis aimed to investigate whether bergamot lipid components (BLCs) remaining in the bergamot discarded biomass could be a functional excipient for the preparation of dosage forms for pharmaceutical or cosmetic purposes. Keeping in mind this aim, a suitable extraction method was developed and the composition of the obtained BLCs extract was determined by using Gas Chromatography with Mass Selection Detector (GC/MS) and ATR-FTIR spectroscopy. The raw extract was predominantly composed of long and medium-chain fatty acids with 70 % saturated and 30 % unsaturated acids. ATR-FTIR spectroscopy suggested that the extract appeared to be primarily composed of waxes and, to a lesser extent, free fatty acids. Since waxes are among the most used components—alongside triglycerides—in the preparation of solid lipid nanoparticles (SLNs), the possible application of BLCs as main components of SLNs was investigated. However, SLNs have limitations such as low drug encapsulation efficiency and poor long-term stability, often due to lipid polymorphic transitions. Therefore, in addition to formulating SLNs using only BLCs, the production of nanostructured lipid carriers (NLCs) by incorporating a liquid lipid, which can prevent the crystallization of primary lipid, was also investigated. The most promising formulations were finally evaluated for delivering solid or liquid drug through the skin and pre-gastric mucosae. For what concerns transdermal drug delivery, these nanosystems were found to be effective skin penetration enhancer due to their ability to induce a conformational change in stratum corneum lipids, shifting them from an ordered configuration to a liquid-like organization upon penetration of BLCs. The hypothesis of perturbation of the stratum corneum lipid network was further demonstrated by a second set of in vitro permeation studies performed by the co-administration of placebo BLCs nanosystems added to ibuprofen solutions or gels. The co-administration did not lead to significant differences compared to drug-loaded nanosystems but highlighted a significant increase in drug skin penetration compared to the corresponding dosage forms (solution and gel). Finally, the lack of interaction with keratins, as confirmed by the ATR spectra, suggested that the perturbation of the human stratum corneum occurred in a reversible manner, ensuring the BLCs safety. To definitively confirm that the mechanism of action of BLCs was exclusively based on the perturbation of the packing of the stratum corneum, the performance of BLCs nanosystems loaded with curcumin was also tested after application on another stratified epithelium, namely the oesophagus, using liposomes as references. As expected, the penetration of porcine oesophageal mucosa occurred be less efficient than the liposomal formulations. Besides clarifying the skin penetration effect of BLCs, the results also elucidated other technological aspects of BLCs related to the formulation of lipid nanosystems. Firstly, monodispersed nanoparticles can be easily obtained at relatively low temperatures (60-70°C) by a melting and emulsification method assisted by ultrasounds without the use of stabilizers, which are necessarily required in the formulation of SLNs and NLCs prepared with other excipients. Secondly, the peculiar composition of BLCs led to a characteristic lipid-shell structure which was able to accommodate large amounts of drug, avoiding drug leakage phenomena over time. Finally, the data also proved that BLCs can be used in the formulation of nanoemulsions capable of carrying large quantities of liquid drugs. Indeed, BLCs proved to be an optimal stabilizer of these colloidal systems even when the drug/BLCs ratio was 6/1, as in the case of perfluorodecalin. In conclusion, BLCs appear to be a promising chemical skin penetration enhancer which can also be advantageously used in the formulation of lipid nanosystems to be applied on the skin.","language":"eng","citation":"EVALUATION OF PHARMACEUTICAL AND COSMETIC USE OF EXCIPIENTS OBTAINED FROM CITRUS PROCESSING WASTE PRODUCTS / P. Volonte' ; tutor: P. Minghetti ;  supervisore e coordinatore: G. Vistoli. Dipartimento di Scienze Farmaceutiche, 2025 May 13. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13638_2.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open from 28-OTT-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1157520"},"title":"A MULTILEVEL EXPLORATION OF SCIENCE DYNAMICS WITH COMPUTATIONAL AND QUANTITATIVE TECHNIQUES.","internalauthor":"DEBERNARDI, CARLO","type":"Tesi di dottorato","year":"2025","abstract":"While contemporary societies are increasingly reliant on science, our   understanding of how exactly the scientific community works is still limited. The   research work has experienced tremendous changes during the past few decades,   and it is still evolving both as a result of endogenous dynamics and explicit science   policies. For relatively easy to measure dimensions, like the number of   publications and citations, we have solid evidence of strategic adaptation to   incentives by individual scholars – e.g. self-citations. However, we know very   little regarding the more elusive – yet central –  dimension of the research topics,   i.e.   what scholars choose to investigate. Are there general patterns of   specialisation? Do the many filters of academia – i.e., peer-review, recruitment,   competitive funding, etc. – have an impact on the research topic distribution? Can   these factors affect the breadth of individual research agendas, by widening or   narrowing down the freedom of choosing the research questions? This dissertation   aims to investigate such questions by using quantitative techniques – borrowing   recently developed language modeling tools – to measure research topics starting   from the textual content of scientific publications. The dissertation is composed of   a Part I, introducing theory and methods, and a Part II, presenting three   independent empirical studies. The first is a global overview of the climate change   literature, exploring country-level specialisation patterns. The second is an   investigation of the role of research topics in determining the success rate of ERC   proposals, thus exploring the role of institutional filters on the research topic   distribution. Finally, the third study examines a sample of scholars across four   disciplinary areas and four countries, tracking how their individual research   agendas changed over their careers, in relation to their academic seniority, mobility   and scientific collaboration.","language":"eng","citation":"A MULTILEVEL EXPLORATION OF SCIENCE DYNAMICS WITH COMPUTATIONAL AND QUANTITATIVE TECHNIQUES / C. Debernardi ; M. Seeber, F. Squazzoni. - University of Agder (Kristiansand, Norway). Dipartimento di Scienze Sociali e Politiche, 2025 Feb 07. 36. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R12899.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1157520/2765568/phd_unimi_R12899.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1154660"},"title":"LEGITIMACY FOR HOGS: THE SELFISH CASE FOR EXPRESS CONSENT THEORY","internalauthor":"SARACINO, DAVIDE","type":"Tesi di dottorato","year":"2025","abstract":"This dissertation investigates the source, if any, of political legitimacy. To answer this question, I examine conceptual, methodological, empirical, and normative issues. First, I define political legitimacy as the state’s claim-right to coerce, correlative to subjects’ duty to accept coercion through political obedience. Second, I argue that practical relevance is the sole desideratum for a theory of legitimacy. Maximising it requires determining how individuals with the most prevalent basic desires should rationally choose among competing theories. Third, drawing on experimental psychology, I identify these desires as predominantly selfish. It follows that the most practically relevant theory of legitimacy must be the one that best serves selfish desires. Fourth, in the normative section, I evaluate major theories of legitimacy and conclude that express consent theory most effectively fulfils predominantly selfish desires. Therefore, rational selfish individuals should endorse express consent theory, making it the most practically relevant theory of legitimacy.","language":"eng","citation":"LEGITIMACY FOR HOGS: THE SELFISH CASE FOR EXPRESS CONSENT THEORY / D. Saracino ; supervisor: F. Pasquali ; coordinatore: F. Franchino. Dipartimento di Scienze Sociali e Politiche, 2025 May 26. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13257.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1154660/2715508/phd_unimi_R13257.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1076353"},"title":"AB-INITIO DYNAMICS IN STRONGLY INTERACTING MANY-BODY SYSTEMS","internalauthor":"APOSTOLI, CHRISTIAN","type":"Tesi di dottorato","year":"2024","abstract":"Understanding strongly interacting quantum many-body systems remains a key problem in modern physics due to the quantum correlations they develop, which result in highly nontrivial macroscopic phenomena which still defy our efforts of a thorough theoretical understanding, like quantum phase transitions, collective excitations, topological quantum order, and high-temperature superconductivity. Among these challenges, a special place is reserved to the description of the dynamics of strongly correlated systems, which is key to understanding out-of-equilibrium phenomena and the evolution of entanglement.  Gaining insight into the latter is crucial for the advancement of quantum technologies, including computation and communication protocols, where a major concern is the control and preservation of coherence and entanglement. This Thesis explores the numerical simulation of the dynamical properties of strongly interacting quantum many-body systems.      A recent technique that tackle this problem is the time-dependent variational Monte Carlo (t-VMC), developed by G. Carleo [1, 2]. This method builds on the basic idea of the standard variational Monte Carlo (VMC): the optimization of a variational Ansatz wave function depending on a set of parameters. While the VMC looks for the set of parameters that provide the best approximation of the ground state, the t-VMC, given a starting set of parameters, prescribes how they should be updated at each time step in order to produce an approximation of the dynamics of the true quantum state. The t-VMC technique has been successfully applied especially to the class of neural-network quantum states (NNQS), which employs machine learning to represent the variational wave function.      In the first part of this work, encompassing the first four chapters, we extend the t-VMC to the class of shadow wave functions (SWF) [3, 4], that incorporate many-body correlations by introducing a set of auxiliary “shadow” variables. SWFs can be interpreted as particular neural networks in which the shadow variables represent a layer of neurons having a specific connectivity. SWFs are especially attractive because they are related to the path integration formalism (a SWF can be seen as a single step of path integration [5]), so they are solidly grounded in the physics of a system.      In Chapter 2 we mainly address the main novelty of our work, that is the extension of t-VMC to SWFs, which presents nontrivial problems, like the need of a reweighting procedure. We also introduce, in Chapter 3, a specific example of SWF, which we call the Baeriswyl-Shadow wave function (BSWF). Its structure takes a cue from the Physics of the transverse-field Ising model (TFI) and it is very concise, having only three parameters in the translation-invariant case.  We develop from scratch a C++ code that allows us to perform t-VMC simulations of spin systems using various Ansatzë, including SWFs, and in particular the BSWF. In Chapter 4 we present some of the results of the simulations we performed with our code, and discuss some nontrivial details of the implementation. The results of our computations allow us to assess the strengths and weaknesses of the BSWF Ansatz, by checking its results against the ones yielded by other popular Ansatzë, like the Jastrow wave function or the restricted Boltzmann machine (RBM), the latter being a particular case of NNQS.  We find that the BSWF achieves a description of the one-dimensional (1D) TFI ground state which is competitive with the translation-invariant RBM. This is remarkable since the BSWF only uses a very small number of parameters, that moreover do not scale with the size of the system. This comes at the cost of performing the Monte Carlo sampling of the “shadow” configurations of spins along with the “real” ones.      On the other hand, the real-time simulation of a quantum quench in 1D shows that for short times the BSWF is very accurate, but it loses accuracy as time progresses. We attribute this result to the lack of explicit long-range correlations in the BSWF functional form. However, we find that the BSWF can significantly improve other Ansatzë, if used in conjunction with them as a multiplicative factor. We also generalize the BSWF architecture by introducing additional explicit long-range terms. The Ansatzë thus obtained are even more accurate than the BSWF in the description of the 1D TFI ground state, and in real-time 1D simulations are more consistent with the exact evolution, but, after a certain amount of simulation time, they suffer from an explosion of noise due to the reweighting technique needed to simulate the evolution of SWFs. We also perform some computations of the 2D TFI ground state, finding that the BSWF is accurate also in this dimensionality, considering its very low number of  parameters.      The second part of this work, represented by Chapter 5, is devoted to the use of different techniques to study the dynamical correlations of a two-dimensional dilute system of attractive fermions. We are motivated by a recent paper [6] suggesting the possibility of detecting the celebrated Higgs (or amplitude) mode of Fermi superfluids in the spin density dynamical structure factor. Specifically, we leverage generalized random phase approximation (GRPA) [7, 8, 9, 10, 6] and the unbiased auxiliary-field quantum Monte Carlo method (AFQMC) [11, 12, 13] to compute the dynamical structure factors in the density and spin density channels. Our AFQMC calculations, which are exact within the error bars, provide a benchmark for the approximate results of GRPA, although the computational cost does not allow us to achieve the very large sizes needed to test the suggestion of Ref. [6] because of the computational cost. The AFQMC results for smaller systems show good qualitative accordance with GRPA, the main effect being related to a renormalization of the superfluid gap due to many-body correlations. The results are also compatible with the presence of the peak in the spin mode that was first observed by the Authors of Ref. [6], and identified by them with the Higgs mode. However, a more detailed analysis, based on the GRPA dynamical correlations of the order parameter for large system sizes, shows that this peak cannot be identified with the Higgs mode. We suggest a different interpretation of its origin, rooted in the kinematics of the system.      References   [1] Giuseppe Carleo. Spectral and dynamical properties of strongly correlated systems. PhD thesis, SISSA, October 2011.   [2] Federico Becca and Sandro Sorella. Time-Dependent Variational Monte Carlo, page 156–163. Cambridge University Press, 2017.   [3] Silvio Vitiello, Karl Runge, and M. H. Kalos. Variational Calculations for Solid and Liquid 4 He with a ”Shadow” Wave Function. Phys. Rev. Lett., 60:1970–1972, May 1988.   [4] S. A. Vitiello, K. J. Runge, G. V. Chester, and M. H. Kalos. Shadow wave-function variational calculations of crystalline and liquid phases of 4 He. Phys. Rev. B, 42:228–239, Jul 1990.   [5] L. Reatto and G. L. Masserini. Shadow wave function for many-boson systems.  Phys. Rev. B, 38:4516–4522, Sep 1988.   [6] Huaisong Zhao, Xiaoxu Gao, Wen Liang, Peng Zou, and Feng Yuan. Dynamical structure factors of a two-dimensional Fermi superfluid within random phase approximation. New J. Phys., 22(9):093012, sep 2020.   [7] R. Ganesh, A. Paramekanti, and A. A. Burkov. Collective modes and superflow instabilities of strongly correlated Fermi superfluids. Phys. Rev. A, 80:043612, Oct 2009.   [8] Patrick Kelly and Ettore Vitali. On the Accuracy of Random Phase Approximation for Dynamical Structure Factors in Cold Atomic Gases. Atoms, 9(4), 2021.   [9] Yoshihiro Yunomae, Daisuke Yamamoto, Ippei Danshita, Nobuhiko Yokoshi, and Shunji Tsuchiya. Instability of superfluid Fermi gases induced by a rotonlike density mode in optical lattices. Phys. Rev. A, 80:063627, Dec 2009.  [10] R. Combescot, M. Yu. Kagan, and S. Stringari. Collective mode of homogeneous superfluid Fermi gases in the BEC-BCS crossover. Phys. Rev. A, 74:042717, Oct 2006.  [11] S. Zhang. Auxiliary-Field Quantum Monte Carlo for Correlated Electron Systems. In E. Pavarini, E. Koch, and U. Schollwöck, editors, Emergent Phenomena in Correlated Matter: Modeling and Simulation Vol. 3. Verlag des Forschungszentrum Jülich, Jülich, Germany, 2013.  [12] Ettore Vitali, Hao Shi, Mingpu Qin, and Shiwei Zhang. Computation of dynamical correlation functions for many-fermion systems with auxiliary-field quantum Monte Carlo. Phys. Rev. B, 94:085140, Aug 2016.  [13] M. Motta, D. E. Galli, S. Moroni, and E. Vitali. Imaginary time correlations and the phaseless auxiliary field quantum Monte Carlo. J. Chem. Phys., 140(2):024107, 01 2014.","language":"eng","citation":"AB-INITIO DYNAMICS IN STRONGLY INTERACTING MANY-BODY SYSTEMS / C. Apostoli ; supervisor: D. E. Galli ; co-supervisor: G. Bertaina ; director of the school: A. Mennella. - Università degli Studi di Milano. Dipartimento di Fisica Aldo Pontremoli, 2024 Jul 29. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R12810.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1076353/2476508/phd_unimi_R12810.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/808352"},"title":"MICROENVIRONMENT FACTORS PROMOTING THE QUALITY OF IMMATURE VITRIFIED OOCYTES IN THE DOMESTIC CAT MODEL","internalauthor":"COLOMBO, MARTINA","type":"Tesi di dottorato","year":"2021","abstract":"Domestic cat immature vitrified oocytes (VOs) are a useful research model to develop gamete cryopreservation protocols for fertility and biodiversity preservation in wild, endangered felids. Although vitrification of immature oocytes is convenient for its practical advantages (availability of gametes, speed and field-feasibility of the technique), VOs often degenerate after warming, and their in vitro maturation and embryo development rates are poor compared to fresh oocytes. Therefore, improvements are necessary to fully exploit their potential. Physico-chemical enrichments to the vitrification protocol or to the post-warming culture conditions could be useful to improve VOs developmental competence.  In this project, minimum volume vitrification of immature oocytes with the Cryotop method resulted in high (90.8%), consistent and reproducible post-warming viability rates. To improve VOs maturation and development outcomes, two strategies were then employed. The creation of 3D follicle-like structures (i.e. granulosa cells cultured in alginate microcapsules) to be used as enriched culture condition for the in vitro maturation of VOs resulted in maintenance of steroidogenic activity of granulosa cells and in meiosis resumption of co-cultured VOs (11.8% maturation). Instead, after the assessment of apoptotic activation in VOs, the addition of a chemical pan-caspase inhibitor resulted in maturation rates (53.1%) similar to those of fresh control oocytes and in good embryonic developmental rates (34.4%).  Embryo development to late embryo stages remained scarce, and further investigation to enhance VOs developmental competence are needed. Molecular investigation on the mechanisms of cryopreservation-induced damages and on the peculiarities of the embryos derived from cryopreserved oocytes could improve VOs in vitro outcomes and therefore foster the creation of feline gamete biobanks.","language":"eng","citation":"MICROENVIRONMENT FACTORS PROMOTING THE QUALITY OF IMMATURE VITRIFIED OOCYTES IN THE DOMESTIC CAT MODEL / M. Colombo ; tutor: G. C. Luvoni ; coordinator: V. Grieco. Dipartimento di Scienze Veterinarie per la Salute, la Produzione Animale e la Sicurezza Alimentare, 2021 Jan 28. 33. ciclo, Anno Accademico 2020. [10.13130/colombo-martina_phd2021-01-28].","filename":"phd_unimi_R12068.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/808352/1684264/phd_unimi_R12068.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1018171"},"title":"IDENTIFICATION OF FACTORS INVOLVED IN DOUBLE STRANDED RNA-INDUCED CELL DEATH THROUGH GENOME-WIDE CRISPR SCREENS","internalauthor":"TRASTULLI, DEBORAH","type":"Tesi di dottorato","year":"2023","abstract":"Double-stranded RNAs (dsRNAs) are potent immunostimulatory nucleic acids of viral origin but also physiologically produced by mammalian cells. Increased levels of dsRNAs, due to viral infection or failure of endogenous repression, trigger an immune response that leads to cytokines production or cell death. Recent studies demonstrated that several cancer types already contain sufficient quantities of dsRNA to activate immune responses. Moreover, some clinical trials proved the efficacy of Polyinosinic-polycytidylic acid (pI:C), a synthetic analog of dsRNA, as adjuvant treatment in breast cancer patients, in terms of overall survival and longer relapse-free survival. The 2′,5′-oligoadenylate synthetase (OAS)-RNASEL system is widely thought to be the main responsible for dsRNA-induced cell death, through mechanisms not fully understood. To elucidate these mechanisms, we employed a candidate-based manner investigation and an unbiased approach. As death-inducing stimulus we used the combination of pI:C, and Interferon-α (IFN-α), which upregulates OAS enzymes thus maximizing the efficiency of dsRNA sensing in IFN-saturating condition. RNASEL-KO cells were, as expected, refractory to IFN-α+pI:C induced cell death; interestingly however, interfering with protein synthesis or RNA transcription with Cycloheximide (CHX) or Actinomycin D (ActD), caused RNASEL-KO cells to undergo apoptosis although CHX/ActD alone had no cytotoxic effect. This finding suggests the activation of RNAseL-independent systems different from those activated by canonical dsRNA receptors. In view of the partial knowledge in this field and the strong impact that clarification of dsRNA-dependent cell death mechanisms could have in development of new therapeutical strategies, we performed a Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening and integrative analysis to prioritize gene targets that favour/inhibit dsRNA-dependent cell death. The screen revealed that RNA surveillance, RNA Polymerase II Transcription Initiation, Mitochondrial translation and respiratory chain and DNA Repair genes have a protective role against dsRNA increase. Among multiple candidates with synergistic/inhibitory role with dsRNA, we validated the most translationally relevant BRCA1, commonly mutated in hereditary forms of breast, ovarian and several other cancers. Thus, our work shed light on potential new mechanisms involved in dsRNA dependent cell death, tracing a connection with DNA damage and BRCA1. We, therefore, will explore the interaction between dsRNA sensing and BRCA1 as a target for synthetic lethal combinations in BRCA1-deficient tumours.","language":"eng","citation":"IDENTIFICATION OF FACTORS INVOLVED IN DOUBLE STRANDED RNA-INDUCED CELL DEATH THROUGH GENOME-WIDE CRISPR SCREENS / D. Trastulli ; internal advisor: F. Iorio ; tutor: L. Mazzarella ; phd coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2023 Dec 12. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12756.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1018171/2326839/phd_unimi_R12756.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1225837"},"title":"IDENTIFICATION OF MICROBIAL FUNCTIONS INTERFERING WITH HOST-CELL PHYSIOLOGY: A QUICK VIEW INTO STREPTOCOCCUS THERMOPHILUS METABOLIC POTENTIAL","internalauthor":"ZANCHETTA, YLENIA","type":"Tesi di dottorato","year":"2026","abstract":"Streptococcus thermophilus, long typecast as a dairy workhorse, is ready for a role upgrade. Despite decades of safe use in fermentation in large volume consumer products, this species has been largely sidelined in probiotic research, overshadowed by genera like bifidobacteria and strains belonging to the group formerly classified within lactobacilli, such as Lactiplantibacillus, Lacticaseibacillus, and Limosilactobacillus. This thesis redefines S. thermophilus as a metabolically dynamic, functionally relevant, and therapeutically promising candidate in the probiotic field.  In the first part of this work, we present a safe metabolic activation strategy that enhances lactose catabolism in S. thermophilus, starting from the biomass production phase, without compromising cell viability. Within just 30 minutes, activated cells exhibited up to a 30% increase in lactose conversion, compared to not-activated cells. Interestingly, in the presence of both urea and a carbon source, lactic acid release was significantly enhanced, alongside a marked improvement in glycolytic activity, without altering the optimized lactose uptake. This distinctive metabolic behavior of activated cells appears to modulate glycolysis and enhance acidification, positioning S. thermophilus as a promising tool not only for more efficiently supporting lactose digestion but also for additional applications requiring optimized biomass performance, rapid lactose consumption, and controlled glycolytic and lactate output. Importantly, these activated cells are currently being evaluated in a forthcoming in vivo study, where their enhanced metabolic profile is expected to translate into measurable reduced symptoms and improved subject well-being in individuals with lactose intolerance. This therapeutic potential, directed toward specific targets (e.g., lactose maldigestion), reinforces the concept of precision probiotics: microbial products designed not just for general health promotion, but for targeted interventions, tailored to specific conditions and consumer needs. The reproducibility of these effects across different substrates and at production scale underscores both the physiological relevance and industrial feasibility of this strategy, offering a compelling alternative to generalized probiotic strategies in favor of a novel approach in probiotic development.  The second study focuses on urease activity, an often overlooked yet highly relevant functional trait in S. thermophilus, closely associated with nitrogen and energy metabolism. Recent findings have linked urease activity in S. thermophilus to a specific beneficial effect on the host: administration of adequate amounts of viable biomass resulted in decreased fecal urease activity, suggesting that this effect may be mediated by the modulation of urea metabolism and a reduction in urease-positive pathogenic bacteria. Building on this and considering that targeting urease in conditions such as Irritable Bowel Syndrome (IBS) could be key to alleviate symptoms, we sought to determine whether this reduction is solely due to S. thermophilus urease contribution or whether additional microbial or host-related factors play a role. To this end, we controlled urease activity levels of S. thermophilus biomass through process-condition control. By fine-tuning fermentation parameters, we successfully modulated urease expression at both laboratory and industrial scales, generating distinct biomasses with tailored metabolic phenotypes. These engineered biomasses are currently being prepared for a forthcoming in vivo study in IBS patients to assess their effects on host symptoms and their influence on gut nitrogen metabolism, based on their urease activity levels. This is particularly relevant given that disruptions in the urea–ammonia balance, arising from the dysbiosis state that characterizes IBS, are known to exacerbate symptoms through altered microbial composition, increased intestinal permeability, and elevated luminal ammonia levels, which can aggravate mucosal inflammation and visceral hypersensitivity, leading to discomfort, abdominal pain, bloating, and other digestive disturbances typical of this syndrome. This work aims to open new avenues for developing targeted probiotic interventions and provides valuable insights into the complex and evolving interplay between urease activity and energy metabolism in S. thermophilus. Most importantly, it highlights a crucial yet often overlooked point: the fermentation process itself can be strategically optimized to predefine specific microbial functionalities. By establishing a direct link between upstream fermentation conditions and downstream functionality, this study reinforces the importance of precision at every stage of probiotic production, from fermentation to functional application, particularly when the effect is driven by the activity level of the administered biomass itself, rather than by downstream growth or adaptation in the host.  The final part of the thesis explores an innovative therapeutic application: leveraging S. thermophilus DSM 20617T/ATCC 19258T as a delivery vector of β-galactosidase in situ via prophage-mediated lysis, motivated by the recent evidence that intracellular β-galactosidase from S. thermophilus exerts protective effects against colorectal cancer by inhibiting cancer cell proliferation and tumor development. The strain’s ability to survive gastrointestinal transit, interact with the host microbiota, and potentially release therapeutic molecules in situ represents a novel intersection of microbiology, biotechnology, and therapeutic design. While challenges remain, particularly in controlling prophage induction and ensuring consistent release of bioactive enzymes, such as β-galactosidase, at the site of action in the intestine following administration and cell lysis, this work lays the foundation for using S. thermophilus as a microbial chassis in the design of live biotherapeutics.   Together, these studies reposition S. thermophilus as a precision-engineered tool for the future generation of microbiome-based health solutions.   In an industry still dominated by one-size-fits-all products and vague probiotic claims, this work challenges the standard narrative. It delivers measurable, mechanism-based evidence that S. thermophilus has been underestimated for too long. As the demand for personalized, effective, and evidence-based microbial therapies continues to rise, this thesis highlights the potential of S. thermophilus and advocates for its greater consideration. Moreover, by expanding the functional framework of S. thermophilus, this research paves the way for formulas designed with precision and purpose, moving probiotic science into a new era.","language":"eng","citation":"IDENTIFICATION OF MICROBIAL FUNCTIONS INTERFERING WITH HOST-CELL PHYSIOLOGY: A QUICK VIEW INTO STREPTOCOCCUS THERMOPHILUS METABOLIC POTENTIAL / Y. Zanchetta ; tutor: D. Mora ; cotutor: S. Arioli ; company supervisor: S. Colombo ; phd dean : D. Mora. - Milano. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2026 Feb 09. 38. ciclo","filename":"phd_unimi_R13926.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 01-MAR-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/816457"},"title":"DEVELOPMENT, VALIDATION, AND APPLICATION OF ANALYTICAL ASSAYS FOR THE HUMAN BIOMONITORING OF VOLATILE AND PERSISTENT ORGANIC COMPOUNDS","internalauthor":"FRIGERIO, GIANFRANCO","type":"Tesi di dottorato","year":"2021","abstract":"Biomonitoring is a useful approach to assess the exposure to pollutants in human subjects. The aim of this project was the development of new analytical methods for the biomonitoring of exposure to volatile and persistent organic pollutants, their application to selected groups of subjects, and a comparison between different approaches (untargeted vs targeted approaches).  A high-throughput isotope dilution tandem mass spectrometric method coupled with reversed-phase liquid chromatography (HPLC-MS/MS) was developed for the analysis of a total of 17 urinary mercapturic acids, as metabolites of several volatile organic compounds. A complete validation was carried out including precision, accuracy, linearity, sensibility, process efficiency, and external verification.  This method was applied to a group of 49 coke-oven workers and 49 individuals living in the same area. Active tobacco smoking was an exclusion criterion for both groups. Urinary levels of the metabolites of benzene, styrene, acrylonitrile, and 1,3-butadiene were 2–10 fold higher in workers than in controls.  The method was also applied to a group of subjects with different smoking habits, in particular: 38 non-smokers (NS), 7 electronic cigarette users (ECU), and 22 traditional tobacco smokers (TTS). Most of the measured mercapturic acids were 2 - 165 fold-higher in TTS compared to NS. The metabolites of acrylonitrile and acrolein were 1.8 and 4.9 fold-higher higher in ECU than NS, respectively. Furthermore, comparing smokers to non-smoking coke oven workers, the first were exposed to a greater amount of volatile organic compounds.  An untargeted metabolomic approach was applied to the same population of subjects with different smoking habits. Samples were analysed by liquid chromatography/time-of flight mass spectrometry. Among putatively annotated compounds there were the glucuronide conjugated of 3-hydroxycotinine and the sulfate conjugate of methoxyphenol. Considering mercapturic acids, the coherence between the targeted and untargeted approach was found for a limited number of chemicals, typically the most abundant.  Finally, an HPLC-MS/MS method for the determination of some endocrine-disrupting persistent chemicals was developed. Targeted molecules were bisphenol A and metabolites of phthalates, including emergent terephthalates. A complete validation was carried out and the method was applied to 36 non-occupationally exposed adults.","language":"eng","citation":"DEVELOPMENT, VALIDATION, AND APPLICATION OF ANALYTICAL ASSAYS FOR THE HUMAN BIOMONITORING OF VOLATILE AND PERSISTENT ORGANIC COMPOUNDS / G. Frigerio ; supervisor: A. Moretto ; coordinatore: C. La Vecchia. Dipartimento di Scienze Biomediche e Cliniche L. Sacco, 2021 Mar 10. 33. ciclo, Anno Accademico 2020. [10.13130/frigerio-gianfranco_phd2021-03-10].","filename":"phd_unimi_R11966.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/816457/1709514/phd_unimi_R11966.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1155336"},"title":"PROCESS MINING FOR REENGINEERING CIRCULAR AND RESILIENT PRODUCTION PROCESSES","internalauthor":"OYAMADA, RAFAEL SEIDI","type":"Tesi di dottorato","year":"2025","abstract":"This thesis explores the integration of process mining techniques with deep learning models to enhance the understanding, analysis, and optimization of complex business processes. Process mining bridges the gap between model-driven and data-driven approaches through a set of techniques that extract insights from event logs. Meanwhile, deep learning has the potential to model and learn intrinsic patterns and dependencies from data. By combining these fields, the research carried out throughout this thesis addresses key challenges in a specific subfield of process mining called predictive process monitoring. In this subfield, the goal is to leverage all the historical data to predict future behaviors within a process. Relevant predictive tasks include, for example, predicting the next activity, the remaining time of a current instance, or the outcome of a current instance.      In the past few years, several papers have been published on predictive process monitoring regarding different tasks. Despite the great success and convincing results in terms of predictive accuracy, researchers overlook some principles that are crucial for the advancement of the field. For instance, transforming business and semantic rules from process data into a latent space is a key step for training machine learning models. Usually, most proposals in the literature rely on naive techniques to encode categorical attributes from events, such as the well-known one-hot encoding. Furthermore, a second level of encoding is required to aggregate a trace of events into a single vector array, which is commonly done by simply averaging the attribute values of events. These approaches naturally result in loss of information and fail to properly capture all the intrinsic complexity of process data.      This often-overlooked step introduces significant limitations to modern predictive process monitoring applications. For example, while deep learning models excel at tasks such as predicting the next activity or suffixes in a process, these tasks often fall short of addressing more meaningful, practical needs. In real-world scenarios, the usefulness of next-activity predictors is often questionable. A more impactful application lies in process simulation, where the goal is to model potential new behaviors within a process before actual changes are implemented, ensuring safety and minimizing risk. Unfortunately, current techniques for representing process data are inadequate, making deep learning models inflexible to effectively support this type of simulation. For example, process data is often encoded as sequences of discrete events without capturing the contextual relationships or dependencies between them. This limitation means that a deep learning model trained on such data may accurately predict the next event in a process but cannot simulate complex scenarios, such as how changes in resource allocation or timing constraints might affect the overall workflow.      Therefore, in this thesis, we aim to better understand how to encode process data in latent spaces to improve the performance of learned models. We begin this work by reviewing several encoding techniques from other research areas to assess their applicability in process mining. We also investigate and motivate the development of feature engineering techniques tailored to this particular type of data. To this end, we systematically design and empirically evaluate extensive experiments for different tasks. In addition, we propose the use of declarative languages that capture linear temporal logic over finite traces to improve the data representation of process data for training deep learning models, thus overcoming the inflexibility of these applications for process simulation. Finally, we use all the knowledge and contributions developed in this thesis to propose meaningful solutions in the industrial sector. More specifically, we develop three relevant use cases at an Italian company called Avio Aero: (i) a process mining pipeline to extract insights from their data, (ii) an application of large language models to enrich this data, and (iii) a combination of both research areas to propose improvements and design a more resilient and robust process model.","language":"eng","citation":"PROCESS MINING FOR REENGINEERING CIRCULAR AND RESILIENT PRODUCTION PROCESSES / R.s. Oyamada ; tutor: P. Ceravolo ; school director: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2025 Mar 11. 37. ciclo, Anno Accademico 2024. [10.13130/oyamada-rafael-seidi_phd2025-03-11].","filename":"phd_unimi_R13564.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1155336/2720074/phd_unimi_R13564.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/940416"},"title":"MOLECULAR CHARACTERIZATION OF PROTEINS IN FOOD MATRICES: HOW THEIR STRUCTURE EVOLVE FROM RAW MATERIALS TO FINISHED PRODUCTS","internalauthor":"EMIDE, DAVIDE","type":"Tesi di dottorato","year":"2022","abstract":"Proteins have a fundamental importance for their peculiar chemical characteristic, implication in metabolism and structure for all living organisms. In food systems, proteins provide both nutritional and non-nutritional functionalities and, with other macromolecules, contribute in define the characteristics of the food systems. Technological and biotechnological treatments used in food processing are also responsible for the formation of new inter- and intra-molecular interactions, driven by changes in the structure of proteins, often in association with other food components.  In the present PhD thesis, the structural evolution of proteins from raw materials to finished products was studied in different food systems, with the aim of connecting protein molecular features - and the changes they undergo upon processing - with their functional properties. This PhD thesis aims at improving the current understanding of the structure/function relationship of macromolecules in various food systems, and of how the new relationships affect their technological properties. The approaches and results presented are of practical relevance for the food industry, that require to understand how to tailor processes in order to fit the nutritional, sensorial and environmental requests from the consumers.  The introduction (Chapter 2) provides a review of the current knowledge and of the approaches used to study the structure of proteins in food systems. The gluten network is used as a model system in this context, because of its high level of complexity and of its importance in defining the properties of cereal-based food systems. The first four sections (4.1, 4.2, 4.3 and 4.4) of the Results presents the structural and geometrical events leading to the formation of the gluten-network, and discusses some novel approaches set-up to investigate the three- dimensional rearrangements resulting from a transformation process (such as bread making). These approaches were also applied to clarify the impact of other macromolecules (amylose and amylopectin) in the gluten-network development, that in turn affects the properties of the derived products.  Sections 4.5, 4.6 and 4.7 discusses the impact of technological treatments on proteins in gluten-free flours, using lentils as a model and analyzing protein structural changes as a function of different technological treatments. Biochemical characterization was one prong of a multidisciplinary approach (rheology and calorimetry) that showed how the technological treatments affect the protein structure, improving the transformability of lentis flour in gluten- free pasta.  Pseudo cereals, such as buckwheat (Section 4.8), represent a suitable system to show how biotechnological treatments like sprouting can positively affect the nutritional properties, also thanks to modification of the protein pattern and structure. The overall features of proteins in sprouted grains made them more suitable for the formation of protein network, useful for appropriate texturing of specific foods, like couscous. The nutritional properties were assessed in couscous fortified with the sprouted flour, after a simulation of an in vivo digestion.  Finally, proteins can also impact the flavor of the products acting as a source of reactive and/or bioactive components, often originated by breakdown by endogenous or added proteases. In Sections 4.9, 4.10 and 4.11, the nature and amount of peptides and amino acids released during fermentation of cocoa was related to the selected inoculum and to the flavor of the final product.","language":"eng","citation":"MOLECULAR CHARACTERIZATION OF PROTEINS IN FOOD MATRICES: HOW THEIR STRUCTURE EVOLVE FROM RAW MATERIALS TO FINISHED PRODUCTS / D. Emide ; tutor: A. Barbiroli ; cotutor: S. Iametti ; coordinatore: D. Mora. Università degli Studi di Milano, 2022 Oct 20. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12652.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/940416/2077070/phd_unimi_R12652.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1016188"},"title":"ECOLOGICAL RESTORATION: BETWEEN LAW, POLICY, AND GOVERNANCE","internalauthor":"CISCATO, ELEONORA","type":"Tesi di dottorato","year":"2023","abstract":"The pressing climate, biodiversity, and pollution crises are showing the limitations of traditional environmental policies, calling for different, more radical interventions. In this context, restoration activities aimed at reconstructing damaged environments have captured the attention of international and national regulatory bodies, and restoration projects have been proliferating. However, despite this trend, ecological restoration remains largely unexplored in terms of its potential for influence and transformation. To fill this gap, this dissertation explores the scientific and ethical foundations of the practice, and their translation into legal norms. Moreover, the research examines the norms and institutions that are likely to facilitate or hinder ecological restoration activities.  Adopting an interdisciplinary approach, this work combines comparative legal analysis with political economic theories to effectively address the research questions identified. Overall, the research demonstrates that the current implementation of restoration activities is scattered, uncoordinated and often inadequate, lacking the capacity to ensure ecological recovery in face of pervasive degradation. Moreover, since ecological restoration is frequently not legally mandated, its achievement is discretionary and reliant on individual public or private initiatives. This situation has implications not only for the effectiveness of restoration efforts but also for the ability of local communities to benefit from rehabilitated ecosystems. This research argues that a combination of policy instruments and incentives should be further studied to stimulate better and more just practices and strategies.","language":"eng","citation":"ECOLOGICAL RESTORATION: BETWEEN LAW, POLICY, AND GOVERNANCE / E. Ciscato ; tutors: S. Valaguzza, V. Cecchini Manara ; doctoral programme coordinator: L. Sacconi. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2023 Nov 14. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12738.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1016188/2322132/phd_unimi_R12738.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/945754"},"title":"TREMELIMUMAB AND DURVALUMAB COMBINATION FOR THE NON-OPERATIVE MANAGEMENT OF MICROSATELLITE INSTABILITY HIGH RESECTABLE GASTRIC OR GASTROESOPHAGEAL JUNCTION CANCER: RESULTS OF COHORT 1 OF THE MULTICENTRE, SINGLE-ARM, MULTI-COHORT, PHASE II INFINITY STUDY","internalauthor":"PRISCIANDARO, MICHELE","type":"Tesi di dottorato","year":"2022","abstract":"Backgound: In resectable gastric or gastroesophageal junction cancer (GC/GEJC), the powerful positive prognostic effect and the potential predictive value for a lack of benefit from the combination of adjuvant/peri-operative chemotherapy for the MSI-high status was demonstrated. Given the high sensitivity of MSI-high tumors for immunotherapy, exploratory trials showed that combination immunotherapy induces a high rate of complete pathological response (pCR), potentially achieving cancer cure without surgery.   Methods: INFINITY is a phase II, multicentre, single-arm, multi-cohort trial investigating the activity and safety of tremelimumab and durvalumab as neoadjuvant (Cohort 1) or potentially definitive (Cohort 2) treatment for MSI-high/dMMR/EBV-negative, resectable GC/GEJC. Enrolled patients received the combination of tremelimumab 300 mg single-dose on cycle 1 and durvalumab 1500 mg every 4 weeks for 3 cycles and, after that, they will undergo standard surgery and clinical follow up. The primary endpoint of Cohort 1 is rate of pCR (ypT0N0) and as secondary endpoints the safety of the neoadjuvant combination immunotherapy was explore, defined as the incidence of AEs during the treatment and follow-up phases, assessed according to common terminology criteria for adverse events (CTCAE v5.0).  Results: Eighteen MSI-high were enrolled in the Cohort 1 of this study. The evaluation of pathologic responses to neoadjuvant treatment was performed only in 15 of the 18 enrolled patients. Of the 15 analyzed patients 9 achieved pCR, with a pCR rate in of 60%, while a major pathologic response was observed in the 87% of treated patients.  Interestingly, a significant difference in pCR rate was observed in patients with initial T4 tumor compared to T3/T2 tumors (16% vs 88.9% OR=26.03 [95% CI: 1.39-NE; p=0.011]), while only a trend toward of differences in baseline TMB value were observed in those patients who had pCR with immunotherapy and those who did not. Regarding safety, no unexpected AEs or treatment-related deaths were reported, discontinuation rate was low and none of the described AEs compromised the subsequent surgical treatment.  Conclusion: Immunotherapy combination of durvalumab and tremelimumab demonstrated a clinically meaningful activity and a manageable safety profile of the in patients with MSI-high early GC/GEJC, allowing to open new scenario in which a non-operative management can even be proposed to these patients.","language":"eng","citation":"TREMELIMUMAB AND DURVALUMAB COMBINATION FOR THE NON-OPERATIVE MANAGEMENT OF MICROSATELLITE INSTABILITY HIGH RESECTABLE GASTRIC OR GASTROESOPHAGEAL JUNCTION CANCER: RESULTS OF COHORT 1 OF THE MULTICENTRE, SINGLE-ARM, MULTI-COHORT, PHASE II INFINITY STUDY / M. Prisciandaro ; tutor: F. de Braud ; co-tutor: F. Pietrantonio ; coordinatore: M. Del Fabbro. Dipartimento di Oncologia ed Emato-Oncologia, 2022 Dec 14. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12691.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/945754/2096823/phd_unimi_R12691.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/944449"},"title":"DEVELOPMENT OF SUSTAINABLE AND EFFICIENT TAILOR-MADE PROCESSES FOR PHARMA AND FOOD APPLICATIONS","internalauthor":"ANNUNZIATA, FRANCESCA","type":"Tesi di dottorato","year":"2022","abstract":"The ecological burdens of chemical processes could not be underestimate anymore and a change of direction is required from the industry as well as from academia. In this scenario, my Doctoral Thesis is focused on the development of tailor-made processes for the production of fine chemicals relevant for food and pharma applications which could be considered efficient and sustainable thanks to the employment of techniques with a low environmental impact (i.e., continuous synthesis, biocatalysis, new solvent systems).   The main focus of this project was to display how versatile and tuneable the combination of biocatalysis and flow chemistry could be for the synthesis of different chemical compounds, improving established classic but polluting chemical approaches or clearing the way for larger scale manufacturing. Where possible media engineering was applied to further improve the sustainability of the newly designed protocols. In all the processes studied, I also focused my attention on a crucial point of process optimisation: the development of in-line purification steps. The aim was to reduce manual downstream processes by including continuous purification steps, i.e., extraction, catch and release strategies, and/or suitable immobilised scavengers.   The Doctoral work developed during these years could be divided into three major area based on the main reactions that have been explored, which were catalysed by different classes of enzymes. In the Thesis I presented and discussed: i) reactions of functional group transfer (from one molecule to another), ii) redox reactions and iii) condensation reactions for the synthesis of different functional groups (i.e., esters, carbonate, carbamate). These reactions were selected due to their wide use in classical organic synthesis that usually required harsh conditions, expensive or toxic reactants, to obtain at the end the desired product with low selectivity and high environmental impact. In some cases, a combination of more than one biocatalyst was used in the same protocol to perform further modifications of the high value chemicals obtained.   Biocatalysts were employed in different physical forms (immobilised or free), as isolated enzyme or whole cells. The best approach was evaluated case by case. For example, in the transfer reaction, acyl transferase from Mycobacterium smegmatis was immobilised on glyoxyl agarose by our research group while lipase-mediated reactions were performed using the commercial preparation Novozyme® 435. Redox reactions were mainly catalysed by commercial enzymes as free biocatalyst (i.e., tyrosinase from Agaricus bisporus and laccase from Trametes versicolor). Moreover, the advantages of a self-sufficient system as whole cells were also investigated providing the opportunity to implement the immobilisation procedure of Rhodotorula rubra cells for continuous applications.   Where possible the stability or the possibility to reuse the biocatalyst was evaluated in order to reduce the costs of the procedure. The choice of the right solvent was a key point in all the protocols developed and the replacement of classical organic solvents was the path followed whenever the experimental condition allowed it. This also allowed me to evaluate the operational conditions of well-known enzymes in unconventional reactions media (e.g., lipase in tert-amyl alcohol or cyclopenthylmethyl ether) expanding their possible synthetic applications.","language":"eng","citation":"DEVELOPMENT OF SUSTAINABLE AND EFFICIENT TAILOR-MADE PROCESSES FOR PHARMA AND FOOD APPLICATIONS / F. Annunziata ; tutor: L. Tamborini ; coordinatore: D. Passarella. Dipartimento di Scienze Farmaceutiche, 2022 Nov 15. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12504.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/944449/2091543/phd_unimi_R12504.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1197118"},"title":"AORTIC STIFFNESS MODIFICATIONS AFTER ENDOVASCULAR AORTIC REPAIR","internalauthor":"BISSACCO, DANIELE","type":"Tesi di dottorato","year":"2025","abstract":"Background: Endovascular aortic repair (EVAR and TEVAR) has transformed the management of aortic aneurysms and dissections through its minimally invasive approach and favorable short-term outcomes. However, concerns regarding the long-term cardiovascular implications of endograft implantation have emerged, particularly related to aortic stiffness, a known predictor of cardiovascular morbidity and mortality.  Objective: This study aimed to evaluate the modifications in aortic stiffness in patients undergoing endovascular aortic repair by measuring pulse wave velocity (PWV) using non-invasive applanation tonometry before and after intervention. Moreover, other parameters measuring cardiac performance have been included as secondary outcomes.  Methods: A prospective study was conducted at Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico in Milan, Italy, from October 1, 2023, to April 30, 2025. Patients aged 18 and older, indicated for elective TEVAR or EVAR, were enrolled. Exclusion criteria included emergency procedures, significant comorbidities hindering measurement with tonometer or wave analysis (e.g. atrial fibrillation, compromised skin integrity). Data collection encompassed demographic information, comorbidities, medication use, vital signs, and laboratory values. PWV was calculated  preoperatively and postoperatively, and waveform analysis was performed to assess arterial stiffness and hemodynamic parameters.  Results: A total of 76 patients underwent endovascular aortic procedures, with 53 included in the analysis (38 EVAR/FEVAR and 15 TEVAR). Preoperative mean cf-PWV was 9.4 ± 2.8 m/s and increased significantly to 11.1 ± 3.8 m/s postoperatively (p = 0.019), representing an approximate 18% increase. Additionally, the Subendocardial Viability Ratio (SEVR) decreased significantly from 132.9 ± 32.1% preoperatively to 110.7 ± 29.4% postoperatively (p < 0.001), indicating potential implications for myocardial perfusion. Waveform analysis revealed significant alterations in several parameters, including reductions in Peak Time and changes in wave reflection dynamics, which suggest increased arterial stiffness.  Conclusions: The findings indicate that endovascular aortic repair is associated with a significant increase in arterial stiffness and alterations in arterial hemodynamics. These changes highlight the need for ongoing monitoring of arterial stiffness and cardiovascular health in patients following EVAR and TEVAR. Future research should focus on larger cohorts to further elucidate the long-term implications of endograft materials and surgical techniques on cardiovascular outcomes. Understanding these parameters is crucial for optimizing patient management strategies and mitigating risks associated with increased aortic stiffness.","language":"eng","citation":"AORTIC STIFFNESS MODIFICATIONS AFTER ENDOVASCULAR AORTIC REPAIR / D. Bissacco ; tutor: S. TRIMARCHI ;  the chair of the phd program: M. DEL FABBRO. Dipartimento di Scienze Cliniche e di Comunità, 2025 Dec 19. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13816.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 21-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1077628"},"title":"FUNCTIONAL CHARACTERISATION, DISEASE BURDEN AND PREDICTORS OF MORTALITY IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE: PRELIMINARY RESULTS FROM THE ITALIAN COPD REGISTRY","internalauthor":"RADOVANOVIC, DEJAN","type":"Tesi di dottorato","year":"2024","abstract":"Background  Chronic Obstructive Pulmonary Disease (COPD) is a complex and heterogeneous disease characterized by variable respiratory symptoms and by different degrees of small airways dysfunction and emphysema. Patients with COPD are at increased risk of exacerbations, hospitalizations and mortality, but although over the years numerous severity classification systems have been proposed, they often revealed to be poorly associated with clinical outcomes. The degree of disease burden, the role of lung function, comorbidities and pharmacological therapy in real life is still poorly understood.  Aim of the study  The co-primary outcomes of the study were 1) to evaluate the informativeness of different severity classification systems based on lung function characteristics, clinical phenotypes and serum eosinophils and 2) to evaluate the burden of COPD in terms of exacerbations, exacerbation rate and mortality within the Italian COPD registry.  Methods  This was a retrospective, multicenter study based on the preliminary analysis of the data from the novel Italian COPD registry. Patients were retrospectively enrolled from 2014 until 2016 and variables regarding anthropometric, clinical and functional characteristics of patients with a confirmed diagnosis of COPD were reviewed and collected for a cross-sectional analysis. Risk subgroups were based on exacerbation history during the year before entering the study were followed for the incidence of moderate and severe exacerbation during each year of follow up, up to 3 consecutive years. Survival state was assessed at the end of follow up.  Results  In total, 1360 patients (73.4% males) were enrolled in the registry and analyzed. Overall, 37% had very severe airflow obstruction. Inspiratory capacity, diffusion lung capacity for carbon monoxide (DLCO) and the prevalence of emphysema were reflected by the functional Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification only. The proportion of patients with > 200 eosinophils/μl was higher in GOLD  4  III-IV stages compared with GOLD I-II (P=0.008). For the longitudinal analysis 1111 patients were included (73% males); 41.5% had a history of exacerbations. The proportion of patients experiencing ≥1 exacerbation during follow-up increased according to pre-defined study risk categories. Overall, by the end of follow-up, 45.5% of patients without a history of exacerbation experienced an exacerbation (31% severe), and 13% died. Compared with survivors, patients that died were older, had worse airflow obstruction and hyperinflation. Severe exacerbations were more frequent in patients that died (23%, vs 10%; P=0.002). Chronic heart failure and ischemic heart disease were independent risk factors for mortality (OR (95%CI: 2.2 (1.4-3.6), P=0.001 and 1.9 (1.2-2.9), P=0.007).  Conclusions  COPD classifications excluding lung function might miss relevant patients’ clinical characteristics such as hyperinflation, DLCO impairment and clinical phenotypes, which have a significant impact on outcomes and disease severity. Patients at low exacerbation risk are at significant risk of future moderate or severe events. Real life data confirm the strong association between mortality and cardiovascular comorbidities in COPD.","language":"eng","citation":"FUNCTIONAL CHARACTERISATION, DISEASE BURDEN AND PREDICTORS OF MORTALITY IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE: PRELIMINARY RESULTS FROM THE ITALIAN COPD REGISTRY / D. Radovanovic ; tutor: P. Santus ; coordinatore: M. Del Fabbro. - Università degli Studi di Milano - Clinica Mangiagalli, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico. Dipartimento di Scienze Biomediche e Cliniche, 2024 Jul 01. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12926.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1077628/2479252/phd_unimi_R12926.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1161856"},"title":"SUSTAINABILITY, ENERGY AND ANIMAL WELFARE AT SLAUGHTER","internalauthor":"COMIN, MARTA","type":"Tesi di dottorato","year":"2025","abstract":"The PhD project Sustainability, Energy and Animal Welfare at Slaughter (Sostenibilità, Energia e BEnessere alla Macellazione – SEBEM) aimed to enhance the sustainability of sheep production systems by establishing high standards of animal welfare at slaughter and developing innovative strategies for managing slaughter waste. Animal welfare during slaughter raises critical ethical and sustainability questions in livestock production. EU legislation mandates the use of animal-based measures (ABMs) to assess stunning effectiveness and ensure animals do not regain consciousness until the death.  While the 2021 EFSA Scientific Opinion on the “Welfare of Sheep and Goats at Slaughter” provides a list of ABMs for electrical and mechanical stunning (e.g., breathing, posture, tonic-clonic seizures, muscular tone, vocalisations, eye movements, reflexes, and blinking), their practical feasibility remains poorly explored. Variations in slaughterhouse facilities and operations – from small abattoirs to industrial settings – further complicate the application of these indicators. This gap underscores the need for research efficiently apply ABMs in different contexts.  To address these challenges, this PhD project introduces innovative strategies for monitoring sheep welfare at slaughter considering the small (or familiar) and the industrial (or large) context. These studies aimed to investigate the feasibility of ABMs capable of efficiently detecting signs of consciousness and unconsciousness in lambs. Key parameters considered included electrode positioning, the duration of current application, and the stun-to-stick interval under field conditions.  The project comprises three key studies:  • Study 1: A systematic review critically evaluated the feasibility of ABMs for assessing stunning effectiveness and unconsciousness in sheep  • Study 2: A checklist was developed and tested to assess the feasibility of signs of consciousness and unconsciousness in small abattoirs. Direct observations were conducted on 34 lambs individually stunned with a penetrative captive bolt in a small slaughterhouse in Northern Italy.  • Study 3: A on-field study investigated signs of consciousness following head-only electrical stunning in 3047 lambs, using video analysis to correlate these signs with the effectiveness of the stunning process in an industrial abattoir.  The systematic review revealed limited research on the practicality of ABMs in both small and industrial settings, highlighting the need for further investigation. Regarding the small contest, feasible indicators observable from a distance included tonic and clonic convulsions, fixed eyes, eyeball rotation, nystagmus, relaxed jaws, righting reflex, and vocalisations. Collapse was feasible only when lambs lost their quadrupedal stance immediately after stunning without restraint. Indicators such as apnoea, blinking, tongue protrusion, and voluntary kicking were deemed unfeasible due to poor visibility. A limitation of this study was its focus on a single slaughterhouse, a specific animal category, and the small sample size, restricting broader comparisons. While, in industrial context, results indicated excessively long stun-to-stick intervals and the presence of several signs of consciousness. Correlations were found between ABMs observable in the head area, emphasising its importance as a critical hotspot for monitoring multiple indicators of stunning efficacy.  Although these findings cannot be generalised due to the limited sample considered, that could be useful as a starting point, for identifying optimal combinations of feasible ABMs capable of efficiently detecting signs of consciousness in lambs in a small and industrial abattoirs, and enhancing sheep welfare.","language":"eng","citation":"SUSTAINABILITY, ENERGY AND ANIMAL WELFARE AT SLAUGHTER / M. Comin ; supervisor: E. Dalla Costa ; co-supervisor: S. Barbieri; coordinatore: F. Ceciliani. - Lodi. Dipartimento di Medicina Veterinaria e Scienze Animali, 2025 May 23. 37. ciclo","filename":"phd_unimi_R13601.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1161856/2982881/phd_unimi_R13601.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/961901"},"title":"PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9, ATHEROSCLEROSIS AND EXTRACELLULAR VESICLES ¿ EXPERIMENTAL AND CLINICAL EVIDENCE","internalauthor":"GRECO, MARIA FRANCESCA","type":"Tesi di dottorato","year":"2023","abstract":"Vascular smooth muscle cells (VSMCs) are key participants in both early- and late-stage atherosclerosis and influence neighbouring cells possibly by means of bioactive molecules, some of which are packed into extracellular vesicles (EVs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed and secreted by VSMCs. This study aimed to unravel the role of PCSK9 on VSMCs-derived EVs in terms of content and functionality. EVs were isolated from human VSMCs overexpressing human PCSK9 (VSMCPCSK9-EVs) and tested on endothelial cells, monocytes, macrophages and in a model of zebrafish embryos. Compared to EVs released from wild-type VSMCs, VSMCPCSK9-EVs caused a rise in the expression of adhesion molecules in endothelial cells and of pro-inflammatory cytokines in monocytes. These acquired an increased migratory capacity, a reduced oxidative phosphorylation and secreted proteins involved in immune response and immune effector processes. Concerning macrophages, VSMCPCSK9-EVs enhanced inflammatory milieu and uptake of oxidized low-density lipoproteins, whereas the migratory capacity was reduced. When injected into zebrafish embryos, VSMCPCSK9-EVs favoured the recruitment of macrophages toward the site of injection. The results of the present study provide evidence that PCSK9 plays an inflammatory role by means of EVs, at least by those derived from smooth muscle cells of vascular origin.","language":"eng","citation":"PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9, ATHEROSCLEROSIS AND EXTRACELLULAR VESICLES ¿ EXPERIMENTAL AND CLINICAL EVIDENCE / M.f. Greco ; tutor: M. Ruscica; coordinatore: G. D. Norata. Dipartimento di Scienze Cliniche e di Comunità, 2023 Apr 04. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12575.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/961901/2170450/phd_unimi_R12575.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/947848"},"title":"DEVELOPMENT AND IMPLEMENTATION OF CLOUD-ORIENTED BIOINFORMATIC SERVICES","internalauthor":"MANDREOLI, PIETRO","type":"Tesi di dottorato","year":"2022","abstract":"The increase in our capacity to produce biological data has led to a parallel growth in the  number and complexity of the bioinformatics tools and pipelines needed to analyse them,  exacerbating the long-standing issues associated with analytical reproducibility in  bioinformatics. As a matter of fact, the proliferation of bioinformatics software tools and  pipelines, their versioning and multiple dependencies risk not only hindering the daily work  of researchers but also complicating the reproducibility of data analysis procedures, in turn,  of the scientific results they support. The development and introduction of Workflow  Management Systems, like Galaxy, and hardware virtualization and software containerization  technologies are increasingly used to address those issues, making the execution of elaborate  workflows possible while retaining an overall high degree of analytic reproducibility over  time. However, the operation and maintenance of those instruments can still be out of reach  for many researchers due to their infrastructural requirements, not just in terms of computing  resources but also regarding the IT expertise necessary for their administration. To tackle this  issue, our group developed Laniakea, a software framework that, leveraging virtualization,  containerization, and cloud computing technologies, allows the on-demand deployment of  Galaxy instances and other bioinformatics applications over cloud infrastructures. Laniakea  users, performing only a handful of clicks, gain administrator-level access to a ready-to-use,  customizable, Galaxy instance and to the underlying virtual hardware. The Laniakea software  platform has been employed as a foundation for the ELIXIR-IT Laniakea@ReCaS  bioinformatics service that provides researchers with cloud resources for creating  production-grade Galaxy instances, enabling small research groups or organizations to  analyse their data independently using a state-of-the-art scientific computing infrastructure.  In the past few years, the Laniakea framework has proven to be a solid platform, for example,  by facilitating us in the development of novel Galaxy services implementing specific  bioinformatics workflows (i.e., genomic variant prioritization, functional annotation of  Sars-CoV-2 genomic variants, scRNA-Seq). Furthermore, the experience acquired with  Laniakea allowed us to participate in the growth of the Galaxy platform and the associated  distributed computing infrastructure.","language":"eng","citation":"DEVELOPMENT AND IMPLEMENTATION OF CLOUD-ORIENTED BIOINFORMATIC SERVICES / P. Mandreoli ; tutor: F. Zambelli, M. A. Tangaro. -  : . Dipartimento di Bioscienze, 2022. ((35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12693.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/947848/2107968/phd_unimi_R12693.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1197638"},"title":"NUTRITIONAL STRATEGIES FOR IMPROVING THE SUSTAINABILITY OF SWINE FARMING","internalauthor":"SANTORU, MATTEO","type":"Tesi di dottorato","year":"2026","abstract":"The rising demand for animal-based products, alongside the need for a more sustainable livestock sector, presents a major challenge. Nutritional strategies offer a cost-effective and fast-acting solution to address this issue. Swine farming, second only to ruminants in environmental impact, plays a significant role due to its nitrogen emissions, its high consume of feedstuffs in competition with human consumption, such as cereals, and its high reliance on soybean products, an ingredient characterized, especially in Europe because of the high amount imported, by a high carbon footprint, and the use of antibiotics that poses a threaten related with the worldwide increase of the antimicrobial resistance. In this thesis we analysed on these aspects, testing different ingredients potentially interesting in helping improving the environmental sustainability of swine farming in a multisectoral approach involving: i) the use of a Yucca schidigera extract as feed additive to reduce the emissions of nitrogenous and odorous compounds in the finishing phase; ii) the use of alternative protein sources to reduce feed-food competition and the European protein gap in pigs’ early life stages; iii) the use of biochar as an ingredient to improve the health status of post-weaning piglets. The first research project evaluated a commercial Yucca schidigera extract, with 10.8% of saponins, through an in vitro and in vivo trial. The in vitro study aimed to identify the optimal dose to test in the in vivo trial and assess the extract's impact on diet digestibility and fermentation in the large intestine by measuring total gas, ammonia and volatile fatty acid production. The in vivo trial focused on growth performance, diet digestibility, carcass and meat quality, nitrogen balance, blood protein profile, and behaviour in Pietrain-derived finishing pigs. Results showed that yucca supplementation did not affect growth, meat quality or the overall welfare, but may improve nitrogen use efficiency and reduce nitrogen emissions, despite a slight decrease in crude protein digestibility. The second research project investigated the effects of Tenebrio molitor meal in growing pigs and lupin seed meal in post-weaning piglets, with a primary focus on gut microbiota. Tenebrio molitor meal had no impact on growth performance but induced temporary beneficial shifts in microbiota, demonstrating its potential as a sustainable protein alternative. In contrast, lupin seed meal reduced growth performance and crude protein digestibility in post-weaning piglets, though it did not affect diarrhoea incidence or blood parameters. Concluding, lupin can be used as a partial substitute for soybean or alongside other alternative proteins to help mitigate its negative impact on performance. The final study assessed the inclusion of biochar in post-weaning piglet diets over a 28-day period. Biochar improved nutrient digestibility, in particularly of protein, therefore suggesting a possible reduction in the nitrogen emissions. While it did not enhance growth performance, it lowered diarrhoea incidence and reduced blood dROMs, indicating improved oxidative status. In conclusion, biochar shows promise as a functional ingredient that supports piglet health and promotes more sustainable swine production.","language":"eng","citation":"NUTRITIONAL STRATEGIES FOR IMPROVING THE SUSTAINABILITY OF SWINE FARMING / M. Santoru ; tutor: L. Pinotti; co-tutor: L. Rossi; coordinatore: F. Cheli. - Lodi. Dipartimento di Medicina Veterinaria e Scienze Animali, 2026 Jan 20. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13780.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 21-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1075768"},"title":"ROLE OF NATURAL KILLER CELLS IN THE PATHOGENESIS OF PRIMARY BILIARY CHOLANGITIS","internalauthor":"FRANZESE, SARA","type":"Tesi di dottorato","year":"2024","abstract":"\"Background: Primary biliary cholangitis (PBC) is the most prevalent autoimmune liver disease and involves the selective destruction of small intrahepatic biliary epithelial cells (BECs), potentially leading to biliary cirrhosis and liver transplantation, if left untreated. As of now, anticholestatic therapy, in particular Ursodeoxycholic acid (UDCA), stands as the primary treatment approach for PBC, serving as the established first-line therapy irrespective of the disease stage. Unfortunately, up to 40% of PBC patients experience treatment failure with UDCA, facing an elevated risk of disease progression, while the survival rate among biochemical \"\"responders\"\" aligns with that of the general population. Therefore, there is urgent need to better characterize the features of PBC patients and find tools that allow the identification of “non-responders” early in the history of the disease.  Research problem: PBC is characterized by immune dysregulation and increasing evidence suggests that innate immune cells play an active role early in the disease. Despite recent studies demonstrated a central role for Natural Killer (NK) cells in the destruction of BECs, a deep and comprehensive characterization of these cells in PBC patients is still lacking, especially in those patients that fails UDCA treatment.   Methodology: In this project, we characterized the transcriptomic profile of circulating NK cell subsets in PBC patients and healthy donors (HDs) by single-cell RNA sequencing (scRNAseq); we also investigated differences in the transcriptomic profile of NK cells from PBC patients stratified based on their response to UDCA. By using a 23-color flow cytometry panel, we characterized and compared the frequencies and phenotype of NK cell subsets in the PB and liver from PBC patients and HDs. We also investigated differences in the immunophenotype of circulating NK cells from PBC patients based on their response to UDCA. We also set-up an “in vitro” experimental model to investigate the pathogenesis of the disease, by obtaining iPSC-derived BECs to be co-cultured with autologous PBMCs and LMNCs from end-stage “non-responder” patients and HDs.  Key results: When we evaluated the transcriptomic profile of PB NK cells from PBC patients, we observed an overall activated transcriptomic profile compared with HDs, suggestive of higher cytotoxic activity, production of lytic granules and migration to inflammatory sites. We confirmed these results by flow cytometry, demonstrating a higher expression of activation markers and chemokine receptors on circulating NK cells from PBC patients than HDs. We also demonstrated that all subsets of NK cells in “non-responder” patients were characterized by a transcriptomic signature suggestive of higher cellular activation, inflammation, cytotoxic functions and pro-fibrotic profile compared with “responder” patients. Notably, we confirmed an overall activation of PB NK cells from “non-responder” patients also when we analyzed the NK cell phenotype by flow cytometry, as assessed by both manual gating strategies and unbiased PhenoGraph analysis. When we applied PhenoGraph analysis in the liver, we observed that the liver of end-stage “non-responder” PBC patients was infiltrated by a high proportion of liver resident (lr) CD56Bright NK cells that may be likely actively involved in the process of liver cirrhosis though the release of inflammatory cytokines. We also identified a cluster of adaptive-like lr-CD49a+ CD56Bright NK cells enriched in PBC patients that have been reported to have low cytotoxic properties but high cytokine production activity upon stimulation.  Conclusions: By demonstrating an activated and pro-fibrotic profile of NK cells in PBC patients who failed first line treatment with UDCA, the results of this study suggest that NK cells, and in particular the CD56Bright NK cell subset, may play a relevant role in the active uncontrolled disease likely through unleashed production of pro-inflammatory cytokines that may sustain and exacerbate the process of fibrosis. If confirmed in further studies, this result may pave the way to novel therapeutic strategies for the treatment of PBC patients unresponsive to UDCA.\"","language":"eng","citation":"ROLE OF NATURAL KILLER CELLS IN THE PATHOGENESIS OF PRIMARY BILIARY CHOLANGITIS / S. Franzese ; tutor: S. Della Bella ; director: N. Landsberger. Università degli Studi di Milano, 2024 Jul 22. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12865.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1075768/2475219/phd_unimi_R12865.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/963656"},"title":"NF1 AS A REGULATOR OF CYTOSKELETON DYNAMICS AND BIOMARKER FOR DECISION-MAKING IN HER2-POSITIVE BREAST CANCER","internalauthor":"ACHUTTI DUSO, BRUNO","type":"Tesi di dottorato","year":"2023","abstract":"The tumour suppressor NF1 is best characterised as a canonical negative Ras regulator, but sparse evidence suggests additional Ras-independent roles. The interaction of its product neurofibromin with both microtubule (MT) and actin cytoskeleton remains poorly characterised to date but may be of particular therapeutic interest as NF1 is somatically mutated across multiple tumour types. We identified NF1 as the second most differentially mutated gene between metastatic and primary HER2+ breast cancer (BC), so we investigated the biological consequences of NF1 loss on sensitivity to antineoplastic treatment and on the metastatic process. We generated NF1 knockout (KO) HER2+ BC cells (i.e.: BT-474, SK-BR-3, HCC1954) by CRISPR/Cas9. NF1KO cells demonstrated exquisite sensitivity to the antibody-drug conjugate (ADC) trastuzumab emtansine (T-DM1). This hypersensitivity was specific to the mertansine MT-targeting component (DM1) since it was i) replicated by the naked payload but not the antibody alone; ii) absent with other ADCs (i.e.: trastuzumab deruxtecan [T-DXd]); iii) not accompanied by increased T-DM1 uptake; and iv) associated with increased drug-target engagement in NF1KO cells. The mechanism is likely Ras-independent, as oncogenic Ras overexpression did not alter T-DM1 sensitivity. By combining molecular biology with confocal and live-cell imaging, we discovered that NF1KO cells exhibited marked signs of altered mitosis with longer G2/M duration, supernumerary centrosomes, chromosome misalignment and frequent aneuploidy. In agreement, we found that BC patients bearing NF1 mutations from the AACR-GENIE cohort exhibited a higher aneuploidy score (AS). MTs in NF1KO cells were severely hypodynamic and showed imbalanced expression of plus/minus end MT-associated proteins (MAPs). This was also associated with an increased abundance of GTP-bound tubulin, a conformational state known to cause MT stability. This raises the intriguing possibility that NF1 may directly regulate tubulin intrinsic GTP-hydrolysis, similar to its GTPase activity on Ras. Finally, we show that NF1KO cells present with markedly anchorage-independent growth advantage, a feature associated with acquisition of metastatic potential. Assessment of biophysical properties of NF1KO models showed enhanced actin subcortical mesh with upregulation of cell junction markers and marked global stiffening by atomic force microscopy. This study provides extensive mechanistic evidence for a previously underappreciated role of NF1 in MT and actin dynamics, which reshapes our understanding of its tumour-suppressive activity and provides a rationale for the pharmacological targeting of NF1-mutated tumours in prospective clinical trials.","language":"eng","citation":"NF1 AS A REGULATOR OF CYTOSKELETON DYNAMICS AND BIOMARKER FOR DECISION-MAKING IN HER2-POSITIVE BREAST CANCER / B. Achutti Duso ; curators: A. FABRICE, M. MAPELLI ; dissertation mentor: L. MAZZARELLA. Dipartimento di Oncologia ed Emato-Oncologia, 2023 Apr 13. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12441.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/963656/2175887/phd_unimi_R12441.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1212535"},"title":"IL «FIGARO» DEL 1864: EDIZIONE COMMENTATA. UN CONTRIBUTO PER GLI STUDI SU ARRIGO BOITO","internalauthor":"REDAELLI, GRETA MARIA ALESSIA","type":"Tesi di dottorato","year":"2026","abstract":"The thesis presents the complete annotated edition of «Figaro», the weekly periodical co-edited by Arrigo Boito and Emilio Praga in Milan during the first quarter of 1864. This undertaking, rare even within the field of periodical studies, is motivated by an interpretation of the journal as an ‘organism’ composed of elements in close dialogue with one another, and is further justified by the prominence of its contributors, members of the first Milanese group of the so-called ‘Scapigliati’. The Introduction identifies the main features of the periodical (its ‘Programme’, the generative potential of the concept of Carnival, French influence and the problem of ‘realism’, etc.) and situates it within the contemporary publishing context, particularly in Milan, highlighting figures such as Leone Fortis, Emilio Treves, Filippo Filippi, Cletto Arrighi, Marco Marcelliano Marcello, and related journals («Il pungolo», «Il lombardo», «Il museo di famiglia», «La perseveranza», «La cronaca grigia», «Il trovatore», etc.). After several illustrative case studies, the work includes sections devoted to individual contributors (in addition to possible anonymous authors, Bernardino Zendrini, Paolo Ferrari, and Camillo Boito), with particular emphasis on the significance of «Figaro» for the figure of Arrigo Boito; a set of final remarks concludes the first part of the thesis. The Philological Note accounts for the editorial choices adopted and discusses the main textual issues, together with the interventions undertaken. The Text itself, arranged by articles and paragraphs while preserving the original layout, is accompanied by a detailed Commentary aimed at elucidating the wording and resolving its references, especially historical and literary, artistic, and musical ones. The thesis is completed by an analytical Index of the names and works mentioned in the Text.","language":"ita","citation":"IL «FIGARO» DEL 1864: EDIZIONE COMMENTATA. UN CONTRIBUTO PER GLI STUDI SU ARRIGO BOITO / G.m.a. Redaelli ; tutor: E. Buroni ; cotutor: E. Sala ; coordinatore del corso di dottorato: M. Faraguna. - Università degli Studi di Milano. Dipartimento di Studi Letterari, Filologici e Linguistici, 2026 Jan 28. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14002.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 04-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1174564"},"title":"DESIGN OF NOVEL MATERIALS FOR PHOTO-THERMO-CATALYTIC SOLAR FUELS PRODUCTION","internalauthor":"LIVOLSI, SIMONE","type":"Tesi di dottorato","year":"2025","abstract":"The global challenge of transitioning to sustainable energy sources underscores the critical need for innovative technologies that can harness solar energy for fuel production. Among various strategies, the generation of solar fuels, such as hydrogen (H2) through water splitting or alcohol reforming, and the conversion of carbon dioxide (CO2) into valuable chemicals, has emerged as a highly promising route. Photocatalysis, which uses light to drive chemical reactions, offers a sustainable approach, but it faces significant limitations, primarily due to the low efficiency of light absorption and conversion by conventional semiconductor catalysts with wide bandgaps.  A novel approach to overcome these limitations involves integrating heat with photocatalysis, a process known as photo-thermo-catalysis (PTC). PTC advantage the combined effects of light and heat, enhancing reaction rates and improving overall solar energy utilization. This PhD project aimed to develop and optimize catalytic systems for PTC, focusing on methanol steam reforming (MSR) for hydrogen production and CO2 reduction, while also deepening the understanding of reaction mechanisms through advanced in-situ techniques.  The first phase of the project involved designing and building a bench-scale experimental setup capable of simultaneously studying the effects of light and heat on catalytic processes. Titanium dioxide (TiO2)-based materials, a well-known photocatalyst, were chosen as the initial focus. These materials were tested for hydrogen production via MSR, with and without the addition of noble metal nanoparticles like platinum (Pt), which are known to enhance charge carrier separation and improve catalytic activity.  The study revealed that TiO2, both in its pure form and decorated with Pt nanoparticles, exhibited significant photocatalytic activity at room temperature. However, the introduction of heat substantially boosted the hydrogen production rate. Notably, Pt/TiO2 demonstrated two distinct activity regions: at lower temperatures, photocatalysis dominated, while at higher temperatures, thermocatalytic activity became predominant, and light still contributed in increasing the H2 productivity and the modulating the selectivity of the process.   Despite the enhanced hydrogen production, a key challenge remained: the undesired formation of carbon monoxide (CO) as a byproduct, which limits the H2 productivity in the process. To address this, cerium oxide (CeO2) was incorporated into the catalyst formulation to promote the Water Gas Shift (WGS) reaction, which converts CO and water into CO2 and additional H2. Various synthesis methods and compositions were explored, revealing that moderate amounts of CeO2 improved catalytic efficiency and selectivity towards CO2, especially at mid-range temperatures. Interestingly, mechanical mixing of TiO2-based catalysts with higher CeO2 content provided the best overall performance, significantly enhancing hydrogen yield and selectivity through effective WGS activity.  In the second phase, research expanded to explore LaFeO3 (LFO) based materials, a class of perovskite oxides noted for their visible-light activity, stability, and cost-effectiveness. Doping LFO with copper (Cu) and forming heterojunctions with other semiconductors were investigated as strategies to improve charge carrier dynamics and catalytic efficiency.  The LFO-based catalysts showed promising results in both CO2 reduction and methanol reforming. The formation of heterojunctions with TiO2 enhanced CO2 reduction efficiency, while Cu-doping significantly improved hydrogen production via methanol steam reforming. These materials benefited from the combined effects of light and heat, underscoring the potential of PTC to enhance reaction rates and selectivity. Moreover, it was observed that introducing structural defects through mechanochemical treatments, while increasing photothermal conversion, i.e., the conversion of light into heat.  To gain a deeper understanding of the reaction mechanisms, in-situ Diffuse Reflectance Infrared Fourier Transform Spectroscopy (DRIFTS) was employed. This technique allowed real-time observation of surface species under reaction conditions, shedding light on how heat, light, and catalyst composition influence the MSR process. The studies showed that methanol adsorbs onto the TiO2 surface, forming intermediates such as methoxy and formate species. Under light irradiation, the formation of photo-oxidation products like formaldehyde and formic acid was enhanced, confirming the photocatalytic activity. The addition of Pt nanoparticles intensified these processes, facilitating the production and subsequent oxidation of adsorbed intermediates, especially at higher temperatures, where different reaction pathways can be observed due to the synergistic effect of heat and light.  This research successfully demonstrated the potential of photo-thermo-catalysis as a promising route to enhance solar fuel production. TiO2-based materials, when combined with noble metals and co-catalysts like CeO2, showed significant improvements in hydrogen production and selectivity. LaFeO3-based systems further expanded the scope of materials suitable for PTC applications, offering new pathways for visible-light-driven reactions. The in-situ mechanistic studies provided critical insights, revealing how heat and light influence reaction pathways, offering a valid mechanistic description of the PTC process involved.","language":"eng","citation":"DESIGN OF NOVEL MATERIALS FOR PHOTO-THERMO-CATALYTIC SOLAR FUELS PRODUCTION / S. Livolsi ; tutor: G. L. Chiarello ; coordinator: L. Prati. Dipartimento di Chimica, 2025 Jul 14. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13530.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 22-GEN-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1119489"},"title":"OPTIMISATION AND INTERDICTION PROBLEMS FOR NETWORK SAFETY","internalauthor":"BOGGIO TOMASAZ, ALBERTO","type":"Tesi di dottorato","year":"2024","abstract":"In this thesis, we explore optimisation problems related to security, focusing on real-world systems that can be modelled using graphs or binary matrices. The first problem we examine is the Weighted Safe Set Problem, a graph optimisation problem that seeks to identify vertex partitions satisfying specific dominance constraints between the parts. For this problem, we propose an exact combinatorial branch-and-bound algorithm alongside several randomised heuristics.  Next, we introduce a family of Binary Interdiction Problems, referred to as Hard Interdiction Problems, involving two agents: the attacker, who acts as the leader, and the defender, who acts as the follower. The defender solves an optimisation problem after the attacker has interdicted the original instance by blocking certain elements, aiming to degrade the defender’s optimal solution as much as possible. For this family of problems, we improve upon state-of-the-art algorithmic frameworks by proposing new formulations and techniques.  Finally, we define the concept of a Resilient Sample: a set of feasible defender solutions such that the attacker cannot simultaneously interdict all of them. We also present methods to compute Resilient Samples for several families of interdiction problems.","language":"eng","citation":"Optimisation and Interdiction problems for Network Safety / A. Boggio Tomasaz ; supervisore: R. Cordone ; co-supervisore: G. Righini ; coordinator: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2024 Dec 04. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13472.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1119489/2593996/phd_unimi_R13472.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/807858"},"title":"TACKLING BIOFILM-RELATED OPPORTUNISTIC FUNGAL INFECTIONS","internalauthor":"OTTAVIANO, EMERENZIANA","type":"Tesi di dottorato","year":"2021","abstract":"More than 1.5 million people/year die for a biofilm-related fungal  infection. The ability to develop biofilms is widespread among  human opportunistic pathogens, among them fungi. Biofilms are a  community of microorganisms with the ability to attach to surfaces  biotic or abiotic, surrounded by a self-produced extracellular  polymeric matrix. The pathogen clearance and the general  overcoming of the infection are complicated by biofilm presence as  it confers tolerance to antimicrobial treatments. Compromised or  altered immune response and an inflammatory milieu can  exacerbate the pathogenesis and prolong the resolution of the  infection. Candida albicans, between yeasts, and Aspergillus  fumigatus between molds, are pathobionts considered the most  common agents of opportunistic fungi mediated. In our study we  assessed different strategies to eradicate biofilms and counteract  biofilm-related infections, targeting both pathogens and host  immune response. We investigated the efficacy of urinary fractions  after cranberry extract intake by healthy volunteers against C.  albicans biofilm. By mass spectrometry analyses, we identified two  metabolites picking in the most active urine fractions, 5-(3′,4′-  dihydroxy phenyl)-γ-valerolactone and 4-hydroxybenzoic acid,  which revealed a strong inhibitory effect on C. albicans adhesion  and biofilm formation. Both compounds were also able to  downregulate the expression of key genes involved in early phases  of biofilm formation. Due to the spread of the use of catheters or  prostheses in the medical field, the possibility to develop  biomaterials with biofilm inhibitory activity could represent a good  10  strategy to control nosocomial infections. We thus investigated  newly synthesized hydrogels and demonstrated their ability to  prevent C. albicans growth.  To target both pathogen virulence and host immune response, we  conducted two different studies, the first on C. albicans systemic  candidiasis and the second on A. fumigatus infection in cystic  fibrosis patients.  We investigated the possible dual action of pilocarpine, a  muscarinic receptor agonist, in vitro and in vivo using the model  host Galleria mellonella. Pilocarpine showed a direct effect in  inhibiting C. albicans biofilm biomass and metabolic activity, and its  administration to infected larvae increased larval survival. Because  of the different behavior of pilocarpine compared to acetylcholine in  the modulation of larva immune response, we concluded that the  antifungal activity of pilocarpine might rely on muscarinic-like  receptor activation on C. albicans, whereas the strong  immunomodulatory effect of acetylcholine (but not of pilocarpine)  might imply the engagement of nicotinic receptors. A similar  approach, aimed at targeting both infection and inflammation, was  used to investigate A. fumigatus persistence in CF patient lungs.  Indeed, CF monocytes are characterized by altered intracellular  lipid accumulation, that compromise pathogen clearance, and the  infection resolution. We demonstrated that the treatment of patient  monocytes with Myriocin, by inhibiting the synthesis of sphingolipids  and hampering CF inflammation, ameliorate the A. fumigatus  conidia internalization and clearance. On the host side, Myriocin  11  was able to reduce the over expression of genes encoding for proinflammatory  cytokines and at the same time to increase the  expression of gene encoding for pathogen recognizing receptors,  crucial for its clearance.  Our results indicate that, despite we are still far from clinical  practice, exploring alternative anti-biofilm strategies could pave the  way to new target discovery and to integrated approaches able to  promote the infection resolution.","language":"eng","citation":"TACKLING BIOFILM-RELATED OPPORTUNISTIC FUNGAL INFECTIONS / E. Ottaviano ; tutor: E. Borghi ; coordinatore: M. Samaja. Dipartimento di Scienze della Salute, 2021 Jan 21. 33. ciclo, Anno Accademico 2020. [10.13130/ottaviano-emerenziana_phd2021-01-21].","filename":"phd_unimi_R11871.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/807858/1682757/phd_unimi_R11871.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1253755"},"title":"USING ARTIFICIAL INTELLIGENCE FOR DETECTING DISCRIMINATORY LANGUAGE","internalauthor":"MOHAMMADI, FATEMEH","type":"Tesi di dottorato","year":"2026","abstract":"\"The rapid expansion of generative AI and large language models (LLM) has transformed how individuals and institutions communicate online. While these systems offer powerful capabilities for understanding natural language and generating natural language text, their ability to reliably detect linguistic patterns depends critically on the quality, completeness, and representativeness of their training data. As LLM become increasingly central to content moderation and language classification tasks, there is a growing need for robust and reproducible pipelines grounded in well-constructed datasets. However, many existing approaches lack systematic data-centric frameworks, leading to models that may fail to generalise or perpetuate biases present in incomplete or unbalanced training data. This dissertation investigates how data-centric methodologies can be used to construct robust pipelines for language classification, with a particular focus on harmful language detection in Italian. Rather than prioritising algorithmic modifications alone, the research develops an end-to-end pipeline encompassing data collection, dataset curation, synthetic data generation, LLM-based annotation through introducing a \"\"General Data Framework (GDF)\"\", followed by data selection and quality assessment, supervised fine-tuning, and multi-dimensional model evaluation. A central  contribution of this thesis is addressing the challenge of limited human-validated annotations for language detection tasks. Through systematic experimentation across two distinct tasks, we propose two complementary solutions, each tailored to a different data constraint scenario. The first solution targets settings where annotation quality is low: rather than relying on costly human labelling, we leverage a teacher–student framework in which an LLM generates weakly supervised labels that are then used to fine-tune a smaller, open-source model. We demonstrate that carefully curated LLM-generated labels can effectively transfer task-specific knowledge, preserving detection performance as the teacher model while substantially reducing the computational and deployment costs associated with harmful language detection systems using a smaller  open-source model. The second solution addresses settings where annotation quality is high, but quantity is insufficient: starting from a small seed dataset of human-validated examples, we augment the training data with synthetically generated instances and fine-tune on the combined corpus. Applied to the task of detecting non-inclusive language in job descriptions, this approach yields meaningful performance gains despite the scarcity of the original labelled data. Taken together, these two solutions define the core methodological contribution of the thesis: a principled, data-centric framework that begins from a suboptimal starting point — whether low-quality labels or low-quantity annotations — adopts a targeted strategy to overcome the associated limitations, and achieves reliable, reproducible results in both cases. Methodologically, the dissertation draws on insights from NLP, ML, and ethical AI. It introduces a reproducible evaluation framework that integrates standard performance metrics with fairness, bias, and trustworthiness assessments, augmented by text-complexity features that enable semantic-level analysis beyond conventional aggregate metrics. Building on this foundation, the work improves the performance of language models for downstream tasks through LLM-annotated fine-tuning and knowledge distillation into smaller, robust classification systems. The proposed pipeline is validated through real-world case studies, including harmful content detection on social media and inclusive language evaluation in job descriptions, demonstrating that well-curated data and rigorous evaluation are essential for responsible and effective LLM-based language classification.  The outputs and contributions of this thesis can benefit a range of stakeholders. From a research perspective, it provides a reproducible framework for implementing systems that detect harmful language efficiently and at lower cost through the teacher–student approach. Researchers can also use the GDF introduced in this thesis as a guide for data collection or enrichment, while benefiting from deeper evaluation methods that incorporate text complexity features. From a technical perspective, the results can support content moderators, HR tech platforms, and policy makers: the fine-tuned models can be used as internal tools for monitoring content published on  media platforms or as moderation tools within hiring systems. For policymakers, the findings offer insights into the types of language that require more attention, helping guide educational interventions and initiatives to raise awareness about stereotypes or non-inclusive language in society. Regarding adaptability, the GDF is language-agnostic and can be applied to any task requiring structured data collection or annotation enrichment. The overall methodology workflow  makes no language-specific assumptions and transfers directly to other domains or languages. The teacher–student approach embedded within the pipeline of Task 1 can likewise be extended to other domains where large-model annotation is more cost-effective than human labelling, such as medical misinformation detection, legal document classification, or financial sentiment analysis. Finally, the synthetic data generation workflow used for Task 2— based on masking and controlled replacement — can be adopted in scenarios where masking and replacement strategies are appropriate, for example, in anonymizing personal data, generating augmented examples for  sentiment analysis, or expanding low-resource datasets in specialized domains such as legal or medical texts.\"","language":"eng","citation":"USING ARTIFICIAL INTELLIGENCE FOR DETECTING DISCRIMINATORY LANGUAGE / F. Mohammadi ; tutor: P. Ceravolo ; co-tutor: V. Bellandi ; coordinatore: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2026 Apr 29. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R14170.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 09-DIC-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1135496"},"title":"ROLE OF EXTRACELLULAR VESICLES  IN THE ASSOCIATION BETWEEN  AIR POLLUTION EXPOSURE AND MAJOR DEPRESSIVE DISORDER","internalauthor":"MONTI, PAOLA","type":"Tesi di dottorato","year":"2025","abstract":"Introduction: Major depressive disorder (MDD) is a common multifactorial condition, with both genetic and environmental causes. Recently, several epidemiological studies have suggested an association between air pollution exposure and MDD; indeed, inhalation of air pollutants such as particulate matter (PM) may promote blood-brain barrier (BBB) disruption and neuroinflammation, possibly exacerbating MDD symptoms. Nevertheless, the biological mechanisms underlying this association remain largely uninvestigated.   Extracellular vesicles (EVs) are a powerful system of intercellular communication that participates in the response to many environmental cues. EVs can cross the BBB and alter its permeability, thus modulating the bi-directional exchange of information between the brain and the periphery. Since EVs can be found in virtually all biological fluids and carry molecular components originating from parental cells, they might provide a non-invasive strategy to study alterations occurring in otherwise inaccessible organs. Of note, alterations in EV profile have been reported under many pathological conditions, including MDD.   Aims of the project: to clarify the biological mechanisms linking air pollution exposure, EVs, and brain pathophysiology. To achieve this aim, the project was divided in two parts: Part 1 was carried out at the EPIGET lab (University of Milan) and aimed at investigating the complex relationship between air pollution exposure, circulating EVs released by neurons (NdEVs), and MDD severity; Part 2 was carried out at the Edinger Institute (Goethe University Frankfurt) and aimed at investigating the effect of EVs released by PM-treated cultured bronchial epithelial cells on an in vitro BBB model.  Part 1, materials and methods: 93 patients with MDD were randomly selected from the population of the DeprAir study (a study specifically designed to investigate the association between air pollution and MDD). Daily exposures to air pollutants (NO2, fine PM) were estimated through a flexible chemical transport model and assigned to study participants according to their residential address. MDD severity was assessed by five different rating scales. The immunoaffinity capture protocol for the isolation of NdEVs was validated by flow cytometry and nanoparticle tracking analysis. The top miRNAs carried by NdEVs were selected by screening 754 miRNAs and analyzed by target prediction/functional annotation. Then, the expression of such miRNAs was quantified by RT-qPCR in plasma NdEVs from the study population. The collected data were used to evaluate the association between air pollution exposure and the miRNA profile of NdEVs, and between NdEV miRNAs and MDD severity.   Part 2, materials and methods: human bronchial epithelial cells (BEAS-2B) were treated with different concentrations of three types of fine PM (ERM-CZ110, NIST2786, and PM Como), and the effect of such treatment on viability was evaluated by MTT assay and propidium iodide staining. EVs were isolated from the culture supernatant and used to treat a BBB model of mouse brain microvascular endothelial cells (MBMECs). BBB integrity was assessed by measuring trans-endothelial electrical resistance (TEER), as well as by immunocytochemistry.  Part 1, results: The efficacy of the immunocapture protocol of NdEV was higher than 90%. On average, NdEVs accounted for 4.5% of total EVs, and had a smaller size (182 nm vs 218 nm). The top-miRNAs carried by NdEVs were mainly implied in intracellular signaling, cellular responses to stress/external stimuli, immune system regulation, and cell senescence. After performing NdEV miRNA analysis on the 93 study subjects, short-term NO2 exposure was found to be associated with increased levels of 4 miRNAs (miR-1274B, miR-320, miR-720, miR-451). Instead, miR-19b was positively associated with long-term exposures to both NO2 and PM with an aerodynamic diameter ≤2.5 µm (PM2.5). Besides, 10 miRNAs were associated with at least one MDD severity scale. Among them, the brain-enriched, anti-inflammatory miR-451 was found to be negatively associated with MDD severity; similarly, the anti-apoptotic miR-19b was associated with lower MDD severity scores.    Part 2, results: Different PM types were found to elicit different effects on BEAS-2B cell viability, with NIST2786 causing cell death in dose-independent manner. EVs released by BEAS-2B cells treated with 100 µg/ml NIST2786 strongly reduced the TEER of MBMEC monolayers, if compared to EVs released from untreated cells. Such PM-induced EVs also affected the spatial organization of junctional proteins implied in BBB integrity.  Discussion and conclusions: Overall, this study provides novel epidemiological and molecular insights into the role of EVs in mediating the effects of air pollution exposure on the brain. The profiling of NdEV miRNAs could pave the way for the identification of novel prognostic biomarkers for MDD. Understanding the influence of PM-induced EVs on the BBB might provide new perspectives on the complex mechanisms modulating brain biology in response to peripheral environmental stimuli.","language":"eng","citation":"ROLE OF EXTRACELLULAR VESICLES  IN THE ASSOCIATION BETWEEN  AIR POLLUTION EXPOSURE AND MAJOR DEPRESSIVE DISORDER / P. Monti ; supervisore: M. Carugno ; phd program coordinator: C. V. B. La Vecchia. Dipartimento di Scienze Cliniche e di Comunità, 2025 Jan 28. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13387.pdf","fileformat":"Adobe PDF","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1135496/2635686/phd_unimi_R13387.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/874603"},"title":"NOVEL SMART DEVICES FOR THE ADMINISTRATION OF DRUGS INTO HOLLOW MUSCULAR ORGANS","internalauthor":"UBOLDI, MARCO","type":"Tesi di dottorato","year":"2021","abstract":"In this PhD thesis, the potential of smart materials, and particularly of shape memory polymers (SMPs), in pharmaceutics has been widely investigated. SMPs, with their ability to dynamically respond to specific external stimuli by changing their shape over time, currently represent one of the topics at the forefront of research. Within the pharmaceutical field their use was demonstrated able to provide innovative performance and to overcome limitations associated with the already available therapeutic approaches, e.g. poor patient compliance, ability to ensure effective drug levels at the target area for a prolonged period of time, fine tuning and customization of the overall performance. This was the main topic of a comprehensive overview of the scientific literature available, focused on SMP-based drug delivery systems (DDSs) and aimed at highlighting the objective for which the shape changes were pursued. From an experimental point of view, the possibility of using SMPs of pharmaceutical-grade in the development of DDSs intended for long-lasting retention into hollow-muscular organ, such as bladder and stomach, was approached for the first time. In this respect, the shape shifting process would ensure safe administration and enable prolonged retention at the site of interest. Feasibility of prototypes was investigated using quite novel techniques for pharmaceutical manufacturing, i.e. hot melt extrusion and fused deposition modeling 3D printing, the latter providing the tool for 4D printing when dealing with SMPs as starting materials. Film-coating of SMPs-based prototypes having complex geometries was also demonstrated as a viable strategy to prolong the release duration without affecting the shape memory behavior. Moreover, the comprehensive experimental campaign carried out was coupled with computer-aided simulation modelling to accelerate the R&D stages and to improve the overall performance of the DDSs proposed. In fact, thanks to this approach, it would be possible to predict the shape memory behavior of complex prototypes while reducing the number of physical samples to be attained.","language":"eng","citation":"NOVEL SMART DEVICES FOR THE ADMINISTRATION OF DRUGS INTO HOLLOW MUSCULAR ORGANS / M. Uboldi ; tutor: L. Zema ; coordinatore:  G. Aldini. Università degli Studi di Milano, 2021 Oct 14. 34. ciclo, Anno Accademico 2021. [10.13130/uboldi-marco_phd2021-10-14].","filename":"phd_unimi_R12179.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/874603/1887058/phd_unimi_R12179.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1215642"},"title":"ALTERNATIVE AL CARCERE, ESECUZIONE DELLA PENA NELLA COMUNITÀ E IMPATTO SULLA RECIDIVA","internalauthor":"COLOMBO, DAVIDE","type":"Tesi di dottorato","year":"2026","abstract":"The thesis critically examines the system of alternatives to imprisonment in Italy, focusing in particular on the modalities of sentence execution within the community and on the impact of non-custodial sanctions on recidivism rates. Starting from the structural and functional crisis of the prison system – characterized by chronic overcrowding, poor rehabilitative efficiency, and conditions often detrimental to human dignity –, the research investigates the actual capacity of community-based sanctions to fulfill the constitutional aim of rehabilitating the offender, using the reduction of reoffending rates as a benchmark. Through an interdisciplinary approach and a comparison with the French experience, the study highlights the need to construct individualized sanctioning paths capable of identifying and addressing the specific risk factors related to each offender, as the most effective strategy to ensure the punitive response to crime is also effective in preventing recidivism. Furthermore, a methodological model for the empirical evaluation of the effectiveness of different sanctioning modalities is developed. The conclusions outline the prospect of a reformed punitive system praeter carcerem founded on the centrality of the rehabilitative function, the principle of proportionality, and the use of prison as an extrema ratio, within a framework of criminal justice genuinely oriented toward social reintegration.","language":"ita","citation":"ALTERNATIVE AL CARCERE, ESECUZIONE DELLA PENA NELLA COMUNITÀ E IMPATTO SULLA RECIDIVA / D. Colombo ; tutor: G.L. Gatta ;  cotutor: A.P.A. Della Bella ;  coordinatore: E. Damiani. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2026. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14082.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1215642/3250380/phd_unimi_R14082.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1198762"},"title":"LINKING TRANSCRIPTIONAL AND MORPHOLOGICAL HETEROGENEITY TO THERAPEUTIC VULNERABILITIES IN GLIOBLASTOMA","internalauthor":"IANNUZZI, RAFFAELE MARIA","type":"Tesi di dottorato","year":"2025","abstract":"This thesis is the result of my doctoral studies conducted within the Iorio  Laboratory at Human Technopole and whose overarching goal has been to  design and use data-driven approaches for the integration of molecular and  functional-genetics data from preclinical models with the aim of prioritizing  subtype-specific therapeutics vulnerabilities in Glioblastoma (GBM).  Particularly, in an initial phase of my activities, I have designed and  implemented computational methods for reliability and reproducibility  assessment of “essentiality profiles” from genome-wide recessive pooled  CRISPR-Cas9 screens. Furthermore I have contributed methods and analyses  for benchmarking state-of-the-art computational methods aiming at  preprocessing CRISPR screening data, and correcting technology-specific  biases, such as the tendency of the CRISR-Cas9 system to elicit a  gene-independent detrimental effect on cellular survival when targeting  genomic copy-number amplified regions (CN bias) and spurious effect due to  Cas9-mediated whole chromosome arm truncations (proximity bias).  Subsequently, I have focused on the integration of transcriptomics and  CRISPR-based genome-editing data for prioritizing potential therapeutic  targets that regulate Glioblastoma stem cells (GSCs) morphology and  survival, in collaboration with the Kalebic research group. A key result of this  collaboration has been the identification of adducin-γ (ADD3), a previously  known  morpho-regulator  of human neural progenitor cells, as a  context-specific essential gene in GBM. I further investigated ADD3  expression at the single-cell level in GBM primary tumours, where I found it  to be associated with an oligodendrocyte-progenitorlike (OPC-like) signature,  suggesting a specific role of ADD3 in this transcriptional subtype. Adopting  this specific case as a proof-of-concept, I have then designed an analytical  framework that integrates pharmacogenomics and CRISPR genome-editing  with single cell RNA sequencing (scRNA-seq) data, leveraging the Cancer  13Dependency Map (DEPMAP) resource. This framework aims to prioritize  GBM subtypes’ vulnerabilities upon a broad spectrum of genetics and drugs  perturbation, aiding in the identification of new potential targets and  therapeutic compounds that may be most effective in reducing viability of  specific subtypes.","language":"eng","citation":"LINKING TRANSCRIPTIONAL AND MORPHOLOGICAL HETEROGENEITY TO THERAPEUTIC VULNERABILITIES IN GLIOBLASTOMA / R.m. Iannuzzi ; supervisor: F. Iorio, N. Kalebic, L. Calviello, E. Petsalaki. Dipartimento di Scienze della Salute, 2025 Dec 16. 37. ciclo, Anno Accademico 2025.","filename":"phd_unimi_R13484_1.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1198762/3191917/phd_unimi_R13484_1.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1128001"},"title":"LINE1 MODULATE HUMAN T CELL FUNCTION BY REGULATING PROTEIN SYNTHESIS DURING LIFE SPAN","internalauthor":"BURATTIN, FILIPPO VITTORIO","type":"Tesi di dottorato","year":"2025","abstract":"The composition and function of the T cell pool evolve throughout human life to adapt to varying environments and immune challenges. Neonatal T cells constitute a distinct developmental subset of rapidly responsive naïve T cells, primarily consisting of recent thymic emigrants with no memory function. In contrast, elderly individuals have predominantly memory T cells, which exhibit signs of exhaustion and diminished reactivity, characteristic of immunosenescence. The molecular mechanisms underlying the rapid activation of neonatal T cells and the reduced responsiveness in the elderly remain unclear. Our previous research identified that quiescent adult naïve CD4+ T cells express alternative transcript isoforms containing sequences of LINE1 retrotransposons at their chromatin. We also demonstrated that the downregulation of these RNAs species marks the transition to activation. In this study, we unveil that neonatal naïve T cell quiescence is characterized by enhanced energy production and protein synthesis. This phenotype is associated with absence of LINE1 expression attributed to tonic TCR/mTORC1 signalling and PTBP1-mediated LINE1 splicing suppression. We discovered that the absence of LINE1 expression primes these cells for rapid execution of the activation program by directly regulating protein synthesis. LINE1 expression progressively increases in childhood and adults, peaking in elderly individuals, where, by decreasing protein synthesis, contributes to immune senescence in ageing. Overall, our study proposes LINE1 as a critical player of human T cell function across human lifespan.","language":"eng","citation":"LINE1 MODULATE HUMAN T CELL FUNCTION BY REGULATING PROTEIN SYNTHESIS DURING LIFE SPAN / F.v. Burattin ; tutor: B. Bodega ; coordinatore: R. Mantovani. Dipartimento di Scienze Cliniche e di Comunità, 2025 Jan 09. 37. ciclo [10.13130/burattin-filippo-vittorio_phd2025-01-09].","filename":"phd_unimi_R13357_2.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1128001/2617325/phd_unimi_R13357_2.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1226715"},"title":"The Other Option","internalauthor":"DUCA, GIOVANNI","type":"Tesi di dottorato","year":"2026","abstract":"Hanti Lin and Kevin Kelly [LK12] introduce a way of relating probability functions and binary beliefs, referred to as odds-threshold method, which is based on comparing the probabilities of the elementary outcomes. Outcome o1 is preferred to outcome o2 if o1 is sufficiently more likely than o2; the agent’s belief-set is the set of mostly preferred outcomes. As main contribution, we give a probability-independent definition of the preferential orders generated by the odds-threshold method. This allows for a logical characterization of the belief revision properties induced on binary beliefs by Jeffrey conditioning (JC) on a piece of evidence. Specifically, we show that if JC is assumed to be successful – namely, the evidence is implied by the belief-set induced by the posterior probability – then the corresponding belief revision on binary beliefs satisfies all the rules of the nonmonotonic system P together with Disjunctive Rationality [Fre93] and a  new rule named Plausible Monotonicity. As JC does not require the evidence to be certain, we also considered rules for iterated belief revision. In the case of successful JC, the induced iterated belief revision satisfies the rules (C1), (C2) and  (C3), proposed by Darwiche and Pearl [DP97]. In addition, if JC is also assumed to be confirmatory – i.e. the posterior probability of the evidence is strictly greater than its prior – then the rule (C4) is satisfied as well.","language":"eng","citation":"The Other Option / G. Duca ; tutor: H. Hosni ; co-tutor: M. Piazza ; coordinatore: F. Guala. Dipartimento di Filosofia Piero Martinetti, 2026 Mar 25. 38. ciclo","filename":"phd_unimi_R13776.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1226715/3279554/phd_unimi_R13776.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1121621"},"title":"IMPIEGO DI CEREALI PIGMENTATI E PSEUDOCEREALI NELLA DIETA SENZA GLUTINE: ANALISI DELLE PROPRIETÀ BIOATTIVE DI ZEA MAYS L., ORYZA SATIVA L., FAGOPYRUM ESCULENTUM M. E FAGOPYRUM TATARICUM (L.) GAERTN","internalauthor":"BANI, CORINNE","type":"Tesi di dottorato","year":"2025","abstract":"Celiac disease is an autoimmune disorder that occurs in genetically predisposed individuals due to the ingestion of prolamins present in cereals such as wheat, barley, and rye. Even after following a gluten-free diet, many celiac patients continue to experience symptoms related to inflammation and oxidative stress. Therefore, it is crucial to identify new gluten-free ingredients that can provide additional benefits, reducing inflammation and oxidative stress, and improving the quality of life for individuals with celiac disease.  In this regard, pigmented cereals such as two samples of Zea mays L. (varieties Rostrato di Rovetta and Scagliolo Rosso), three samples of Oryza sativa L. (varieties Violet, Venere, and Nerone), and the pseudocereal Fagopyrum esculentum Moench (nine varieties, eighteen samples) and one variety of Fagopyrum tataricum (L.) Gaertn (one sample) have been studied to evaluate their potential inclusion in the diet of celiac patients.  Spectrophotometric and chromatographic methods (HPTLC, LC-HRMS, HPLC-DAD and HPLC-FLD) were used to characterize the phenolic profile and antioxidant capacity of the varieties included in the study. An interesting phenolic profile in the pigmented cereals was obtained. Additionally, tartary buckwheat (Fagopyrum tataricum (L.) Gaertn) exhibited a polyphenolic profile and antioxidant activity higher than the common buckwheat (Fagopyrum esculentum Moench). Extracts of pigmented rice and corn were assayed on CaCo-2 cells, demonstrating inhibitory effects on reactive oxygen species (ROS) and anti-inflammatory capacities. Finally, the buckwheat varieties were subjected to different biological assays (e.g., Dumas method, SDS-PAGE, total starch analysis, phytic acid assay, glycemic index assay) integrated with enzymatic assays (α-amylase, α-glucosidase, and DPP-IV activity).  The results suggest that these matrices, thanks to their antioxidant and anti-inflammatory properties in vitro, could represent valuable functional food ingredients, potentially improving celiac patients’ health.","language":"ita","citation":"IMPIEGO DI CEREALI PIGMENTATI E PSEUDOCEREALI NELLA DIETA SENZA GLUTINE: ANALISI DELLE PROPRIETÀ BIOATTIVE DI ZEA MAYS L., ORYZA SATIVA L., FAGOPYRUM ESCULENTUM M. E FAGOPYRUM TATARICUM (L.) GAERTN / C. Bani ; tutor: C.M. DI LORENZO ; coordinatore: F. CHELI. Dipartimento di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti, 2025 Jan 13. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13308.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1121621/2599201/phd_unimi_R13308.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1152715"},"title":"LA GENESI DELL¿EPIGRAMMA ITALIANO: PROPOSTE TEORICHE, MODELLI, SPERIMENTAZIONI LETTERARIE, SOLUZIONI EDITORIALI","internalauthor":"CASIRAGHI, CHIARA","type":"Tesi di dottorato","year":"2025","abstract":"\"This doctoral thesis explores the origins of the Italian epigram, focusing on its development in the sixteenth and early seventeenth centuries through both theoretical frameworks and compositional practices. It begins with a comparative analysis of key theoretical texts, including those by Robortello, Minturno and Scaligero, as well as Jesuit manuals, to identify recurring themes and their evolution. Special attention is also given to the specifically Italian debate surrounding the genre, particularly focusing on the relationship between the epigram and the brief lyrical forms of the Italian vernacular tradition (sonnet and madrigal). Following the theoretical framework, the analysis shifts to the poetic production itself, considering significant collections explicitly labeled as epigrammatic. After exploring Eurialo d’Ascoli’s \"\"Stanze sopra il Laocoonte, la Venere e l’Apollo\"\" and Gabriele Simeoni’s \"\"Metamorfoseo d’Ovidio\"\", which are examined for their strategies in adapting the ottava rima to an epigrammatic style, the investigation focuses on two major vernacular projects aimed at the re-foundation of the classical epigram: the epigrammatic collections of Luigi Alamanni and Bernardino Baldi. The thesis analyzes their intentions, textual traditions, classical sources and references, various epigrammatic types explored, as well as stylistic choices and metric solutions.\"","language":"ita","citation":"LA GENESI DELL¿EPIGRAMMA ITALIANO: PROPOSTE TEORICHE, MODELLI, SPERIMENTAZIONI LETTERARIE, SOLUZIONI EDITORIALI / C. Casiraghi ; tutor: G. Barucci ; coordinatore: F. Slavazzi. Dipartimento di Studi Letterari, Filologici e Linguistici, 2025 Mar 14. 37. ciclo [10.13130/casiraghi-chiara_phd2025-03-14].","filename":"phd_unimi_R13314.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 31-DIC-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/961403"},"title":"GREEN CATALYTIC STRATEGIES FOR THE PRODUCTION OF BIOBASED BUILDING-BLOCKS","internalauthor":"CAVUOTO, DENISE","type":"Tesi di dottorato","year":"2023","abstract":"Green chemistry is an important tool in the roadmap towards a sustainable economy system. Biomass-waste valorization, in particular ligno-cellulosic wastes, and the use of sustainable processes are pillars of the green chemistry approach. Notably, biobased lactones can be valorized into new valuable molecules such as diols and amines that are ubiquitous chemicals in today’s chemical industry. The use of simple and cheap heterogeneous copper catalysts supported on various materials, prepared with the Chemisorption-Hydrolysis method, will avoid toxic and expensive noble metal catalysts. These materials are easy to prepare, resistant and provide reliable results. Depending on the nature of the support they can have different acidic/basic or wettability properties making them very versatile in organic synthesis. Deep characterization was performed on the catalytic system to enlighten the relationship between physicochemical properties of the catalysts with their performances. Particularly, a focus was given on the study of copper phase morphology, wettability and acidity of the surfaces.  The first part of the Ph.D project was devoted to study the hydrogenation of γ- valerolactone (GVL) to 1,4-pentanediol (1,4-PDO) (scheme A1), using silica supported copper catalysts under the green solvent cyclopentylmethylether (CPME).  Scheme A1. Hydrogenation of GVL to give 1,4-PDO.  Notably, two different methods have been implemented to obtain low hydrophilic  catalysts namely the right choice of the support and the post-metal deposition hydrophobization through silane grafting. In the first case, two different SiO2 materials, namely one less hydrophilic pyrogenic and one hydrophilic gel, were chosen to prepare two copper catalysts CuO/SiO2 A and CuO/SiO2 B respectively. The wettability properties of the two supports were confirmed through static contact angle measurements and with hydroxyl density determination using TGA. The catalysts were tested in the hydrogenation of GVL to give 1,4-PDO (T=160 °C, P(H2) = 50 bar, t = 22h) after catalysts pre-reduction under CPME. The best performances were obtained using Cu/SiO2 A achieving 78% in the diol while 47% was achieved by Cu/SiO2 B. The catalysts performances were ascribed to the SiO2 support wettability: a low hydrophilicity allows the diol product a better desorption, preventing methyltetrahydrofuran formation by dehydration side reaction. Moreover, as confirmed by XPS analysis, a low -OH surface density allows to achieve a higher Cu dispersion, thus a higher hydrogenation activity compared to the catalyst CuO/SiO2 B prepared with the more hydrophilic silica. Furthermore, the activity was found to be dependent on the nature and on the effective number of the acid sites on the surface measured in CPME through FT-IR after pyridine adsorption and through liquid-solid titration using phenylethylamine (PEA) as a probe molecule respectively. In fact, the presence of a lower quantity and density (1 μmolPEA/m2 vs 5 μmolPEA/m2 for CuO/SiO2 A and CuO/SiO2 B respectively) of strong acid sites observed with CuO/SiO2 A in CPME could therefore be the main reason for its much higher selectivity (98% vs 82% for CuO/SiO2 A and CuO/SiO2 B respectively). This has a more pronounced masking effect on the case of CuO/SiO2 A Lewis acid sites.  Successively, an uncomplicated procedure of surface functionalization of the more hydrophilic CuO/SiO2 B catalyst using trietoxyoctylsilane (TEOCS), was set up to explore the possibility to obtain low hydrophilic systems with a post metal deposition method. Four samples with different silane loading were obtained (namely 1, 5, 10 and 15% wt/wt) and the catalysts properties were investigated by several characterization techniques. The effective silane grafting was confirmed by IR and XPS while the stability at the reaction temperature (T=160 °C) was assessed using TGA. The progressive reduction of hydrophilicity was confirmed by SCA measurements and water adsorption isotherms. The results obtained showed that the functionalization significantly lowers the hydrophilicity of the surface with a decrease of SCA of 20% from the bare CuO/SiO2 to the CuO/SiO2 B - 15% TEOCS. The materials were tested in the hydrogenation reaction under the same conditions and an increase in the diol yield from 47% in the case of the unfunctionalized one to 80% in the case of the 10% wt/wt TEOCS was observed. However, a further organosilane loading, as in the case of 15%, gives rise to a decrease in activity due to the scarce accessibility of GVL to the copper sites. This behavior was corroborated by 29Si CP MAS solid state NMR measurements that is able to distinguish the silicon of the bulk silica and the organosilicon. The spectra showed a dense surface silane layer on the 15% loaded sample with a T3 configuration, namely in a reticulated-type structure, if compared to the 10% one. From the results it was possible to deduce that the capability to easily tune the wettability properties of the metal supported catalysts paves the way to a wide range of applications in which both the metallic phase activity and the polarity of the surface play a pivotal role in affecting the catalytic reaction.  7    The second part of the Ph.D thesis was focused on the synthesis of N-heterocycles once again starting from GVL. N-alkyl-5-methyl-2-pyrrolidinones and pyrrolidines are an important class of chemicals that can be used as benign alternative solvent or as the starting material for the synthesis of agrochemicals and pharmaceuticals. GVL has been coupled with butylamine to obtain N-butyl-5-methyl-2-pyrrolidone (NBPO) and N-butyl-5-methyl-2- pyrrolidine (NBPE) (Scheme A2) utilizing similar copper catalysts supported on different materials.  Scheme A2. Reaction of amination of GVL to give NBPO and NBPE.  Initially, copper was deposited on three different supports widely used in catalysts preparation: one amphoteric, namely hydroxyapatite (HAP), one acidic, namely SiO2-Al2O3 and one moderately acidic, namely SiO2 and the acidity of the readily made catalysts was deeply characterized through FT-IR after pyridine adsorption and solid-liquid acid-base titration using PEA as basic probe molecule. Copper phase morphology was investigated through TEM, UV-DRS and TPR analysis. Subsequently the catalysts were tested in the lactamization of GVL with butylamine. (T=200 °C, P(H2) = 10 bar and GVL:BuNH2 = 1:1) The reaction conditions and the set up were improved to lower the impact avoiding catalyst pre- treatment and high hydrogen pressure. The best results were achieved by CuO/HAP with the highest conversion and selectivity towards the green solvent product NMPO (77% and 61% respectively) while the most selective toward NBPE was CuO/SiO2. This behavior was ascribed to the high density while low strength Lewis acidity of the CuO/HAP if compared to the other samples. Once again, this moderate Lewis acidity allows to coordinate the C=O group and activate the GVL to the amine nucleophilic attack. On the other hand, the higher reducibility of CuO/SiO2 gives account for its higher activity in the deoxygenation of NBPO to NBPE, due to the in situ easier formation of reduced copper phase. Considering these results, other supports, namely Al2O3 A, Al2O3 B, ZrO2 and TiO2, were chosen to prepare the corresponding copper catalysts that were also tested in the lactamization reaction. The best performances were observed with the CuO/Al2O3 B achieving 75% conversion of GVL with a selectivity towards NMPO of 75% while the worst results were obtained using CuO/Al2O3 A (30% conversion and 70% selectivity). The reasons were found in the higher copper dispersion and in the lower particle size of Cu on the CuO/Al2O3 B catalyst  8    investigated by TEM and XRD. The system also showed its efficacy for the lactamization of other biobased lactones.  Also in this case, the characterization of the morphology of the copper phase and of the acidity of the systems was of great importance to understand the catalytic behavior of the samples. Moreover, the activity and selectivity can be easily tuned by varying the hydrogen pressure in the reaction environment and the acidic properties of the support. In particular, modulating the acidity properties of the catalysts is an important tool to drive the reaction selectivity towards each product.","language":"eng","citation":"GREEN CATALYTIC STRATEGIES FOR THE PRODUCTION OF BIOBASED BUILDING-BLOCKS / D. Cavuoto ; tutor: A. Gervasini ; co-tutor: F. Zaccheria. Dipartimento di Chimica, 2023 Apr 04. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12557.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/961403/2168450/phd_unimi_R12557.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/978728"},"title":"THE USE OF PRIVATE MILITARY AND SECURITY COMPANIES BY BUSINESS ENTERPRISES: ISSUES OF INTERNATIONAL CRIMINAL RESPONSIBILITY.","internalauthor":"NIZZI, LORENZO","type":"Tesi di dottorato","year":"2023","abstract":"The legal issue underlying this thesis is the attribution of criminal responsibility when more than one individual is involved in the commission of an international crime. Imagine a business enterprise operating in a risky place and retaining a private military and security company. Imagine now that, while rendering military/security services, the private contractors commit crimes against humanity with the help of the firm’s directors and the host State’s public officials. Who is responsible for that? Absent any legal precedent squarely applicable to this set of facts, I attempted to answer this query by: (i) designing four factual scenarios, where security contractors, business enterprise’s executives, and public officials contribute to varying degrees to the offense; (ii) examining case law on accomplice (and command) liability under Dutch law and the Rome Statute, focusing in particular on cases where business actors were convicted for aiding and abetting international crimes; and (iii) applying the rules developed by the case law to the four case studies. The “who is responsible” analysis is fact based, so the outcome largely depends on how the factual scenario has been designed. However, two broader conclusions can be drawn. First, the presence of private contractors determines a fragmentation of military/security services. This may be a source of difficulties, as responsibility correspondingly becomes more diffused and therefore difficult to ascertain. Second, criminal justice systems—domestic and international—ensure that criminal liability is not stretched too far. (Corporate) defendants are convicted for their own conduct, not for their association with the perpetrator of the crime.","language":"eng","citation":"THE USE OF PRIVATE MILITARY AND SECURITY COMPANIES BY BUSINESS ENTERPRISES: ISSUES OF INTERNATIONAL CRIMINAL RESPONSIBILITY / L. Nizzi ; tutor: M. Pedrazzi ; phd coordinator: F. Biondi. Dipartimento di Studi Internazionali, Giuridici e Storico - Politici, 2023 Jul 04. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12648.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/978728/2228210/phd_unimi_R12648.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/957979"},"title":"An Analysis Of The (Post)Modern Hunting: exploring consumers’ perception towards hunted wild game meat and insights into the role of hunters in the contemporary era","internalauthor":"CORRADINI, ANNA FRANCESCA","type":"Tesi di dottorato","year":"2023","abstract":"Although not practiced for subsistence, hunting is still popular in Western countries and hunted wild game meat (HWGM) is its product. Consumer science literature reports that HWGM is increasingly appreciated by consumers, who link to this product several positive attributes (i.e., HWGM is healthy, comes from a non-farmed animal, and its production is proved to be more environmentally sustainable than farmed meat). On the other hand, the debate around hunting legitimacy in the contemporary era is still heated. Hunters are often condemned, since hunting is considered by some parts of the public to be obsolete, cruel, and unacceptable, as long it is practiced for recreational purposes. Based on these premises, the objective of this thesis is to investigate and understand, both from the perspective of the consumer and the producer (the hunter), how hunting and HWGM are perceived by them. This thesis is based on three studies. The first study (Chapter II) seeks to identify which variables are connected to consumers' perceptions and attitudes towards HWGM by reviewing the existent body of literature on the topic. The second study presented (Chapter III) aims to assess the presence of Optimistic Bias in Italian hunters, since the presence of this cognitive bias may alter the hunter's perception of the risk connected to the implementation of improper behaviours during HWGM manipulation, threating consumers’ health. The third study (Chapter IV) aims to understand how hunting (and, thus, hunters) is reframing its role into society, by providing an in-depth analysis of (new) hunters identities.    The results of this thesis want to shed light on different features that characterize i) the HWGM consumers and ii) the hunter, analysing them as two key-actors involved in the contemporary re-negotiation of the image of contemporary hunting.","language":"eng","citation":"An Analysis Of The (Post)Modern Hunting: exploring consumers’ perception towards hunted wild game meat and insights into the role of hunters in the contemporary era / A.f. Corradini ; supervisor: A.M. Gaviglio; co-supervisor: M. Gibbert; curatore: E. Demartini, M.E. Marescotti, L. Märcz, R. Viganò. Dipartimento di Medicina Veterinaria e Scienze Animali, 2023 Mar 17. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12518.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/957979/2158609/phd_unimi_R12518.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/892091"},"title":"BOUNDARY VALUE PROBLEMS FOR QUASI-LINEAR AND HIGHER-ORDER  ELLIPTIC OPERATORS AND APPLICATION TO BIFURCATION AND STABILIZATION.","internalauthor":"ZONGO, WEND BENEDO EMMANUEL","type":"Tesi di dottorato","year":"2022","abstract":"In this thesis, we are interested in the study of nonlinear eigenvalue problem and the controllability of partial differential equations in a smooth bounded domain with boundary.    The first part is devoted to the analysis of an eigenvalue problem for quasilinear elliptic operators involving homogeneous Dirichlet boundary conditions.  We investigate the asymptotic behaviour of the spectrum of the related problem by showing on the one hand the bifurcation results from trivial solutions using the Krasnoselski bifurcation theorem and bifurcation from infinity using the Leray-Schauder degree on the other hand. We also prove the existence of multiple critical points using variational methods and the Krasnoselski genus.    At last, we show a stabilization result for the damped plate equation with logarithmic decay of the associated energy. The proof of this result is achieved by means of a proper Carleman estimate for the fourth-order elliptic operators involving the so-called Lopatinskii-Šapiro boundary conditions and a resolvent  estimate for the generator of the damped plate semigroup associated with these  boundary conditions.","language":"eng","citation":"BOUNDARY VALUE PROBLEMS FOR QUASI-LINEAR AND HIGHER-ORDER  ELLIPTIC OPERATORS AND APPLICATION TO BIFURCATION AND STABILIZATION / W.b.e. Zongo ; supervisor: R. Bernard ; supervisor: J. Le Rousseau ; coordinator: D P. Bambusi, O. Bodini. Dipartimento di Matematica Federigo Enriques, 2022 Jan 10. 34. ciclo, Anno Accademico 2021. [10.13130/zongo-wend-benedo-emmanuel_phd2022-01-10].","filename":"phd_unimi_R12326.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/892091/1938206/phd_unimi_R12326.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1133795"},"title":"A STUDY OF DE BRANGES - ROVNYAK AND DIRICHLET SPACES","internalauthor":"DELLEPIANE, EUGENIO ALBERTO","type":"Tesi di dottorato","year":"2025","abstract":"This doctoral thesis is devoted to the study of certain spaces of analytic functions on the unit disk $\\mathbb{D}$ of the complex plain, $\\mathbb{D}:=\\{z\\in\\mathbb{C}\\colon |z|<1\\}$. This work lies in the intersection between complex analysis, operator theory and harmonic analysis. In particular, we are interested in the de Branges-Rovnyak spaces $H(b)$, that is a class of spaces that arise from the Hardy space $H^2(\\mathbb{D})$, and in the harmonically weighted Dirichlet spaces $\\mathcal{D}_\\mu$, an important generalization of the classical Dirichlet space $\\mathcal{D}$. Special attention is given to a specific subclass of $H(b)$ spaces, the so-called \\emph{model spaces} $K_u$.   The first chapter contains the relevant background definitions and results. The remaining three chapters contain the original results, and they stem from three different papers or preprints.    In Chapter 2, we study a special class of operators on the spaces $H(b)$, the \\emph{difference quotient operators} $Q_\\zeta^b$. The idea is to study from an operator-theoretic point of view the fundamental quantities  \\[\\frac{f(z)-f(\\zeta)}{z-\\zeta},\\]  for functions $f\\in H(b)$ and boundary points $\\zeta\\in\\mathbb{T}:=\\partial\\mathbb{D}$. A priori, the values $f(\\zeta)$ are not defined for analytic functions on the unit disk $\\mathbb{D}$. However, as we carefully motivate in the thesis, the operator $Q_\\zeta^b$ can be properly defined for special points $\\zeta$. We conduct a spectral analysis of such operators and we deduce two estimates for the operator norm $\\|Q_\\zeta^b\\|$, that allow us to completely characterize the boundary points for which these operators can be bounded. Also, this analysis leads to a complete characterization of a property of the function $b$ that defines the space $H(b)$: when $b$ is \\emph{inner}, we prove that $b$ is \\emph{one-component} if and only if the norm $\\|Q_\\zeta^b\\|$ is uniformly bounded by the modulus of the first derivative $|b'(\\zeta)|.$    In Chapter 3, we investigate the relations between $H(b)$ spaces and $\\mathcal{D}_\\mu$ spaces. This is connected to the content of Chapter 2, as the operator norm $\\|Q_\\zeta^b\\|$ plays a role in the membership in Dirichlet spaces. In the last three decades, it has been shown that for special functions $b$ and measures $\\mu$ we may have an equality of sets $H(b)=\\mathcal{D}_\\mu$, with equality or equivalence of norms. This is very interesting, since the two classes of spaces arise from very different contexts and are apparently unrelated. This problem is also fairly difficult, as the structure of both spaces is rather mysterious, except for very special cases. We obtain necessary and sufficient conditions for the embedding $H(b)\\hookrightarrow \\mathcal{D}_\\mu$. These conditions also produce a complete characterization in some special cases. Using different techniques, we study in detail another special class of embeddings $H(b)\\hookrightarrow\\mathcal{D}_\\mu$, namely, when the function $b$ is non-extreme and $\\mu$ is a sum of finitely many Dirac deltas. We completely characterize the conditions for these embeddings, and we manage to complete this result with a characterization of the full identity $H(b)=\\mathcal{D}_\\mu$.     In the last part of the thesis, we study in detail a problem of polynomial approximation in Dirichlet spaces, using the tools of the Hadamard multipliers on such spaces. Given the analytic function $f(z)=\\sum_{k=0}^n a_kz^k$ in an appropriate weighted Dirichlet space, we study the generalized Ces\\`{a}ro means   \\[ (\\sigma_n^{\\alpha} f)(z)=\\binom{n+\\alpha}{\\alpha}^{-1}\\sum_{k=0}^n\\binom{n-k+\\alpha}{\\alpha}a_kz^k, \\]  where $\\alpha$ is a parameter in the interval $[0,1]$. We point out that, for $\\alpha=0$, we recover the $n$-th partial Taylor sum, while for $\\alpha=1$, we obtain the standard Cesàro mean. We investigate the convergence $\\sigma_n^\\alpha f \\to f$ as $n\\to\\infty$. In particular, we are interested in the asymptotical behavior of the norm $\\|\\sigma_n^\\alpha\\|$, as $n\\to\\infty$, and its dependence on the parameter $\\alpha\\in[0,1]$.","language":"eng","citation":"A STUDY OF DE BRANGES - ROVNYAK AND DIRICHLET SPACES / E.a. Dellepiane ; tutor: M. M. Peloso ; coordinatore: D. Bambusi. Dipartimento di Matematica Federigo Enriques, 2024. 37. ciclo","filename":"phd_unimi_R13517.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1133795/2631756/phd_unimi_R13517.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/946408"},"title":"NON-GENETIC MECHANISMS OF CHEMORESISTANCE IN ACUTE MYELOID LEUKEMIA","internalauthor":"MILOVANOVIC, SARA","type":"Tesi di dottorato","year":"2022","abstract":"Acute Myeloid Leukemia (AML) is the most common type of acute hematological malignancy in adults. 40–60% of patients relapse due to the emergence of cellular resistance to anti- leukemic drugs. Drug resistance in leukemic cells has been associated with intratumoral heterogeneity, among which quiescence, specifically, is considered a key factor for cell survival. Experimental evidence collected both from patients and model systems suggests that relapse is due to rare persistent AML cells which survive chemotherapy. Chemotherapy persistent cells are not yet biologically and molecularly defined. Open questions are whether persistent cells are drug-resistant, what are their cellular and molecular features, as well as their content in leukemic stem cells. My working hypothesis is that chemoresistance in AMLs is associated with specific phenotypic states that characterize rare cell populations found within the pool of quiescent leukemic cells. These cells are selected by chemotherapy and represent the cellular basis of the relapse. To test my hypothesis, I explored transcriptional and functional characteristics of quiescent leukemic cells and tested the effect of chemotherapy. Here, I present two newly established xeno-models of chemoresistant human AMLs that closely recapitulate clinical data. My data show that quiescent cells accumulate over time and quiescent and proliferating cells can switch from one state to another. Notably, quiescent cells are selectively spared by chemotherapy and show resistance to additional rounds of treatment. Finally, quiescent cells appear as the only carrier of tumorigenic capacity in AMLs and are, therefore, deemed essential for leukemia development and, possibly, relapse.","language":"eng","citation":"NON-GENETIC MECHANISMS OF CHEMORESISTANCE IN ACUTE MYELOID LEUKEMIA / S. Milovanovic ; added supervisor: E. Colombo, T. Vlachou ; supervisor: P. G. Pelicci ; internal advisor: G. Natoli ; coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2022 Dec 16. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12428_2.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/946408/2100536/phd_unimi_R12428_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1172054"},"title":"MOUNTAINHYDRO: INTEGRATING GEOLOGY, GEOPHYSICS AND HYDROGEOLOGY IN A MULTIDISCIPLINARY APPROACH","internalauthor":"LUCCHELLI, ALICE","type":"Tesi di dottorato","year":"2025","abstract":"Spring water represents a vital source of drinking water for local communities in mountain areas worldwide. As water demand and pressure on groundwater resources increase in a context of changing climate, there is a growing commitment to assess groundwater availability and to develop sustainable water supply strategies.  Effective groundwater management relies on a comprehensive characterization of aquifer systems. In this regard, karst-fractured terrains pose unique challenges due to their complex and heterogeneous nature. This study focuses on the assessment of aquifer systems in karst-fissured mountain environments, by employing a multidisciplinary approach based on three pillars: geology, geophysics, and hydrogeology.  The geological pillar centers on the construction of a 3D geological model derived from a combination of existing geological maps and targeted field observations. The model captures the spatial distribution of geological units and major structural lineaments and serves as a framework for the interpretation of groundwater preferential flow paths.   The geophysical pillar involves the use of high resolution DC resistivity surveys and densely spaced transient electromagnetic (EM) methods, both ground-based and airborne. Geophysical surveys play a key role in capturing the subsurface heterogeneity and identifying preferential flow paths within the rock volumes. The integration of the geological model into the geophysical inversion through an iterative process provides insights into the hydrogeological characteristics of the investigated system and enhances reliability of the interpretations. Moreover, the 3D inversion of airborne EM data has proven effective in increasing model accuracy in topographically and geologically complex terrains.  The hydrogeological pillar consists of groundwater chemical and stable isotope analyses, as well as hydrodynamic characterization. These analyses support the delineation of recharge areas of the springs and help characterize the behavior of the aquifer system. In addition, numerical simulations of groundwater flow were carried out to test different scenarios of recharge and flow paths in order to validate the conceptual model.  The results demonstrate the strength of an iterative, integrated modelling strategy in improving the understanding of complex karst-fissured aquifers.  Two representative study areas were selected to implement and validate the multidisciplinary approach: one in northern Italy (Val Sabbia, Lombardy), and the other in southern Spain (Sierra de Aracena, Andalusia). These sites exemplify geologically complex mountain terrains, providing robust testing ground for the methodology.","language":"eng","citation":"MOUNTAINHYDRO: INTEGRATING GEOLOGY, GEOPHYSICS AND HYDROGEOLOGY IN A MULTIDISCIPLINARY APPROACH / A. Lucchelli ; advisor: D. Pedretti ;  co-advisor: G. Fiandaca, R. Bersezio ;  coordinator: G. Muttoni. Dipartimento di Scienze della Terra Ardito Desio, 2025 Jun 25. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13581.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1172054/3095213/phd_unimi_R13581.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1156155"},"title":"ELECTROCHEMICAL IODINATION AND DEIODINATION PROCESSES FOR GREEN SYNTHESIS AND WATER REMEDIATION","internalauthor":"SORTI, LETIZIA","type":"Tesi di dottorato","year":"2025","abstract":"This project is devoted to highlight the importance and the great innovation that the application of electrochemistry could bring in the protection of the environment. The aim was to develop cost-effective and eco-friendly methods in both environmental remediation and green chemistry fields, to make electrochemistry considered as a valid alternative to classical methods in the contrast media industry. The first part of the thesis is focused on the study of the electrochemical iodination of N,N’-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (idroamide, IA), an important intermediate for the synthesis of iomeprol (IMP). It has been demonstrated that the use of a carbonaceous anode can successfully transform I-/I2 in iodinating species, leading to a complete iodination of the reagent and almost no by-products. The experimental conditions have been optimized and the potentiostatic electrolysis in a recirculating divided cell (cation exchange membrane) has been successfully scaled for the treatment of 0.8 L of IA 23.5% w/w. A pre-pilot system has been designed and installed and the first tests showed the way forward from here. Parameters related to increasing volumes will be studied, also optimising them for flow chemistry. The success of the scale-up of this study will provide a concrete, as well as green, alternative to the current use of ICl, a highly corrosive iodinating agent that must be handled with great caution. The second part of this work is instead focus on iodinated contrast media (ICM) electrochemical degradation, and, in particular, on reductive processes. Gold was found to be a powerful electrocatalyst in the case of C-I bond breaking and a preliminary study on sputtered 10 nm bilayer films showed promising results about a powerful synergy between gold and silver. The reductive mechanism was also investigated for IMP deiodination, allowing the optimization of the experimental parameters in conditions similar to those of real polluted matrices. Iodine was almost completely recovered as iodides in this case, while in simulated urine and industrial wastewater, where an undivided cell was chosen to promote mineralization, it was accumulated as iodates. Further development will be focused on iodides separation from the polluted matrix, in a iodine circular economy perspective.","language":"eng","citation":"ELECTROCHEMICAL IODINATION AND DEIODINATION PROCESSES FOR GREEN SYNTHESIS AND WATER REMEDIATION / L. Sorti ; tutor: A. Minguzzi ; supervisori: A. Vertova, F. Uggeri ; coordinatore: L. Prati. Università degli Studi di Milano, 2025 Apr 11. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13361_1.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1156155/2730419/phd_unimi_R13361_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/954702"},"title":"LA RISOLUZIONE DEI CONFLITTI TRA TRATTATI: METODI TRADIZIONALI ALLA PROVA DEI REGIMI AUTONOMI","internalauthor":"LIEBMAN, ANNA","type":"Tesi di dottorato","year":"2023","abstract":"The work aims to investigate the adequacy of traditional norm conflict resolution principles to manage and solve contradictions between autonomous regimes of international law. The analysis starts from the observation that, with the expansion and specialization of international law, traditional types of conflict between conventional provisions have been replaced by a new type of treaty antinomy: between autonomous regimes of international law, such as WTO law and environmental law. These are treaty- based systems governing a specific area of law, institutionally organized (around international organizations and specialized dispute settlement centers) and characterized by a common value base, objectives, ethics, and language. Considering this, the work critically examines the norm conflict resolution principles discussed in academia, applied by international courts and tribunals and in state practice, and codified in the Vienna Convention on the Law of Treaties (1969). Given the inadequacy of those traditional principles (lex prior, lex posterior and lex specialis), the thesis then examines whether other techniques, foreign to public international law (in particular, private international law methods and the balancing test) could better respond to the issues raised by regime conflicts. Finally, a reflection is offered about the convenience (and necessity) of a change of perspective and the abandonment of the individuality of regimes in favor of an integrated approach.","language":"ita","citation":"LA RISOLUZIONE DEI CONFLITTI TRA TRATTATI: METODI TRADIZIONALI ALLA PROVA DEI REGIMI AUTONOMI / A. Liebman ; tutor: L. Fumagalli ; coordinatore: F. Biondi. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2023. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12599.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/954702/2141206/phd_unimi_R12599.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1130855"},"title":"PATIENT-DERIVED ORGANOIDS AND EXTRACELLULAR VESICLES: UNLOCKING NEW FRONTIERS IN BREAST CANCER DRUG TESTING AND BIOMARKER DISCOVERY","internalauthor":"SIGNATI, LORENA","type":"Tesi di dottorato","year":"2025","abstract":"Despite significant advancements in cancer research, Breast cancer (BC) is still the most common cancer diagnosed in women and the second leading cause of death. In fact, therapies used against BC are not satisfactorily tailored to individual patients and often result in failure. The main reason of that is tumor heterogeneity, resulting in different levels of aggressiveness and treatment sensitivity. To address this challenge, personalized medicine strategies are crucial; achieving this requires preclinical models that can replicate the complexity of BC in vitro. Furthermore, identifying new biomarkers through liquid biopsy could help in detecting and stratifying BC risk.  In this context, the development of patient-derived organoids (PDOs) has revolutionized 3D culture models in oncology, offering a way to closely mimic the original tumor’s characteristics, including inter- and intra-tumoral heterogeneity. Moreover, their potential as a source of cancer biomarkers is also recently emerging. Besides this, liquid biopsy, a non-invasive method, shows promise in monitoring disease progression by analyzing Extracellular vesicles (EVs). EVs could help stratify patients by risk, allowing for targeted treatment. Despite their potential, traditional quantification methods remain challenging, necessitating further research to identify specific and reliable biomarkers for clinical use.  In my PhD project, I explored innovative strategies in the study of BC, focusing on patient-derived organoids (PDOs) and extracellular vesicles (EVs). The primary goal was to develop PDO-based platforms that closely mimic tumor characteristics, providing a reliable in vitro model for several applications: (1) study of tumor evolution, (2) drugs screening, (3) nanodrugs development and (4) biomarkers discovery. Furthermore, I presented an emerging application of the PDO model in the biomarker discovery field, by setting up a protocol for isolating PDO-derived EVs (EVs-PDO) and defining their biochemical signature with the aim of identifying promising BC biomarkers. Six candidate biomarkers (HER2, EpCAM, EGFR, Survivin, and Galectin-3) were validated through biochemical signature analysis on EVs-PDO and confirmed on clinical plasma samples.  Additionally, to demonstrate the potential of EVs as non-invasive biomarkers for the detection and risk stratification of BC, we used Raman spectroscopy (RS) to analyze the biochemical profile of EVs circulating in the blood. Although EVs interact with other extracellular particles, such as lipoproteins, in the bloodstream, RS has been shown to be a useful tool in defining the typical spectroscopic fingerprint of EVs and also to distinguish it from that of possible contaminants. Supporting the potential of RS as a diagnostic tool for BC, the results showed that this method can identify unique biochemical signatures in the BC group, specifically attributed to higher levels of nucleic acids and lipids.  The findings underscore the potential of integrating PDOs and EVs in BC research, with significant implications for early detection, personalized treatment, and monitoring of therapeutic responses. The use of PDOs as platform for the identification of novel BC biomarkers through EV analysis contribute to the advancement of precision medicine. The study concludes that the PDOs and EVs together provide powerful tools for improving BC risk assessment and guiding tailored therapeutic approaches.","language":"eng","citation":"PATIENT-DERIVED ORGANOIDS AND EXTRACELLULAR VESICLES: UNLOCKING NEW FRONTIERS IN BREAST CANCER DRUG TESTING AND BIOMARKER DISCOVERY / L. Signati ; tutor: S. Mazzucchelli ; coordinatore: C. Sforza. - Milano. Dipartimento di Scienze Biomediche e Cliniche, 2025 Jan 23. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13275.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1130855/2623560/phd_unimi_R13275.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/945938"},"title":"HIDDEN IN THE COAT: GEOMICROBIOLOGICAL INVESTIGATIONS OF ROCK ART ECOSYSTEMS AND CHALLENGES FOR THEIR SUSTAINABLE PRESERVATION","internalauthor":"WU, YING LI","type":"Tesi di dottorato","year":"2022","abstract":"Rock art is a precious heritage that prevailed from prehistory into the modern times, it holds significant implications to past cultures and climate changes and are found in most of the world. It indicates the development of human cognition and modern behavior, while recording the fauna and flora that were long gone due to shifting landscape and climate. Rock art is also increasingly fragile, under the threats of human development, vandalism, looting, inadequate tourist management and natural weathering.   It is fundamental to understand how rock art was made and its state of preservation before we can proceed with any preservation issues. Technical analysis of pigments and ochre investigate ancient technologies and provides clues for the manufacture of rock art that could also relate to the cultural choices and available resources of the people that made them. Major processes affecting rock art sites include natural and human influences. To understand the above, inorganic and organic components could be identified by a variety of analytical instruments, but concerning the long-term preservation of rock art, non-invasive or micro-invasive investigations have priority over invasive sampling that will result in ultimate loss. Because rock art is a fragile heritage of high value, we proposed a sustainable approach toward its analysis and preservation that will minimize sampling, but at the same time acquire important information about technology and weathering state. In Oman we sampled rock varnish adjacent to petroglyphs on the same boulder, and obtained weathering, microbial activity and radiocarbon dating information that gave us a limit ante quem for the making of engravings to establish a proposed chronology of past events, meanwhile keeping the petroglyphs unharmed.  Weathering of the rock surface involves complex interactions between minerals and microorganisms, in which the contribution of microbes to rock surface decay has long been noticed. Biotic weathering caused by lichen and other biological organisms on rock art and stone materials is well known in literature and involves the dissolution of the substrate and precipitation of new minerals formed by producing acids such as oxalic acid and carbonic acids. But in some cases microorganisms are suggested as beneficial to rock preservation. Biological organisms can hold fragile rock surfaces in place and produce protective rock coatings of oxalic crusts.   Microorganisms are associated with the biomineralization of biological rock coatings, for example oxalate crusts are often formed by lichens and fungi. Research in rock coatings is important to the preservation of rock art, and microorganisms play an important role in changing both the composition and color of rock art surfaces. We visualized the biofilm structure and extracted genomic material on rock art samples with different colored coatings from Ethiopia, then identified bacterial communities by amplifying and sequencing the 16S rRNA gene. Bacteria with mineralization potentials that could form patinas were identified, as well as animal microbiome that could result from herding activities at the site. The results imply that different colored coatings from the same rock art panel could harbor microbial communities with different compositions and functions. Cultural heritage made of stone is often discolored by pigments from biofilms, therefore a review was made to discuss microorganism-produced pigments concerning their role in the broader ecological context, and the possibility of using microbial pigments as an indicator of microbial impact on stone.   The formation of rock coatings is a complicated issue that needs expertise in both geology and biology, therefore we combined interdisciplinary methods in geochemistry, molecular biology and bioinformatics to further understand how microbial communities are involved in the formation of rock art coatings. In the last part of this thesis we present a paper that utilized cross-disciplinary scientific methods to understand bacterial communities on rock coatings from rock art, and reveal new insights into bacterial diversity and functions related to the formation of rock coatings.","language":"eng","citation":"HIDDEN IN THE COAT: GEOMICROBIOLOGICAL INVESTIGATIONS OF ROCK ART ECOSYSTEMS AND CHALLENGES FOR THEIR SUSTAINABLE PRESERVATION / Y.l. Wu ; TUTORS: A. ZERBONI, F. VILLA, G. D. GATTA ;  COORDINATORE DEL DOTTORATO: M. I. SPALLA. Dipartimento di Scienze della Terra Ardito Desio, 2022 Nov 22. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12300.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/945938/2098368/phd_unimi_R12300.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/967784"},"title":"CHINA'S BELT AND ROAD INITIATIVE (BRI): CHINESE LINKAGE AND LEVERAGE, DEMOCRATIZATION, AND REGIME CHANGE IN ASIA","internalauthor":"SHAHZAD, GUL I HINA","type":"Tesi di dottorato","year":"2023","abstract":"This thesis examines China’s global connectivity plan – the Belt and Road Initiative (BRI) and its political implications in partner countries, specifically focusing on its impact on democratization and regime change. With the rise of China, amidst declining levels of democracy, and changing nature of autocratization, this research examines if the increased Chinese engagement under BRI poses challenges to democratization in partner regimes.   This thesis puts forth a novel and multidimensional conceptual framework of ‘Chinese Linkage and Leverage’ based on the seminal work of Levitsky and Way’s Western Linkage and Leverage that they use for analyzing regime change (Levitsky and Way 2010). Based on their theoretical framework, I conceptualize the Chinese Linkage and Leverage to analyze various layers and levels of Chinese engagement, specifically in the BRI partner regimes. I operationalize the independent variable of Chinese Linkage along five dimensions namely, economic, social, cultural, communication, and intergovernmental ties for 32 countries in Asia using China’s Public Diplomacy data from AidData. I operationalize the dependent variable of democratization using the Liberal Democracy Index (LDI) from the Varieties of Democracy (V-Dem) data and examine any trends toward de-democratization in partner countries. Additionally, I use the Regimes of the World (ROW) measure from V-Dem data to examine the effects on regime type for diverse regimes in Asia.   My research uses a mixed methods (MM) research design by employing a quantitative method of the time-series cross-sectional or panel data analysis, and a qualitative case study approach. I conduct a panel regression analysis with a fixed-effects (FE) model with both disaggregated and aggregated Chinese Linkage Index (CLI). My findings show mixed evidence. At a disaggregated level analysis, the Confucius Institutes (CIs) indicate a negative and significant effect, whereas the journalist visits show a positive and significant result on democratization levels in the BRI partner countries. However, the aggregated Chinese Linkage Index (CLI) did not have any significant effect on de-democratization levels in partner countries. Since linkage is assumed to have a cluster effect, the thesis negates the claims of the de-democratizing effect of China’s influence under BRI. Moreover, the findings from the case of Pakistan also did not find a substantial observable China impact on hindering democracy as the domestic influences have been stronger as compared to the external Chinese influences on de-democratization in Pakistan.","language":"eng","citation":"CHINA'S BELT AND ROAD INITIATIVE (BRI): CHINESE LINKAGE AND LEVERAGE, DEMOCRATIZATION, AND REGIME CHANGE IN ASIA / G.i.h. Shahzad ; tutor: M. Bogaards; coordinator: M. Jessoula. Dipartimento di Scienze Sociali e Politiche, 2023. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12332.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/967784/2192016/phd_unimi_R12332.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/974210"},"title":"CONTESTED TERRITORY: VIOLENCE, ORGANISED CRIME AND TERRITORIAL PRACTICES IN CONTEMPORARY HONDURAS","internalauthor":"ZIOSI, EMILIA","type":"Tesi di dottorato","year":"2023","abstract":"The relationship between organised crime and territory is a complex one, and one which affects extensively security dynamics. Especially in countries plagued by violence and insecurity, like Honduras, territory is strategically important for criminal actors, that usually seek to obtain territorial control in certain areas and often compete over it with their rivals and authorities. Despite this, Honduras remains a highly understudied country in academic and policy discourses on the issue, especially due to the objectively dangerous nature of the criminal groups present in the country and the elevated levels of corruption and impunity that permeate it. As a result, the ways in which criminal groups shape the country’s territory, affecting local communities and security dynamics, remains an underexplored aspect in the literature. Especially, little is known about the way in which criminal groups’ presence, activities, and interactions shape space and territory across different scales in Honduras.    By drawing upon thirty semi-structured interviews with Honduran residents, ex-residents, and experts on criminal groups, activities, and dynamics in the country, and the analysis of official judicial documents, secondary literature, available public reports, and media outlets, this qualitative case study explores the ways in which criminal, state, and non-state actors shape the territory in Honduras in the context of a liberal market democracy. By focusing on different scales, respectively the local, regional, and national, and the interplay among these, this study aims at painting a picture of the bordering and territorial practices that different actors – especially criminal groups – have been carrying out in the country approximately in the last three decades. Adopting an interdisciplinary approach, this thesis consolidates and integrates the literature on organised crime, violence, the state-crime nexus, territory and territorial practices, and borders and bordering practices with original empirical research.  By focusing on gangs in urban areas of the country, drug trafficking organisations in rural ones, and state-crime relationships across the national territory, I argue that these actors have been able to actively produce and shape the country’s territory along micro, meso, and national lines, often establishing authority on it, and have contributed to shaping the Honduran territory as a deeply contested space. In doing so, I argue, these groups mirror – and, at the same time, are embedded into – the dynamics of capital accumulation and resource commodification entrenched in the country’s history of capitalist and neo-colonial exploitation and occupation throughout the centuries.","language":"eng","citation":"CONTESTED TERRITORY: VIOLENCE, ORGANISED CRIME AND TERRITORIAL PRACTICES IN CONTEMPORARY HONDURAS / E. Ziosi ; tutor: C. Castellano, M. Rosti; coordinatore: F. Basile. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2023 Jun 26. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12667.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 30-GIU-28"}
,{"handle":{"url":"https://hdl.handle.net/2434/924372"},"title":"NEW PLANT BREEDING TECHNIQUES AND PRIMING AS A MULTIPLE LEVEL STRATEGY FOR THE CONTROL OF DOWNY MILDEW INFECTION IN GRAPEVINE","internalauthor":"GIUDICE, GAETANO","type":"Tesi di dottorato","year":"2022","abstract":"The present thesis relates on three complementary approaches for a more sustainable control of Plasmopara viticola: cisgenesis, RNAi and plant defence priming. A brief general introduction is presented in the first chapter, touching the main aspects relative to viticulture in Europe, characteristics of the disease, new biotechnological strategies and priming of plant defence. The second chapter consists of a review article describing with detail the most recent biotechnological approaches for crop protection, including cisgenesis, genome editing, RNAi and epigenetics. In the third chapter the activities concerning cisgenesis for grapevine downy mildew resistance are reported, the study initially focuses on the induction of somatic embryogenesis from elite germplasm, optimising the cultivation of floral tissues for the generation of embryogenic calli. The resistance genes TNL2a and TNL2b belonging to the RPV3-1 locus, which confers resistance to Plasmopara viticola, were then selected for the development of cisgenic varieties, with the construction of a cisgenic vector harbouring those two genes. Finally, the chapter reports on the Agrobacterium tumefaciens transformation of embryogenic calli that are currently cultivated on selective medium, and on the future activities for the regeneration of transformed cisgenic plants.  In the fourth and fifth chapters, two papers addressing different aspects related to the exploitation of plant immune system are presented: the first study aimed at clarifying the effects of arbuscular mycorrhiza priming on the grapevine growth-defence trade-off while the second study was focused on the use of alternative protection protocols for the control of downy mildew in a commercial vineyard. Particularly, in the fourth chapter “Mycorrhizal symbiosis balances rootstock-mediated growth-defence tradeoffs”, the potential benefits of an inoculum formed by two arbuscular mycorrhiza fungal species, with or without a monosaccharide addition, were evaluated on young grapevine cuttings grafted onto 1103P and SO4 rootstocks. The influence of the different treatments was assessed by combining the analysis of agronomic features with biochemical and molecular techniques. The results showed that despite the opposite behaviour of the two selected rootstocks, in mycorrhized samples the whole root microbiome is actively involved in the growth-defence trade off balance.   Finally in the fifth chapter the submitted paper “Novel sustainable strategies to control Plasmopara viticola in grapevine unveil new insights on priming responses and arthropods ecology” is presented. The study addresses the reduction of fungicide consumption in viticulture and its associated risks by the exploitation of alternative protocols for the control of downy mildew infection in grapevine, compared to a standard winery protection protocol. In the first protocol, only resistance inducers were used, while the second and third protocols followed the standard protocol but substituting phosphonates with phosphorus pentoxide and Ecklonia maxima extract. The results showed that, at véraison, downy mildew incidence and severity were significantly reduced on both canopy and bunches in the plants treated with all tested protocols compared to non-treated controls. The study also revealed interesting insights about the direct effect of protocols for phosphite substitution on the crosstalk between salicylic and jasmonic acid signalling pathways. Interestingly, by priming plant defences, the resistance inducers caused a short delay in bunch ripening, involving changes in carbohydrate metabolism, regulation of defence related genes, systemic acquired resistance and reactive oxygen species detoxification.  In the thesis conclusion, the main findings are then summarised for each chapter, by examining the most critical aspects and including a brief discussion on the preliminary activities that were conducted to exploit the RNAi technique for silencing two essential genes of Plasmopara viticola.","language":"eng","citation":"NEW PLANT BREEDING TECHNIQUES AND PRIMING AS A MULTIPLE LEVEL STRATEGY FOR THE CONTROL OF DOWNY MILDEW INFECTION IN GRAPEVINE / G. Giudice ; advisory board: L. Nerva, C. Pagliarani ; supervisor: G. De Lorenzis, W. Chitarra ; phd coordinator: D. Bassi. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2022 Apr 27. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12362.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/924372/2024686/phd_unimi_R12362.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/946269"},"title":"BRAZILIAN PROPOLIS: A MULTIFACETED NATURAL PRODUCT WITH HEALING PROPERTIES - A COMPREHENSIVE STUDY ON THE ABILITY TO IMPROVE CUTANEOUS WOUND HEALING THROUGH HIF-1 MODULATION","internalauthor":"MAGNAVACCA, ANDREA","type":"Tesi di dottorato","year":"2022","abstract":"Cutaneous wound healing is a dynamic multi-step process, encompassing the four cascading, partially overlapping, phases of haemostasis, inflammation, proliferation, and remodelling, that occurs in response to injuries and requires a well-orchestrated intervention of cellular and non-cellular elements to regain tissue integrity and restore local homeostasis. The ultimate outcome of skin wound healing is most commonly repair, a form of incomplete regeneration implying fibrosis and the formation of scars proportional to the duration and severity of inflammation. An early condition of mild hypoxia can trigger cell survival. Apart from being master regulators of cellular responses under hypoxia, hypoxia-inducible factors (HIFs) play a key role in upregulating the expression of several genes that enhance wound healing. Recent evidence suggests that also the non-hypoxic pharmacological stabilisation of HIF-1α can evoke a regenerative phenotype, claiming a role for HIFs in tissue regeneration. Natural products able to elicit multifaceted activities on the wound microenvironment, modulating the HIF-1 pathway while counteracting the deleterious drawbacks of inflammation, are promising candidates to enhance repair, and possibly regeneration, of skin injuries. Propolis is a resinous, polyphenol-rich, product elaborated by honeybees from plant exudates, and traditionally used for wound healing due to its renowned anti-microbial, antioxidant, anti-inflammatory, and immunomodulatory properties. The biological activities depend on the chemical composition and vary according to geographic origin, environmental conditions, and botanical sources from which bees gather the resins. Numerous chemotypes of propolis have been classified, including several Brazilian varieties. The aim of this study was a comprehensive in vitro evaluation of green and red Brazilian propolis biological activities on human keratinocytes (HaCaT) and dermal fibroblasts (HDF), exploring the ability to modulate the HIF-1 pathway to substantiate their application as innovative healing agents. The preliminary chemical characterisation conducted through HPLC-UV, GC-MS, and HPLC-HRMS determined the presence of artepillin C and drupanin in green propolis, and vestitol/neovestitol and medicarpin in red propolis as major components. The ability of propolis to impair NF-κB-driven transcription was evaluated upon TNF-α or IL-1β stimulation, showing a greater activity of red propolis (IC50s < 10 μg/mL in HaCaT cells, IC50 = 23.6 μg/mL in HDF cells), prominent also on TNF-α-induced IL-8 secretion (IC50 = 11.89 μg/mL in HaCaT cells, IC50 = 5.89 μg/mL in HDF cells). On the other hand, red propolis proved able to induce the overexpression of IL6 gene, encoding a pleiotropic cytokine with pro-resolving functions, and enhance IL-6 release under pro-inflammatory stimulation. The investigation of HIF-1α stabilisation and nuclear translocation suggested the activity of both propolis in HaCaT cells, while only red propolis was active in HDF cells. These results have been confirmed through immunocytochemistry, western blot, and qPCR of the HIF-1 target gene VEGFA. Finally, a bioguided fractionation has been performed to better clarify the chemical species responsible for the biological activities. Following an initial fractionation by partitioning between immiscible solvents, the biological activity was screened in a HIF-1 reporter assay. Active fractions were further subfractioned by Sephadex LH-20 column chromatography, enabling to the qualification of the putative molecules responsible for HIF-1 stabilisation. Taken together, the results of this study contribute to elucidate the molecular mechanisms behind the promising activity of Brazilian propolis in wound healing, shedding light on the possible exploitation of these natural products in skin regeneration.","language":"eng","citation":"BRAZILIAN PROPOLIS: A MULTIFACETED NATURAL PRODUCT WITH HEALING PROPERTIES - A COMPREHENSIVE STUDY ON THE ABILITY TO IMPROVE CUTANEOUS WOUND HEALING THROUGH HIF-1 MODULATION / A. Magnavacca ; tutor: M. Dell'Agli, F. Calabrese ; coordinatore: G. D. Norata. Dipartimento di Scienze Farmacologiche e Biomolecolari, 2022 Dec 12. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12574.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/946269/2099337/phd_unimi_R12574.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1232438"},"title":"A CULTURAL BACKLASH ALL OVER EUROPE? INVESTIGATING THE LINK FROM VALUES TO VOTES IN A COMPARATIVE PERSPECTIVE","internalauthor":"KLOETZER, CHRISTIAN ALEXANDER","type":"Tesi di dottorato","year":"2026","abstract":"\"A common strand in the literature on electoral behavior in Western democracies explains voter support for far-right parties through increasing alienation of social conservatives from mainstream society in the context of progressive value change. This account of electoral change relies on a pathway from social conservatism to authoritarian personality traits and subsequent electoral behavior, and it also predicts when that sequence is most likely to be triggered. This dissertation critically reviews the theoretical argument for the mechanism, maps voters' attitudes on relevant issue dimensions, and then subjects the argument to an empirical test in a comparative European perspective using analyses of survey data.     At the theoretical level, many authors converge on a reading of electoral change benefitting  the far right as driven by newly emerged cultural preferences. The argument is made most forcefully by Pippa Norris and Ronald Inglehart in their theory of a \"\"cultural backlash\"\". But upon closer inspection, the argument is not persuasive. Norris and Inglehart's pathway to the renewed popularity of the far right in Western countries relies on a congruence of socially conservative and authoritarian attitudes that is not convincingly demonstrated. And the wider literature that aligns with their argument often suffers from blending different types of cultural issues into single indicators, which may mask differences between countries in how preferences on individual items are associated with far-right support.   In order to clarify whether there is a uniform cultural backlash that has boosted the European far right, the empirical part of the dissertation proceeds in several steps. First, three dimensions of socio-cultural issues are identified in the relevant literature: nationalism and European integration, immigration, and traditional morality. For each of these dimensions, attitudes between supporters of the far right and supporters of other parties are compared. A uniform pattern emerges across countries for attitudes towards immigration and European integration. The domain of traditional morality, by contrast, shows considerable divergences across countries. The pattern of socially conservative supporters of the far right, that are alienated by a progressive societal mainstream, does not hold everywhere. In the next two chapters, several hypotheses are developed to investigate the predictive power of socially conservative attitudes on support for far-right parties. They include both individual-level predictors and contextual variables that should moderate the hypothesized link if the theory holds. Multilevel logistic regression techniques are employed to test the hypotheses. But the results often do not match the theoretical predictions. Evidence for a cultural backlash, in the form of an association between socially conservative attitudes and far-right support, is absent in many countries. And where the link is confirmed, there is a mismatch between these findings and the long-running historical trends that are invoked in the literature to explain cultural change, and by implication also cultural alienation, in Western societies. Conversely, in countries where the theorized conditions for a cultural backlash are met, the evidence for this dynamic is particularly weak. The final chapter then concludes by discussing what these findings mean for our understanding of today's European far-right. It is possible that far-right electorates across Europe exhibit enduring differences in their socio-cultural attitudes. Alternatively, it may be that the diverging findings on this dimension reflect a process of interaction between national history, public opinion patterns and far-right party strategies. In any case, in light of the evidence accumulated throughout the analysis, the argument for a universal backlash against progressive norms and ideals as the driver of the resurging far-right in European societies is found unconvincing.\"","language":"eng","citation":"A CULTURAL BACKLASH ALL OVER EUROPE? INVESTIGATING THE LINK FROM VALUES TO VOTES IN A COMPARATIVE PERSPECTIVE / C.a. Kloetzer ; relatore: A. Pedrazzani ; coordinatore: F. Franchino. Dipartimento di Scienze Sociali e Politiche, 2026 Apr 16. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13295.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1232438/3296008/phd_unimi_R13295.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1025922"},"title":"LEARNING, FORECASTING AND CAUSATION AS COMPRESSION.","internalauthor":"FACCIUTO, FRANCESCO","type":"Tesi di dottorato","year":"2024","abstract":"Two main guidelines can be adopted to investigate a system and forecast its future behavior. The first kind of strategy emphasizes the role of general principles, which guide us in building models that embody the background knowledge available. The second class of techniques refers to phenomena ruled by unknown laws and directly probed by data-driven protocols. While the Scientific Method encodes the first kind of procedure, Data Science embraces more inductive schemes. In the last twenty years, many scholars have developed growing expectations about the impact of the latter family of methods, and the role of inductivism seems to be re-evaluated. This enthusiasm is - to some extent - justified. Despite the numerous successes achieved by model-driven science, many systems seem to resist being understood through a modeling approach. Conversely, valuable advances in performing practical tasks have been obtained by adopting Machine Learning and Pattern Recognition techniques. While a detailed analysis of these protocols' performances is beyond the scope of this discussion, some methodological aspects can be considered on a conceptual level, keeping in the background the possibility of proceeding with formally rigorous arguments. The comparison between modeling and automatic methods will allow for a better framing of the role of intelligence in their respective fields of application.      Research Plan. This dissertation starts by examining the properties of a generic database based on simple results from Dynamical Systems. The Analogs Method is considered an archetypal case to illustrate the consequences of an inductivist approach from a broader viewpoint. In this regard, Statistical Learning theory will provide some essential ingredients, allowing us to reformulate the Principle of Induction. This perspective will be elaborated more by using informational language. The compression-generalization trade-off is adopted as a general paradigm, discussing the effectiveness of Deep Learning protocols and drawing parallelisms with coarse-graining procedures. The analysis proposed will naturally lead us to re-read causality as a tool to manage information when some distribution shift comes into play. Moreover, some formal ways of characterizing cause-effect relations will be critically examined, and the potential connections that alternative frameworks may have will be explored to establish a more unified viewpoint. As we critically discuss the challenges inherent in inductive protocols, we aim to shed light on the following general questions. To what extent is mathematical modeling still a necessary pursuit? What role could be played by Artificial Intelligence in this regard?","language":"eng","citation":"LEARNING, FORECASTING AND CAUSATION AS COMPRESSION / F. Facciuto ; advisor: H. Hosni. Dipartimento di Filosofia Piero Martinetti, 2024 Jan 29. 35. ciclo","filename":"phd_unimi_R12707.pdf","fileformat":"Adobe PDF","fileversion":"preprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1025922/2352257/phd_unimi_R12707.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1128595"},"title":"ON THE METABOLIC AND MECHANICAL DEMANDS OF WALKING: THE EFFECTS OF SLIDING FRICTION, LIMB SWING WORK, AND BOUT DURATION.","internalauthor":"LUCIANO, FRANCESCO","type":"Tesi di dottorato","year":"2025","abstract":"Researchers have long investigated the metabolic and mechanical demands of locomotion. Discoveries in such field not only have advanced our understanding of the physiology of movement and energy transformations, but have also impacted anthropology, zoology, sports science, and clinical medicine. However, the relation between how much metabolic energy animals use to move and how much mechanical work they produce remains partially understood. In this thesis, I summarize some key concepts and discoveries about the bioenergetics, mechanics, and efficiency of locomotion; I then present three novel studies that examine how the bioenergetics and mechanics of human locomotion are linked.    The first study investigates walking in a virtual reality emulator, where participants slide their feet on the surface of a multidirectional treadmill. In this gait, mechanical work is required to overcome sliding friction, and the metabolic cost is hence relevantly greater than normal walking. The second study compares bipedal walking in chimpanzees and humans. Humans walk with less than half the metabolic cost of chimpanzees, and we propose that the difference is due to the lower work needed to swing limbs. In the third study, we quantified how the duration of a walking bout influences its metabolic cost and efficiency. We found that shorter bouts have a greater metabolic cost and lower efficiency than longer ones.","language":"eng","citation":"ON THE METABOLIC AND MECHANICAL DEMANDS OF WALKING: THE EFFECTS OF SLIDING FRICTION, LIMB SWING WORK, AND BOUT DURATION / F. Luciano ; tutor: G. Pavei ; tutor: A. E. Minetti ; coordinator: C. Sforza. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2025 Jan 23. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13222.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1128595/2619069/phd_unimi_R13222.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/988548"},"title":"VISIBLE LIGHT SENSITISED WO3−BASED PHOTOANODES FOR SOLAR ASSISTED WATER OXIDATION","internalauthor":"NOMELLINI, CHIARA","type":"Tesi di dottorato","year":"2023","abstract":"The need for stable, storable, accessible and renewable forms of energy has been insistently growing in the last decades, along with the concern about the ongoing climate changes connected to the extensive use of fossil fuels. The efficient exploitation of solar energy, that strikes the Earth’s surface with a great amount of energy everyday, is a promising, though challenging, approach to the problem, with hydrogen produced from solar energy using photoelectrochemical water splitting representing an encouraging alternative.  This PhD thesis aims at contributing to deepening the knowledge of the working principles and intrinsic characteristics of photoanode materials, responsible for driving the water oxidation reaction, the kinetic bottleneck of overall water splitting. Focus of the work is the study of photoactive metal oxide-based materials, such as tungsten trioxide (WO3), its ternary oxide derivative copper tungstate (CuWO4) and bismuth vanadate (BiVO4), which are among the most promising materials to be employed for these scopes.  Most of the experimental work here presented has been conducted at the UniMi Photocatalysis Group of the Università degli Studi di Milano, Italy, under the supervision of prof. Elena Selli; a fruitful collaboration with the group of prof. Sixto Giménez at the INAM Institute of the Universitat Jaume I of Castellón de la Plana, Spain, has led to the results outlined in Chapter 7 and partially in Chapter 5.    The present PhD thesis is organized as follows.  Chapter 1 presents an introduction to the grounds and aims at the origin of the work. An outline on the global energy demand and consumptions is drawn, evidencing that fossil fuels still represent the most widely used energy source. A brief description of the new, emerging renewable energy sources is presented, with a more detailed view on the hydrogen fuel, in particular on that produced from solar assisted water splitting.  Chapter 2 aims at giving the theoretical principles at the basis of photoelectrochemical water splitting. The main category of photocatalysts, i.e., metal oxide semiconductors, is presented along with their physico-chemical properties. The peculiar characteristics that make them suitable photoactive systems for driving the water oxidation reaction are highlighted. Finally, the working mechanism and the requirements of combined tandem PEC cells are illustrated.  Chapter 3 is dedicated to both the experimental and theoretical methods, as well as the synthetic and characterization techniques, that have been used throughout my PhD for producing and interpreting the data presented in this thesis. A careful description of the employed experimental set ups, located in the laboratories of both prof. Selli and prof. Giménez, is also reported.  Chapter 4 starts with the description of the experimental work carried out during my studies, which was firstly focused on copper tungstate, a ternary oxide deriving from the more investigated tungsten oxide, which is characterized by a relatively smaller band gap enabling its sensitisation towards the visible portion of the solar spectrum. For the first time, the effects on photoactivity induced by doping this material with nickel ions have been systematically investigated and demonstrated by means of multiple physical and photoelectrochemical methods.  Chapter 5 deals with the study of the well-known WO3−BiVO4 heterojunction, a system combining two of the most promising photoanode materials. My work was focused on disclosing the effects on the overall performance of the composite material induced by selectively tuning the morphology of the tungsten oxide underlayer. WO3 and WO3−BiVO4 photoanodes characterized by either a planar or a nanostructured morphology have been synthetized and multiple experimental techniques have been applied to ascertain the intrinsic characteristics as well as the photoelectrochemical performances of the so obtained photoactive materials layers.  Chapter 6 is focused instead on the role played by the thickness of either the WO3 and the BiVO4 layer and their reciprocal balance in tuning the overall efficiency of the WO3−BiVO4 composite systems. Multiple heterojunction samples displaying a planar morphology have thus been systematically prepared by varying both the under- and the overlayer thicknesses. The thorough screening of these photoelectrodes allowed an in-depth investigation of the mechanisms of photocurrent generation, and in particular on the detrimental charge recombination paths which can be activated when varying the thicknesses of the two oxides.  Chapter 7 is dedicated to the characterization of the photoanodes presented in Chapter 6 by means of two advanced techniques: Electrochemical Impedance Spectroscopy (EIS) and Spectroelectrochemical (SEC) analyses. These techniques provide information on the charge storage and charge transfer mechanisms occurring in the WO3−BiVO4 heterojunction, in comparison with single-component samples. Additional insight was thus obtained into the role exerted by the metal oxides thickness on the overall behaviour of the composite photoanodes.  Finally, Chapter 8 provides an overview of the results discussed in this thesis, as well as the future perspectives of each investigated research line.","language":"eng","citation":"VISIBLE LIGHT SENSITISED WO3−BASED PHOTOANODES FOR SOLAR ASSISTED WATER OXIDATION / C. Nomellini ; tutor: E. Selli ; co-tutor: M. V. Dozzi ; PhD course coordinator : D. Passarella. Università degli Studi di Milano, 2023 May 08. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12587.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/988548/2255589/phd_unimi_R12587.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1101368"},"title":"PUBLIC PROCUREMENT AND HUMAN RIGHTS: A CHALLENGE AND OPPORTUNITY FOR PUBLIC AND PRIVATE ACTORS TO FOSTER RESPONSIBLE BUSINESS CONDUCT ALONG GLOBAL SUPPLY CHAINS","internalauthor":"BOTTA, GIULIA","type":"Tesi di dottorato","year":"2024","abstract":"Exploring spaces of intersection between public procurement and human rights law represents a core challenge and opportunity in the current globalized economy. Global supply chains play a crucial role unleashing socio-economic development. However, the exposure to human rights risks and labour standards abuses has been extensively documented in many market sectors, extending to goods, works, services purchased by States – as megaconsumers - through public procurement procedures. In a context of current regulatory and accountability gaps, dominated by soft law initiatives, responses by procuring entities and suppliers to address human rights risks and adverse impacts have been poorly adequate.   Shedding lights in a context of legal uncertainty and ambiguity, where “unaware” and irresponsible State purchasing may inevitably feed a vicious cycle of transnational abuses, the aim is to clarify whether there is an international obligation and consequent international responsibility of public procurement stakeholders (the State as public buyer and business as private suppliers) to prevent human rights harms in public procurement. Further, the focus is on whether and how public procurement may induce more compliance to the Business & Human Rights (B&HR) recently developed subfield of international law, which addresses human rights risks of violation at business level.  In terms of relevance, given the economic leverage of public procurement and its ubiquity, the potentials to use public contracts as means of strategic regulation for more responsible supply chains are high. Considering challenges of low compliance and enforcement, linked to the inherent voluntary nature of B&HR instruments, public procurement could be used to indirectly hardening soft law. It could enhance the State duty to protect human rights while purchasing, so leading by example. At the same time, human rights considerations and social criteria in public contracts could support private actors meeting their corporate responsibility to respect human rights.  The interplay between public procurement and human rights is scrutinized in depth adopting an international law perspective on role and responsibility of public and private actors through a bipartite research approach. Then, narrowing down the research focus, a human rights lens is applied to the European Union (EU) regional public procurement framework, selected to explore hardening the soft processes through EU Public Procurement Law. Finally, to understand “how” to include human rights considerations in public procurement and standardize further a B&HR based public procurement, insights from practice are collected in selected EU Member States – Sweden and Italy - to showcase the possibility to reverse human rights risks into opportunities, essential for an effective paradigm change towards more responsible business.","language":"eng","citation":"Public Procurement and Human Rights: A Challenge and Opportunity for Public and Private Actors to Foster Responsible Business Conduct along Global Supply Chains / G. Botta ; Tutors: A. Bonfanti, S. Valaguzza; External tutor: Claire Methven O'Brien; PhD Coordinator: L. Sacconi. - University of Milan. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2024 Nov 21. 36. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13113.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1101368/2539829/phd_unimi_R13113.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1040037"},"title":"DECIPHERING AND EXPLOITING ANEUPLOIDY IN CANCER","internalauthor":"IPPOLITO, MARICA ROSARIA","type":"Tesi di dottorato","year":"2024","abstract":"Aneuploidy - a state of karyotype imbalance – arises from errors in the process of chromosome segregation and induces a multitude of cellular stresses that are mostly detrimental in untransformed cells. Importantly, aneuploidy is a pervasive feature of tumors, being present in the vast majority of both solid and blood cancers. In the first part of my PhD, I have been focusing on understanding how cancer cells can exploit aneuploidy-associated stresses for their survival and proliferation. My work sheds light on how cancer cells capitalize on aneuploidy-induced genome instability and associated gene copy-number changes caused by aneuploidy to withstand selective pressures, such as chemotherapy. The development of resistance to chemotherapeutic drugs appears to be influenced by the emergence of recurrent karyotypes, suggesting that gene dosage could contribute to chemoresistance. This establishes a direct correlation between aneuploidy-induced gene copy number alterations and chemoresistance, potentially explaining the failure of some chemotherapy treatments.  While aneuploidy is recognized as a characteristic of human cancer, the cellular processes that cells employ to manage the resulting stresses are not well understood. These processes may reveal vulnerabilities that could be exploited to target cancer cells. In the second part of my PhD, I generated and characterized several stable clones with varying degrees of chromosome imbalances. Through comprehensive genomic profiling of six isogenic clones via whole-exome and RNA sequencing, along with extensive CRISPR/Cas9 and drug screening, I explored their cellular dependency landscapes. In line with earlier findings, I observed increased DNA damage and p53 pathway activation in aneuploid cells. These cells also showed an increased DNA damage response (DDR), leading to greater resistance against further DNA damage. Notably, aneuploid cells had increased RAF/MEK/ERK pathway activity and were particularly sensitive to drugs targeting this pathway, especially those inhibiting CRAF. CRAF activity was also identified as a key factor in the resistance to DNA damage induction, with its inhibition increasing the sensitivity of aneuploid cells to DNA-damaging drugs.  Additionally, I observed that aneuploid cells had ramped up RNA synthesis and degradation, with a consequent increase in the activity of the nonsense-mediated decay (NMD) and microRNA-mediated mRNA silencing pathways, making them more vulnerable to disruptions in RNA degradation pathway. Importantly, the elevated dependency of aneuploid cells on the RAF/MEK/ERK pathway and intact RNA degradation pathways was not only confirmed in another isogenic aneuploid model but also a study of numerous human cancer cell lines, reinforcing their significance in cancer. In conclusion, my study serves as a comprehensive resource of genetically-matched, karyotypically stable cells in different states of aneuploidy and uncovers new, therapeutically relevant cellular dependencies in aneuploid cells.","language":"eng","citation":"DECIPHERING AND EXPLOITING ANEUPLOIDY IN CANCER / M.r. Ippolito ; tutor: S. Santaguida ; supervisori: S. Taylor, S. Minucci ; coordinatore: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2024 Apr 11. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12697_03.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1040037/2385261/phd_unimi_R12697_03.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1023728"},"title":"UPPER MOTOR NEURON BURDEN IN AMYOTROPHIC LATERAL SCLEROSIS: CLINICAL AND IMAGING FEATURES, AND THE ROLE OF IRON METABOLISM","internalauthor":"BERSANO, ENRICA","type":"Tesi di dottorato","year":"2024","abstract":"Background. Amyotrophic Lateral Sclerosis (ALS) is a rare fatal neurodegenerative disease selectively affecting upper and lower motor neuron system, with a heterogeneity of phenotypes which cannot currently be distinguished by specific biomarkers. The present research focuses on iron metabolism as one of the pathogenetic mechanisms of ALS. Ferritin and transferrin are well-known biomarkers of iron metabolism in ALS, while the role of Glutathione Peroxidase 4, one of the main factors of ferroptosis, is still unknow as it has only been explored in ALS mice. In vivo, iron accumulation in brain is detectable by Quantitative Susceptibility Mapping (QSM) technique on Magnetic Resonance Imaging (MRI) and correlates with the upper motor neuron damage.   The aim of the project is to investigate the correlation between upper motor neuron (UMN) impairment detected by clinical and neuroimaging techniques and serum biomarkers of iron metabolism.   Methods. 68 ALS patients, followed at ALS Center of “IRCCS Istituto Neurologico Carlo Besta” of Milan, were recruited for this study, collecting demographic features and clinical data on severity of disease, and the involvement of Upper motor neuron involvement detected with PUMNS scale at time of visit. 60 also provided blood samples to dose ferritin, transferrin and GPX4 enzyme in serum, and 52 additionally performed a brain MRI with QSM value. 67 Healthy Controls (HC) were also recruited.   Statistical analyses. To assess whether serum biomarkers can be considered as indicator of disease, it was first explored the possible correlation between iron serum biomarkers and clinical data with U Mann Whitney test and Pearson correlation, then it was investigated the association of biomarkers with radiological features (QSM values) by applying Spearman test, also testing the correlation between radiological and clinical features.  Results. ALS and HC were homogeneous for age and gender. A statistically significant difference of ferritin (p = 0.009) and GPX4 (p = 0.001) levels was found when comparing 60 ALS with 53 age-matched HC. In the ALS cohort: ferritin was inversely related to transferrin; transferrin correlated with the Body Mass Index; ferritin, transferrin and GPX4 had no correlation with genetic assessment or severity of disease. Instead, a positive correlation (p < 0.005) was found between GPX4 and PUMNS score. Regarding the evaluations of QSM values on brain MRI, variations of magnetic susceptibility in ALS patients as compared to HC were found in specific motor areas of brain (p < 0.001). By comparing MND with the subgroup of HC who both underwent MRI and blood withdrawal, no correlation was found between GPX4 and QSM values. However, when excluding subjects with outlier values of GPX4, a positive correlation was revealed in right M1 region (p < 0.001). Regression analysis across ALS group showed positive correlations (p < 0.05): with GPX4 in primary motor cortex area on left side (M1); with transferrin in ventral and dorsal premotor cortex and in supplementary motor area (SMA); and with ferritin in left lobules IV-V cerebellum, caudato, thalamo and in right SMA. Instead, no significant correlation was found with clinical score of upper motor neuron (UMN) burden, except for sub-score about upper district in right preSMA and right SMA (p < 0.04). By performing a trend analysis with rank of UMN involvement, a positive trend in left M1 (p < 0.004) and a negative trend in left lobules IV-V of cerebellum (p < 0.04) were identified.   Discussion. Compared to age-matched HC, there is a higher level of serum ferritin in patients, but it does not correlate with any specific phenotype. Instead, the present research first shows that serum levels of GPX4 are statistically higher in ALS than HC. Moreover, the analyses of GPX4 trend in ALS cohort did not find any correlation with features of disease, with the exception of the UMN burden. Regarding MRI features, in M1 region higher levels of QSM are associated with the degree of UMN involvement, and with GPX4 levels.  Conclusion. The findings of the present research suggest that GPX4 can be a useful biomarker of UMN involvement in ALS patients, linked to iron brain accumulation evaluated with QSM technique, with a potential impact on phenotypes differentiation and disease progression prediction.","language":"eng","citation":"UPPER MOTOR NEURON BURDEN IN AMYOTROPHIC LATERAL SCLEROSIS: CLINICAL AND IMAGING FEATURES, AND THE ROLE OF IRON METABOLISM / E. Bersano ; tutor: G. Lauria Pinter ; coordinatore: G. D. Norata. - Milano. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2024 Jan 19. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13177.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1023728/2344871/phd_unimi_R13177.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1127448"},"title":"PEPTIDOGLYCAN REMODELLING FACTORS: KEY PLAYERS IN CELL DIVISION AND HOMEOSTASIS MAINTENANCE OF ESCHERICHIA COLI","internalauthor":"ZACCARIA, MARTA","type":"Tesi di dottorato","year":"2025","abstract":"In Escherichia coli, the structural integrity and coordinated growth of the cell envelope are crucial for survival, especially under environmental stress conditions. The lipopolysaccharide-containing outer membrane (OM) acts as a selective barrier against toxic molecules and provides additional mechanical support that complements the role traditionally attributed to the cell wall. Coordination between the OM and peptidoglycan (PG) growth is essential for maintaining cell envelope stability, particularly during cell division, when septal PG must be cleaved to allow daughter cell separation. This process is mediated by PG amidases, AmiA, AmiB, and AmiC, that are activated by LytM-domain proteins both from inside the cell, with the periplasmic protein EnvC that is anchored to the divisome components FtsEX, and the outside of the cell thanks to the OM lipoproteins NlpD and ActS. In the first manuscript included in this thesis, it is shown the identification of the periplasmic deacetylase SddA, responsible for modifying the amidase cleavage products. The expression of the non-essential sddA gene is linked with that of EnvC, highlighting the involvement of SddA in cell separation. Consistently with this speculation, the overexpression of sddA leads to the formation of long chains of unseparated cells, indicating that amidase activity at the septum is inhibited.  The amidase activator ActS also displays a central role in envelope stress conditions. It has been shown that when OM biogenesis is disrupted, DpaA, the enzyme that detaches the OM lipoprotein Lpp from PG, is critical for preventing cell lysis. The lysis phenotype of dpaA deleted cells with defective LPS export is suppressed by the deletion of actS, suggesting that under LPS stress DpaA is capable of modulating ActS activity. A second manuscript included in this thesis shows that a DpaA-mediated modulation occurs at the ActS protein level.  Together, these findings reveal a complex regulatory mechanism linking OM and PG growth, septal PG cleavage, and cell envelope remodeling under stress. This coordination ensures structural stability and viability of E. coli by integrating responses to envelope stress with the mechanical demands of cell division.","language":"eng","citation":"PEPTIDOGLYCAN REMODELLING FACTORS: KEY PLAYERS IN CELL DIVISION AND HOMEOSTASIS MAINTENANCE OF ESCHERICHIA COLI / M. Zaccaria ; tutor: A. Polissi ; phd coordinator: S. Ricagno. Università degli Studi di Milano, 2025 Jan 10. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13352.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1127448/2616043/phd_unimi_R13352.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1273604"},"title":"ESSAYS IN MACROECONOMICS AND MONETARY POLICY: TOPICS AND CHALLENGES FOR CENTRAL BANKS","internalauthor":"MURAKAMI, DAVID HIROYUKI","type":"Tesi di dottorato","year":"2026","abstract":"This dissertation comprises six essays in macroeconomics, the culmination of my studies of monetary policy, financial frictions, and international macroeconomics. It is perhaps an orthodox view, but I have come to believe that the primary purpose of macroeconomics is to understand economic fluctuations and to inform the design of policy. I hope these essays serve as an ode to this view; at the core of each, readers will find an application of the New Keynesian framework.    The New Keynesian framework has come under much scrutiny in recent years, and understandably so: my fellow doctoral students and I have witnessed not one but two macroeconomic crises during our most formative years. As I write this foreword, a third may well be brewing, driven by a combination of factors including another episode of financial market overvaluation, high public debt, continual global supply chain disruptions, and ongoing geopolitical tensions. I understand, perhaps more than most, the scepticism about the New Keynesian framework's ability to explain these phenomena.    Nevertheless, I believe the New Keynesian framework remains invaluable. It is remarkably adaptable to new empirical evidence and theoretical developments. Like most paradigms, in economics or elsewhere, it is a powerful tool that must be applied appropriately. My concern is that we, as macroeconomists, risk throwing the baby out with the bathwater: abandoning the framework because of its poor performance when misapplied in the 2010s and early 2020s would be a mistake. Over the past few years, I have met many doctoral students who express no interest in the New Keynesian framework or lack even an intermediate understanding of it. I find this odd and troubling. It is precisely because these are such turbulent times that we must remain vigilant and keep a firm grasp of the intuition the New Keynesian framework offers about the macroeconomy. It cannot speak to, say, recent developments driven by micro data, but it remains a powerful tool for understanding aggregate prices, output, and interest rates.    I should make clear that my views on the function of macroeconomics and the strengths of the New Keynesian model differ from how I view the core purpose of economics as a discipline. While it may seem at odds with my orthodox view of macroeconomics, I believe that we – as economists more broadly – must avoid dogmatism when confronting the more fundamental and pressing questions of our time: global wealth and income inequality, fascism and the shortcomings of capitalism in the 21st century, racial and sexual justice, and peace and the sanctity of human life and rights. Economists have not been vocal enough on these issues, and I think this has created a vacuum for nefarious political actors to exploit.    I now briefly describe each chapter. The chapters are ordered chronologically, by when I wrote them or completed a first draft, and each is self-contained and can be read independently:    Chapter 1: Gone with the Wind: Monetary Policy and the Global Financial Cycle. This chapter grew out of my MPhil dissertation at the University of Oxford. The core research question is unchanged: how important is the exchange rate regime in buffering the domestic economy from global financial cycles? The approach and methodology, however, have been substantially updated. I build a small open economy New Keynesian model to inform the Mundellian Trilemma versus Dilemma debate and, as a key contribution, estimate it on South Korean data with an occasionally binding constraint. I also use nonlinear solution methods that allow agents to behave precautionarily to avoid hitting the constraint, in stark contrast to other papers, which typically estimate models with ‘always-binding’ constraints. To the best of my knowledge, this is the first paper to study the interaction among global financial cycles, the Mundellian Trilemma, and occasional episodes of financial crisis or stress. I find that the Mundellian Trilemma remains relevant, and that the economy's dynamics depend not only on the exchange rate regime but also on whether it is in a crisis or stress regime.    Chapter 2: Cryptocurrencies in Emerging Markets: A Stablecoin Solution? (co-authored with Ganesh Viswanath-Natraj; published in the Journal of International Money and Finance, June 2025). Motivated by El Salvador's 2021 experiment in making Bitcoin legal tender, which increased financial inclusion at the cost of a volatile medium of exchange, we study the macroeconomic effects of introducing cryptocurrencies in a workhorse small open economy model. The model builds on my experience with the bank financial frictions of Aoki, Benigno, and Kiyotaki and of Akinci and Queralto in open economy settings. Relative to an economy without cryptocurrency, introducing a low-volatility currency such as a stablecoin yields net welfare gains for the unbanked population, whereas a high-volatility currency such as Bitcoin yields net welfare costs. Cryptocurrency adoption attenuates the transmission of both domestic and foreign monetary policy, and flexible exchange rates provide an effective buffer against cryptocurrency price shocks. Our findings rationalise the growing use of stablecoins in emerging markets as a hedge against macroeconomic uncertainty.    Chapter 3: CBDCs, Financial Inclusion, and Optimal Monetary Policy (co-authored with Ganesh Viswanath-Natraj and Ivan Shchapov; revision requested at Macroeconomic Dynamics). This chapter is a natural follow-up to the previous one, written as I became more familiar with the Gertler–Kiyotaki–Karadi financial frictions framework and the heterogeneous agent literature. We study the interaction between monetary policy and financial inclusion in an economy that introduces a central bank digital currency (CBDC). Using a two-agent New Keynesian framework with banked and unbanked households, we show that a CBDC gives the unbanked a more efficient savings device with which to smooth consumption, raising welfare. Under Ramsey optimal policy, the CBDC rate is set at a constant spread to the policy rate. We identify a policy trade-off: a higher CBDC rate benefits the unbanked but disintermediates banks and reduces the welfare of banked households. Taken together, our findings highlight the importance of tailoring CBDC design to an economy's level of financial inclusion.    Chapter 4: Productivity over the Life-Cycle and its Effects on the Interest Rate (co-authored with Momo Komatsu and Ivan Shchapov; published in the Japanese Economic Review, special issue on Heterogeneity and Macroeconomics, February 2025). This chapter builds on the Blanchard–Yaari–Gertler overlapping generations framework and began as my master's dissertation at Keio University. That early version was quite simple, with almost no role for fiscal transfers. Given the pressing challenges of demographics and fiscal sustainability, however, my co-authors and I rewrote the paper and extended it substantially. Japan has faced rapid ageing, persistently low interest rates, sluggish growth, and deflation for decades, while the productivity of young and elderly workers has gradually converged. Using an overlapping generations two-agent New Keynesian (OTANK) DSGE model, we explore the relationship between productivity, demographic shifts, and interest rates in Japan during the post-bubble era. The narrowing productivity gap between younger and older cohorts puts upward pressure on interest rates, whereas longer life expectancy and negative population growth push them down; the latter effect dominates. A central bank that fails to account for this when setting monetary policy may induce deflationary pressure. Two policy implications emerge: raising productivity over workers' entire life-cycle and bridging the gap between younger and older workers can help offset the decline in interest rates, and monetary policy ought to account for shifting demographics.    Chapter 5: Restoring Existence and Uniqueness at the Effective Lower Bound with Simple Fiscal Policy (co-authored with Ivan Shchapov and Yifan Zhang; second-round revision requested at the Journal of Economic Dynamics and Control). My interest in the nonexistence and multiplicity of equilibria began when I worked as a research assistant for Guido Ascari and Sophocles Mavroeidis on their paper ‘The Unbearable Lightness of Equilibria in a Low Interest Rate Environment’, later published in the Journal of Monetary Economics. Around the same time, I began researching nonlinear solvers – most notably OccBin – and the numerical difficulties posed by the effective (or zero) lower bound (ELB). In New Keynesian models, the occasionally binding ELB constraint often leads to multiple equilibria or none. The problem stems from a strong feedback loop between expectations of inflation and output and current outcomes at the ELB. We show that simple fiscal policy rules can introduce additional stabilising forces that dampen this loop, thereby ensuring the existence and uniqueness of a minimum state variable (MSV) solution.    Chapter 6: Global Determinacy According to HANK (co-authored with Ivan Shchapov and Yifan Zhang). A natural follow-up to the previous chapter, this chapter builds on the approach of Ascari and Mavroeidis (2022) to test whether Bilbiie's workhorse tractable heterogeneous agent New Keynesian (HANK) model exhibits multiplicity or nonexistence of MSV solutions in the presence of an occasionally binding constraint – in this case, the ELB. We show that the HANK model generally suffers from the same nonexistence or multiplicity problem as the representative agent New Keynesian model. However, when calibrated to have procyclical income and consumption inequality, such that aggregate demand is inverted, the HANK model has a unique MSV solution and satisfies local determinacy conditions – a property we term global determinacy.","language":"eng","citation":"ESSAYS IN MACROECONOMICS AND MONETARY POLICY: TOPICS AND CHALLENGES FOR CENTRAL BANKS / D.h. Murakami ; tutors: G. Ascari, A. Ferrero, F. Zanetti ;  coordinator: F. Iacone, M. Nicolini. Università degli Studi di Milano, 2026 Sep 30. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13729_7.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1273604/3410206/phd_unimi_R13729_7.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/827808"},"title":"I LIBRI XXX-XXXIII DI POLIBIO NEL CODEX PEIRESCIANUS: INTRODUZIONE, TESTO CRITICO E COMMENTO","internalauthor":"FERRARA, FRANCESCO MARIA","type":"Tesi di dottorato","year":"2021","abstract":"This Ph.D. thesis consists in a commented critical edition of 15 fragments of Polybius’s Histories from the Books XXX-XXXIII handed down through the Codex Peirescianus (Turonensis 980). The edition is also preceded by two introductory chapters that aim to analyze some palaeographical features of the manuscript that may suggest a plausible dating and establish the nature of the relationships among the various topics of the Excerpta Constantiana and above all with the Suda Lexicon, since a methodical survey on how the lexicographers have obtained many entries or quotations from T (or rather from its draft copies) has not been accomplished so far. The key features of this procedure were identified in the rich and multi-layered paratext of the manuscript, which was intently inspected as regards the section of Polybius but which would deserve a thorough overview extended to every author excerpted in the codex. The critical edition takes into great account these preliminary and methodological conjectures and does not omit to revise and update the bushy bibliography on which the last edition (1904) was based: all this also finds complete explanations in the comment, a companion to the critical text, as much as a stance on the issue concerning the order of the excerpts and the role played by authors such as Livy, Diodorus, and Athaeneus in the constitution of the Polybian text.","language":"ita","citation":"I LIBRI XXX-XXXIII DI POLIBIO NEL CODEX PEIRESCIANUS: INTRODUZIONE, TESTO CRITICO E COMMENTO / F.m. Ferrara ; supervisore: S. MARTINELLI TEMPESTA ; coordinatore: P. PIACENTINI. Università degli Studi di Milano, 2021 Mar 26. 33. ciclo, Anno Accademico 2020. [10.13130/ferrara-francesco-maria_phd2021-03-26].","filename":"phd_unimi_R12002.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/827808/1746624/phd_unimi_R12002.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1126178"},"title":"HABILIDAD ARGUMENTATIVA EN HISPANOHABLANTES CON AFASIA PROGRESIVA PRIMARIA: UNA COMPARACIÓN TRANSCULTURAL SEGÚN EL NIVEL DE ESCOLARIZACIÓN Y EL REPERTORIO LINGÜÍSTICO","internalauthor":"DONATI, ALESSANDRA","type":"Tesi di dottorato","year":"2025","abstract":"Primary Progressive Aphasia (PPA) is a neurological syndrome related to several neurodegenerative diseases and characterised by a progressive loss of speech. Within the discourse studies on APP, there is a lack of focus on one of the most complex discursive skills, i.e. argumentative skills. For this reason, the aim of of this thesis is to detect and quantitatively analyse the argumentative ability of a group of patients with PPA compared to a control group, according to two parameters of comparison: the level of schooling and their background linguistic knowledge. During a research stay at the San Carlos Clinical Hospital in Madrid, 30 PPA patients and their controls were given an argumentative test, created ad-hoc. The test, which was audio-visually recorded to capture gestures and proxemics, is structured in three parts, each corresponding to a different argumentative stimulus (textual, graphic, conversational). By means of a text, images and a debate, it was possible to collect data from three different perspectives of argumentative production or comprehension. After the test, two questionnaires were administered in order to collect information on levels of schooling (My linguistic biography) and the languages spoken before (Levels of language proficiency). After having transcribed the tests with the audio transcription software WhisperAI and merging the transcripts into a corpus of PPA argumentative discourse, it was possible to insert the answers to the textual analysis questions and the interpretations of the images into a matrix of SPSS programme, in order to make a statistical analysis of the data. At the same time, it was possible to create a PPA argumentative profile model by classifying the arguments used by patients (according to the Wagemans’ classification, 2020) and calculating the frequency of use of the argumentative markers. By means of the Chi-square test in SPSS, it was possible to see the percentage of success of the PPA patients in the textual analysis and in the interpretation of the images, with respect to the controls and, consequently, the survival or not of certain persuasive skills. The influence of schooling level and linguistic background was  calculated through a comparison of means and, in the case of schooling, also through Spearman's correlation index. The main finding of the study is that patients with APP show impaired argumentative ability and no significant correlations are observed with school level or linguistic reserve. The finding that a subgroup of APP patients show preserved argumentative ability opens the door for future studies to better understand the reasons underlying such preservation in APP. In addition, there are qualitative differences in argumentative procedures that could be addressed in future research.","language":"spa","citation":"HABILIDAD ARGUMENTATIVA EN HISPANOHABLANTES CON AFASIA PROGRESIVA PRIMARIA: UNA COMPARACIÓN TRANSCULTURAL SEGÚN EL NIVEL DE ESCOLARIZACIÓN Y EL REPERTORIO LINGÜÍSTICO / A. Donati ; tutor: M. V. Calvi ; co-tutor: O. Ivanova, J. Matías-Guiu. Dipartimento di Lingue, Letterature, Culture e Mediazioni, 2025 Jan 27. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13206.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1126178/2613325/phd_unimi_R13206.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1205651"},"title":"PHARMACEUTICAL PATENTS AND ACCESS TO MEDICINES IN GLOBAL PANDEMICS. MUTUALLY EXCLUSIVE OR MUTUALLY REINFORCING? A POST COVID-19 INQUIRY INTO THE TRIPS AGREEMENT AND HUMAN RIGHTS.","internalauthor":"NATALI, JACOPO","type":"Tesi di dottorato","year":"2026","abstract":"The COVID-19 pandemic struck the world in 2020 causing an unprecedented global public health crisis and economic disruption. The deep inequalities that characterised the distribution of vaccine among States rekindled longstanding debates that have surrounded the role and effects of patent protection for pharmaceuticals on access to medicines. Pharmaceuticals are an extremely socially sensitive area of patents from both the legal and economic perspective: on the one hand, the monopoly it confers is arguably a necessary incentive to develop medicines which we would not have otherwise; on the other hand, the scarcity and high prices it implicates result in access to life-saving medicines being denied to millions of people worldwide. The outbreak of a global pandemic spawns the urgent need for rapid innovation and distribution of vaccine and antivirals, and for countries to cooperate to rapidly achieve both these public health objectives on a global scale. The TRIPS Agreement has globalised patents as the model for pharmaceutical innovation in 1995. At the same time, access to medicines is increasingly recognised as a human right which States are obliged to ensure to everyone under the ICESCR and the ICCPR. The tragedy of the HIV pandemic at the turn of the century led to the adoption of the Doha Declaration on the TRIPS Agreement and public health and to new public health approaches to medical patents in domestic and international law, mostly relating to the use of public interest safeguards inbuilt in the TRIPS – the so-called flexibilities. However, how the structure of international patent law affects the development and distribution of vaccines and antivirals at the global level, as well as whether patent law mechanisms developed for protecting public health and the human right to access to medicines can apply successfully to ensure the development and access to medicines, when the public health challenge is a global infectious disease pandemic is largely unexplored.   This thesis combines a legal analysis with an analysis of the relevant economic, law and economics, and epidemiological literature to respond to the fundamental question of whether the patent-access balance, as currently regulated in international law, facilitates or hinders the pharmaceutical response strategies required by a global pandemic public health response. It argues that improving the global pandemic response requires a new international IP law norm that reshapes the incentives for States towards cooperating for a broader global allocation of pandemic medicines.","language":"eng","citation":"PHARMACEUTICAL PATENTS AND ACCESS TO MEDICINES IN GLOBAL PANDEMICS. MUTUALLY EXCLUSIVE OR MUTUALLY REINFORCING? A POST COVID-19 INQUIRY INTO THE TRIPS AGREEMENT AND HUMAN RIGHTS / J. Natali ; tutor: N. Boschiero, S. Silingardi, M.A. Rossi coordinatrice: D. U. Galetta. - Milano. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2026 Jan 16. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13385.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 07-LUG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1158576"},"title":"GLI ULTIMI ORIZZONTI DELLA RIGENERAZIONE URBANA: DIRITTO DELL¿ENERGIA E COMUNITÀ ENERGETICHE RINNOVABILI.UNA SFIDA POSSIBILE?","internalauthor":"SCUTO, LEONARDO","type":"Tesi di dottorato","year":"2025","abstract":"The aim of this thesis is to assess the distinctive features of the phenomenon of ‘urban regeneration’ as an expression of the principle of sustainable development, from a multidisciplinary perspective and with particular attention to the legal issues that characterise it.  Focusing on the main coordinates of land consumption and urban regeneration, attention has been placed, inter alia, on the benefits deriving from the potential, as yet unexpressed, of urban regeneration thanks to the use of information and communication technologies (ICT) in urban planning, from the perspective of environmental and energy law, and - in particular - on the theorisation of models such as the so-called Smart Cities and Renewable Energy Communities, capable of combining environmental and energy benefits with the increasingly emerging needs imposed by human development.  The dissertation is composed of four chapters. In the first part of the thesis, urban law is studied with specific regard to the issue of land consumption in the prism of urban regeneration. The study is necessary for two reasons. Firstly, in order to understand the models theorised in the following part of this work, a preliminary reconnaissance of the concept of urban regeneration and the related fight against land consumption, both in the interaction and European perspective, is necessary. Secondly, from a critical point of view, this first analysis allows to highlight the problematic situation resulting from the persistent lack, in the Italian legal system, of an organic discipline on soil protection. In this sense, in addition to an institutional framework of the subject matter of this study, the first chapter allows the reader to focus precisely on the problems dictated by a regulation that is in itself inadequate and unsuitable to face the related challenges of the environmental and energy transition.  The second chapter, starting from this acquisition, moves on to analyse the potential, as yet unexpressed, of urban regeneration. In particular, it examines the Smart Cities model, understood, as far as it is of interest here, as a driver for urban and energy regeneration, inquiring into the possibility of declining urban regeneration policies from an energy perspective and – in the final instance – theorising innovative figures underlying the full realisation of so-called smart cities.  Thus, the third chapter focuses on the study of a new paradigm of urban regeneration, namely the Renewable Energy Communities (hereinafter, the “RECs”), analysing its origin, development and possible applications of the model. In this chapter, in which a systematic reconstruction of RECs is initially proposed, a number of specific profiles are analysed, such as the key role of the citizen/prosumer – considered as the protagonist of the energy transition process – and the urban impact that RECs can have within the framework of urban regeneration policies.  Finally, the fourth chapter, with the intention of incorporating all the elements disseminated in the previous chapters, focuses specifically on the role of digitalisation at the service of the Renewable Energy Community within the scope of urban regeneration policies.  Therefore, it concludes by stating, inter alia, that the realisation of an innovative Smart Cities development model – based not only on the use of technology, but also on the implementation of RECs – will enable citizens to be oriented towards concrete forms of regeneration and innovative governance, oriented towards energy, environmental, social and economic sustainability, in which consumers – as previously mentioned – play an increasingly active role; a factor – the latter – that is fundamental to the success of the energy transition.","language":"ita","citation":"GLI ULTIMI ORIZZONTI DELLA RIGENERAZIONE URBANA: DIRITTO DELL' ENERGIA E COMUNITÀ ENERGETICHE RINNOVABILI. UNA SFIDA POSSIBILE? / L. Scuto ; tutor: D.U. Galetta co-tutor: G. Ragucci coordinatore: F. Biondi. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2025 May 15. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13550.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open from 08-OTT-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/920095"},"title":"ATR CONTROLS THE EXCITATORY/INHIBITORY RATIO IN THE CENTRAL NERVOUS SYSTEM AND ITS INHIBITION LEADS TO ANTICONVULSANT EFFECTS","internalauthor":"CAMBRIA, CLARA MARIA","type":"Tesi di dottorato","year":"2022","abstract":"ATR (ATM and Rad-3 related) is a kinase protein of approximately 301 KDa, mainly known for its nuclear function played in proliferating cells. Indeed, in these cells it is recruited and activated at the site of DNA damage, promoting the phosphorylation of numbers of substrates directly involved in the cell cycle regulation and DNA damage repair, such as CHK1, p53 and BRCA1. Mutations in the Atr gene are responsible for the onset of the Seckel Syndrome (SS), an autosomal recessive disorder mainly characterized by intrauterine growth retardation, craniofacial abnormalities, dwarfism, chromosomal instability and mental retardation. Recent studies have revealed a much wider role of ATR, in particular it is present into the neuronal cytoplasm participating in the regulation of the synaptic vesicles trafficking; also, genetic deletion of the protein seems to be responsible for an increased excitatory activity and subsequently for the onset of sporadic non-lethal epileptic seizures in 12 months-old mice. Therefore, the abnormal synaptic transmission due to ATR mutations could partially explain the neurological dysfunctions found in SS patients. Despite the evidence related to the genetic deletion of ATR, up to now, no data regarding the pharmacological inhibition of ATR kinase activity have been provided. Thus, in this thesis, we aimed at filling this scientific gap investigating the impact mediated by a specific ATR kinase activity blocker on hippocampal function and neuronal transmission. This drug can penetrate inside the brain and it is currently involved in oncological pre- clinical studies, indeed it prevents the ATR-mediated signaling and inhibit the DNA damage checkpoint activation, promoting cancer cells apoptosis. Hence, hippocampal neuronal cultures have been treated with the ATR inhibitor in the attempt to block the ATR pathway and study related consequences at different stages of neuronal maturation. The treatment was administered both in acute, a single day treatment, and in chronic, one-week protocol. First of all, Ca2+ imaging experiments in 7 DIV neurons demonstrated that reduced ATR activity in immature neurons has no impact on the GABAergic development. Subsequently, electrophysiological and immunofluorescence experiments in mature hippocampal neurons revealed that both acute and chronic ATR inhibition are responsible for neuronal transmission defects, inducing a marked imbalance between excitation and inhibition, thus favoring the establishment of a more inhibited tone. Also, synaptic plasticity was found affected, resulting in defective long term potentiation and depression. Real time PCR experiments performed in vitro and RNA sequencing in vivo were useful to investigate the molecular mechanism at the basis of the defects here described. In particular, data collected by both these approaches suggest the immediate early gene Egr1 as one of the main factors deregulated by ATR inhibition. Importantly, several findings describe Egr1 as a key transcriptional regulator of genes contributing to the development of hyperexcitability during epileptogenesis. Also, increased Egr1 expression levels have been detected in hippocampal biopsies collected from epileptic individuals. Thus, we evaluated the effect mediated by pharmacological ATR inhibition in a mouse model of acute seizures and, coherently, we found a strong anticonvulsant effect. These results highlight ATR as a novel target in acute seizures onset and the ATR inhibitor as an innovative therapeutic tool in neurological disorders characterized by increased excitability. As a matter of fact, RNA profiling also unveiled similarity with other conventional antiepileptic drugs. Altogether, our data demonstrating that ATR kinase inhibition prevents the hyperactivity-induced Egr1 expression nicely fall with the recent theory of “master regulators candidates” in epilepsy, given that among the transcriptional activators and repressors suggested there is Egr1.  On the other hand, we performed biochemical investigations of the active ATR levels in the attempt to monitor changes of ATR activity along life. Data obtained from mouse and human hippocampal tissues collected at increasing age display a reduction of the phosphorylated ATR (the active form of the protein) suggesting that ATR levels variations participate in the establishment of cognitive defects during the physiological aging. It remains to investigate the role of Egr1 in this field. Overall, the results collected in this thesis suggest a novel role of ATR in the maintenance of the proper neuronal transmission and plasticity in mature hippocampal neurons and highlight ATR inhibition as an important therapeutic tool for neurological disorders characterized by hyperexcitability.","language":"eng","citation":"ATR CONTROLS THE EXCITATORY/INHIBITORY RATIO IN THE CENTRAL NERVOUS SYSTEM AND ITS INHIBITION LEADS TO ANTICONVULSANT EFFECTS / C.m. Cambria ; tutor: F. ANTONUCCI ; PhD coordinator: M. LOCATI, N. LANDSBERGER. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2022 Apr 08. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12365.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/920095/2013487/phd_unimi_R12365.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/841435"},"title":"COSA NOSTRA E LE FRODI COMUNITARIE NEL SETTORE AGRO-ZOOTECNICO: L'ATTIVITA' DI CONTRASTO ALLA LUCE DEI RECENTI INTERVENTI LEGISLATIVI","internalauthor":"MINI', GABRIELE","type":"Tesi di dottorato","year":"2021","abstract":"This research investigates, from a legal point of view, the issue of mafia infiltration in agriculture. Specifically, the analysis focuses on the community fraud perpetrated by Cosa Nostra in the agro-zootechnical sector and the respective regulatory instruments of contrast and prevention, deepening the case of the Nebrodi Park. In the first chapter, the relationship between the Sicilian mafia and the agricultural sector is reconstructed from a historical and sociological point of view, deepening the role played by the land as a symbol of mafia power and an instrument for the accumulation of wealth. The second chapter illustrates the EU agricultural policy, focusing both on the weaknesses in the supply procedures, and on the forms of control against abuses in the collection and management. The third chapter analyzes the story connected to the presence of mafia organizations in the territory of the Nebrodi Natural Park, which saw the adoption of innovative preventive tools (legality protocol) in the allocation of land. The fourth chapter illustrates the administrative tools aimed at preventing the abusive phenomenon under examination, with particular reference to anti-mafia information and changes to its discipline to make it more effective precisely in relation to access to European funding in agriculture. In the fifth chapter, the main methods used by mafia organizations and subjects who support them also from the outside are examined in depth to carry out the abuses of funds in the field of support for agricultural and livestock businesses. Finally, the last chapter illustrates the central core of the regulatory system for the repression of the phenomenon considered: the case of aggravated fraud to obtain public funds and its interpretation in the light of the jurisprudence of legitimacy.","language":"ita","citation":"COSA NOSTRA E LE FRODI COMUNITARIE NEL SETTORE AGRO-ZOOTECNICO: L'ATTIVITA' DI CONTRASTO ALLA LUCE DEI RECENTI INTERVENTI LEGISLATIVI / G. Mini' ; tutor: F. Basile ; co-tutor: S. Pellegrini ; coordinatore: F. Basile. Università degli Studi di Milano, 2021 Apr 19. 33. ciclo, Anno Accademico 2020. [10.13130/mini-gabriele_phd2021-04-19].","filename":"phd_unimi_R11921.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/841435/1794032/phd_unimi_R11921.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1212377"},"title":"TREE PLANTING STRATEGIES AS NATURE-BASED SOLUTION FOR THE PROVISION OF ECOSYSTEM SERVICES","internalauthor":"GIBERTINI, CHIARA","type":"Tesi di dottorato","year":"2026","abstract":"Abstract  Climate change, biodiversity loss, ecosystem degradation, and rapid urbanization are intensifying environmental pressures worldwide, with growing impacts on ecological integrity and human well-being. In this context, Nature-based Solutions (NBS), and particularly tree-based interventions such as urban afforestation and agroforestry, are increasingly promoted as effective strategies to enhance biodiversity, mitigate climate change, and improve regulating ecosystem services. However, the outcomes of tree planting practices are highly context-dependent and may involve trade-offs, highlighting the need for evidence-based approaches to guide planning and management across different landscapes and scales.  This thesis investigates the ecological and social benefits of tree-based interventions through three complementary studies.   • CHAPTER 1: Urban afforestation and meadow management as key drivers for wild pollinator conservation  This study aims to advance the understanding of the role of urban afforestation in biodiversity conservation, using wild bees as bioindicators. By adopting a chronosequence approach in forests of different ages and integrating information on forest structure and adjacent grassland management, this study addresses the gap in understanding how forest maturation and management practices jointly influence pollinator communities in highly anthropogenic environments. The results provide insights into functional biodiversity responses to urban afforestation and highlight management strategies capable of enhancing habitat quality and ecological connectivity at the local scale.  • CHAPTER 2: Assessing the future of coffee agroforestry: carbon dynamics and climate resilience through forest modelling - A Preliminary Study  This study represents the initial application of the FORMIND forest model for agroforestry systems, specifically simulating coffee crops to assess how shade trees affect carbon balance and crop resilience under future climate scenarios. Its aim is to contribute to addressing the lack of long-term, mechanistic assessments of agroforestry performance, and to clarifying trade-offs and synergies between shade trees and crop productivity, as well as the limits of agroforestry as a climate adaptation and mitigation strategy under increasing climatic stress. However, some relevant processes still need to be implemented in the model to fully capture the complexity of agroforestry systems.  • CHAPTER 3: Afforestation priority for multiple objectives at national scale: Italy as a case study  This study proposes a workflow to identify priority areas for afforestation at the national scale, considering four distinct objectives related to different ecosystem services: ecological connectivity, human health, climate mitigation, and water regulation. This approach makes it possible to highlight areas where benefits are maximized, thereby providing a strategic national perspective to support political decision-making in land management and planning. Using Italy as a case study, environmental and social spatial indicators were integrated into a goal-specific multi-criteria analysis, generating priority maps at a 1 km resolution.","language":"eng","citation":"TREE PLANTING STRATEGIES AS NATURE-BASED SOLUTION FOR THE PROVISION OF ECOSYSTEM SERVICES / C. Gibertini ; suoervisor: G. Vacchiano ; coordinatore: M. Guarino. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2026 Jan 22. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14021.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1212377/3240872/phd_unimi_R14021.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/966036"},"title":"LITHIUM ENRICHMENT IN ANATECTIC PEGMATITES: NEW INSIGHTS FROM THE THERMOMETAMORPHIC AUREOLE OF THE ADAMELLO BATHOLITH","internalauthor":"MAGNANI, LORENZO","type":"Tesi di dottorato","year":"2023","abstract":"In the contact aureole of the collisional metaluminous Adamello pluton (Italy), pelites reached hornfels facies conditions locally undergoing partial melting, forming Crd-bearing and Crd-absent migmatities. This small-scale migmatitic field is spatially associated with barren and Lithium-Cesium-Tanatalum (LCT) pegmatitic dykes of granitic composition, suggesting a direct link between low-pressure partial melting and generation of Li-enriched felsic melts. Phase equilibria modelling reveals that the Crd-bearing metapelitic migmatites produced around 20 vol.% melt fraction through fluid-assisted melting reactions, while the Crd-absent stromatic metatexites produced ca. 35 vol.% of melt during fluid-rich partial melting. Peak P-T metamorphic conditions were calculated at 690-700°C and 300 MPa for both rock types. Because of the steep contact thermal gradient, the underlying and older conglomerates of the Verrucano Formation, of which the pelitic succession is part of, as well as rock of the Collio Formation experienced comparably lower temperature metamorphism. Their mica-poor mineral compositions prevented them from melting and influencing the local anatectic processes. Crd-bearig migmatites leucosomes are compositionally similar to anatectic melts obtained by phase equilibria modelling, connected to fluid-assisted melting and defined as unfractionated, while the leucosomes dominated by Kfs-Bt cumulus structures and extremely enriched in K2O, Sr and Ba are connected to fluid-rich melting and Crd-absent migmatites. Major and trace element modelling suggests that part of the melt formed in the latter case was extracted from the source and that the composition of this evolved anatectic magma is compatible with the chemical composition of the migmatites-hosted LCT pegmatites. Whole rock Sr-Nd isotopic data confirm that the Li-rich pegmatites of the Forcel Rosso area are indeed crustally derived, marking them as produced by direct anatexis of metapelites. They also show that they were formed by two melt batches of different trace element composition originated by differential in-source fractionation. Conversely, isotopic data characterizes the pluton-hosted pegmatites as mantle-derived and directly linked to the Adamello batholith, clearly marking the lack of direct relationship existing between this magmatic intrusion and pegmatites featuring Li enrichment in its contact aureole. The data from this study shows that cordierite, or the absence of it, plays a key role in regulating the lithium transfer during partial melting in low pressure migmatites. Zircon U-Pb ages for all pegmatites in the area, point to the same age of the Adamello pluton intrusion, ca. 38 Ma, and trace elements compositions helped to outline the differences in the geochemical signature between pluton-derived and metapelite-derived pegmaties. The Ti-in-zircon geothermometer confirms that anatectic pegmatites crystallized at the peak metamorphic temperature calculated through phase equilibria modelling. Once defined that Li-enriched pegmatites are anatectic, tourmaline was used to study the continous evolution of the metapelitic system from unmetamorphosed up to the conditions of pegmatite crystallization. This mineral is the main boron carrier among the rock forming minerals and it’s obiquitous in the studied rocks. Studying the major element composition and boron isotopic signature several changes and trends are identified highlighting how this mineral evolves through the metamorphic history of metapelites, revealing a seemingly more complex picture compared to what is reported in the published literature data. Also, the data show how this mineral records variations during pegmatites crystallization processes making it valuable in the interpretation of their complex internal evolution processes. This PhD project proved that Li-enriched pegmatites may be anatectic and originate through fluid present melting of metapelites, even in the thermometamorphic aureole of plutons. We identify the mineral cordierite as the main regulator of lithium liberation during low pressure anatexis of suitably Al-rich pelitic rocks. We highlight that in-source and en_route melt fractionation play an extremely important role each time magma is extracted from its source and that this process is the one ultimately responsible for the formation of Li-enriched melts. Pegmatitic zircons, although complex, can be used as tracers in order to help define the origin of pegmatitic dykes, particularly in cases in which these bodies are too old for Sr isotopic determination. The studied area shows that small scale variations in the pre-anatectic abundance and presence of aqueous fluids influences melt production and melt composition of different migmatitic areas. Finally, the metamorphic and magmatic history of the studied tourmaline crystals highlights how this mineral may record almost every boron-involving reaction and help unravel the complex history of migmatites, pegmatites and Tur-bearing plutons.","language":"eng","citation":"LITHIUM ENRICHMENT IN ANATECTIC PEGMATITES: NEW INSIGHTS FROM THE THERMOMETAMORPHIC AUREOLE OF THE ADAMELLO BATHOLITH / L. Magnani ; co-tutor: F. Pezzotta ; tutor: F. Farina ; coordinatore: M. I. Spalla. Dipartimento di Scienze della Terra Ardito Desio, 2023 Apr 17. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12519.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/966036/2183676/phd_unimi_R12519.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1214076"},"title":"POTESTÀ REGOLAMENTARE E DIRITTO INTERNAZIONALE DEGLI INVESTIMENTI: LA TUTELA DELL¿AMBIENTE TRA CRISI DI LEGITTIMITÀ E PROPOSTE DI RIFORMA","internalauthor":"LONGHI, TESSA","type":"Tesi di dottorato","year":"2026","abstract":"The international regime for the protection of foreign investments has consolidated though a dens network of agreements, so-called international investment agreements (IIAs), aimed at ensuring stability and security of foreign investments. Conceived to safeguard the interests of capital-exporting States, these instruments establish treatment standards in favor of investors and grant them the right to initiate international arbitration proceeding against the host States in the event of an alleged breach   of its obligations.   For a while, the investor-State dispute settlement (ISDS) mechanism was rarely used. Since the 1990s, however, its application has significantly increased, thereby revealing certain shortcomings and raising doubts as to its suitability for resolving disputes involving matters of public interest.   In particular, arbitral practice has often yielded inconsistent outcomes, due to the ad hoc nature of ISDS arbitration, making it difficult to distinguish between measures incompatible with IIAs obligations and legitimate acts of the State’s sovereign regulatory powers. States have repeatedly denounced the unpredictability of arbitral awards as well as the insufficient consideration given to public regulatory needs.   These shortcomings have contributed to a growing legitimacy crisis of the system and to the emergence of the so-called regulatory chill phenomenon, whereby States refrain from adopting measures in the public interests for fear of arbitral proceedings.   Considering this, the thesis will seek to analyze the instruments that international law provides to States to rebalance the protection of investments with the exercise of regulatory authority, with particular reference to environmental law.   Following the historical overview of the regime and the examination of its main features presented in the first chapter, the second chapter will focus on the interpretation of the standards of treatment set forth in IIAs within arbitral practice, with regard to cases in which State measures adopted in the protection of collective interests have been challenged. The analysis will show how case law has displayed elements of inconsistency and a tendency to broadly expand the scope of guarantees accorded to investors and will highlight the consequences of this approach on the legitimacy of the systema and on States’ regulatory discretion in the field of environmental protection.   The third chapter will examine the causes of jurisprudential inconsistency, which may be traced back to substantive issues and will identify possible international law instruments designed to limit arbitral discretion in ISDS disputes. The analysis will focus on features of so-called new generation IIAs, which introduce more precisely defined treatment standards, explicit clauses safeguarding regulatory autonomy, carve-outs and exceptions. Special attention will be devoted to provisions expressly recognizing environmental protection as an interest deserving consideration.   The fourth chapter will turn to international law instruments of procedural nature, useful for reforming the ISDS mechanism, including those ensuring greater transparency of the proceeding. The role of amici curiae or of non-disputing States interventions and the possibility for States to bring counterclaims will also be examined, as mechanisms that promote consideration non-economic interests during disputes. Finally, possible solutions to enhance consistency in arbitral decisions will be analyzed, such as joint interpretation by investment committees and the potential establishment of an appellate mechanism or a multilateral investment court.    This comprehensive analysis will allow for an assessment of the effectiveness of those instruments in promoting a balanced international investment framework, capable of reconciling the protection of investors with the safeguarding of States’ regulatory powers, particularly in the context of environmental protection.   The fifth chapter will ultimately assess the impact of these reforms, which on the one hand reduce the protection granted to investors, while on the other mitigate the features that ISDS shares with commercial arbitration, on the original function of IIAs and the potential disinterest of State in such instruments. In this regard, particular attention will be paid to the termination of numerous treaties and to the growing withdrawal from the 1965 ICSID Convention, underlining the tendency of certain   States to promote alternative treaty models for this purpose.   In particular, the growing importance of investment facilitation agreements will be examined. Unlike traditional IIAs, such agreements limit treatment standards and exclude ISDS. The analysis will assess whether these instruments may represent a more effective alternative for the development of a more balanced system.","language":"ita","citation":"POTESTÀ REGOLAMENTARE E DIRITTO INTERNAZIONALE DEGLI INVESTIMENTI: LA TUTELA DELL' AMBIENTE TRA CRISI DI LEGITTIMITÀ E PROPOSTE DI RIFORMA / T. Longhi ; tutor: G. Adinolfi ;  co-tutor: D. Diverio ;  coordinatore: F. Biondi. Dipartimento di Studi Internazionali, Giuridici e Storico - Politici, 2026 Feb 02. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13810.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 11-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/813859"},"title":"MYCOSIS FUNGOIDES AND SEZARY SYNDROME THE JANUS BIFRONS OF THE CUTANEOUS T-CELL LYMPHOMAS: EVALUATION OF SPECIFIC PHENOTYPE AND GENETIC ALTERATIONS.","internalauthor":"ALBERTI VIOLETTI, SILVIA","type":"Tesi di dottorato","year":"2021","abstract":"Mycosis fungoides (MF) and Sézary syndrome (SS) are two variants of cutaneous T-cell lymphomas (CTCL). These entities are considered two distinct diseases, based on phenotypic and genetic analyses. Neoplastic cells in MF seem to derive from T effector memory cells, instead, neoplastic SS cells have a central memory (TCM) profile. Moreover, evidence of a resident memory T cell (TRM) profile in early-stage MF, compared to migratory memory T cells (TMM) profile in advanced-stage MF, seems to explain the clinical behavior of MF during progression. Recent studies have shown more heterogeneity in CTCL phenotypes compared to that theory. Differences between MF and SS also involve the microenvironment, which predominantly expresses Th1 phenotype compared to Th2 phenotype in advanced stages and SS.  A series of studies have identified multiple molecular changes in CTCL, showing a heterogeneous landscape of numerous genetic alterations without a strong differential signature between the two diseases. Molecular mutations could be found more frequently in the pathways of epigenetic and/or chromatin regulation, TCR and T-cell/ cytokine signaling, JAK/STAT signaling, and phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt) and NF-kB pathway.   The aim of this project is to delineate the differences between MF and SS about the phenotypic and genetic point of view, taking into account all stages of the diseases.  In the first phase of the project, 15 patients with a new diagnosis of MF and SS were selected, including 5 early-stage MF (IA-IIA), 3 advanced MF (2 III MF, 1 IIB MF), 5 classical SS, 2 non-erythrodermic SS. Neoplastic T-cell immune phenotypes were evaluated on paraffin-embedded formalin-fixed sections of skin biopsies and on CD4+CD7- sorted T cells of the peripheral blood by flow cytometry (except for two CD7+ cases).  About the 3 patients with stage IB MF, two of them revealed a TRM phenotype (CD69+CD103+CCR7-CD62L-). In the third of them, T cells aberrantly showed expression of CD69 and also CD62L. One IIA-MF patient showed expression of CD69 and CD103 (TRM markers) but also a partial expression of CCR7 with the negativity of CD62L, as TMM phenotype. Erythrodermic and tumoral MF patients were characterized by an infiltrate with a TMM phenotype. In SS, 3 patients showed a typical TCM phenotype (CD45RO+CD27+CCR7+CD62L+).  Out of 5 CD45RA+ cases, 4 of them evidenced a T naïve phenotype (CD62L+), including an early MF (IIA). One SS showed complete negativity of CD62L and CCR7, arguing a TEMRA phenotype. Immunophenotype of blood samples revealed a better correlation with the skin of SS patients compared to MF patients. Neoplastic T cells in MF mainly had a Th1 phenotype, also in advanced stages, compared to Th2 phenotype of SS patients.   This first step of the project confirmed that MF and SS are characterized by heterogeneity of phenotypes with partial correlation to the clinical features. Evidence of the same TCM phenotype in patients with classical and atypical SS suggests that criteria of this disease should be revised, including also non-erythrodermic forms.  In the second phase of the project, we performed a gene expression analysis using a 770-genes panel by NanoString technologies (PanCancer Immune Profiling Panel). To obtain more statically significant data, we included 95 FFPE slides of CTCL. Total RNA from 87 samples was extracted (36 SS and 51 MF at any stage). NanoString data were processed and statistical analysis was performed within the statistical environment R. A principal component analysis was performed on all samples together, but we found a homogeneous group without any evidence of clustering between MF and SS. So, we decided to study separately the two entities.  About MF, 12 differentially expressed genes (DEGs) between advanced stages and early stages were found (p-value <0.01): 9 of them resulted upregulated (CCR3, PRAME, FPR2, PMCH, AMBP, TRL7, TNFRSF10C, CFI, HAVCR2) and 3 were down-regulated (KLRB1, CD1B, CD5). Gene ontology (GO) enrichment analysis showed that those genes were significantly enriched in the regulation of the immune system, macrophage activation and Toll-like receptor (TLR) signaling. (FDR <0.05) KEGG pathways analysis revealed a not significantly representation in any pathways. Then, MF cohort was divided into two groups based on the median expression for each gene and the effects of high or low expression levels on OS were examined using the Kaplan-Meier (KM) survival curve. A list of 39 genes was identified as significant associated with OS (p-value <0.05). The HRs and p-values of those selected 39 genes were calculated through Cox regression model, revealing a 9-genes signature, which did not match with DEGs but showed a high significance from KM survival analysis. The increased expression of the following genes is significantly associated with poor prognosis: CDK1 (HR=2.06), IL6ST (HR=1.49), CCR4 (HR=1.66), ITK (HR=1.78), NOS2A (HR=1.38), IL2RA (HR=2.06), LRRN3 (HR=1.39), DUSP4 (HR=1.74). Instead, the lower expression of CCL26 (HR=0.53, p-value 0.028) is significantly associated to poor prognosis. A prognostic score was developed based on the incidence of each gene of the signature on overall survival and was defined as the linear combination of logarithmically transformed gene expression levels weighted by average Cox regression co-efficient. Patients with a high score of expression of the signature had a significantly poorer prognosis compared to patients with a low score (p-value < 0.05). Similarly, considering advanced versus early stages, the two groups with high score confirmed to have a statistically significant poorer prognosis compared to low score (p-value <0.05). This result is particularly evident comparing the score in early stages. KEGG pathway analysis showed that the 9-genes signature was significantly enriched in cytokine and JAK-STAT signaling. For SS samples, we did not evaluate DEGs because of the absence of different stages like in MF, but we performed the same analyses based on OS. A 14-gene signature was found, characterized by the association of their high expression and poor prognosis. The genes identified were IL12A (HR=2.12), IL5RA (HR=2.80), IFNL2 (HR=2.21), NT5E (HR=1.97), IL18RAP (HR=1.89), ABCB1 (HR=1.74), CCL16 (HR=1.89), CCL1 (HR=1.95), IL22RA2 (HR=1.67), IFNA17 (HR=1.69), C9 (HR=1.79), CCR9 (HR=3.31), SPANXB1 (HR=1.62), TREM1 (HR=1.76). We applied the prognostic score, showing that patients with a high score had a worse prognosis compared to patients with a low score. GO analysis showed that this 14-gene signature was significantly involved in defense response and Th1 cytokine production (FDR <0.05). KEGG pathway analysis was able to confirm a statistically significant involvement of these genes in JAK-STAT and TLR signaling.   In this second phase of the project, we were able to find a gene signature for each disease with a significant prognostic value that could be useful in clinical practice, especially in early stages. Evidence of a strong involvement of JAK-STAT pathway in analysis of both MF and SS is interesting because this pathway is well known to be involved in CTCL pathogenesis and its pharmaceutical inhibition is still studied.","language":"eng","citation":"MYCOSIS FUNGOIDES AND SEZARY SYNDROME THE JANUS BIFRONS OF THE CUTANEOUS T-CELL LYMPHOMAS: EVALUATION OF SPECIFIC PHENOTYPE AND GENETIC ALTERATIONS / S. Alberti Violetti ; tutor: E. Berti ; phd coordinator: M. Locati. Dipartimento di Oncologia ed Emato-Oncologia, 2021 Mar 12. 33. ciclo, Anno Accademico 2020. [10.13130/alberti-violetti-silvia_phd2021-03-12].","filename":"phd_unimi_R12046.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/813859/1702158/phd_unimi_R12046.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1156138"},"title":"PARADIGMI GEOGRAFICI E IDENTITARI IN ELIAS CANETTI ETHOMAS BERNHARD: UNA PROSPETTIVA COMPARATIVA","internalauthor":"MANENTI, ILARIA","type":"Tesi di dottorato","year":"2025","abstract":"This dissertation investigates the works of Thomas Bernhard and Elias Canetti, examining their narratives through an interdisciplinary approach that considers the relationship between geography and literature. The authors, whose personal relationship fluctuated between cordiality and conflict, shared a profound Herkunftskomplex – understood as a troubled relationship with their origins – which significantly influenced their literary engagement with space. The purpose of this study is to investigate how this problematic connection to places tied to their roots shaped the construction of the literary geography within their works, where spatial dynamics function as central narrative elements.  The thesis is divided into four chapters. The first chapter outlines the theoretical and methodological framework of the study, emphasizing the significance of the ongoing dialogue between geography and literature in contemporary culture.  The second chapter delves into the intricate relationship between Elias Canetti and Thomas Bernhard, tracing their personal and literary affinities and divergences. Their acquaintance, initially based on mutual admiration, gradually evolved into a bitter public rivalry. Despite personal tensions, both recognized each other’s literary value. Notably, Canetti’s suggestion that his novel Die Blendung may have influenced Bernhard’s Frost prompts a close examination of the interaction between their poetics.  Consequently, the third chapter shows how the concept of Herkunftskomplex is consistently and systematically developed throughout the work of both authors, albeit in distinct ways. Canetti reconstructs his fragmented identity through memory within a cosmopolitan context, while Bernhard uses places as repositories of traumatic experiences, thereby reflecting on the identity crisis of postwar Austria.  The fourth chapter undertakes a comparative analysis of Canetti’s Die Blendung and Bernhard’s Frost, examining how these paradigmatic works employ spatial dynamics to shape their narratives. Considering Canetti’s hypothesis regarding the influence of his novel on the genesis of Frost, the comparison focuses on the role of space as a structural narrative element capable of both orienting and disorienting the narrative.","language":"ita","citation":"PARADIGMI GEOGRAFICI E IDENTITARI IN ELIAS CANETTI ETHOMAS BERNHARD: UNA PROSPETTIVA COMPARATIVA / I. Manenti ; tutor: M. Castellari ; coordinatrice: L. Pinnavaia. Dipartimento di Lingue, Letterature, Culture e Mediazioni, 2025 Apr 02. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13243.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1156138/2728015/phd_unimi_R13243.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1174615"},"title":"NEW ADVANCES IN QUANTITATIVE RADIOLOGY:MRI IMAGING IN MYOPATHIES","internalauthor":"MOSCATELLI, MARCO ELVIO MANLIO","type":"Tesi di dottorato","year":"2025","abstract":"Abstract    This PhD thesis explores recent advancements in quantitative radiology applied to the diagnosis and characterization of myopathies using magnetic resonance imaging (MRI). The work integrates artificial intelligence (AI), radiomics, and advanced imaging techniques to improve diagnostic accuracy and pattern recognition in muscle diseases. The thesis is structured into three main studies.    First, a systematic review evaluates the state of AI-assisted pattern recognition in MRI of myopathies, highlighting the potential of deep learning and machine learning models to outperform human experts in distinguishing between myopathy subtypes, despite heterogeneity in datasets and methodologies.    Second, an original radiomic study applies texture analysis to whole-thigh fat fraction (FF) maps derived from Dixon sequences in a cohort of patients with genetically or histologically confirmed myopathies. Manual segmentation and PyRadiomics feature extraction enabled unsupervised clustering, revealing two distinct radiomic patterns corresponding to different clinical phenotypes. The study demonstrates that volumetric radiomics can identify pathophysiological differences beyond visual interpretation, especially when applied to full muscle volumes rather than single slices.    Third, the thesis presents a multidisciplinary study of the split-hand syndrome (SHS) in Charcot-Marie-Tooth disease type X1 (CMTX1), combining clinical, neurophysiological, and radiological data. SHS, previously associated mainly with motor neuronopathies, was identified in over half of CMTX1 patients using standard criteria and FF-based MRI metrics, suggesting a broader pathological spectrum and underlining the importance of imaging in early and differential diagnosis.    Altogether, the thesis underscores the transformative potential of AI and radiomics in neuromuscular imaging, proposing reproducible, quantitative, and non-invasive tools for diagnosis and disease monitoring. Future directions include multicenter collaborations, automated segmentation, and integration with explainable AI to enhance clinical applicability.","language":"eng","citation":"NEW ADVANCES IN QUANTITATIVE RADIOLOGY:MRI IMAGING IN MYOPATHIES / M.e.m. Moscatelli ; tutor: L. M. Sconfienza ; coordinatore: M. Del Fabbro. Dipartimento di Scienze Biomediche per la Salute, 2025 Jul 15. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13443.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1174615/3107504/phd_unimi_R13443.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-nc-nd/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1156532"},"title":"RECONSTRUCTING PHOENICIAN POTTERY PRODUCTION IN SARDINIA: A MULTI ANALYTICAL CHARACTERIZATION OF SAMPLES FROM THE SITE OF PANI LORIGA (8-7TH CENTURY BC) AND MONTE SIRAI (6-5TH CENTURY BC)","internalauthor":"MORABITO, GIULIA","type":"Tesi di dottorato","year":"2025","abstract":"This study contains the results of a multi-analytical archaeometric characterization of 53 pottery samples from two archaeological sites, Monte Sirai and Pani Loriga. Both sites are Phoenician-Punic colonies (7th-8th century BCE for Pani Loriga and 5th-6th century BCE for Monte Sirai) located in southwestern Sardinia, Italy. The analyses aimed to unveil the archaeological context, with provenance, raw materials and production processes.  Seven amphora samples from Monte Sirai were first analysed as comparative materials for the largest group of samples from Pani Loriga, including amphoras, jugs, cups, plates, and pots, representative of the various shapes and types found at the site.  Investigations were firstly focused on microstructure, matrix composition, and inclusion types, as well as to identify newly formed phases resulting from firing. Based on these analyses, five fabric groups were identified. Two of these groups, encompassing most of the samples, are characterized by coarse inclusions, suggesting minimal processing or purification of raw materials during the ceramic body preparation. In contrast, the other three groups display purified clay, with minimal inclusions. Optical petrography, combined with X-ray diffraction analysis, provided insights into the mineralogical associations, firing temperatures, and rock inclusions. In the most populated groups, the presence of minerals such as quartz, plagioclases, feldspars, and hydro-silicates, compatible with igneous rocks from pyroclastic and epiclastic deposits (including dacites and rhyolites), suggests the local production of these samples. Conversely, a high calcite content, along with microfossils observed in thin sections, indicates that some samples were likely imported. These imported specimens exhibit distinct features, suggesting different manufacturing techniques and, possibly, a higher level of production quality, if compared to the local ceramics. X-ray diffraction analyses further identified three distinct mineralogical groups based on their assemblages. The identification of minerals such as hydro-silicates, (primary) calcite, gehlenite, and diopside reflect different firing conditions and allow the estimation of firing temperature ranges. Such temperature ranges are further supported by archaeomagnetic analyses, which provided additional insights into the thermal history of the pottery confirming the firing process reconstructions based on XRD data (and the mineral stability fields). This first characterization allowed to select some samples to perform micromorphological analyses by scanning electron microscopy (with SEM-EDS), in order to describe matrix structure, slips and engobes, inclusion types, and degree of vitrification. SEM-EDS investigation was also combined with a portable X-ray fluorescence analysis to obtain the chemical composition of the ceramic samples. Even this approach provided experimental evidence to distinguish locally produced ceramics from potential imported ones.","language":"eng","citation":"RECONSTRUCTING PHOENICIAN POTTERY PRODUCTION IN SARDINIA: A MULTI ANALYTICAL CHARACTERIZATION OF SAMPLES FROM THE SITE OF PANI LORIGA (8-7TH CENTURY BC) AND MONTE SIRAI (6-5TH CENTURY BC) / G. Morabito ; advisor: G.D. Gatta ; co-advisor: N. Marinoni ; external co-advisor: C. Colombo, E. Possenti. Dipartimento di Scienze della Terra Ardito Desio, 2025 Apr 03. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13408.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1156532/2736814/phd_unimi_R13408.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/956505"},"title":"QUASI STATIC GRAVITY SIGNATURES IN SLOW TECTONIC ZONES: ASSIMILATION OF NOVEL AEROSPACE DATA AND GEOPHYSICAL MODELING","internalauthor":"BOLLINO, ARCANGELA","type":"Tesi di dottorato","year":"2023","abstract":"The main aim of my Ph.D. research project was to investigate the gravitational signatures of the mechanisms that regulate slow rate tectonic deformation in areas where the earthquakes enucleate.  2D thermo-mechanical numerical models are used to simulate the crust-mantle dynamics; in particular, complexities such as compositional stratification of crust-lithosphere system, mantle hydration, phase changes and degree of plate coupling are investigated, exploring how they affect the gravity field and its rate of change in different tectonic environments.  A strongly integration between modelling, gravitational and GNSS (Global Navigation Satellite System) data has provided valuable constraints to the analysis. In fact, this work  is part of the GravSeis-Gravitational Seismology project, an ESA-founded research project whose objective is to establish a theoretical framework for the detection and characterization of earthquake precursors based on the observations of the gravitational field made by satellite. Gravitational Seismology concept expresses the idea that earthquakes are not generated only by surface displacements but are closely connected to deep masses redistribution involved in the subduction systems. This rearrangement generates density anomalies, which in turn are responsible for the Earth's gravity field anomalies.  A first study has been conducted on the Sumatra and Mariana complexes,  representative of the two major types of subduction: ocean–continent and ocean–ocean, respectively. In a first phase, a set of numerical tests has been developed, varying three main parameters:        prescribed subduction velocity, prescribed subduction dip angle and degree of plate coupling, exploiting how their variation affect the gravity pattern.  In a second phase, the study of the EIGEN-6C4 gravitational disturbance patterns of the Sumatra and Mariana subductions has been carried out, allowing  to strengthen the analysis of the gravitational signature in ocean–continent and ocean–ocean subductions in terms of the physics of the processes occurring during the convergence of the plates. Model predictions show a good agreement with gravity data, both in terms of wavelengths and magnitude of the gravity anomalies measured in the surroundings of the Sumatra and Marina subductions, supporting that the differences in the style of the gravity anomaly observed in the two areas are attributable to the different environments – ocean-ocean or ocean-continental subduction – that drives a significantly different dynamic in the wedge area.  A second study has been carried out developing 2D finite-element thermo-mechanical models, in which the formation of oceanic crust and serpentinite due to the hydration of upwelling mantle peridotite is implemented, to simulate the evolution of the Gulf of Aden from the rift initiation to the development of an active oceanic spreading center.  The thermo-mechanical analysis support the hypothesis that the Gulf of Aden developed as a slow passive rift in thin lithosphere with thick crust and that the variations in features along the passive margins could be related to lateral variations in the amount of H2O in the mantle, which determines the different times of mantle melting.","language":"eng","citation":"QUASI STATIC GRAVITY SIGNATURES IN SLOW TECTONIC ZONES: ASSIMILATION OF NOVEL AEROSPACE DATA AND GEOPHYSICAL MODELING / A. Bollino ; tutors: A. M. Marotta, A. Regorda ; coordinatore del dottorato: M. I. Spalla. Dipartimento di Scienze della Terra Ardito Desio, 2023 Feb 22. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12593.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/956505/2149103/phd_unimi_R12593.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1230095"},"title":"PHENOTYPING OF GRAPEVINE ROOT SYSTEM FOR DROUGHT ADAPTATION","internalauthor":"BOLOGNINI, MARTINO","type":"Tesi di dottorato","year":"2026","abstract":"Drought events increasingly affect many viticultural regions worldwide, negatively influencing grape yield and quality and threatening the sustainability of the wine sector. Among the available adaptation strategies, the adoption of drought tolerant rootstocks has emerged as one of the most promising and sustainable approaches. Since the outbreak of Phylloxera in the 19th century grapevine has been predominantly propagated through grafting and rootstocks have become essential tools to regulate plant vigour, nutrient uptake and tolerance to abiotic stresses, including drought. However, currently available rootstocks derive from a relatively narrow genetic base highlighting the need to select new genotypes with enhanced adaptive potential under changing environmental conditions. Rootstock shapes root system architecture, thereby defining the plant’s capacity to explore the soil and to access and absorb water under limiting conditions. Despite their central role, knowledge of grapevine root systems and their regulation under drought remains limited, mainly due to the intrinsic difficulty of root observation. Recent advances in root phenotyping, improving the feasibility of root trait characterization, open new perspectives for the study of root system involvement in grapevine drought adaptation.  In this context, the present PhD project aimed to study grapevine root system at different scales adopting distinct phenotyping approaches to characterize its role in grapevine adaptation to water limiting conditions.   The first part of the project assessed how soil properties, scion genotype and rootstock influence grapevine root system architecture in vineyards within an environment prone to water scarcity. Below-ground organs of six rootstock varieties grafted with Grillo and Nero d’Avola were observed in loamy sand and clay soil through the profile wall method. Four M rootstocks, recently released by the University of Milan were compared with traditionally adopted 1103 Paulsen and 140 Ruggeri. Soil type, scion and rootstock all significantly affected root system development. M2 and M4 exhibited the overall best performance showing the highest root densities, whereas 140 Ruggeri was characterised by lower root development.   The second part of the project evaluated root system regulation adopted by Vitis plants under limited water availability. A first experiment focused on whole root system architecture and included a core collection of 70 genotypes grown in rhizotrons under controlled conditions. Plants were phenotyped under progressive soil drying adopting a smartphone-based approach.  Plant water consumption, and growth rates at both aerial and root levels were monitored. Four groups displaying contrasting physiological behaviours and root system architectures were identified. One group of 23 genotypes exhibited the most promising behaviour for drought prone environments combining reduced water consumption, tight stomatal control, sustained growth under water deficit, and a well-developed root system. The number of lateral roots emerged as a key trait in root system plasticity under water scarcity. A second experiment focused on root anatomy and involved two groups of genotypes identified as contrasting in their response to drought at root level. Plants grown in pots under controlled conditions were subjected to different levels of water deficit. Plants water status, above-ground growth and gas exchanges were recorded and root sections were sampled for anatomical traits observation. The two groups exhibited distinct responses to drought at both physiological and anatomical level. One group displayed a tolerance-oriented strategy maintaining root hydraulic conductivity and intrinsic water use efficiency even under severe water deficit whereas the second group displayed an avoidance-based strategy.  In conclusion the integration of different phenotyping approaches and plant developmental stages enabled a multi-scale interpretation of grapevine drought adaptation mechanisms at root level. The results highlight the central role of root system architecture, plasticity, and hydraulic properties in grapevine responses to water deficit and support the selection and breeding of more drought-tolerant rootstocks.","language":"eng","citation":"PHENOTYPING OF GRAPEVINE ROOT SYSTEM FOR DROUGHT ADAPTATION / M. Bolognini ; tutor: G. Cola, L. Brancadoro ; coordinatore: S. R. Pilu. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2026. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13892.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 30-SET-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/937002"},"title":"VOLTAGE GATED SODIUM CHANNEL AND NEURONAL DIFFERENTIATION. IMPLICATIONS IN AMYOTROPHIC LATERAL SCLEROSIS PATHOGENESIS","internalauthor":"COLOMBO, MARIA NICOL","type":"Tesi di dottorato","year":"2022","abstract":"Voltage gated sodium channels (VGSCs) are multimeric protein complexes formed by one alpha subunit, responsible of pore formation and of the regulation of the state of the channel, and by one or two accessory beta subunits that have an important role in the regulation of alpha subunit localization and kinetics and in the interaction with the extracellular environment. VGSCs, together with Calcium and Potassium voltage dependent channels, are involved in the definition of cellular electrical properties. In particular, a small percentage (1%) of the voltage dependent Na+ current generated by VGSCs is a non-inactivating component (Persistent Sodium Current, INaP).  Recent evidence pointed out an involvement of VGSCs and INaP in promoting neurite  elongation in health and disease. Indeed, NaV 1.6 and b1 subunits were reported to be fundamental in axonal outgrowth in mouse neuron primary culture. Moreover, our previous studies on a zebrafish model of Amyotrophic Lateral Sclerosis, that express the mutant G93R form of the superoxide dismutase 1 (SOD1) enzyme, show that alteration in the INaP  of spinal inter- and moto- neurons induced neuron hyperexcitability that finally leads to hyperactive zebrafish locomotor behaviour together with morphological alterations of motoneuronal phenotype.  In this scenario, we decided to deeper investigate the role of VGSCs in neurite elongation, by taking advantage of the NSC34 cell line, an in vitro model often used in the study of motoneuron disease. Thus, we used two different NSC34 model of ALS, the first one expressing the human wild-type (WT) or G93A form of the SOD1 enzyme and the second one that lacks for the expression of the vesicle-associated membrane protein associated protein B (VAPB) protein.  By mean of different experimental approaches we study the expression of VGSCs protein and mRNA levels, the localization of the channel and the ability of the cell to respond to a depolarizing stimulus in health and disease in vitro models. Then, taking advantage of pharmacological approaches we evaluate whether changes in VGSCs functionality cause impairments in neurites elongation.  Surprisingly, we found a strong correlation between VGSCs expression, localization and functionality and neuron differentiation in all the model we analysed. In particular, VGSCs increased expression seems to be functional to the increase in the percentage of differentiated cells during NSC34 differentiation. Moreover, NSC34 defective neurite outgrowth correlates with VGSCs defective expression or localization in NSC34 ALS models.  In conclusion, the study that I have conduct during the three years of my PhD project point out an interesting correlation between VGSCs and motoneuron differentiation with possible implication in ALS pathogenesis.","language":"eng","citation":"VOLTAGE GATED SODIUM CHANNEL AND NEURONAL DIFFERENTIATION. IMPLICATIONS IN AMYOTROPHIC LATERAL SCLEROSIS PATHOGENESIS / M.n. Colombo ; tutor: M. Francolini ; coordinatore: N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2022 Sep 21. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12270.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/937002/2062438/phd_unimi_R12270.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/951504"},"title":"L'IMPATTO DELL¿INVECCHIAMENTO SULLA CAPACITÀ LAVORATIVA E SULLA SALUTE DEI LAVORATORI TURNISTI E NON TURNISTI NEL SETTORE SANITARIO","internalauthor":"CANTARELLA, CARLO","type":"Tesi di dottorato","year":"2023","abstract":"Introduction and Objectives    In the context of accelerating technical and organizational changes at work and increasing life expectancy, the delayed retirement paradigm makes it important for people to remain healthy and professionally active longer than before. The interaction between age and working conditions (working hours, workload, stress, etc.) can have a significant effect on important outcomes such as work ability (performance efficiency, errors, accidents) and health (e.g., sleep, psychosomatic symptoms, chronic diseases). Aging can lead to reduced tolerance to shift and night work through a mechanism of weakening the circadian system, resulting from molecular, epigenetic, and functional changes in the biological clock. As a result, health deterioration with advancing age may be more pronounced in shift workers than in day workers.  The main objective of the study is to evaluate the impact of working time organization (night shift work or day work) on some biological functions and health conditions of aging workers, after adjusting for relevant contextual factors. Specifically, age-related changes were assessed in relation to exposure to night shift work with regard to interference with perceived health and well-being, hormonal patterning, and biological age.    Materials and Methods    Twenty-seven hundred and seventy-four shift and daily healthcare workers of both sexes and aged 24-66 years (divided into three age groups 24-35; 36-50; 51-66) were recruited from different departments of the Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico di Milano. The study sample includes all healthcare personnel (nurses, medical assistants, auxiliary staff, laboratory and radiology technicians) with a work history of at least one year; physicians were excluded from the recruitment. Data collected for each study subject through self-administered questionnaires included: demographic data, medical history, job task and seniority, socioeconomic/work conditions, shift work, work ability (Work Ability Index - WAI), stress (Effort/Reward Imbalance Index - ERI-I), physical and mental well-being. In addition, a number of biomolecular markers were assessed through blood samples to evaluate two factors: 1) levels of steroid hormones of the hypothalamic-pituitary-adrenal axis (stress hormones) and sex hormones; and 2) relative telomere length as an epigenetic and biological age expression marker. Blood samples were collected in the morning (between 7 a.m. and 9 a.m.) after a normal night's sleep from a rest day or previous day shift. Subjects were assigned to nine different departments: High Intensity Care Internal Medicine (MIAIC), Emergency Surgery (CDU), Analytical Laboratories (virology, biochemistry, microbiology, genetics, cytogenetics, pathological anatomy), Radiology, Neuroradiology, Occupational Medicine, Adult Intensive Care Unit (VECLA) and Pediatric, and Puerperium.    Results    Seventy-two percent of participants were female and 28% male, with an average age of 42 years. The most frequent job title is nurse (57%), followed by laboratory/radiology technician (24%) and OSS/ASA (19%). Fifty-nine percent of the participants work one or two day shifts (morning and afternoon), while 41% work three shifts including night shift. Eighty percent of subjects reported a good balance (ERI-I ≤1) between workload and rewards, while 84% of participants reported a high WAI score (>36), reflecting “good” or “excellent” work ability. Multivariate analyses did not show an effect of night shift on stress and performance indicators, although a negative influence of work stress on work ability emerged.  Regarding hormones, the comparison of male and female hormone levels reflects the physiological difference in the general population, as well as the tendency for blood concentrations to decrease with increasing age. Mean levels of cortisol, cortisone, and corticosterone were found to be higher in female workers and particularly in night shift workers. Estradiol was found to be higher in female shift workers than in female day shift workers, especially in young shift workers, with a downward trend as age increased. Multivariate analyses, however, did not show an effect of night shift on hormones. Regarding the possible influence of perceived work-related stress (ERI-I) on stress hormones (cortisol axis), a slightly positive, although not statistically significant, trend was observed between increased ERI-I scores and cortisol blood levels.  Analysis of mean telomere length values showed female workers to be longer than their male counterparts. Stratifying by shift type, in the lower age groups telomere length was greater among daytime workers, while in the higher age group telomere length was always greater among night shift workers. Multivariate analyses showed no significant effects of shift type, indicators of well-being/work ability (ERI-I/WAI) and hormonal blood values on telomere length.    Discussion and Conclusion    The study sample was representative of the hospital’s working population. Regarding indicators of well-being and work performance, most employees reported favorable scores for all scales, reflecting satisfactory working conditions. A negative association was observed between WAI and ERI-I scores: a decrease in work capacity corresponds to an increase in ERI-I scores, reflecting a negative influence of work stress on work capacity, although not statistically significant. The comparison of male and female hormone levels reflects the physiological difference in the general population as well as the tendency to decrease with aging, for almost all hormones. Interestingly, night-shift workers showed higher serum levels of all hormones analyzed than daily workers. In particular, cortisol was higher in female night-shift workers. However, no association was observed between hormone levels and stress conditions (ERI-I). Higher levels of estradiol were also found in night-shift women, and since some experimental studies have identified estrogen as one of the risk factors for breast cancer, it would be important to ensure closer health surveillance for night-shift women workers, especially those with a family history of breast cancer. Regarding epigenetic markers, telomere length was not found to be affected by type of work shift, well-being/performance indicators or blood hormone levels. The higher values in night shift workers over 50 may be explained by the so-called Healthy Worker Effect.   The pandemic that began in March 2020 unfortunately affected adversely the progress of the study, stopping it altogether due to the inability to interfere with hospital activity. One of the main objectives set in the project design was the analysis of the trend of biomolecular markers contextualized with the work characteristics of the study population. Since this type of marker is based on biological mechanisms that change and show their effect over time, a longitudinal development of the study could have emphasized more this effect of biomolecular markers in the specific context of shift work. The study, however, provides additional data on the field of biological markers in association with work ability and psychophysical health, including possible epigenetic changes (telomere length and biological age). The combined use of self-reported data together with biomolecular indicators and reports on work organization can provide better insight into the aging process of the workforce. These findings can sensitize the relevant and responsible authorities toward interventions aimed at maintaining the well-being and health of hospital staff, and useful in selecting appropriate prevention targets.","language":"ita","citation":"L'IMPATTO DELL¿INVECCHIAMENTO SULLA CAPACITÀ LAVORATIVA E SULLA SALUTE DEI LAVORATORI TURNISTI E NON TURNISTI NEL SETTORE SANITARIO / C. Cantarella ; relatore: M. Bonzini. Dipartimento di Scienze Cliniche e di Comunità, 2023 Jan 17. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12723.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/951504/2123870/phd_unimi_R12723.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1100508"},"title":"THE INTERPLAY OF STATE AND FIRM IN ZAMBIA: PATH DEPENDENCY IN THE MINING SECTOR","internalauthor":"ROCH, MAXIMILLIAN ALEXANDER JOHN","type":"Tesi di dottorato","year":"2024","abstract":"Zambia is a mineral-dependent state with a history inextricably tied to the mining of copper. The relationship between state and firm in Zambia has been contentious since independence from Britain in 1964. Since then attempts to nationalise or curb the power of the mining firms have failed owing to the path dependence of the sector. Path dependence has led to an uneasy equilibrium in the modern day, whereby the optimal economic choice is foreign firm control over the mining sector. This optimal choice comes at the expense of the social and environmental well-being of the state. This choice is constrained and is a result of the historic development of the sector, the legacy of debt and the limited domestic capacity for large-scale mining projects in the modern day. This consequence of constrained choices has resulted in the further entrenching of imbalance between firm and state over time. This path dependence was codified through one-sided investor-state agreements through the use of stabilisation clauses and consequently, mining firms have committed environmental violations and tax evasion with impunity. Path dependence and mineral dependence are connected, and this has led to options missed through disincentive. Such as diversification and as a consequence of that, the development of international investment law and regional integration. This research utilises the critical juncture framework to determine the genesis of path dependence in the Zambian mining sector, that of the split between mines and state. In 1924 the British South African Company retained the nation’s mineral rights after the establishment of the British Protectorate. The company only ceded the administrative rights of the territory which created a clear barrier between the precursor of the Zambian state and the mining sector. The mining sector continued and developed on the basis of being as attractive as possible for external firms. In plain terms, Zambia’s mining sector was born out of a split between the functions of the mines and the functions of the state. Over time this has developed a sector that operates outside of the state, whilst simultaneously exercising influence over it. This reality has rendered nationalisation and legislation relatively futile.","language":"eng","citation":"THE INTERPLAY OF STATE AND FIRM IN ZAMBIA: PATH DEPENDENCY IN THE MINING SECTOR / M.a.j. Roch ; tutor: L. Crema, V. Cecchini Manara, M. Atal ; coordinator: L. Sacconi. - Università degli Studi di Milano. Università degli Studi di Milano, 2024 Nov 21. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13112.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1100508/2537772/phd_unimi_R13112.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1025564"},"title":"PHYSIOLOGICAL APPROACH TO THE STUDY OF AUTOCHTHONOUS SMALL RUMINANTS BREEDS OF ITALY","internalauthor":"AGRADI, STELLA","type":"Tesi di dottorato","year":"2024","abstract":"The loss of biodiversity is a worldwide issue. Many local livestock breeds are threatened by the risk of extinction, mainly due to the progressive abandonment of some of these breeds in favor of few transboundary high-performance ones. Maintaining and protecting the autochthonous breeds is pivotal to guarantee food and agriculture sustainable development and food security in the future.  In Italy, the husbandry of local goat breeds plays a multifunctional role, and expanding the knowledge of these native breeds is fundamental to allow the development of a correct strategy of conservation and improvement.  Our project has focused on the study of physiological productive, reproductive, immunological, and metabolic aspects of four local goat breeds of Northern Italy (Frisa Valtellinese, Orobica, Lariana, and Verzaschese goats), on which the information is still very limited. Moreover, we have compared the results obtained from these breeds with those from the Camosciata delle Alpi, a transboundary dairy goat breed spread all over the world.   Our results have shown the peculiarities and variabilities of the milk production of local breeds, despite their yields being lower than the cosmopolitan breed. We also investigated the polymorphism of a gene strictly related to the reproductive seasonality, showing the existence of no differences among local and cosmopolitan breeds belonging to the same macrogroup of breeds. However, when investigating different metabolic and immunological aspects, we demonstrated the greater variability among breeds and the greater rusticity of local ones. Specifically, a better quality of colostrum was found in local breeds when compared to a cosmopolitan breed, considering also the typical farming system of each of them. Moreover, evaluating the hematological parameters in different goat breeds under identical farming conditions, our study revealed a greater adaptability of local breeds to environmental stressors. Finally, this study evaluated the stress reaction to the environment during the vertical transhumance in a local breed, together with the possibility to use autochthonous breeds as biomonitoring tools, specifically for heavy metals and trace elements.  In conclusion, this project has demonstrated, with a multidisciplinary approach, the great variability of physiological adaptations existing between different breeds, and the greater rusticity and hardness enjoyed by local breeds compared to transboundary breeds.","language":"eng","citation":"PHYSIOLOGICAL APPROACH TO THE STUDY OF AUTOCHTHONOUS SMALL RUMINANTS BREEDS OF ITALY / S. Agradi ; tutor: G. Brecchia; coordinatore: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2023. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12900.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1025564/2351221/phd_unimi_R12900.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1027710"},"title":"USING TRANSCRANIAL MAGNETIC STIMULATION TO EXAMINE AND MODULATE BRAIN CIRCUITS IN SCHIZOPHRENIA","internalauthor":"DONATI, FRANCESCO LUCIANO","type":"Tesi di dottorato","year":"2024","abstract":"Schizophrenia is a highly heterogeneous disorder that affects up to 1% of the world's population and ranks among the leading causes of disability worldwide. The clinical picture is characterized by chronic psychotic symptoms, episodic relapses, and significant disruption of social functioning. Symptoms are often divided into “positive”, including hallucinations and delusions, and “negative”, such as social withdrawal and anhedonia. In most patients, these are associated with a gradual deterioration in cognitive functions. Of note, while current treatments based on antipsychotic medications are effective at treating positive symptoms and, to a lesser extent, negative symptoms, there is a dearth of available interventions able to ameliorate the cognitive deficits associated with schizophrenia. Furthermore, the causes and mechanisms underlying this condition remain elusive.  Accumulating evidence suggests that abnormalities in the ability of neurons to synchronize their oscillatory activity, particularly in the beta and gamma frequency bands, might be implicated in the pathophysiology of schizophrenia. Evidence from studies employing electroencephalography (EEG) across several paradigms (resting state, steady state, sensory event-related, task-related, etc.) suggests that deficits in these “fast” brain rhythms in the frontal lobe are common in schizophrenia and might be associated with its clinical symptoms, particularly cognitive dysfunction. These alterations are believed to reflect an imbalance between excitatory and inhibitory function, particularly related to a dysfunction of specific populations of cortical and subcortical GABAergic interneurons. However, conventional EEG studies, particularly when investigating task-related neural activity, can be affected by the subject’s engagement, attention, motivation, or clinical symptoms. This represents an inherent limitation to their application for the development of useful biomarkers in severe psychiatric disorders such as schizophrenia. Furthermore, a large gap remains between the abundance of evidence on altered fast oscillations in schizophrenia and the lack of effective interventional strategies developed around these putative biological targets.  Transcranial magnetic stimulation (TMS) is a neurostimulation technique that leverages electromagnetic induction to non-invasively induce targeted electric currents in the brain cortex. One important advantage of TMS over other brain stimulation techniques is that it can be employed as both an exploratory technique, when coupling single pulses of TMS with EEG recordings (TMS-EEG), and as an interventional tool, when TMS is used in repetitive patterns to induce brain plasticity (rTMS).  TMS-EEG allows for non-invasively probing brain areas and circuits and extracting quantitative measures of excitability, oscillatory function, and connectivity. Importantly, the perturb-and-measure nature of TMS-EEG makes it relatively independent from subject-specific behavioral confounders, such as attention, motivation, and cognitive abilities, making it an ideal tool to assess the integrity (or lack thereof) of brain circuits in neuropsychiatric populations. One prominent TMS-EEG measure of (thalamo)cortical function is the main oscillatory EEG frequency recorded after the TMS pulse, or “natural frequency”. In the healthy brain, different brain areas respond with different natural frequencies: the prefrontal natural frequency is in the gamma (30-40 Hz) frequency band, the premotor natural frequency is in the high beta/low gamma (25-34 Hz) range, the parietal natural frequency is in the beta-1 (13-25 Hz) band, and the occipital natural frequency is in the alpha (8-12 Hz) range. This rostrocaudal gradient likely reflects differences in the intrinsic oscillatory properties of these brain areas, which may underlie their functional specificities. Recent evidence from TMS-EEG has revealed that, in chronic schizophrenia, brain areas of the frontal lobe - including motor, premotor, and prefrontal areas - show alterations in several TMS-evoked EEG parameters, compared to healthy control (HC) subjects. In particular, one study found that the natural frequency is significantly reduced in these areas in chronic schizophrenia, compared to HCs, with the prefrontal natural frequency showing a complete separation between patients and healthy subjects. Furthermore, in schizophrenia patients, the prefrontal natural frequency correlated negatively with clinical symptoms and working memory performance. However, it is unclear whether these deficits are related to confounding factors linked to the chronicity of the illness, such as length of exposure to antipsychotic medications, comorbidity, or neurodegenerative processes, or rather are present since early in the course of schizophrenia, thus being more likely linked to core pathophysiological mechanisms associated with this disorder.  When TMS pulses are delivered repetitively, as in rTMS, they can induce neuronal plasticity and modify local excitability and long-distance connectivity. rTMS protocols include “excitatory” high-frequency stimulation (where pulses are delivered at a frequency of 5-10 Hz), “inhibitory” low-frequency stimulation (1 Hz), and novel theta burst stimulation (TBS) paradigms. In TBS, 50Hz triplets of TMS pulses are delivered at 5-8 Hz (i.e., theta frequency) in either intermittent blocks (iTBS, excitatory) or continuously (cTBS, inhibitory). Administering multiple sessions of rTMS (over 3-4 weeks) is a currently approved treatment for medication-resistant depression, obsessive-compulsive disorder, and migraine, as well as for smoking cessation. However, its potential role in ameliorating oscillatory dysfunction and cognitive deficits associated with schizophrenia is still underexplored.  In this PhD thesis, I will first report on three studies that were recently conducted at Prof. Fabio Ferrarelli’s lab at the University of Pittsburgh. In these studies, we employed TMS-EEG to explore the oscillatory properties of different cortical areas and their association with clinical symptoms in patients in the early stages of schizophrenia. The overarching goal of these studies was to test the role of TMS-EEG measures, including the natural frequency, as candidate pathophysiological biomarkers of schizophrenia. I will then outline the study design of a recently funded mechanistic clinical trial that leverages findings from study 3 to test the efficacy of iTBS in acutely ameliorating TMS-EEG parameters and cognitive performance in subjects with schizophrenia. Preliminary results from an initial subset of subjects will be briefly discussed.  In study 1, we used TMS-EEG to probe the left motor and left posterior parietal areas in 23 acutely ill, first-episode psychosis (FEP) patients and 13 age and gender-matched HC subjects. Patients were assessed with clinical scales by experienced raters at baseline and during a six-month follow-up. From TMS-EEG data, we calculated the natural frequency as well as the EEG spectral power in each frequency band relative to the broadband power, or Relative Spectral Power (RSP). The natural frequency did not show any significant group difference in either the motor or posterior parietal cortices. No significant differences were found in any other TMS-EEG parameter for the posterior parietal cortex. However, when stimulating the motor cortex, FEP patients showed a local deficit in the high beta/low gamma RSP, relative to HC participants, corresponding to a large effect size (Cohen’s d = 1.5). High beta/low gamma deficits correlated with worse positive symptoms at baseline and predicted their severity at the six-month assessment. Given its association with positive symptoms in acutely ill patients, this reduction may represent a state biomarker of acute psychosis.  In study 2, we used TMS-EEG to target the left premotor cortex in 16 outpatients with early-course schizophrenia patients (<2 years from onset) and 16 age and gender-matched HCs and found that the natural frequency of the premotor cortex was significantly reduced in early-course schizophrenia, corresponding to a large effect size (Cohen’s d = 1.06). No correlation was found between the natural frequency and age, clinical symptom severity, or dose of antipsychotic medications.  In study 3, we applied TMS-EEG to the left dorsolateral prefrontal cortex (DLPFC) in 30 outpatients with early-course schizophrenia and 28 age and gender-matched HCs. Goal-directed working memory performance was assessed using the “AX” Continuous Performance Task (AX-CPT). The natural frequency of the left DLPFC was significantly reduced in patients compared to HCs, which corresponded to a very large effect size (Cohen’s d > 2.0). Patients also showed a higher local RSP in the beta band, relative to HCs. The AX-CPT performance was significantly worse in patients relative to HCs. Across all participants, the beta-band RSP in the left frontal EEG channels correlated inversely with the AX-CPT performance.  Altogether, these findings indicate that intrinsic oscillatory deficits are present in frontal areas since the early stages of schizophrenia and may relate to its clinical symptoms, supporting their role as candidate pathophysiological biomarkers of this disorder. Interestingly, these EEG deficits exhibit a postero-anterior progression similar to what is seen in chronic patients, with prefrontal areas showing the largest impairment. Particularly, results from study 3 suggest that a reduction in the natural frequency of the DLPFC may represent an early neural signature associated with working memory deficits often seen in schizophrenia, supporting the existence of a link between prefrontal fast oscillatory dysfunction and cognitive impairment in schizophrenia. These findings may indicate a potential avenue for intervention to address a historically unmet need in these patients.  Finally, we report the study design and preliminary findings of an interventional double-blind, placebo-controlled, randomized, cross-over mechanistic clinical trial in a cohort of early-course schizophrenia patients (current n=20; projected recruitment n=75). Building on findings from study 3, this ongoing study combines TMS-EEG and rTMS to test the effectiveness of a single session of iTBS of the DLPFC to acutely a) revert the abnormalities in prefrontal TMS-evoked oscillatory EEG activity, including the reduction of the DLPFC natural frequency; and b) improve the working memory performance.","language":"eng","citation":"USING TRANSCRANIAL MAGNETIC STIMULATION TO EXAMINE AND MODULATE BRAIN CIRCUITS IN SCHIZOPHRENIA / F.l. Donati ; tutor: O. Gambini, F. Ferrarelli ; coordinatore: M. Del Fabbro. Dipartimento di Scienze della Salute, 2024 Jan 23. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13056.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1027710/2357134/phd_unimi_R13056.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1152177"},"title":"ASSISTIVE TECHNOLOGIES SUPPORTING BLIND AND LOW VISION PEOPLE DURING NAVIGATION","internalauthor":"GALIMBERTI, GABRIELE","type":"Tesi di dottorato","year":"2025","abstract":"The thesis investigates navigation systems for blind and low vision people, proposing three main contributions. First, the thesis proposes two sonification techniques to provide guidance instructions to blind and low vision people during navigation. The proposed solutions are compared with a state-of-the-art technique showing that they improve the precision with which users move while navigating, in particular during rotations. Second, the thesis identifies a set of data management problems that have mostly been overlooked in the scientific literature, such as how to model the space. The contribution consists of designing innovative solutions for these problems and in showing that they significantly improve the navigation experience in terms of safety and clarity. The third contribution explores the problem of screen reader intelligibility in the presence of high levels of acoustic noise in the environment. Noise adaptation techniques are proposed and experimentally evaluated, showing that they significantly improve the screen reader intelligibility while also not distracting the user.","language":"eng","citation":"ASSISTIVE TECHNOLOGIES SUPPORTING BLIND AND LOW VISION PEOPLE DURING NAVIGATION / G. Galimberti ; tutor: S. Mascetti, D. Ahmetovic ; coordinatore: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2025 Mar 11. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13597.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1152177/2709147/phd_unimi_R13597.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1212777"},"title":"BIORELEVANT RELEASE TESTING OF LONG-ACTING INJECTABLES INTENDED FOR PARENTERAL ADMINISTRATION","internalauthor":"FRIGERIO, GIORGIA","type":"Tesi di dottorato","year":"2026","abstract":"In vitro release testing is pivotal in supporting various stages of pharmaceutical development, from formulation design to routine quality control. Its implementation ensures the consistent quality, performance, and regulatory compliance of medicinal products. For orally administered small-molecule drugs, in vitro testing has been extensively studied to establish a quantitative relationship between the dissolution data and plasma drug concentration-time profiles (in vitro-in vivo correlation (IVIVC)). However, the applicability of IVIVC models is limited when interactions of complex drug product (complex in the characteristics of the drug substance, the formulation and/or the route of administration) with the physiological environment occur.  These limitations are particularly evident for parenteral administration routes, such as subcutaneous and intradermal delivery, where the structural and compositional complexity of the injection site can markedly influence drug release, diffusion, and bioavailability. Consequently, there is a growing need of reliable dissolution methods that mimic key aspects of human physiology, both in terms of the composition and physicochemical properties of bodily fluids and hydrodynamics at the specific site of drug administration.   This PhD project aimed to advance the development of biorelevant in vitro testing strategies for complex drug delivery systems intended for parenteral administration, as well as for innovative oral formulations. The first part of the work focused on the subcutaneous tissue, evaluating current methodologies for assessing drug release following subcutaneous administration. Poly(lactide-co-glycolide) microspheres loaded with naltrexone or flurbiprofen were used as model delivery systems to investigate the impact of interstitial fluid and extracellular matrix components on release behavior under different hydrodynamic conditions. Biorelevant media were developed based on an extensive analysis of subcutaneous tissue characteristics, and human tissue samples were analyzed to clarify discrepancies in reported glycosaminoglycan content.  The second part of the project addressed intradermal administration by developing a synthetic model that reproduces the key mechanical properties of the dermis, enabling a more reproducible assessment of drug diffusion compared with conventional ex vivo approaches. Finally, the performance of orodispersible dosage forms containing β-galactosidase was investigated in simulated gastric conditions to evaluate the influence of variability in gastric fluid volumes on in vitro lactose hydrolysis.  Overall, this work contributes to a deeper understanding of the role of biorelevant testing in predicting drug release and performance for complex drug products, supporting more reliable formulation development and regulatory assessment.","language":"eng","citation":"BIORELEVANT RELEASE TESTING OF LONG-ACTING INJECTABLES INTENDED FOR PARENTERAL ADMINISTRATION / G. Frigerio ; tutor: F. Selmin co-tutor: S. Franzè coordinatore: G. Vistoli. Dipartimento di Scienze Farmaceutiche, 2025 Jan 28. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13982.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 06-FEB-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1025693"},"title":"TECHNOLOGY-DRIVEN WORK ENVIRONMENTS: AN ATTRIBUTIONAL PERSPECTIVE ON EMPLOYEES' WELL-BEING","internalauthor":"COLAIACOVO, BENEDETTA","type":"Tesi di dottorato","year":"2024","abstract":"This dissertation adopted attribution theory to explore the relationship between employees’ interpretations of technology-driven work configurations and their well-being. Overall, this thesis is composed of three, highly interrelated studies, one review study and two empirical ones. In the review study, I explored the application of attribution theory in studying employee reactions to workplace digitalization. The main findings suggest that two streams of attribution theory (i.e. causal attributions and attribution of intent) have been adopted in the multidisciplinary literature that characterize this topic. Moreover, this first study provides evidence of how attribution theory contributes to explaining employees’ different responses to digitalized work environments. Being this dissertation developed during the COVID-19 pandemic, in Chapters II and III I shifted my research focus from workplace digitalization to technology-mediated work configurations, such as remote work. For this reason, both studies are focused on the effects of employees’ attributions concerning remote work on work-related well-being and mental health. The findings of both studies confirm a positive relationship between benevolent attributions (i.e. employees' perception that remote work is introduced to increase their well-being) concerning remote work and work-related well-being indicators as well as mental health. On the contrary, a negative association is found between malevolent attributions (i.e. employees perception that remote work is introduced to exploit them) and work-related well-being as well as mental health indicators. This thesis contributes theoretically to Human Resource (HR) attribution literature by adopting an alternative conceptualization of individuals’ attributions with respect to dominant research in this area. Indeed, in Chapter II the concept of environmental-centric attributions is introduced, while in Chapter III I have proposed the concept of stakeholder and shareholder-centric attributions. Moreover, in the empirical studies, I have adopted a two-wave design which represents an advancement with respect to cross-sectional, which is the dominant design in this field. This dissertation offers valuable insights to companies struggling to define technology-mediated work configurations that can effectively balance diverse stakeholders' demands and preserve individuals' well-being.","language":"eng","citation":"TECHNOLOGY-DRIVEN WORK ENVIRONMENTS: AN ATTRIBUTIONAL PERSPECTIVE ON EMPLOYEES' WELL-BEING / B. Colaiacovo ; supervisors: S. Gilardi ; M. Guerci. Università degli Studi di Milano, 2024 Jan 18. 35. ciclo [10.13130/colaiacovo-benedetta_phd2024-01-18].","filename":"phd_unimi_R12657.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1025693/2350037/phd_unimi_R12657.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1225332"},"title":"PROBING THE HIGGS BOSON WITH THE ATLAS DETECTOR: PRECISION MEASUREMENTS OF THE MASS AND SEARCH FOR RARE DECAYS TO A LOW-MASS DILEPTON SYSTEM AND A PHOTON IN PROTON-PROTON COLLISIONS AT THE LHC","internalauthor":"NASELLA, LAURA","type":"Tesi di dottorato","year":"2026","abstract":"This thesis presents three analyses based on proton--proton collision data recorded by the ATLAS detector at the Large Hadron Collider,   using the full Run~2 dataset collected between 2015 and 2018 at a centre-of-mass energy of $\\sqrt{s} = 13$~TeV, corresponding to an   integrated luminosity of 140~fb$^{-1}$, and data recorded during the first part of Run~3 between 2022 and 2024 at $\\sqrt{s} = 13.6$~TeV,   corresponding to 165~fb$^{-1}$. The analyses focus on a detailed investigation of the Higgs boson within the Standard Model (SM), through the   precision measurement of one of its fundamental parameters, the Higgs boson mass $m_H$, and the search for a rare SM decay mode not yet   observed, namely the decay into a low-mass dilepton system and a photon.    \\noindent The first analysis presents a precision measurement of the Higgs boson mass in the diphoton decay channel, $H \\rightarrow \\gamma\\gamma$,   using the full Run~2 dataset. The Higgs boson mass is measured to be $m_H = 125.17 \\pm 0.11\\,(\\mathrm{stat.}) \\pm 0.09\\,(\\mathrm{syst.})~\\mathrm{GeV}   = 125.17 \\pm 0.14~\\mathrm{GeV}$. The improved precision with respect to previous measurements is driven by the larger dataset and by significant   advances in the calibration of the photon energy response, resulting in a measurement that is now statistically limited. A combination with   the corresponding Run~1 measurement yields $m_H = 125.22 \\pm 0.14~\\mathrm{GeV}$.    \\noindent The second analysis furthermore combines the Higgs boson mass measurements obtained in the $H \\rightarrow \\gamma\\gamma$ and   $H \\rightarrow ZZ^* \\rightarrow 4\\ell$ decay channels using ATLAS Run~1 and Run~2 data. The combined result, $m_H = 125.11 \\pm 0.09\\,(\\mathrm{stat.}) \\pm 0.06\\,(\\mathrm{syst.})~\\mathrm{GeV}   = 125.11 \\pm 0.11~\\mathrm{GeV}$, achieves a relative precision of 0.9 per mille and represents the most precise determination of the Higgs   boson mass to date. All mass measurements are found to be consistent with each other and with previous ATLAS and CMS results.    \\noindent The third analysis presents a search for the rare Higgs boson decay into a low-mass dilepton system with a photon,   $H \\rightarrow \\ell\\ell\\gamma$ ($\\ell = e, \\mu$), using partial Run~3 data. The search targets the low dilepton mass region   $m_{\\ell\\ell} < 30$~GeV, where the decay proceeds predominantly via an off-shell photon. The analysis is currently under ATLAS internal   review, and preliminary expected results based on statistical uncertainties only are reported. The expected 95\\% confidence level upper   limit on the production cross section times branching ratio is 1.65 (0.70) times the SM prediction under the signal-plus-background   (background-only) hypothesis, and an expected significance of $Z = 2.53\\,\\sigma$ is obtained for a SM signal.    \\noindent In addition, studies of the ATLAS detector performance relevant for these analyses are presented, including the optimisation of   the multivariate Monte Carlo--based energy calibration for electrons and photons in Run~2 and Run~3, and dedicated studies of merged-electron   identification, which are essential for the rare-decay $H \\rightarrow \\ell\\ell\\gamma$ search.","language":"eng","citation":"PROBING THE HIGGS BOSON WITH THE ATLAS DETECTOR: PRECISION MEASUREMENT OF THE MASS AND SEARCH FOR RARE DECAYS TO A LOW-MASS DILEPTON SYSTEM AND A PHOTON IN PROTON-PROTON COLLISIONS AT THE LHC / L. Nasella ; tutor: L. Carminati, R. Turra, S. Manzoni ; coordinatore: A. Mennella. - via Celoria, 16, Milano. Dipartimento di Fisica Aldo Pontremoli, 2026 Mar 25. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13865.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1225332/3276156/phd_unimi_R13865.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1021895"},"title":"ASSURANCE-AWARE 5G EDGE-CLOUD ARCHITECTURES FOR INTENSIVE DATA ANALYTICS","internalauthor":"BERTO, FILIPPO","type":"Tesi di dottorato","year":"2024","abstract":"Modern data-intensive applications are increasingly demanding in terms of non-functional properties such as performance, latency, security, and privacy. In order to achieve such non-functional properties, modern applications benefit from being developed as a composition of services and deployed in a heterogeneous continuum infrastructure that includes Edge and Cloud facilities. In this scenario, the infrastructures used to deploy services play a crucial role in providing or supporting non-functional properties of the applications. For instance, low latency can be achieved via deployment of services in the far edge nodes. Most of the current literature addresses the problem of deployment of single (stateless)services mainly with the aim of ensuring and verifying requirements in terms of resources and performance. Only few solutions exist to deploy applications made of services workflows, and in most of the cases they are focused on functional composition. In general, they fail to address composition deployment preserving advanced non-functional properties such as security and privacy. This thesis proposes novel assurance methodology for modern continuum infrastructures, enabling lightweight in-depth verification and assessment of non-functional properties constituting the key cornerstone for a fully non-functional-aware deployment of service based applications.  The thesis proposes an advanced continuum infrastructure, where the 5G MEC is integrated as an Edge node. It also considers a continuum which is empowered with a big data ecosystem of services, where data-intensive analytic workflows can be executed to support critical applications.  The assurance methodology defined in the thesis is collaborative and lightweight, and is based on i) transparent collection of evidence representing measurements of relevant continuum states (obtained via monitoring or testing of standard infrastructure-level hooks), ii) aggregation of measurements into metrics and iii) contracts linking metrics to specific non-functional properties.  The assurance methodology decouples infrastructure assurance from data processing assurance and application-level assurance. It is the first attempt to suggest that infrastructure and data processing assurance can effectively complement application-level assurance with a limited increase in computational effort while fully applicable in modern continuum infrastructures.    The contributions of this thesis are manifold: i) a generic assurance methodology for modern infrastructures ii) a set of specific verticalization of the generic assurance for 5G MEC, Big Data pipelines and CDN networks, iii) a novel notion of continuum empowered by 5G, iv) property aware deployment solution for the continuum integrating assurance controls, v) a complete realization of a continuum infrastructure with simulated 5G nodes and a real data-intensive application for robotic agronomy vi) full experimental evaluation of utility usability and performance.    The assurance approaches developed in the thesis have been applied to a real-world scenario through the construction of a complete 5G-enabled Edge-Cloud continuum infrastructure. This was achieved by integrating a 5G network simulator, a MEC deployment infrastructure, a Big Data engine, and a data analysis pipeline platform.  This continuum was used to realize a concrete application in the area of IoT-based automated agronomy. Such application is capable of handling the collection, ingestion, analysis and visualization of on-field data. Such complex modern application requires guarantees on a set of advanced non-functional properties that were verified adopting the assurance methodology defined in the thesis.    The obtained results demonstrate the utility and usability of the assurance in the context of modern data-intensive application as well as the limited impact in terms of performance obtained thanks to the approach based on infrastructure-level monitoring and lightweight evidence collection.","language":"eng","citation":"ASSURANCE-AWARE 5G EDGE-CLOUD ARCHITECTURES FOR INTENSIVE DATA ANALYTICS / F. Berto ; supervisor: M. Anisetti ; co-supervisor: C. A. Ardagna ; external supervisor: M. Valla ; PhD course coordinator: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2023. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12977.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1021895/2340617/phd_unimi_R12977.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1043255"},"title":"IL POTENZIALE TRASFORMATIVO DELLE ESPERIENZE DI AGRICOLTURA URBANA. UN'INDAGINE SUI SERVIZI ECOSISTEMICI CULTURALI GENERATI ALL'INTERNO DEL TERRITORIO MILANESE","internalauthor":"CAPOCEFALO, VALENTINA","type":"Tesi di dottorato","year":"2024","abstract":"Nowadays the Ecosystem Services (ES) analytical framework is often used to promote environmental protection and biodiversity conservation or restoration at different geographical scales.  Quantitative approaches, methods and tools have been privileged in the international scientific debate for a long time. This condition appears almost entirely unchanged in Italy, where the paradigm has been introduced in the early 2010s. The marginality of qualitative aspects, that related to sociocultural  issues, is clearly manifested by the law 221/2015. A second paradigm, called Nature Contribution to People (NCP), has emerged in the international scene starting from 2015. It includes and expands the ES one and it has not yet been introduced in the national debate. NCP analytical framework does not  priority aim to categorize the benefits produced by the ecosystems, but rather aims to reach a deep knowledge of the socio-ecological relations at the local scale. ES analytical framework has been applied to the analysis of urban agricultural experiences in several geographical contexts. In contrast,  the author is not aware of any analyses that have applied the most recent paradigm to this field. The PhD thesis moves from a precise purpose: detect the benefits generated by two urban agriculture experiences located at the eastern and western edges of the Municipality of Milan and representative  of two different historical phases of the development of urban agriculture in this city. The older one, Boscoincittà, lies on the western edges, close to the district Figino. The most recent one, Cascina Sant’Ambrogio, is located at the eastern edges, in the district Forlanini. The features here observed,  detected through qualitative research methods and tools, permit to gain a complex and deep knowledge of this phenomena. The study does not want just to enrich the academic knowledge in this research field and highlight the processes, with their controversial aspects, that permits or prevent the  production of benefits, which in some cases can be categorized as ecosystem services. Rather, the contribution presented aims to produce a transformative knowledge which could be useful for the territorial actors to make this kind of experiences more environmentally sustainable or regenerative  and socially inclusive.","language":"ita","citation":"IL POTENZIALE TRASFORMATIVO DELLE ESPERIENZE DI AGRICOLTURA URBANA. UN'INDAGINE SUI SERVIZI ECOSISTEMICI CULTURALI GENERATI ALL'INTERNO DEL TERRITORIO MILANESE / V. Capocefalo ; tutor: F. M. Lucchesi ; coordinatore: F. Slavazzi. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2024 Jan 24. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R12820.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1043255/2393960/phd_unimi_R12820.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/959236"},"title":"QUALITATIVE ANALYSIS OF LIPOPROTEINS AND STUDY OF THE METABOLIC PROFILE IN DIFFERENT CLINICAL SETTINGS BY RAMAN SPECTROSCOPY","internalauthor":"BONIZZI, ARIANNA","type":"Tesi di dottorato","year":"2023","abstract":"Raman spectroscopy (RS) is a promising optical technique, able to offer a rapid specific overview of the biochemical composition of the analyzed sample without any preparation or labeling. This non-invasive technique is based on the radiation/matter interaction where a sample is illuminated by a laser which interacts with the vibrational motions of the molecules, leading to the emission of light at wavelengths different from the incident one. This property is used to obtain a spectrum characterized by peaks referable to the biochemical composition of the sample analyzed.  This approach has been integrated with conventional biochemical assay to study metabolic disorders such as: obesity (Ob) and type 2 diabetes mellitus (T2DM). RS was used to study the metabolic/biochemical profile of obese diabetic patients undergoing bariatric surgery (BS), to evaluate the impact of the surgery on body composition and systemic metabolism. The results obtained showed that, despite the improvement of the clinical parameters and levels of adipokines, ghrelin and FGF-19 dosed, Raman data identified a persistent alteration of the patients’ biochemical profile in the post-operative follow-up period (6-12 months), underlining the need for more extended longitudinal studies to assess the powerful of RS to monitor the progression of the disease.  This method has also been used to study the quality of lipoproteins (LPs), multimolecular complexes responsible for the transport of lipids in the body. Currently, the amount of cholesterol carried by LPs is one of the main parameters used in clinical practice to assess the risk of cardiovascular events. In particular, the level of circulating low-density lipoprotein cholesterol (LDL-C) is considered one of the main risk factors for cardiovascular disease (CVD). It can deposit on the wall of the arteries, causing the formation and progression of atherosclerotic plaques. Conversely, elevated levels of circulating high-density lipoprotein (HDL-C) cholesterol have long been associated with decreased risk of CVD, given their ability to remove cholesterol deposited on arterial walls. However, recent clinical studies have challenged the concept that high HDL-C levels would automatically translate into clinical benefits. In this regard, the research is focusing on the study of the composition and function of the LPs which are altered in different pathological contexts. However, the study of the quality of LPs lacks a universally accepted gold standard. The development of new methods capable of providing indications on the biochemical profile of the LPs, in a rapid and simple way, is therefore of great interest. In this context, LPs extracted from a cohort of obese patients and a control group of healthy subjects were analyzed by RS. The results obtained demonstrated the suitability of RS to obtain an immediate measure of the LPs quality, defined by their biochemical composition and oxidative state.  Overall, this thesis work reveals the potential efficacy of the RS in clinical studies and opens the way to a better understanding of metabolic disorders, for an improved definition of CVD risk.","language":"eng","citation":"QUALITATIVE ANALYSIS OF LIPOPROTEINS AND STUDY OF THE METABOLIC PROFILE IN DIFFERENT CLINICAL SETTINGS BY RAMAN SPECTROSCOPY / A. Bonizzi ; tutor: F. R. M. Corsi ; co-tutor: S. Mazzucchelli ; coordinator: L. Pinotti. Dipartimento di Scienze Biomediche e Cliniche, 2023 Mar 30. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12545.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/959236/2161850/phd_unimi_R12545.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/820988"},"title":"SYNTHESIS OF CARBOHYDRATE ANTIGENS AND THEIR STRUCTURAL ANALOGUES FOR VACCINES DEVELOPMENT","internalauthor":"SANTI, CRISTINA MANUELA","type":"Tesi di dottorato","year":"2021","abstract":"Carbohydrates are multifunctional, stereochemical rich natural molecules. Together with their well-known role of energy sources (glucose, glycogen, amylose) and structural components (cellulose, chitin), they serve important functions in biological processes relevant for health and disease1 such as molecular recognition, cell communication and adhesion.  A dense layer of oligosaccharides (proteoglycans, glycoproteins, glycolipids and other glycoconjugates) named glycocalyx, covers the membrane of most of cells. Glycocalyx of bacteria often exhibits oligosaccharides different from those found in mammalians, which have an important role in pathogen recognition and immune system activation. For this reason, pathogenic bacteria polysaccharides are widely used for vaccines production. Moreover, the role of symbiont bacteria glycocalyx in immune system activation, development and modulation is object of increasing interest.  In this thesis, the important connection between carbohydrates and immune system is discussed by two different examples.  The first section of the thesis deals with the synthesis of a structural analogue of Neisseria meningitidis A (MenA) capsular polysaccharide (CPS), with the final goal of producing a stable glycoconjugate vaccine against meningococcal infections.   Neisseria meningitidis is the major cause of bacterial meningitis. In particular, the serogroup A had been for a long time the leading cause of periodic meningitis epidemics in the area of Africa nicknamed “African meningitis belt”2. Despite the introduction a new vaccine named “MenAfriVac” led to a drastic decrease of MenA-related infections3, the WHO highlighted the importance to persist with a strict vaccination programme.   MenAfriVac, as well as all the other vaccines targeting MenA, is obtained from the extraction and size fragmentation of the capsular polysaccharide of the bacterium.   The natural CPS of MenA is made of N-acetylmannosamine repeating units linked through α-(1\uf0e06) phosphodiester bonds, prevalently acetylated in position 3 and partially acetylated in position 4. This structure, once isolated from the bacterium, is not stable in water due to the hydrolysis of the phosphodiester bond. Due to the instability issues, most of the licensed vaccines targeting MenA are distributed in a lyophilized form and the cold chain must be maintained during all the process of distribution and storage. In order to achieve a more stable vaccine, which could be distributed in the more convenient liquid formulation without the need of a strict temperature control, some more stable structural analogues have been developed4–8. In particular, the group of Professor Lay synthesized MenA CPS non-acetylated phosphonoester-linked oligomers up to the trimer4,5. These analogues showed good stability, however, they resulted to be poorly immunogenic.   Since the acetylation in position 3 was proven to have an important role in the immunogenicity of natural MenA CPS6,9, this thesis project focused on the synthesis of the 3-O acetylated phosphonate analogues up to the trimer.   The synthetic work developed for the preparation of the 3-O acetylated phosphono analogues is reported in detail and critically discussed in chapter 2.3 of the thesis.  The second section of this thesis deals with the synthesis of glycolipids with the aim of elucidating the structure of new lipid A molecules extracted from Bacteroides fragilis and studying their biological potential.  Bacterial lipid A modulate human’s innate immune system through their interaction with Toll like receptors (TLR), proteins expressed on dendritic cells and macrophages which play a key role in the development of the innate immunity. TLR activation by bacterial lipid A (di-glucosamines differently O- and N-acylated and phosphorylated) can cause a strong, uncontrolled infection which can even lead to septic shock10. However, the use of Monophopshoryl lipid A (MPL) as vaccine adjuvant is the proof that low-toxicity lipid A molecules can also be exploited to boost the efficiency of vaccines via a controlled immune system activation11,12.   Since symbiont bacteria are well tolerated by the human immune system, the study of their influence on human’s immune system is particularly interesting. Potentially, symbiont bacteria’s lipid A could be used as a tool to modulate the human immune response.   In 2019, the group of Professor Kasper, isolated novel lipid A molecules from the commensal bacterium Bacteroides fragilis13. The mixture isolated was composed of tetra- and pentaacylated di-glucosamines (acylated with 15 to 17 carbon atoms linear fatty acid chains), containing one or no phosphate groups13. However, the precise structure of the isolated compounds is still unknown.   As a part of a collaboration with Professor Kasper’s group (Harvard Medical School, Boston), a small library of lipid A molecules was designed as a tool to help with B. fragilis lipid A structural elucidation. Moreover, structure-activity relationship studies will be performed on the different compounds of the library to achieve a better understanding of the biological potential of symbiont bacteria lipid A.    Preliminary stages of the synthesis of a small library of lipid A molecules from B. fragilis are described in chapter 3.4 of this thesis.","language":"eng","citation":"SYNTHESIS OF CARBOHYDRATE ANTIGENS AND THEIR STRUCTURAL ANALOGUES FOR VACCINES DEVELOPMENT / C.m. Santi ; tutor:  L. Lay ; coordinatore del corso di dottorato: E. Licandro. Dipartimento di Chimica, 2021 Mar 18. 33. ciclo, Anno Accademico 2020. [10.13130/santi-cristina-manuela_phd2021-03-18].","filename":"phd_unimi_R11861.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/820988/1723766/phd_unimi_R11861.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/926571"},"title":"STRUCTURE, DYNAMICS AND PHASE TRANSITIONS OF BIOLOGICAL MATTER","internalauthor":"RAVAZZANO, LINDA","type":"Tesi di dottorato","year":"2022","abstract":"The work presented in this PhD Thesis aims to investigate, with the methods of  soft matter physics, systems of biological interest. Inspired by the observation  of algae, migrating cells and and protein complexes inside the single cell,  simple mathematical models have been implemented to obtain computer  simulations of complex systems of biological interest and to deepen our  understanding on their physical properties. The first part of the work deals with active matter systems, in which each  particle is able to self-propel. Active self-rotations are rarely studied in this  context, although present in biological systems such as Chlamydomonas  reinhardtii algae. We built a simple model for active particles in 2D based on  ABPs (Active Brownian Particles) model, accounting for inter-particle  interactions and adding an active torque to each particle to simulate the  ability of self-rotating. Employing MD simulations, we studied this model system  of active rotators in different conditions, to shed light on the role of self-  rotation in active matter systems at the jammed-unjammed transition. We  then applied our model based on ABPs to the study of interacting active  matter invading narrow channels, to investigate the role of single particles  properties in determining invasion behavior. The second part of the work deals with nuclear pores, protein complexes  inserted in the nuclear envelope of eukaryotic cells, acting as  communication gates between nucleus and cytoplasm. Nuclear pores  spatial organization and geometric arrangement on the nuclear surface are  still poorly understood. Hence we propose the use of tools commonly  employed to study the atomic structural and topological features of soft  matter, to study nuclear pores spatial organization. Furthermore, to interpret  the experimental results, we hypothesize an effective interaction among  nuclear pores and implemented it in extensive numerical simulations of  octagonal clusters, mimicking typical pore shapes.","language":"eng","citation":"STRUCTURE, DYNAMICS AND PHASE TRANSITIONS OF BIOLOGICAL MATTER / L. Ravazzano ; supervisor of the thesis: S. Zapperi ; director of the school: M. Paris. Università degli Studi di Milano, 2022 Apr 13. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12235.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/926571/2030143/phd_unimi_R12235.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1069430"},"title":"IL CONTRATTO DI ASSICURAZIONE IN GIAPPONE TRA TRADIZIONE, INNOVAZIONE E LEGAL TRANSPLANT","internalauthor":"TOTARO, DAVIDE LUIGI","type":"Tesi di dottorato","year":"2024","abstract":"This thesis aims to examine the regulation of insurance contracts in Japan as amended following the   introduction of the Insurance Act of 2008. The study of this reform, embedded within the context of a   fundamental process of modernization of the country's Private Law, provides significant insights into   framing the general principles underlying Japanese Contract Law, the relationship between   negotiation autonomy, technical-structural elements of insurance, and consumer’s rights protection,   as well as the role played by courts in this field of law. Building upon numerous comparative studies   focusing on Japan, the work begins with a review of the state of the art, particularly addressing the   general characteristics of the system, comparative issues, and key taxonomic classifications. Having   defined the methodology, the research proceeds with an analysis of the sources of Japanese insurance   contract law, with particular attention to the interaction between positive law and general principles,   and the innovative role played by the judiciary in this matter’s development. Subsequently, the   regulation of insurance contracts will be analytically examined, taking into account how case law,   doctrine, and contractual practice supplement and complement sector-specific legislation. Finally,   considering the significant integration of Artificial Intelligence systems in the creation, underwriting,   and management of insurance contracts in recent years, some remarks will be devoted to the   Japanese approach to the governance of Artificial Intelligence systems and Insurtech.","language":"ita","citation":"IL CONTRATTO DI ASSICURAZIONE IN GIAPPONE TRA TRADIZIONE, INNOVAZIONE E LEGAL TRANSPLANT / D.l. Totaro ; tutor: R. E. Cerchia ; cotutor: A. Candian ; coordinatore: G. Ludovico. Università degli Studi di Milano, 2024 Jul 03. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12949.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1069430/2458752/phd_unimi_R12949.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/804119"},"title":"PRODUZIONE E COMMERCI DELLE ANFORE DRESSEL 1TRA L'ETRURIA MERIDIONALE E ROMA","internalauthor":"RAZZA, ANDREA","type":"Tesi di dottorato","year":"2021","abstract":"The Dressel 1 amphorae are traditionally deemed to be the export carriers of the Tyrrhenian wine produced during the Roman Republican age. The project aims to investigate the production and the circulation of this amphoric type in the area between Southern Etruria and Rome, with a special focus on Ostia. For this region, indeed, we lack adequate data, due to the deficiency of a unitary study taking into account the economic-productive aspects in regards of the investigated period.  The transition from the small property - at the foundation of agricultural production during the third and part of the second century BC - to the intensive agricultural exploitation of the first century BC, coincides with the period of production and export of Dressel 1 amphorae.  The study of these amphoric containers, therefore, aims to deepen the knowledge of wine production - as well as amphoric - in the survey area, where, as proof of a thriving agricultural activity, a series of villas and rock-cut units for the wine production has been certified, especially in the Ager caeretanus. Through the comparison with known data and new knowledge about amphoric production, the study of these economic and social dynamics will allow a broader understanding of the rural economy of the area.","language":"ita","citation":"PRODUZIONE E COMMERCI DELLE ANFORE DRESSEL 1TRA L'ETRURIA MERIDIONALE E ROMA / A. Razza ; coordinatore UNIMI: D. Bassi; supervisore e tutor UNIMI: O. Failla; tutor UNIMI: G. Olcese; coordinatore UB: F. J. Laviña Gómez; supervisore e tutor UB: M. A. Cau. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2021 Jan 15. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12461.pdf","fileformat":"Adobe PDF","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/804119/1671538/phd_unimi_R12461.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1179295"},"title":"CLINICAL APPLICATION AND PROGNOSTIC VALUE OF COMPUTED TOMOGRAPHY EXAMINATION IN FOALS DIAGNOSED WITH HEMATOGENOUS OSTEOMYELITIS","internalauthor":"GUSTAFSSON, KAJSA EMMA VIKTORIA","type":"Tesi di dottorato","year":"2025","abstract":"Bacterial sepsis in foals is associated with high morbidity and mortality. Bacteremia often arises from localized infections, with septic arthritis and osteomyelitis serving as potential gateways for bacterial spread or as sequelae of bacteremia.  Computed tomography (CT) is increasingly utilized for the diagnosis and preoperative planning of osteomyelitis in foals. However, the association between CT findings and clinical prognosis is lacking in the literature.   The objectives of this thesis were to; Provide a detailed resource of descriptive data of foals diagnosed with osteomyelitis, to compare findings obtained by conventional imaging methods and CT, and to investigate correlations between clinical and imaging findings and survival.   Inclusion criteria were; 1. Foals under 9 months of age, 2. Presumptive clinical diagnosis of osteomyelitis, 3. CT examination used for further evaluation.  Fifty-six foals were included in the final analysis. Thirty-six foals survived to discharge (36/56, 64%) and 26 foals survived long term (26/50, 52%). Variables with a significant negative effect on survival to discharge included articular involvement (p=0.04, OR 0.06 95%CI 0.04-0.89) and long transition zone (p=0.03, OR 0.133 95%CI 0.23-0.78). Variables with a significant negative effect on long-term survival included lesions in multiple locations p=0.03, OR 0.05 95%CI 0.04-0.77.  In 93% of cases, CT examination modified the diagnosis, revealing improved lesion localization (72%), lesion size (76%), or detecting additional lesions (45%)  These findings underscore the critical role of CT in identifying and localizing complex lesions ultimately improving prognostic assessments.","language":"eng","citation":"CLINICAL APPLICATION AND PROGNOSTIC VALUE OF COMPUTED TOMOGRAPHY EXAMINATION IN FOALS DIAGNOSED WITH HEMATOGENOUS OSTEOMYELITIS / K.e.v. Gustafsson ; supervisor : D.D. Zani ;  coordinator F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2025 Sep 02. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13402.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1179295/3126043/phd_unimi_R13402.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/986877"},"title":"COMBINING GEOCHEMICAL AND NUMERICAL MODELING FOR CHLORINATED SOLVENTS GROUNDWATER CONTAMINATION","internalauthor":"CASIRAGHI, GIULIA","type":"Tesi di dottorato","year":"2023","abstract":"Chloroethenes represent a serious risk to aquatic ecosystems and human health on a worldwide scale. Chloroethenes contamination is difficult to solve due to the different optimal redox conditions needed to obtain efficient degradation of each chloroethene. The more chlorinated ones such as tetrachloroethene (PCE) and trichloroethene (TCE) are better degraded via reductive dechlorination (RD) under anaerobic conditions, while the less chlorinated compounds such as dichloroethene (DCE) and vinyl chloride (VC) are better degraded via oxidation (OX) under aerobic conditions. Thus, sequential bioremediation systems (SBSs) able to stimulate anaerobic and aerobic biodegradation are preferred over traditional bioremediation systems targeting single degradation pathways.  Assessing the efficiency of SBSs is a challenging task that requires a multidisciplinary approach, spanning from hydrogeology, organic geochemistry and microbiology. While expert knowledge and laboratory analyses provide initial inputs for the design of SBS, field monitoring data are needed to evaluate if and how bioremediation is carried out.  Reactive transport models (RTMs) are suitable tools to assist decision makers when designing and monitoring bioremediation efficiency. To date, no applications to SBSs have been reported, possibly owing to the relative novelty of SBS and to the additional modeling challenges (e.g., more complex parameterization) that sequential systems pose over traditional bioremediation systems. RTMs have the capability to integrate and harmonize multiple data and, when properly tailored, to make useful predictions about a system’s behavior when different remediation set-ups are tested in order to optimize the cleanup operations.  The general objective of this thesis was to develop methodologies for the evaluation of the efficiency of SBSs applied to chloroethenes aquifer contamination. As case study, we investigated one the largest SBS currently implemented in a polluted alluvial aquifer in Italy. The SBS is about 800 m-long and was created to remediate organic pollutants such as chloroethenes and petroleum hydrocarbons (PHCs). The SBS is made up of a hydraulically upgradient anaerobic (AN) biobarrier, where a reducing substrate is injected to stimulate RD of higher chloroethenes (PCE, TCE), and downgradient aerobic (AE) biobarrier, where OX of lower chloroethenes (DCE, VC) is stimulated through nutrients and oxygen injection. In addition, P&T wells are active downgradient of the two biobarriers in order to intercept the remaining contaminants exfiltrating from the SBS.  The first part of the thesis evaluates the initial characterization activities propaedeutic to the installation of the operational (full) scale SBS: Microcosm experiments and in situ tests were carried out to assess the biodegradation potential of the autochthonous microbial communities in the laboratory and in the site under both natural and biostimulated conditions. Both investigations showed a satisfactory efficiency of aerobic and anaerobic degradation only after biostimulation, proving the feasibility as well as the necessity of the full-scale SBS for the cleanup of the site. The analysis of these data constitutes an improvement of the current state of the art in the design and implementation of large-scale SBS.  The second part of the thesis is dedicated to the analysis of time series of chloroethenes concentrations and environmental parameters observed during periodic monitoring of groundwater in the site piezometers of the full-scale SBS. Carbon compound-specific isotopic analysis (C-CSIA) were carried out on chloroethenes PCE, TCE, cis-DCE and VC in samples acquired along a flow path crossing both biobarriers. Target chloroethenes concentrations and isotopic compositions were interpreted through a one-dimensional (1D) geochemical model in order to assess the processes controlling the sequential bioremediation and to obtain a first-cut evaluation of the effectiveness of the SBS. The active SBS proved to be efficient in reducing chloroethenes concentrations along the investigated flow path (reduction of concentrations up to 100%). The AN barrier proved to be able to significantly enhance RD of PCE and TCE mainly, increasing natural anaerobic degradation up to 30 times. The AE barrier, instead, proved to have a fundamental role in enhancing OX of cis-DCE and VC.  The third part of the thesis focuses on the development of a multidimensional model with enhanced predictive capabilities compared to the 1D model.  Different degrees of spatial heterogeneity of degradation efficiency were taken into consideration by setting up two models with different parametrization of degradation constants (i.e. homogeneous and heterogeneous distribution). Moreover, it was also possible to model the P&T system.  and simulate different scenarios by deactivating the P&T to determine the most efficient setup of the system (i.e. with or without P&T). Contaminant loadings exfiltrating from the site were quantified and compared between the different scenarios and Damköhler numbers (Da) were calculated to evaluate the spatial heterogeneity of degradation efficiency. The 2D model showed the importance of choosing a spatially heterogeneous configuration rather than a homogeneous one in order to obtain an accurate reproduction of contaminant loadings. Da permitted to prove the heterogeneity of degradation efficiency and pinpoint critical areas in the site where bioremediation is less efficient. Another important result was the demonstration of the P&T importance in abating contaminant loadings and providing a better containment of the plume of contaminants, specifically the more toxic VC whose loadings resulted to be the highest in the site.  Overall, the multiscale experimental activities were fundamental for the assessment of the site suitability to sequential bioremediation and for the subsequent implementation of the SBS. The multidisciplinary approach adopted permitted to evaluate the efficiency of the remediation system.","language":"eng","citation":"COMBINING GEOCHEMICAL AND NUMERICAL MODELING FOR CHLORINATED SOLVENTS GROUNDWATER CONTAMINATION / G. Casiraghi ; tutor: D. Pedretti, G.P. Beretta ; coordinatori: M.I. Spalla, F. Camara Artigas. Dipartimento di Scienze della Terra Ardito Desio, 2023 Jul 25. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12561.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/986877/2250724/phd_unimi_R12561.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/924610"},"title":"STUDY OF THE PALEONTOLOGICAL RECORD OF THE BESANO FORMATION (MIDDLE TRIASSIC) AT ¿SASSO CALDO¿, VARESE, UNESCO WHL MONTE SAN GIORGIO","internalauthor":"BINDELLINI, GABRIELE","type":"Tesi di dottorato","year":"2022","abstract":"The Besano Formation consists of an alternation of laminated dolomitic banks and bituminous shales, and sparse cineritic tuffs that are dated as Late Anisian–Early Ladinian. It is one of the richest fossil-bearing formations from the Monte San Giorgio area; on the Italian side of Monte San Giorgio, the Sasso Caldo site is the one from which the greatest part of the Besano collection housed at the Museo di Storia Naturale di Milano is from. This Ph.D. thesis aims to the study of the Besano Formation macrofauna, through biochronostratigraphic zonation of the Sasso Caldo Site, revision of the large ichthyosaur Besanosaurus leptorhynchus), and study of the most important specimens, chosen for their preservation and rarity, but also to test the hypothesis of variations in the influence of open sea on the Besano basin.  All the available ammonoids and bivalves from the Sasso Caldo site (Besano Formation), housed in the collections of the Museo di Storia Naturale di Milano, were examined and determined. The systematic study led to the recognition of 15 ammonoid taxa belonging to 10 genera, and five species belonging to the bivalve genus Daonella. The study of bed-by-bed collected specimens allowed the biochronostratigraphic classification of the Sasso Caldo section and the time-calibration of invertebrate and vertebrate bioevents. Results evidence that at Sasso Caldo site crops out almost the entire middle to upper Besano Formation. corresponding the Nevadites secedensis ammonoid zone. The trend of distribution of specimens reflects the establishment of an intraplatform basin with discontinuous open-marine influence in the middle Besano Formation, while the upper Besano Formation corresponds to a shallower subtidal restricted platform environment.  Among the terrestrial taxa recovered at Sasso Caldo from the upper Besano Formation, a remarkably well-preserved fossil scorpion (BES SC 1973) is described in this thesis. This finding corroborates the hypothesized existence of a near shoreline during the deposition of the upper Besano Formation. BES SC 1973 is assigned to a new taxon gen. et sp. nov., included in the family Protobuthidae. This finding represents the first arachnid recorded from the Besano Formation, and the second genus attributed to the family Protobuthidae. This specimen is also the first reported Italian Mesozoic fossil scorpion.  Regarding vertebrates, MSNM V927 and 928, a portion of the axial skeleton of a large diapsid, is attributed to Helveticosaurus zollingeri, a rare diapsid known only from the Besano Formation. This animal was recovered in association with the ammonoid Ticinites, at the base of the N. secedensis Zone, in coincidence with the establishment of the intraplatform basin of the middle Besano Formation. This specimen is the first record of skeletal remains and the second specimen assigned to the taxon in Italy. In this work the niche occupied by this animal in the Middle Triassic coastal ecosystems and its swimming style are also revised and discussed.  MSNM V926, and SMNS 50010, respectively a portion of ribcage and an isolated partial forefin of a large ichthyosaur, were attributed to Cymbospondylus buchseri. MSNM V926 represents the first specimen attributed to this taxon and recovered on the Italian side of Monte San Giorgio.   A great part of this thesis is dedicated to the revision of Besanosaurus leptorhynchus. The specimens studied and attributed to Besanosaurus leptorhynchus preserve a remarkably complete cranial and postcranial anatomy so that this taxon can be now accounted among the best-understood Middle Triassic ichthyosaur taxa. The revision of the skull morphology of this taxon clarified long-standing controversies regarding its cranial anatomy and the taxonomy of shastasaurids from Monte San Giorgio. The six specimens here described represent a potential ontogenetic series composed of an embryo (inside the maternal cavity of BES SC 999), likely two subadults, and four adults. They can be ordered by increasing size as follows: embryonic material of BES SC 999, PIMUZ T 4376, PIMUZ T 1895, BES SC 999, BES SC 1016, GPIT 1793/1, PIMUZ T 4847. Also, Besanosaurus resulted the largest Middle Triassic ichthyosaur taxon of the Western Tethys to date, since a full adult size is confidently estimated to be almost 8 m in PIMUZ T 4847. Besanosaurus is characterized by a long, slender, and gracile snout, representing an ecological specialization never seen before the Anisian in a large-sized diapsid.  The study of the postcranial anatomy of Besanosaurus leptorhynchus is based on four specimens: PIMUZ T 4376, PIMUZ T 1895, BES SC 999, PIMUZ T 4847. The results suggest that this taxon possesses a peculiar bauplan, which in its proportions fits in between Cymbospondylus and the shastasaur-grade ichthyosaurs. Swimming capabilities of Besanosaurus leptorhynchus were tested and compared with Cymbospondylus and Mixosaurus. Among the ichthyosaurs from the Besano-Monte San Giorgio fauna (Cymbopondylus, mixosaurids, and Besanosaurus), different hunting strategies, demonstrated by different morphologies and dimensions of the rostra, as well as different body proportions and swimming styles, should have led to niche partitioning.   The key phylogenetic position occupied by Besanosausurus leptorhynchus in the ichthyosaurian phylogeny was investigated: the analysis shows that this taxon represents the basalmost member of shastasaur-grade ichthyosaurs, recovered to be a paraphyletic group.  Eventually is addressed a study of the embryonic material preserved in BES SC 999. We deem the material in the body cavity of BES SC 999 unambiguously embryonic and attributable to Besanosaurus leptorhynchus. Here the embryonic material is described in detail and qualitatively compared with the maternal specimen and to other known ichthyosaur prenatal specimens.","language":"eng","citation":"STUDY OF THE PALEONTOLOGICAL RECORD OF THE BESANO FORMATION (MIDDLE TRIASSIC) AT ¿SASSO CALDO¿, VARESE, UNESCO WHL MONTE SAN GIORGIO / G. Bindellini ; tutor: M. Balini ; co-tutor: C. Dal Sasso ; coordinatore: M. I. Spalla. Dipartimento di Scienze della Terra Ardito Desio, 2022 May 06. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12303.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/924610/2025256/phd_unimi_R12303.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1175505"},"title":"STRUCTURAL ANALYSES OF TRANSCRIPTION FACTOR/DNA COMPLEXES: NFI-X AND NF-Y","internalauthor":"TIBERI, MICHELE","type":"Tesi di dottorato","year":"2025","abstract":"Binding of transcription factors (TFs) to discrete sequences in gene promoters and enhancers is crucial to the process by which genetic information is transferred to biological functions. TF structural analysis is the key to understanding their DNA-binding mode and for the design of specific inhibitors. In this context, the present PhD project focuses on two TFs: (1) NFI-X, a TF with unknown structure that binds to the palindromic motif TTGGC(n5)GCCAA and plays an essential role in skeletal muscle development; and (2) NF-Y, a histone-like TF that binds the CCAAT box in promoters of cell cycle genes.  (1) The crystal structure of NFI-X was obtained in our lab a few years ago. However, no structural information regarding the DNA-binding mode of NFI-X was available until now. We were able to obtain a functional truncated DNA-binding domain (DBD) construct of NFI-X and purify it for cryo-EM analysis. This allowed us to solve a cryo-EM structure at 3.86 Å resolution, revealing for the first time the architecture of the NFI-X/DNA complex. Surprisingly, the NFI-X/DNA sample formed filaments in the grid after vitrification, which allowed to solve the structure by helical processing. This structure provides critical insights into how NFI-X recognizes its DNA target and mediates dimerization.  (2) A new crystal structure of an extended NF-Y construct, termed the NF-Y long-minimal domain (NF-Yl-md), were obtained, which included additional regions of the NF-YC subunit not present in previous structures. These additional regions could potentially influence the DNA-binding and cooperative interactions of NF-Y with other TFs. In parallel, two cryo-EM structures of NF-Y in complex with ATF6 and two cryo-EM maps of NF-Y in complex with USF1 have been elucidated, demonstrating how NF-Y cooperates with these transcription factors to recognize composite DNA elements. These structures provide unprecedented insights into the cooperative assembly of multi-TF complexes on DNA.  These findings contribute to the broader understanding of TF-DNA interactions, offering potential avenues for the design of targeted inhibitors that could modulate TF activity in various biological processes.","language":"eng","citation":"STRUCTURAL ANALYSES OF TRANSCRIPTION FACTOR/DNA COMPLEXES: NFI-X AND NF-Y / M. Tiberi ; tutor: M. Nardini. - Università degli studi di Milano, Dipartimento di Bioscienze. Dipartimento di Bioscienze, 2025 Jul 15. 37. ciclo","filename":"phd_unimi_R13368_3.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 22-GEN-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/949531"},"title":"MEASURING AND MODELLING COVER CROP GROWTH AND AGRONOMIC EFFECTS","internalauthor":"GABBRIELLI, MARA","type":"Tesi di dottorato","year":"2022","abstract":"Cover crops are cultivated during the bare soil period between the harvest of a cash crop and the sowing of the next one. Their cultivation puts into effect the permanent soil organic cover principle of conservation agriculture and exerts several agro-ecological services, among which the most relevant are nitrate leaching reduction, weed growth control, soil organic matter increase, soil structure and water infiltration improvement. In temperate climates when crop rotations include summer cash crops (such as maize or soybean), autumn-winter cover crops are sown between late July and October and terminated from March to April of the following year. When sown in autumn, frost-sensitive cover crops may also be terminated efficiently by frost damage: this termination method is frequently called ‘winterkill’. Black oat (Avena strigosa Schreb.) and white mustard (Sinapis alba L.) are two of the most interesting and widespread frost-sensitive cover crops due to their adaptability to various environmental conditions and cropping systems. Even if these species are widely adopted as cover crops, there is a lack of information concerning both crop management and agronomic effects, as well as winterkill termination occurrence frequency and efficiency in temperate climates. Dynamic cropping systems simulation models can be used to determine crop management scenarios convenience for a wide range of weather and soil conditions, while the field trial assessments require large resource investments. However, the application of a simulation model to white mustard and black oat cover crops presents several knowledge gaps, as the limited number of studies focused on winterkilled cover crops growth and agronomic effects carried out in northern Italy. Furthermore, an integrated simulation model dealing both with cover crop growth and winterkill termination, and its consequent effect on the crop-soil system, including cover crop residue degradation on soil surface, is lacking.   This work aimed at representing, within the ARMOSA cropping system model framework, frost sensitive cover crop species growth, development, and agronomic effects by enriching the simulation model with two additional modules, dealing respectively with winterkill events and cover crop superficial residue decomposition. The model was calibrated for white mustard and black oat cover crops using experimental data deriving both from a three-year field trial, from a commercial field monitoring campaign and from previous experiments, carried out in the region of interest. During the three-year field trial, white mustard, black oat and their mixture with purple vetch (Vicia benghalensis L.) have demonstrated a good aboveground biomass production potential (2-3 t DM ha-1), particularly when planted before the first half of September. Their nitrogen uptake (45 kg N ha-1 on average, up to 148 kg N ha-1) follows the biomass accumulation patterns, while their weed species control ability has proven to be consistently high. Overall, the improved ARMOSA model correctly simulated these species development (RRMSE equal to 27.3 and 29.5% respectively for black oat and white mustard), as well as soil water content and temperature (RRMSE equal to 8.4% and 19.2%). The employment of the new ARMOSA version to simulate black oat and white mustard cultivation, generally improved significantly both aboveground biomass simulation (RRMSE was decreased by 56.3% in comparison to the use of the original model version), leaf area index (RRMSE reduction of 31.6%) and C:N ratio simulations (RRMSE reduction of 8.8%). The convenience of the new model version employment was assessed in a wide range of sites (six sites of several provinces of Lombardy region in northern Italy), pedological conditions (soil textures from sandy-loam to silty-clay), weather conditions (calibration seasons ranged from 2019/2020 to 2021/2022) and management practices (minimum and no till seed bed preparation, slurry application, early and late sowing dates). To summarize, the new model version was able to successfully capture the main crop-related variables trends over time, as well as to correctly reproduce soil water content and temperature dynamic.","language":"eng","citation":"MEASURING AND MODELLING COVER CROP GROWTH AND AGRONOMIC EFFECTS / M. Gabbrielli ; tutor: L. Bechini; coordinatore: P.A. Bianco. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2022 Dec 09. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12610_7.pdf","fileformat":"Adobe PDF","fileversion":"preprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/949531/2114220/phd_unimi_R12610_7.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1017831"},"title":"MODULATING TFEB ACTIVITY IN THE BIRT-HOGG-DUBE' SYNDROME BY TARGETING THE VACUOLAR ATPASE","internalauthor":"VILARDO, CLAUDIA","type":"Tesi di dottorato","year":"2023","abstract":"The transcription factor EB (TFEB) is a master regulator of lysosome biogenesis and autophagy, and its activity is primarily controlled by the kinase complex mTORC1. In the Birt-Hogg-Dubé (BHD) syndrome, a genetic disease caused by germline mutations in FLCN gene, TFEB was found to be constitutively active and to promote the development of kidney cysts and cancer. Therefore, inhibition of TFEB activity represents a challenging opportunity for the treatment of the BHD syndrome.  We performed a high content siRNA screening to identify correctors of TFEB activation in FLCN-KO cells. Interestingly, top hits were genes encoding subunits of the vacuolar ATPase (V-ATPase). The V-ATPase is a proton-pump protein complex responsible for maintaining the low pH of lysosomes, and it has been described as a positive regulator of mTORC1 signaling, although the exact contribute of the V-ATPase to the amino acid sensing has not been fully elucidated. Our results indicate that the V-ATPase inhibition promotes a mTORC1-dependent TFEB cytosolic re-localization in FLCN-KO cells, thus pointing to a novel mechanism of regulation of TFEB activity in BHD cellular models mediated by the V-ATPase. Besides, our data suggest that the Ragulator-Rag GTPases complex plays a crucial role in controlling TFEB subcellular localization, even in absence of FLCN, through its interaction with the V-ATPase.  This study aims at dissecting how the V-ATPase regulates mTORC1 signaling and TFEB activity, while searching for compounds able to target this axis, with the purpose to identify novel and effective therapeutic approaches to limit kidney pathologies associated with BHD syndrome.","language":"eng","citation":"MODULATING TFEB ACTIVITY IN THE BIRT-HOGG-DUBE' SYNDROME BY TARGETING THE VACUOLAR ATPASE / C. Vilardo ; supervisor: A. Ballabio ; added supervisor: C. Di Malta ; internal advisor: P. Grumati ; external advisor: P. Saftig. Dipartimento di Oncologia ed Emato-Oncologia, 2023 Dec 04. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12757.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1017831/2325822/phd_unimi_R12757.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/959896"},"title":"LIPID COMPOSITION OF MICROGLIAL CELLS AND EFFECTS OF A REMYELINATION-PROMOTING ANTIBODY ON THE SPHINGOLIPID PATTERNS","internalauthor":"D'APRILE, CHIARA","type":"Tesi di dottorato","year":"2023","abstract":"Multiple sclerosis (MS) is one of the most prevalent demyelinating diseases among young adults (Lemus et al., 2018). Myelin damage and oligodendrocyte death are caused by the autoimmune attack of T cells that cross the blood-brain barrier  resulting in the formation of sclerotic plaques (Pearce, 2005, Lubetzki and Stankoff, 2014). In the early stages of the disease, damaged myelin is to some extent repaired, however the process is inefficient due to several factors, including impairment in OPCs recruitment and/or OLs differentiation likely due to the inflamed environment, and the inhibitory effect of myelin debris present at the lesion sites (Barres, 2008, Lassmann, 2014, Domingues et al., 2016). There are currently no cures for multiple sclerosis, only treatments that aim at alleviating its symptoms or slowing down its progression. Therefore, interventions that stimulate and promote endogenous myelin repair mechanisms may be a feasible treatment option (Lemus et al., 2018).   In animal models of demyelination, the ability of certain monoclonal antibodies to stimulate myelin sheath synthesis has been proven. In this regard, the rHIgM22 monoclonal antibody has showed particularly promising results. This antibody seems to act mainly on cells of the oligodendrocyte lineage, in particular on oligodendrocyte precursor cells promoting their proliferation and inhibiting their apoptosis (Warrington et al., 2000). However, experimental evidence suggests that not only OPCs and OLs are targeted by rHIgM22, but also other glial cells, e.g., astrocytes and microglia, In particular, it has been shown that rHIgM22 stimulates an increase in the phagocytic activity in microglia (Zorina et al., 2018). The phagocytosis of myelin debris by microglia is one of the most delicate and limiting steps in the myelin repair mechanism (Neumann et al., 2009, Domingues et al., 2016, Napoli and Neumann, 2009, Lloyd and Miron, 2019).  The protective effects exerted by rHIgM22, at least towards the primary targeted glial cells, appear to be mediated by the reorganisation of membrane lipids leading to the recruitment of a multimolecular complex that results in the development of numerous signalling mechanisms (Watzlawik et al., 2010, Watzlawik et al., 2013a). Indeed, data obtained in our laboratory showed that different glycosphingolipids were involved in rHIgM22 binding at the cell surface but also that rHIgM22 treatment induced changes in the sphingolipid pattern of oligodendroglial cells (Grassi et al., 2015; S. Grassi et al., 2021).   Since microglia seem to be a crucial player in the processes that are at the center of myelin repair, they have been the focus of this thesis. We used as an experimental model the BV-2 microglial cell line. The BV-2 cell line is widely used because it retains the morphological, phenotypical, and functional characteristics described for freshly isolated primary microglia and has functional markers of macrophages (Blasi et al., 1990). BV-2 is a semi adherent cell line, where adherent and floating cells may represent two different sub-populations.   Due to the paucity of information in the literature regarding the lipid composition of microglia, as the first step, we analysed the lipid composition of BV-2 cells using a combination of traditional chemical analysis and lipidomic using ESI-mass spectrometry. We analysed lipids in different culture conditions since it is well known that culture conditions affect the composition of certain lipid classes (Frechin et al., 2015). We identified differences in the lipid pattern depending on cell culture conditions but also some differences in the lipid composition among adherent and floating cells. Specifically, we observed key differences between adherent and floating cells at 80–90% confluence. In this experimental condition, ceramide was present at higher levels in the floating cells while sphingomyelin was more enriched in the adherent cells; in the cells collected at over confluence, these distinctions were absent. In addition, we identified the absence of specific lipids, including galactosylceramide and sulfatide, and a generally low amount of gangliosides in both sub-populations, irrespective of confluence.  Then, we studied the sphingolipid turnover in more detail using a metabolic labeling approach. Our results showed that BV-2 cells are characterised by a rapid sphingolipid turnover rate.   Finally, based on our previous findings indicating that rHIgM22 was able to modify sphingolipid patterns in OPCs and OLs, we evaluated the effects of rHIgM22 on the sphingolipid pattern of BV-2 cells using different experimental settings and culture conditions. Our findings showed that rHIgM22 could influence sphingolipid patterns in microglia as well.   Comparing different experimental approaches, the effects of the two antibodies, rHIgM22 and the human IgM used as the negative control, are distinct. Specifically, rHIgM22 decreases GlcCer, SM, GM1, and PE in adherent cells relative to control IgM, whereas increases GlcCer and GD1a in floating cells. Moreover, in another experimental approach, rHIgM22 decreases GlcCer, SM, GM1, and PE in adherent cells relative to control IgM, whereas GlcCer and GD1a increase in floating cells.   Therefore, it is plausible to hypothesise that also in microglia the effects of the treatment with rHIgM22 might be due to the reorganisation of the membrane lipid microenvironment, possibly affecting the function of membrane-associated signalling complexes.","language":"eng","citation":"LIPID COMPOSITION OF MICROGLIAL CELLS AND EFFECTS OF A REMYELINATION-PROMOTING ANTIBODY ON THE SPHINGOLIPID PATTERNS / C. D'aprile ; tutor: A. PRINETTI ; coordinatore: C. SFORZA. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2023 Apr 18. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12728.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/959896/2164066/phd_unimi_R12728.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1255118"},"title":"FUSARIUM MUSAE AND FUSARIUM  VERTICILLIOIDES CROSS-KINGDOM PATHOGENS: GENOMICS AND DIAGNOSTIC INNOVATION","internalauthor":"DEGRADI, LUCA","type":"Tesi di dottorato","year":"2026","abstract":"Fusarium species comprise a diverse group of filamentous fungi that include major plant pathogens, food contaminants, and opportunistic human pathogens. Among them, transkingdom species capable of infecting both plants and humans represent an emerging challenge within the One Health framework. Fusarium musae exemplifies this dual ecological behavior, acting as the causal agent of postharvest banana crown rot while increasingly being reported in human infections. Despite its growing relevance, the biology, genomic diversity, and mechanisms underlying host adaptation in F. musae remain insufficiently characterized, and available genomic resources have been largely restricted to plant-derived isolates. Moreover, the widespread use of azole antifungals in both agricultural and clinical settings has further intensified this concern, as the shared modes of action of these compounds contribute to the emergence of resistant strains and may facilitate cross-environment adaptation.  This PhD research addressed these knowledge gaps by integrating genomics, comparative analyses, and diagnostic tool development to investigate mechanisms of host adaptation in F. musae and its closely related species Fusarium. verticillioides.  In Chapter I, sixteen F. musae isolates obtained from both plant and human sources were sequenced and annotated, substantially expanding the genomic representation of the species. This dataset enabled the first comparative assessment of genomic diversity across ecological origins, providing insights into intraspecific variability and establishing a foundation for investigating traits potentially associated with transkingdom pathogenicity.  Chapter II focused on the generation of a high-quality reference genome through hybrid assembly combining long and short read sequencing technologies, followed by RNA-Seq–guided annotation refinement. Beyond improving genome completeness and annotation accuracy, this work contributed methodological advances for manual genome curation in filamentous fungi, addressing common challenges associated with fragmented assemblies.  In Chapter III, comparative genomic analyses were extended to F. verticillioides, including the sequencing and characterization of clinical isolates for the first time. Structural and functional analyses of CYP51 paralogs revealed candidate genetic determinants linked to azole resistance, providing novel insights into antifungal adaptation mechanisms and highlighting evolutionary pathways relevant to both agricultural and clinical environments within the F. fujikuroi species complex.  Finally, Chapter IV translated genomic knowledge into practical diagnostic applications. Comparative mitochondrial genomics enabled the identification of species-specific markers used to design PCR assays capable of discriminating F. musae and F. verticillioides through direct amplicon-based detection. In parallel, volatile organic compound profiling using an electronic nose system demonstrated the feasibility of rapid, non-destructive species identification based on metabolic signatures, establishing a complementary phenotypic diagnostic approach.  Collectively, this thesis provides the first integrated genomic and diagnostic framework for F. musae, significantly expanding available genomic resources, improving understanding of fungal transkingdom pathogenicity, and delivering accessible tools for accurate species identification. By bridging fundamental genomics with applied diagnostics, this work supports improved surveillance, risk assessment, and management strategies across agricultural and clinical contexts, contributing to proactive One Health approaches for emerging fungal pathogens.","language":"eng","citation":"FUSARIUM MUSAE AND FUSARIUM VERTICILLIOIDES CROSS-KINGDOM PATHOGENS: GENOMICS AND DIAGNOSTIC INNOVATION / L. Degradi ; tutor: M. Pasquali ; cotutor: M. Saracchi ; coordinatore: D. Mora. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2026 May 05. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R14160.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1255118/3355242/phd_unimi_R14160.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1050928"},"title":"INJECTABLE HYBRID HYDROGELS FOR LOCAL CHEMOTHERAPY OR TUMOR-SPECIFIC RESECTION","internalauthor":"AJO, ALESSANDRO","type":"Tesi di dottorato","year":"2024","abstract":"The aim of my thesis is to develop cutting-edge and innovative delivery system able to encapsulate active molecules against cancer.   The purpose is to have a material that can target directly the tumoral environment, avoiding the toxicity to surrounded organs and enhancing the local pharmacological activity.  Moreover, the use of a polymeric material, that can serve as a scaffold to deliver nanoparticles crosslinked between the network can increase the efficacy and bioavailability.    For this reason, using both chemical and physical crosslinking strategies to make a hybrid material between polymer and nanoparticles could be investigated as a potential material used for minimally invasive surgery and for cancer treatment. The controlled drug release and the targeted delivery are essential parameters that need to be controlled in order to have active compound in a tumoral environment released at a certain dose over the time.","language":"eng","citation":"INJECTABLE HYBRID HYDROGELS FOR LOCAL CHEMOTHERAPY OR TUMOR-SPECIFIC RESECTION / A. Ajo ; tutor: L. De Cola ; phd coordinator: G. Vistoli. - Milano. Dipartimento di Scienze Farmaceutiche, 2024 May 20. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12886.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1050928/2412744/phd_unimi_R12886.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1164237"},"title":"BEYOND BELIEFS. FROM CLIMATE ATTITUDES TO CLIMATE ACTIONS","internalauthor":"MORONI, MARTA","type":"Tesi di dottorato","year":"2025","abstract":"While scientific and policy experts have identified a wide range of interventions to mitigate the negative impacts of climate change, the translation of these recommendations into effective actions has been limited. Understanding public attitudes toward climate change is crucial to identify some of the barriers to climate action, the social groups more resistant to climate engagement and the strategies that can foster broader support for climate policies. Previous research has shown that despite widespread awareness and concern about climate change, individuals' willingness to contribute to mitigation efforts remains limited. This thesis aims to analyze the mechanisms that facilitate or hinder engagement with climate mitigation and to explore possible strategies to increase social support for climate actions. Especially, it examines (i) the weak relationship between environmental concern and environmental intentions (the climate attitudes-behavior gap), (ii) the economic and climate-related factors influencing individuals’ willingness to pay for environmental protection, (iii) the effect of recalling an extreme weather event in rising support for climate actions, and (iv) the different types of private-sphere environmental behaviors and their economic and political determinants. The results indicate that despite environmental concern is a key predictor of willingness to act for the environment, it is not sufficient alone to explain the engagement in climate action. It should be better integrated with other individual and contextual factors in order to understand the barriers to pro-environmental engagement. The first study reveals that economic conditions—both at the individual and national level—significantly influence not only individuals' willingness to pay for environmental protection, but also how strongly their environmental concerns translate into that willingness. Similarly, the environmental vulnerabilities of the country appear to moderate the impact of environmental concerns on environmental intention. The second study examines how the exposure to natural disasters can influence support for climate action, showing that recalling certain types of disasters can effectively increase individuals' willingness to accept costs to mitigate climate change. Lastly, the third study shifts the focus to private-sphere behaviors, emphasizing the relevance of distinguishing among various types of behaviors – occasional and habitual behaviors - to better understand the factors that influence their adoption. While economic condition influences all types of environmental behaviors similarly, political orientation affects habitual and occasional behaviors differently. In conclusion, the thesis contributes to understanding public opinion on the climate crisis that characterizes contemporary societies, by providing insights into the complexity of individual and contextual factors that shape climate engagement and by identifying potential strategies to enhance support for climate actions.","language":"eng","citation":"BEYOND BELIEFS. FROM CLIMATE ATTITUDES TO CLIMATE ACTIONS / M. Moroni ; supervisor: G. M. Dotti Sani ; coordinatrice: P. A. Rebughini. - Network for the Advancement of Social and Political Studies, via pace 10 Milano. Dipartimento di Scienze Sociali e Politiche, 2025 May 21. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13194.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1164237/3068290/phd_unimi_R13194.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1175505"},"title":"STRUCTURAL ANALYSES OF TRANSCRIPTION FACTOR/DNA COMPLEXES: NFI-X AND NF-Y","internalauthor":"TIBERI, MICHELE","type":"Tesi di dottorato","year":"2025","abstract":"Binding of transcription factors (TFs) to discrete sequences in gene promoters and enhancers is crucial to the process by which genetic information is transferred to biological functions. TF structural analysis is the key to understanding their DNA-binding mode and for the design of specific inhibitors. In this context, the present PhD project focuses on two TFs: (1) NFI-X, a TF with unknown structure that binds to the palindromic motif TTGGC(n5)GCCAA and plays an essential role in skeletal muscle development; and (2) NF-Y, a histone-like TF that binds the CCAAT box in promoters of cell cycle genes.  (1) The crystal structure of NFI-X was obtained in our lab a few years ago. However, no structural information regarding the DNA-binding mode of NFI-X was available until now. We were able to obtain a functional truncated DNA-binding domain (DBD) construct of NFI-X and purify it for cryo-EM analysis. This allowed us to solve a cryo-EM structure at 3.86 Å resolution, revealing for the first time the architecture of the NFI-X/DNA complex. Surprisingly, the NFI-X/DNA sample formed filaments in the grid after vitrification, which allowed to solve the structure by helical processing. This structure provides critical insights into how NFI-X recognizes its DNA target and mediates dimerization.  (2) A new crystal structure of an extended NF-Y construct, termed the NF-Y long-minimal domain (NF-Yl-md), were obtained, which included additional regions of the NF-YC subunit not present in previous structures. These additional regions could potentially influence the DNA-binding and cooperative interactions of NF-Y with other TFs. In parallel, two cryo-EM structures of NF-Y in complex with ATF6 and two cryo-EM maps of NF-Y in complex with USF1 have been elucidated, demonstrating how NF-Y cooperates with these transcription factors to recognize composite DNA elements. These structures provide unprecedented insights into the cooperative assembly of multi-TF complexes on DNA.  These findings contribute to the broader understanding of TF-DNA interactions, offering potential avenues for the design of targeted inhibitors that could modulate TF activity in various biological processes.","language":"eng","citation":"STRUCTURAL ANALYSES OF TRANSCRIPTION FACTOR/DNA COMPLEXES: NFI-X AND NF-Y / M. Tiberi ; tutor: M. Nardini. - Università degli studi di Milano, Dipartimento di Bioscienze. Dipartimento di Bioscienze, 2025 Jul 15. 37. ciclo","filename":"phd_unimi_R13368_2.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1175505/3110596/phd_unimi_R13368_2.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1122218"},"title":"A HISTORICAL INSTITUTIONALIST ACCOUNT OF GALILEO SATELLITE NAVIGATION.","internalauthor":"NETTLES, ADAM CHRISTOPHER","type":"Tesi di dottorato","year":"2024","abstract":"This dissertation addresses the development of the Galileo satellite navigation system, specifically the cases of France and Italy. It uses historical institutionalism to illustrate how institutional changes centered on the European Union caused this change. It also contributes to historical institutionalism by introducing speed controls.","language":"eng","citation":"A HISTORICAL INSTITUTIONALIST ACCOUNT OF GALILEO SATELLITE NAVIGATION / A.c. Nettles ; Andrea Locatelli. - Milano. Dipartimento di Scienze Sociali e Politiche, 2024. 36. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R12888.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1122218/2601524/phd_unimi_R12888.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1199595"},"title":"INSIGHT ON ANGPTL3 IMPACT ON HEPATIC METABOLISM AND FUNCTION","internalauthor":"TERENGHI, OTTAVIA","type":"Tesi di dottorato","year":"2025","abstract":"Background and aim   Angiopoietin-like protein 3 (ANGPTL3) is a hepatokine, that inhibits lipoprotein and endothelial lipase with ANGPTL8, sparing the hydrolyzation of VLDLs. Its deficiency leads to higher lipases activation, resulting into hypolipidemia and protection from cardiometabolic risk. While the role of circulating ANGPTL3 on lipases has been well established, its effect on hepatic homeostasis and metabolism is still unclear. This work aims to unravel the autocrine effects of ANGPTL3 within the liver and its systemic impact on peripheral organs.   The liver plays a key role in systemic metabolism, substrates management and partitioning, xenobiotics clearance, energy production and lipoproteins synthesis. Absence of hepatic   ANGPTL3 - master regulator of lipids partitioning - may therefore alter essential liver functions.   Methods   Angptl3 full knockout (Angptl3KO) and wild-type mice were utilized. In vivo observations included indirect calorimetry, biochemical profiling of glucose lipids and glucose levels and metabolic challenges comprised insulin, pyruvate/lactate and triglycerides (TG) tolerance tests.   After 16-18 weeks on either standard chow diet or high-fat (HFD) diet, mice were sacrificed for blood and organs collection. Ex vivo analyses included transcriptomic analysis of liver, skeletal muscle and heart, as well as metabolomic analysis on liver samples. Spatial gene expression profiling of the liver was evaluated. Obesity development was assessed through histology and immunophenotyping of blood, liver and bone marrow through flow cytometry.   Results   Angptl3KO mice exhibited persistent hypolipidemia regardless of feeding status, with higher TG clearance and a reduced hepatic lipoprotein production, without signs of hepatic steatosis.   Compared to controls, Angptl3KO mice on a chow diet showed altered basal metabolism and a higher susceptibility to fasting, as highlighted by higher gluconeogenesis and as supported by   transcriptomic and metabolomic data. This hypercatabolic phenotype is driven by activation of metabolic stress pathways (cAMP, PPARα, FOXO, NFIL3) leading to biomolecular adaptations reflected in spatially altered gene expression.    These changes involved hepatic and extrahepatic signalling pathways, including thyroid hormones signalling, autophagy and bile acids metabolism. Transcriptomic analyses of the skeletal muscle revealed a preference for oxidative phosphorylation (OxPHOS), while the heart adapted to altered substrate availability.   On chronic HFD, Angptl3KO mice maintained hypolipidemia, accelerated TG clearance and reduced hepatic lipoprotein production, but showed similar degree of hepatic steatosis versus   controls. Notably, the hyper catabolic phenotype is rescued. Obesity onset appears delayed in Angptl3KO mice, and differences were found when immunophenotyping the blood, liver and bone marrow of these animals, suggesting a higher propensity of Angptl3KO mice in sustaining a functional immune response.  Discussion  Angptl3KO mice constantly display hypolipidemia, not only imputable to increased lipases activity but also to intracellular and intrahepatic mechanisms. Hepatic lipoprotein synthesis is   reduced, and mice on chow diet do not display hepatic steatosis, while hypercatabolic phenotype is exacerbated at fasting. This feature is lost when Angptl3KO mice are chronically fed an HFD, despite hypolipidemia is persisting, suggesting an intracellular mechanism of ANGPTL3 that is fasting dependent.   Although Angptl3KO mice present delayed obesity onset, they show sign of insulin resistance and glucose intolerance, suggesting a potential beneficial role of Angptl3 in weight control.   Conclusion   ANGPTL3 is a master regulator of lipid and glucose metabolism, of liver responses during fasting and obesity and has an impact in the periphery, altering oxidative and adipose tissue biology and function.","language":"eng","citation":"INSIGHT ON ANGPTL3 IMPACT ON HEPATIC METABOLISM AND FUNCTION / O. Terenghi ; tutor: G.D. Norata cotutor: F. Bonacina coordinatore: G.D. Norata. Dipartimento di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti, 2025 Dec. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13962.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 27-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/895965"},"title":"ADVANCES IN SEMICLASSICAL DYNAMICS WITH APPLICATIONS TO THE VIBRATIONAL SPECTROSCOPY OF COMPLEX SYSTEMS","internalauthor":"ROGNONI, ALESSANDRO","type":"Tesi di dottorato","year":"2022","abstract":"Vibrational spectroscopy is a primary tool to study solvated and microsolvated systems, hydrogen bond dynamics, complex species in gas phase, and the list goes on and on. Unsurprisingly, great effort has been made to develop theoretical methods able to reproduce the vibrational features of complex molecular systems. In particular, the semiclassical methods have emerged as powerful vibrational spectroscopy techniques as they allow one to gather anharmonicities and quantum mechanical effects at a convenient computational cost. This thesis work focuses on the application of semiclassical methods to compute the vibrational spectra of complex systems. After a detailed derivation of the different semiclassical propagators starting from the path integral formulation of quantum mechanics, these techniques are applied to a variety of problems. These include the determination of the minimum solvation shell of water, the analysis of a popular model potential for computing bulk-like spectroscopic properties, and the deconstruction of the complex infrared spectrum of the formic acid dimer.","language":"eng","citation":"ADVANCES IN SEMICLASSICAL DYNAMICS WITH APPLICATIONS TO THE VIBRATIONAL SPECTROSCOPY OF COMPLEX SYSTEMS / A. Rognoni ; supervisor: M. Ceotto ;  co-supervisor: R. Conte. Dipartimento di Chimica, 2022. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12397.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/895965/1949049/phd_unimi_R12397.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/831912"},"title":"SUPERGRAVITY BLACK HOLE AND BRANE SOLUTIONS IN VARIOUS DIMENSIONS","internalauthor":"FAEDO, FEDERICO MICHELE","type":"Tesi di dottorato","year":"2021","abstract":"Black holes and branes, supergravity solutions and BPS states, they all play a fundamental role in the understanding of quantum theories of gravity; in this thesis we investigate some of their features from different perspectives. We start considering 4-dimensional N=2 FI-gauged supergravity and construct BPS rotating black holes for the CP^n and t^3 models. Moreover, we obtain a non-extremal generalization of the former and study its thermodynamics. Then, we move to D=5 and search for static solutions with solvegeometry cross-sections. The result is a magnetically charged black hole solution of pure gauged supergravity, a magnetic attractor for the general theory and a no-go theorem ruling out the existence of static, non-dyonic, supersymmetric spacetimes with solvegeometry cross-sections. Subsequently, we focus on M-theory and type-IIA backgrounds that exhibit an AdS3 factor. We obtain the brane set-ups giving rise to these solutions and provide a defect interpretation of the dual 2d CFTs as surface defects within higher-dimensional CFTs. Moreover, we construct a new solution to type-IIA supergravity preserving (0,4) supersymmetries. Finally, we analyze four- and three-charge black holes in heterotic string theory--consisting of bound states of strings, NS5-branes and, optionally, a Kaluza-Klein monopole--and derive an $alpha'$-exact expression for the shift that the conserved charges suffer due to the inclusion of higher-curvature terms. To this end, we apply both the Wald entropy formula and the entropy function formalism.","language":"eng","citation":"SUPERGRAVITY BLACK HOLE AND BRANE SOLUTIONS IN VARIOUS DIMENSIONS / F.m. Faedo ; tutor: S. Klemm ; director of the school:  M. Paris. Università degli Studi di Milano, 2021 Mar 05. 33. ciclo, Anno Accademico 2020. [10.13130/faedo-federico-michele_phd2021-03-05].","filename":"phd_unimi_R11991.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/831912/1719529/phd_unimi_R11991.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1175697"},"title":"PROMOTION AND MONITORING OF PHYSICAL ACTIVITY WITH A DIGITAL APP IN PATIENTS WITH IRRITABLE BOWEL SYNDROME: CLINICAL OUTCOMES AND FECAL MICROBIOTA ANALYSIS OF A RANDOMIZED CONTROLLED STUDY","internalauthor":"COSTANTINO, ANDREA","type":"Tesi di dottorato","year":"2025","abstract":"Background and Aim:    Physical activity (PA) improves irritable bowel syndrome (IBS) symptoms.   Digital Apps may increase PA, but whether this intervention can improve symptoms in patients with IBS has not yet been investigated. Gut microbiota plays an important role in IBS.   The aim of this randomized controlled trial was to evaluate the effects of PA prescription with the use of a mobile App.  Methods:   We enrolled 97 consecutive patients with IBS according to Roma IV criteria; 22 patients aged <18/>60 years or with comorbidities limiting PA were excluded.   Patients were randomized to two intervention groups: 1) (Not APP) PA prescription with a 10 min counselling or 2) (APP) PA prescription with the indication to use the mobile App Google Fit after a brief explanation. Patients were evaluated at the first visit (T0) and after 3 months (T3). The severity of IBS symptoms (primary endpoint) was assessed by the Irritable Bowel Severity Scoring System (IBS-SSS). The Structured Assessment of Gastrointestinal Symptoms Scale (SAGIS), the Hospital Anxiety and Depression Scale (HADS), and the Bristol Stool Scale (BSS) were also used.   The adherence to WHO guidelines for aerobic physical activity, and PA levels were measured as Metabolic Equivalent of the Task (MET) minutes per week through the International Physical Activity Questionnaire–Short Form (IPAQ-SF).   Microbiota analysis on stool was performed at T0 and T3 in a group of 50 patients.     Results:   Seventy-five patients with IBS (mean age 41, SD±11.7 years; 70% female) were randomized. Baseline characteristics of two groups were not significantly different. Three patients dropped out in the Not APP group. The improvement in IBS-SSS (88.2±67 vs 47.6±72.0, P=0.021) and in SAGIS total score 9.2±8.7 vs 4.1±8.7, P=0.021) was significantly greater for APP, whereas the difference of the improvement in HADS between groups remained at borderline significance level (4.3±5.0 vs 2.3±3.7, P=0.065). Normalization of stool form was observed in 21% in the Not APP group and in the 41% of patients in the APP group (P= 0.077).   Although PA increased in both groups, the increase was greater in the APP than in the Not APP (MET min global activity at IPAQ-SF=791±1026 vs 262±807; P=0.025).  The increase of PA was significantly correlated with the improvement of IBS-SSS (r=0.33, P=0.03).  Changes in the gut microbiota composition were observed in IBS patients after physical activity. While alpha-diversity remained unchanged, beta-diversity showed significant shifts in microbial community structure from baseline to end of treatment (p=0.001). Specific genera were differentially enriched post-treatment, suggesting possible PA-induced modulation. At the species level, analysis revealed several enriched (amplicon sequence variants) ASVs after intervention.  Conclusions:   A digital APP promoting PA improved symptoms compared to PA counselling alone. Gut microbiota plays a role in symptom improvement, though it is not the sole driver. APP and increased activity may help shape microbial changes in conjunction with other factors to improve IBS symptoms.","language":"eng","citation":"PROMOTION AND MONITORING OF PHYSICAL ACTIVITY WITH A DIGITAL APP IN PATIENTS WITH IRRITABLE BOWEL SYNDROME: CLINICAL OUTCOMES AND FECAL MICROBIOTA ANALYSIS OF A RANDOMIZED CONTROLLED STUDY / A. Costantino ; tutor: M. Vecchi ; coordinator: M. Del Fabbro. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2025. 37. ciclo","filename":"phd_unimi_R13398.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1175697/3111246/phd_unimi_R13398.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-nc-nd/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/945231"},"title":"IMPORTANCE OF SUPPLYING DAIRY COWS WITH ESSENTIAL FATTY ACIDS (EFA) AND CONJUGATED LINOLEIC ACIDS (CLA) DURING THE TRANSITION PERIOD ON METABOLISM AND HEALTH","internalauthor":"VESHKINI, ARASH","type":"Tesi di dottorato","year":"2022","abstract":"Ketogenesis and steatosis are common sequelae of the severe mobilization of fat reserves necessary at the onset of lactation when the energy expenditures for milk and maintenance exceed the energy provided by voluntary feed intake in dairy cows. This situation along with a common state of systemic inflammation during early lactation makes dairy cow vulnerable to further metabolic and infectious diseases which impact their profitability. A periparturient supplementation with essential fatty acids (EFA) and conjugated linoleic acids (CLA) has been shown to influence different aspects of lipid and energy metabolisms as well as markers of immune homeostasis in dairy cows. This study aimed at investigating the synergistic effects of EFA, particularly α-linolenic acid (ALA, n-3 fatty acid (FA), and CLA on the liver and plasma proteome profile of dairy cows during the time spanning 3 weeks before to 9 weeks after parturition.  Late-gestation Holstein cows were infused from 9 wk ante partum (AP) to 9 wk post partum (PP) into the abomasum with either coconut oil (CTRL, n = 8, 38 & 76 g/d during dry period and lactation, respectively) or a mixture of EFA (Linseed + safflower oil) and CLA (Lutalin, BASF) (EFA+CLA, n = 8, 60 and 120 g/d during dry period and lactation, respectively). An untargeted shotgun proteomics approach based on liquid chromatography coupled with tandem mass spectrometry was performed in liver biopsies and plasma samples collected at days -21, +1, +28, and +63 relative to calving. At each timepoint, differentially abundant proteins (DAP) between treatment groups were identified as the proteins at the intersection between a multivariate supervised Partial Least Squares Discriminant Analysis (PLS-DA) and an univariate analysis (proteins with P-value <0.05 according to a t-test and fold change ≥ 1.3).  In liver a total of 1680 proteins was identified at each timepoint, of which 100 DAP between groups were assigned to the metabolism of xenobiotics by cytochrome P450, drug metabolism - cytochrome P450, drug metabolism - other enzymes, arachidonic acid metabolism, cholesterol metabolism and bile secretion, pyruvate metabolism, steroid hormone biosynthesis, glycolysis/gluconeogenesis, glutathione metabolism, and citrate cycle at all timepoints. At each timepoint, cytochrome P450, as a central hub to these annotated pathways, was related to specific CYP enzymes comprising CYP51A1, CYP1A1, CYP4F2, and CYP4V2. A total of 241 unique proteins was identified in the plasma, in which a cluster of apolipoproteins (APO) containing APOC3, APOA1, APOA4, and APOC4 was increased in response to EFA+CLA according to the stage of lactation. Overabundant APO were annotated by GO (gene ontology) terms related to triglyceride (TAG) homeostasis, cholesterol and lipoprotein metabolisms, inflammation, and innate immune response.  Altogether, these findings provided novel insights into the molecular mechanisms involved in cytochrome P450, cholesterol, and TAG metabolism by which dietary supplemented EFA+CLA influences metabolic and immune adaptation around parturition. Our results suggest that EFA+CLA could synergistically attenuate hepatic TAG accumulation and marginally mitigate inflammation. Nevertheless, further research is necessary to confirm our results at the other (metabolome) levels.","language":"eng","citation":"IMPORTANCE OF SUPPLYING DAIRY COWS WITH ESSENTIAL FATTY ACIDS (EFA) AND CONJUGATED LINOLEIC ACIDS (CLA) DURING THE TRANSITION PERIOD ON METABOLISM AND HEALTH / A. Veshkini ; supervisors: H. Sauerwein, F. Ceciliani, M. Bonnet. Università degli Studi di Milano, 2022 May 25. 34. ciclo [10.13130/veshkini-arash_phd2022-05-25].","filename":"phd_unimi_R12471.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/945231/2094727/phd_unimi_R12471.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1119203"},"title":"3D SENSING APPROACHES FOR PRECISION AGRICULTURE: APPLICATIONS TO PLANT FEATURES CHARACTERIZATION AND TO WEED CONTROL IN MAIZE","internalauthor":"TORRENTE, MARCO DAVIDE MICHEL","type":"Tesi di dottorato","year":"2024","abstract":"This PhD thesis investigates the application of 3D data acquired by Time-of-Flight (ToF) sensors and stereo cameras for agronomic measurements. The main objectives are the characterization of plant geometric properties, biomass estimation with non-destructive methods and discrimination between crops and weeds for use in precision agriculture applications.  Following an introductory section, the first part of the work, which corresponds to Chapters 3 and 4, involves the volumetric characterization of lettuce plants to estimate biomass using non-destructive measurements. This was performed both in preliminary laboratory trials and in a field application. In the field application the depth sensor was integrated with a robotic platform to ensure the possibility to collect data at the individual plant level, with all data that can be stored in a data lake. In both cases, the assumed volumetric reconstruction algorithms achieved very satisfactory results, obtaining accurate dry biomass weight (DM) estimates from the developed models for both laboratory scale (with a root mean square error (RMSE) of 0.12 g and a mean absolute percentage error (MAPE) of 12%.) and greenhouse conditions (with a RMSE of 1.07 g and MAPE 16%). The different ability to estimate the DM obtained in the two contexts, although minimal, depends mainly on the different spatial resolutions obtainable with the acquisition setups designed for the two experiments and on the conditions under which the measurements were carried out. Considering the technological characteristics of the ToF sensors, under field conditions they are disturbed by solar radiation, which contributes to decreasing the level of accuracy of the measurement obtained.  The second part of the thesis, which corresponds to Chapters 5, 6, 7 and 8, deals with the comparison of two sensing techniques, two-dimensional based on color (RGB) and three-dimensional that consider distance in addition to color (RGBD) to optimize the process of target identification for use in precision weed control spraying that aims to reduce chemical inputs using advanced techniques. Regarding 2D imagery, a comparative analysis was conducted on images captured using drones (UAV – Remote sensing) and those obtained in proximity to vegetation (proximal sensing). The objective was to assess the capacity of these approaches to estimate soil cover, a critical driver that can indirectly indicate the degree of weed infestation. Proximal images demonstrated superior accuracy in estimating this phenomenon, achieving a coefficient of determination (R²) of 0.93, compared to UAV-acquired images, which yielded an R² of 0.8 in validation tests based on 90 ground control points established within the field. When comparing the two monitoring techniques at a field scale, UAV imagery was found to provide an estimate of soil cover that, in 75% of the sampled area, was lower than that derived from proximal images under experimental conditions.  In this context, which highlights the superior representativeness of information obtainable through proximal monitoring, the contribution of 3D sensing techniques to estimating weed presence was subsequently evaluated in comparison to proximal 2D images. To this end, several algorithms specifically designed to utilize both sensing techniques were developed.  Using 2D images, two algorithms were developed. The first is a simpler approach that enables uniform treatment decisions across areas of 0.75 m² (Management Zones - MZ) based on assessing vegetation soil cover. The second, an innovative algorithm known as Local Cover Fraction (LCF), is more complex, employing a hybrid technique to simultaneously detect weeds between rows and subsequently characterize the spatial distribution of remaining soil cover along each crop row. This allows identification of areas where biomass distribution deviates from the clean-field conditions recorded at the experiment's start.  In parallel, a classification algorithm based on 3D sensing was developed, with two distinct implementation strategies proposed. The first, Treat All Weeds (TAW), aims to target all areas identified as weeds and the second, Treat Weed in Majority (TWM), activates actuators only when they can cover a greater surface area classified as weeds than of crops.  To evaluate the results and quantify the contribution of these methods compared to traditional uniformly distributed (UD) techniques, precision spraying treatments based on the MZ, LCF, and 3D-based algorithms were simulated, and the outcomes were compared.  Simulations yielded promising results, forecasting a reduction in both the quantity of herbicide applied and the environmental impact for most developed algorithms. Herbicide reductions were observed as follows: 10% for the MZ method, 45% for the LCF method, and for the 3D sensing approach, a 22% reduction for the TAW strategy and 28% for TWM. However, the TAW strategy was the only approach to achieve a statistically significant reduction in both herbicide quantity and environmental impacts without a notable decrease in treatment effectiveness, which remained statistically comparable to the uniformly distributed (UD3D) treatment simulation.  The results obtained with both imaging techniques surpassed expectations. Compared to the 2D imaging-based method for estimating weed control treatments, the 3D survey produced even more favorable results, owing to its enhanced capability for target classification, which proved more robust than the 2D method. This advanced classification capability enabled the design of crop-targeted treatments through simulations of localized biostimulant distribution, achieving full crop surface coverage with a sensitivity of 0.99. This approach reduced product waste from ground distribution by 85% and minimized the undesired effect of weed biostimulation by 75%.  Finally, in Chapter 9, a low-cost simulator prototype is proposed for the hardware and software management of highly precise, localized treatments based on proximal imaging. This simulator is designed to perform real-time monitoring and execute the required treatment actions.  In general, considering the results obtained in both fields of application investigated in this thesis work, the use of 3D sensors demonstrated significant outcomes across all evaluated contexts, both in initial laboratory tests and in field application trials.","language":"eng","citation":"3D SENSING APPROACHES FOR PRECISION AGRICULTURE: APPLICATIONS TO PLANT FEATURES CHARACTERIZATION AND TO WEED CONTROL IN MAIZE / M.d.m. Torrente ; tutor: R. Oberti ; co-tutor: A. Calcante ; coordinatore: R. Pilu. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2024 Dec 16. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13214_2.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1119203/2592767/phd_unimi_R13214_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/949952"},"title":"MOLECULAR STUDY OF CHROMATINOPATHIES: THE CASE OF RUBINSTEIN-TAYBI AND RETT SYNDROMES","internalauthor":"DI FEDE, ELISABETTA","type":"Tesi di dottorato","year":"2023","abstract":"Background: Chromatinopathies are defined as a group of disorders displaying mutations in genes of the epigenetic apparatus and sharing clinical features such as intellectual disability and abnormal growth. Among them, Rubinstein-Taybi syndrome (RSTS) is characterized by CBP/p300 lysin-acetyltransferases deficit, while classic form of Rett syndrome (RTT) is caused by mutations in the reader MECP2. Both disorders show neurodevelopmental defects and 10 to 30% of patients remains without a molecular diagnosis.  Methods: In this work, we aim at deepening molecular aspects involving RSTS and RTT etiology and RSTS possible epigenetic treatments. Indeed, we tested exogenous histone deacetylase inhibitors (HDACi) in in vitro cellular models (lymphoblastoid cell lines derived from patients and healthy donors) and on a Drosophila melanogaster model of RSTS (nej) and wild type flies (yw), performing acetylation and viability assays and flies embryos immunostaining respectively. In parallel, we investigated endogenous HDACi in RSTS patients and in fruit flies models, assessing their microbiota. In addition, we applied whole exome sequencing (WES) analysis to RSTS and RTT-like probands negative for mutations in known associated genes and we then characterized two identified variants by genome editing techniques and functional analysis.  Results: In RSTS studies, we observed that patients gut microbiota is significantly depleted in butyrate-producing bacteria and we demonstrate that the effects of the HDACi butyrate, as well as the differences in microbiota composition, are conserved in nej flies. From WES study, we found in one RSTS and three RTT-like patients unreported variants in HDAC2, and NBEA, DYNC1H1 and SLC35F1 genes respectively, whose role is currently under investigation through in vitro models.  Conclusions: The study on microbiota composition could pave the way for novel therapeutic interventions for RSTS, while the identification of new RSTS and RTT genes could expand the genotype-phenotype correlation for these chromatinopathies, and characterization of new candidate genes could give insights into pathogenesis of these disorders.","language":"eng","citation":"MOLECULAR STUDY OF CHROMATINOPATHIES: THE CASE OF RUBINSTEIN-TAYBI AND RETT SYNDROMES / E. Di Fede ; tutor: C. Gervasini ; coordinatore: C. Sforza. Dipartimento di Scienze della Salute, 2023 Jan 23. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12526.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/949952/2116291/phd_unimi_R12526.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/962757"},"title":"POPULATION GENOMICS, DISTRIBUTION AND REPRODUCTIVE ECOLOGY OF AN ITALIAN STENO-ENDEMIC CHASMOPHYTE, CAMPANULA RAINERI","internalauthor":"VILLA, SARA","type":"Tesi di dottorato","year":"2023","abstract":"Plant species distributions are the result of climatic and evolutionary histories. Range restriction in steno-endemic species often results from climate oscillations that have reduced the extent of suitable habitat or limited species dispersion across ecological barriers. Narrow endemics may also be of recent origin (yet to disperse) or relicts of ancient lineages. High-elevation environments tend to be rich in endemism as a result of complex climatic histories (underpinning speciation events) and the survival of relicts. Mountain species typically experience extreme conditions and significant temperature changes across short spatial gradients and timeframes, and are particularly sensitive to climate fluctuations, especially on exposed substrates such as rocky faces and screes. Consequently, mountain chasmophytes (i.e. rupestral plant species), are often range-restricted, characterised by small and fragmented populations. The current thesis aims to better understand the causes and consequences of rarity and predict the possibilities for future conservation of a model chasmophyte species, Campanula raineri Perp. (Campanulaceae), a tetraploid steno-endemic of the Italian Prealps, by addressing the following hypotheses:  1) Polyploidy (chromosome set duplication) is a principle driver for the emergence of new endemics. A global-scale analysis of 4210 species representing the principal clades of angiosperms addressed the relationships between chromosome number, geographic distribution and taxon age (Chapter 2). Polyploidy was shown to be a key driver of endemism in angiosperms, with a significant negative exponential relationship between the maximum number of chromosomes and taxon age (R2adj = 0.49, p < 10-4), and greater maximum chromosome numbers (2n = 164 vs. 111) declining more rapidly with taxon age (decay constant = 0.12 vs. 0.04) compared to non-endemics.  2) The genetic structure of C. raineri populations is consistent with changes in habitat suitability throughout the Quaternary. Demographic history (gene flows, bottlenecks, and reproductive isolation events), can be investigated through population genomics to infer species phylogeography. Phylogeographically informed Species Distribution Models (SDMs) can reconstruct and predict changes in the geographical range of different intraspecific genetic lineages according to their ecological requirements and climate projections. Hypothesis 2 was thus verified by comparing the genetic structure of 14 populations across the entire distributional range of C. raineri with the climatic history of the region during the Quaternary (Chapter 3). Genomic analysis of C. raineri populations revealed two main genetic lineages, probably becoming isolated during the Last Interglacial (~ 120,000 years bp) due to habitat recolonization dynamics and subsequently during the LGM due to the persistence of the Valsassina glacier barrier. Within these two metapopulations, a more recent site-specific differentiation was evident as a result of the upward migration of the species on isolated reliefs (posterior population assignment probability calculated by Markov chain Monte Carlo clustering algorithm always = 1).  3) An upward migration of C. raineri is expected in future decades as a consequence of sub-optimal conditions at lower elevation sites due to climate warming. Predictions based on phylogeography and SDMs can be informative for rare species conservation under current climate change scenarios. Understanding the optimal conditions for species fitness (i.e. survival and reproductive success) and where these could be found in the future is crucial to inform targeted conservation actions such as population reinforcements and assisted migrations. Hypothesis 3 was addressed both by building phylogeographically-informed future SDMs (investigating future decades until 2070; Chapter 3) and testing the impacts of elevation on the reproductive ecology of C. raineri, from pollinator guilds to pollen and seed quality (Chapter 4). Future SDMs suggest a decrease in habitat suitability at lower-elevation sites, where C. raineri populations exhibited reduced fitness (correlation coefficients = 0.62 and 0.93 for seed germination and pollen viability, respectively).  4) In-vitro propagation and plant production is feasible for the conservation of rare chasmophytes. Germination protocols for C. raineri and other rare species (4 chasmophytes and 1 orchid) of northern Italy were tested (Chapter 5): successful in-vitro propagation of target species was performed (mean germination rate of each species generally > 80%, lower for Linaria tonzigii and Saxifraga tombeanensis), with the production of hundreds of new plants.  In conclusion, ecological barriers during the Quaternary resulted in the genetic differentiation of C. raineri into two metapopulations, the ‘lower’ lineage exhibiting genetic uniformity and reduced fitness probably as a consequence of sub-optimal conditions for the species with increasing temperatures. The survival of this lineage is further threathened by the lack of possibilities for spontaneous upward migration, entailing the risk of genetic depletion within the entire species. However, SDMs and successful in-vitro propagation suggest that informed conservation actions could be undertaken to counter this trend.","language":"eng","citation":"POPULATION GENOMICS, DISTRIBUTION AND REPRODUCTIVE ECOLOGY OF AN ITALIAN STENO-ENDEMIC CHASMOPHYTE, CAMPANULA RAINERI / S. Villa ; tutor: S. Pierce, M. Montagna, C. Vernesi ; coordinatore: P. A. Bianco. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2023 Apr 21. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12508.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/962757/2172415/phd_unimi_R12508.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1211196"},"title":"CANCERHUBS: A NETWORK-CENTRIC FRAMEWORK FOR CANCER GENE PRIORITISATION","internalauthor":"FERRARI, IVAN","type":"Tesi di dottorato","year":"2026","abstract":"\"Cancer is a complex disease that originates from genetic mutations, which represent the primary triggering events of neoplastic transformation. Nevertheless,  such lesions alone are not sufficient to account for the full complexity of tumour  development, which also arises from epigenetic and regulatory alterations that remodel cellular networks and molecular circuits. In this framework, conventional  single-gene approaches risk overlooking key elements that, although not frequently  mutated or differentially expressed, play a critical role as network hubs. In this thesis, \"\"CancerHubs\"\" is presented, a systematic data mining and integration pipeline  that combines mutational data, clinical outcome predictions (via PRECOG meta-Z  scores), and protein-protein interaction networks to identify cancer-related protein  hubs. The method computes a composite Network Score that integrates mutational  profiles, prognostic associations, and interactome connectivity, thereby prioritising  genes that may not be strongly mutated or differentially expressed, but are central to the cancer network structure. This approach moves beyond conventional  mutation-centric strategies and provides a network-informed perspective on cancer  gene discovery. Alongside the computational method, \"\"CancerHubs Data Explorer\"\",  a Shiny web application that allows users to interactively explore mutation-enriched  hubs across 11 tumour types was developed. The application provides ranked tables, global interactomes, and neighbourhood visualisations of user-defined genes,  with filtering options for mutational and prognostic data. This ensures that the  results of the pipeline are not only reproducible but also broadly accessible to researchers with varying computational expertise. As a proof of principle, predictions  generated by CancerHubs were validated both in silico and experimentally. These  analyses demonstrated that TGOLN2 displays tumour suppressor features in Multiple Myeloma, Breast, and Prostate Cancer, while EFTUD2 exhibits oncogene-like  behaviour specifically in Multiple Myeloma. This validation highlights the ability  of the framework to uncover genes of clinical and mechanistic relevance that may  be missed by mutation- or expression-centric approaches. Altogether, CancerHubs  provides a exible and extensible framework for interactome-based cancer gene prioritisation. By integrating heterogeneous data layers into a unied network-aware  metric, and by complementing predictions with functional validation and accessibility through the CancerHubs Data Explorer, this work contributes to the advancement of systems oncology. The tools and ndings described here aim to support  hypothesis generation, biomarker discovery, and the identification of novel therapeutic targets, ultimately bridging the gap between large-scale cancer genomics and  translational applications.\"","language":"eng","citation":"CANCERHUBS: A NETWORK-CENTRIC FRAMEWORK FOR CANCER GENE PRIORITISATION / I. Ferrari ; tutor: S. Biffo. Dipartimento di Bioscienze, 2026. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13707_2.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 11-FEB-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1202219"},"title":"ROLE OF CELLULAR STRESS RESPONSES IN THE PATHOPHYSIOLOGY AND TREATMENT OF PSYCHIATRIC DISORDERS","internalauthor":"D'AMELIO, SABRINA","type":"Tesi di dottorato","year":"2026","abstract":"Major Depressive Disorder (MDD) is one of the most serious conditions classified among the stress-related psychiatric disorders. Not only it is one of the leading causes of disability worldwide but is also associated with poor treatment response and high rate of relapse, which dramatically increase the risk of death of affected individuals.  Stressful life events contribute to MDD insurgence in the presence of an underlying genetic susceptibility. However, only a small percentage of the general population who experiences adverse events develops the full-blown disorder. These individuals, defined as vulnerable, fail to appropriately resolve a physiological stress response upon cessation of a stressful event. Conversely, most individuals are resilient, able to respond in a proper and non-pathological manner to stressful stimuli.  Over the past decades, it has been reported that stress might differently affect the molecular asset of vulnerable and resilient subjects. Our lab has also reported alterations of neuroinflammation and redox balance following stress-exposure. These mechanisms are part or consequences of cellular stress responses, namely processes that are activated when an insult disrupts homeostasis to promote either survival or death. However, the precise mechanisms by which stress contributes to the derangements of these systems and how this can be implicated in MDD still needs to be completely elucidated.  In this context, the aim of this project is to evaluate, through both gene candidate and unbiased approaches, if and how specific cellular stress responses are elicited in vulnerable and resilient individuals to MDD when exposed to stressors of different intensities and durations. Also, we investigated whether any alteration could be mitigated by the effect of the chronic pharmacological treatment with venlafaxine.  To this end, we took advantage of a preclinical model of stress-induced MDD, the Chronic Mild Stress (CMS), articulated in multiple designs. These included a short-term (2 weeks) and a prolonged (6 weeks) stress exposure, the latter being followed by a brief and intense acute challenge (1h of acute restraint stress). In this design, a part of Vulnerable animals was also subjected to chronic treatment with the SNRI Venlafaxine for three consecutive weeks, concomitantly with the CMS exposure and prior to ARS. In both designs, the exposure to chronic stress successfully resulted in the stratification of animals in vulnerable and resilient to anhedonia, core symptom of MDD, thus exemplifying the real-life scenario.  In the first part of the project, we assessed through gene-candidate analyses the effects of prolonged CMS on redox balance by evaluating the levels of cardinal mediators in brain areas of interest at the end of the stress exposure and after the ARS to mimic a more  5  dynamic context. We observed that despite CMS alone did not induce any modulation, it was able to affect the acute responsiveness of vulnerable animals. Specifically, they showed upregulation of the antioxidant component after ARS exposure, a potential compensatory mechanism reflecting a higher need to rebalance an oxidative state. Moreover, chronic venlafaxine treatment was able to normalize the observed alterations, suggesting a role for the drug in re-establishing the normal redox balance when needed.  While prolonged CMS exposure did not result in measurable antioxidant modulation for the targets assessed, previous data from our lab showed that a shorter stress exposure was able to induce upregulation of some antioxidant markers, such as Heme-Oxygenase-1 (HO1) only in resilient subjects. We thus took advantage of HO1 to investigate which kinds of brain cells were mainly responsible for the observed modulations, exploiting immunofluorescence technique. We found that HO1-expressing cells were mainly located across the dentate gyrus (DG) of the hippocampus, and we observed that most of the signal was attributable to microglial cells (IBA1+). However, a considerable amount of the HO1 signal specifically located in the hilus of the DG was ascribable to cells with neuron-like morphology. To further explore this hypothesis, we stained slices with GAD65 (inhibitory interneurons marker) and Parvalbumin (marker of a specific subtype of inhibitory interneurons), confirming their partial involvement in the HO1-mediated antioxidant response.  As we are aware that the complexity of the molecular alterations associated with stress response in the context of MDD cannot be limited to redox balance, we adopted a wider perspective on which other systems could intervene in the stress response, specifically examining how would vulnerability and resilience differ. Thus, we moved from a gene-candidate towards a more unbiased approach with proteomics, which eventually led us to assess the time-dependent effects of stress on protein homeostasis alterations and more in detail on the Unfolded Protein Response (UPR). Our findings revealed that vulnerable and resilient individuals do not differ in whether the response occurs, but rather in the specific pathways and timing of their activation. Moreover, venlafaxine treatment was able to normalize the main UPR alterations, indicating that it could ameliorate the vulnerability-associated phenotype also by alleviating ER stress.  While further research is needed to fully elucidate the effects of stress on these processes, the present work contributes to refine our understanding of the molecular mechanisms underlying both vulnerability and resilience to stress-induced anhedonia, providing potential insights of therapeutic relevance.","language":"eng","citation":"ROLE OF CELLULAR STRESS RESPONSES IN THE PATHOPHYSIOLOGY AND TREATMENT OF PSYCHIATRIC DISORDERS / S. D'amelio ; tutor: R. Molteni ; co-tutor: C. De Palma ; coordinatore: N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2025. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13692.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 04-GIU-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1151338"},"title":"IMPACT OF KETOGENIC DIET TREATMENT IN GLUT1 DEFICIENCY SYNDROME: DISCOVERY OF MOLECULAR MECHANISMS RESPONSIBLE FOR PHENOTYPE CHANGES IN BOTH PEDIATRIC AND ADULT PATIENTS","internalauthor":"MAURI, ALESSIA","type":"Tesi di dottorato","year":"2025","abstract":"GLUT1 deficiency syndrome (GLUT1-DS) is a rare, effectively treatable, neurometabolic disease. It is caused by loss-of function mutations in the SLC2A1 gene, encoding GLUT1 protein, which supplies glucose to the brain. A genetic defect in this transporter leads to cerebral energy deficiency, resulting in a complex spectrum of neurological symptoms, including seizures and movement disorders.   Although many clinical and molecular features have been deeply studied, there are still some not completely understood aspects, including (i) clinical variability and wide spectrum of SLC2A1 variations, (ii) phenotype age-related changes, and (iii) response to ketogenic diet (KD) treatment, which are investigated in this research study through a multi-omics approach.  Firstly, we explored the clinical, biochemical and molecular data of 27 pediatric patients with GLUT1-DS, identifying (1) different clinical phenotypes (from early- to late-onset), (2) 25 disease-related SLC2A1 variants of which 10 never reported before, (3) a mutational hotspots in exon 4, suggesting a vulnerable region for glucose uptake associated to clinical manifestations, and (4) strong correlations between variant types, clinical and biochemical severity patterns.  Next, we analyzed the transcriptional profiles and isoform switches in GLUT1-DS patients, before and after KD, focusing on three comparisons: (a) adults versus children, both untreated; (b) children in pre- versus post-KD; and (c) responders versus non-responders to KD in GLUT1-DS children. Overall, enrichment analysis revealed a reduction in inflammatory pathways in GLUT1-DS patients who experienced clinical improvements in seizure frequency and severity, whether in response to KD or during adulthood. These processes involve type I IFN signatures, which have an impact on mitochondrial function and signaling, suggesting a specific role in GLUT1-DS pathogenesis. Supporting these suggestions, the detected lncRNAs are also related to inflammatory response, as RMRP and LINC02555, or to ketone biosynthesis and oxidative phosphorylation processes, like PAX8-AS1, for which emerges its potential regulatory role in KD response. Another significant molecular pathway contributing to mitigate clinical signs is the alternative splicing of ion channel genes, such as P2X7 receptor which is, in turn, liked to inflammasome pathway. As well as this, the methylome profiles, performed by ONT, revealed altered methylation patterns in similar genes, like GRIN3A, suggesting also in this analysis an ion channel signaling deregulation.  Lastly, these novel and suggestive findings underline the complex interplay that transcriptional variations, isoform switching and methylation patterns may have in the phenotype age-dependent changes and response to KD in patients with GLUT1-DS.","language":"eng","citation":"IMPACT OF KETOGENIC DIET TREATMENT IN GLUT1 DEFICIENCY SYNDROME: DISCOVERY OF MOLECULAR MECHANISMS RESPONSIBLE FOR PHENOTYPE CHANGES IN BOTH PEDIATRIC AND ADULT PATIENTS / A. Mauri ; tutor: G.V. Zuccotti, C. Cereda ;  coordinatore: F. Cheli. Dipartimento di Scienze Biomediche e Cliniche, 2025 Mar 26. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13562_4.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1151338/2706001/phd_unimi_R13562_4.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1045528"},"title":"TO FACIAL FEATURES AS A NEW BIOMARKER FOR EARLY IDENTIFICATION OF HIGH-RISK ATHEROSCLEROSIS: A  TRANSLATIONAL APPROACH","internalauthor":"CONTE, EDOARDO","type":"Tesi di dottorato","year":"2024","abstract":"Introduction  Cardiac computed tomography (CCT) emerged as a valuable non-invasive tool for early identification of high-risk coronary atherosclerosis. However, no validated biomarkers or scores are available to identify patients who may benefit from CCT in primary prevention. Aim of the present study was to explore for the first time the potential role of facial features analysis using artificial intelligence (AI) for the prediction of high-risk coronary atherosclerosis at CCT.  Material and Methods  A consecutive cohort of patients with a clinical indication to CCT and without known cardiovascular disease were prospectively enrolled between January 2022 and August 2022. Before CCT, 10 facial photos were collected in each patient from different random angles. An AI model was then built to predict the presence of high-risk coronary atherosclerosis and was compared with traditional risk factors and scores.  Results  The study population included 100 consecutive patients with a mean age of 62±10.7 years (69% male) from whom 1,000 different facial images were recorded. All the models built considering the somatic features demonstrated higher predictive capability when compared to SCORE 2 among asymptomatic subjects regarding high non-calcified plaque volume (AUC=0.89 vs. AUC_SCORE2=0.66, p-value <0.001), high low-density plaque volume (AUC=0.94 vs. AUC_SCORE2 =0.64, p-value <0.001) and the presence of at least one high-risk plaque feature (AUC=0.79 vs. AUC_SCORE2 =0.65, p-value =0.002).  Conclusions  This prospective observational study demonstrates that an AI algorithm applied to facial features may serve as a new “biomarker” for early identification of patients with high-risk coronary atherosclerosis.","language":"eng","citation":"ARTIFICIAL INTELLIGENCE APPLIED TO FACIAL FEATURES AS A NEW BIOMARKER FOR EARLY IDENTIFICATION OF HIGH-RISK ATHEROSCLEROSIS: A TRANSLATIONAL APPROACH / E. Conte ; tutor: C. Sforza ; company tutor: G. Pontone. Dipartimento di Scienze Biomediche per la Salute, 2024. 36. ciclo","filename":"phd_unimi_R13176.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1045528/2399089/phd_unimi_R13176.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1212516"},"title":"FUNCTIONAL CHARACTERIZATION OF THE INTERACTION BETWEENP. AERUGINOSA AND DENDRITIC CELLS TRIGGERING THE DIFFERENTIATION OF PATHOGENIC TH1/17 CELLS IN CYSTIC FIBROSIS.","internalauthor":"CONTE, GIANMARCO","type":"Tesi di dottorato","year":"2026","abstract":"Cystic Fibrosis (CF) is a genetic disease characterized by an exaggerated inflammatory response to persistent bacterial lung infections, predominantly caused by Pseudomonas aeruginosa (Pa). Despite the hostile environment resulting from CFTR dysfunction, Pa promotes sustained activation of both innate and adaptive immunity. While neutrophils and macrophages exert a detrimental pro-inflammatory effect, IFNγ/IL-17 co-producing Th17 lymphocytes appear to play a pivotal pathogenic role. However, the mechanisms linking Pa infection to the generation of lung-infiltrating IFNγ/IL-17 co-producing Th17 cells remain undefined.  To address this, we analysed T cell subsets in blood and lung samples from people with cystic fibrosis (pwCF) and non-CF patients by flow cytometry and we analysed the transcriptomic profile of the isolated subsets by RNA-Seq. Their pathogenic activity was evaluated using lung epithelial cell co-cultures by immunofluorescence and cytokine measurement. Furthermore, a library of Pa clinical isolates was used to assess the Pa-dependent immune response, and an antigen-dependent assay was employed to investigate whether Pa directly induced the trans-differentiation of ex vivo cTh17 into pathogenic IFNγ/IL-17 co-producing cells.  Our data revealed that pathogenic IFNγ/IL-17 co-producing cells (Th1/17+ and pTh17) were significantly enriched in the lungs of pwCF chronically infected with Pa, whereas protective Th1 and cTh17 cells were reduced. Transcriptomic comparison highlighted unique molecular signatures of lung-infiltrating pathogenic subsets. Functionally, Th1/17+ and pTh17 cells, but not cTh17 cells, mediated epithelial damage in vitro. Compared with the laboratory strain PAO1, clinical Pa isolates induced stronger release of IL-1β and IL-23 from dendritic cells, promoting IFNγ/IL-17 co-producing T cells differentiation. Notably, the skewing of IFNγ/IL-17 co-producing cells from cTh17 was strongly driven by clinical isolates, with no significant differences between early and late isolates. During this process, IFNγ/IL-17 co-producing cells showed increased expression of the transcription factors CEBP-δ and PPAR-γ, consistent with transcriptomic data from pwCF lungs.  Altogether, our findings indicate that Pa infection of dendritic cells drives the generation of pathogenic IFNγ/IL-17 co-producing T cells, together with their transcriptional reprogramming. Understanding the molecular mechanisms of Pa-dependent generation of pathogenic T cells may uncover bacterial and immunological targets exploitable for novel therapeutic strategies in CF.","language":"eng","citation":"FUNCTIONAL CHARACTERIZATION OF THE INTERACTION BETWEEN P. AERUGINOSA AND DENDRITIC CELLS TRIGGERING THE DIFFERENTIATION OF PATHOGENIC TH1/17 CELLS IN CYSTIC FIBROSIS / G. Conte ; tutor: M. Paroni ;  coordinatore: S. Ricagno. Dipartimento di Bioscienze, 2026 Jan 26. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13890.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 03-FEB-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1125977"},"title":"P4HB TARGETING HALTS TUMOR GROWTH AND RE-SENSITIZES RESISTANT MELANOMA CELLS TO DABRAFENIB AND TRAMETINIB STANDARD-OF-CARE THERAPY VIA IRE1-⍺ ACTIVATION AND AKT DOWNMODULATION","internalauthor":"ZOCCHI, ANGELICA","type":"Tesi di dottorato","year":"2025","abstract":"BRAF-mutant melanoma patients account for approximately 50% of all cutaneous melanoma cases. The overall survival rate of metastatic melanoma patients was dramatically improved by the introduction of targeted therapy (BRAF and MEK inhibitors) and immune checkpoints inhibitors (anti-PD1, anti-CTLA4). However, a significant proportion of BRAF-mutant patients develop secondary resistance to targeted therapies, while others exhibit even primary resistance. To either prevent or overcome resistance in BRAF-mutant melanoma patients, new combinations are now being tested, exploiting triple-agent combinations (targeted therapy with immunotherapy), but with unsatisfactory results. Additionally, the use of immunotherapy in neo-adjuvant conditions, has shown promise, being still under investigation. Another potential therapeutic approach involves re-sensitizing resistant melanoma cells to targeted therapies. However, clinical trials exploring this strategy in patients with BRAF/MEK inhibitor resistance are currently limited. Hence, identifying new vulnerabilities in resistant melanoma cells, as well as to establish novel strategies to re-sensitize resistant melanoma cells to targeted therapies is crucial to improving patient outcomes.  Herein, I carried out a functional shRNA-based in vivo screen with a library targeting 195 actionable genes (FDAome library), where each gene is linked to specific FDA-approved drugs that can be repurposed for melanoma treatment. A375 parental cells and A375 cells resistant to dabrafenib and trametinib (A375-DT) were used as models to unveil new vulnerabilities. FDAome screen highlighted 37 genes essential for the in vivo tumor growth of DT-resistant cells. I validated two candidates, namely CREB-binding protein (CREBBP) and Prolyl 4-Hydroxylase Subunit Beta (P4HB), whose inhibition reduced tumor growth in vivo and increased overall survival of A375-DT but not of A375 parental cells, suggesting a putative point of intervention in resistant tumors. Additionally, I demonstrated that silencing CREBBP and P4HB reduced the migratory capacity of A375-DT cells but not A375 cells, further corroborating our in vivo findings. I further validated the in vitro results in a different cell line, namely SKMEL-28-DT and in drug resistant patient-derived primary cultures. To further investigate the therapeutic potential of targeting CREBBP and P4HB, I tested the efficacy of CCS1477 and PACMA31, respectively, as monotherapies and in combination with dabrafenib and trametinib. Both compounds effectively inhibited tumor growth in vivo. Notably, PACMA31 demonstrated the ability to re-sensitize resistant tumors to DT. Furthermore, PACMA31 demonstrated significant efficacy in a syngeneic D4M-DT melanoma model, leading to dramatic tumor regression. Mechanistically, I demonstrated that P4HB silencing had an impact on cellular homeostasis, by increasing accumulation of misfolded proteins and activating IRE1⍺ signalling pathway as part of the unfolded proteins response. This resulted in partial cellular death and autophagy induction. Additionally, P4HB knockdown and subsequent ER stress increment reduced AKT phosphorylation, generating a window of opportunity to re-establish sensitivity to dabrafenib and trametinib treatment.","language":"eng","citation":"P4HB TARGETING HALTS TUMOR GROWTH AND RE-SENSITIZES RESISTANT MELANOMA CELLS TO DABRAFENIB AND TRAMETINIB STANDARD-OF-CARE THERAPY VIA IRE1-⍺ ACTIVATION AND AKT DOWNMODULATION / A. Zocchi ; tutor: L. Lanfrancone internal advisor: P. Ferrucci coordinator: D. Pasini. Università degli Studi di Milano, 2025 Jan 21. 36. ciclo","filename":"phd_unimi_R13141.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1125977/2612879/phd_unimi_R13141.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1212937"},"title":"ASSESSMENT OF RELEVANT MOLECULAR TARGETS WITH THERAPEUTIC SIGNIFICANCE IN CANINE NEOPLASMS.","internalauthor":"DELL'AERE, SILVIA","type":"Tesi di dottorato","year":"2026","abstract":"Cancer is the leading cause of death in companion dogs. The high prevalence and impact on animal welfare, combined with biological and environmental similarities to humans, position canine cancers as valuable models for comparative oncology and translational research. Increasing canine life expectancy and advances in diagnostics have highlighted the need for effective, targeted therapies. While targeted therapies such as tyrosine kinase inhibitors, monoclonal antibodies, antibody-drug conjugates, and immunocytokines have transformed human oncology, their application in veterinary medicine remains limited by scant data on druggable targets in dogs.  This doctoral thesis aimed to systematically assess the expression and distribution of selected molecular targets in canine tumors, focusing on aggressive, frequent, or therapeutically challenging neoplasms, and to evaluate their suitability as druggable candidates for targeted therapy and as comparative models for human cancer. The approach combined immunohistochemistry, genetic analyses, and exploratory in vitro studies, focusing on molecules located on neoplastic cells and in the tumor microenvironment: FAP, EDB+FN, KIT (CD117), PDGFR-β, and OXTR. These molecules are involved in tumor progression, stromal remodeling, angiogenesis, and hormonal regulation.  Results confirm that canine tumors can harbor multiple therapeutically relevant molecular targets. FAP and EDB+FN are promising targets for payload-delivery and immunocytokine therapies, especially in soft tissue sarcoma, AGASAC, and melanoma. KIT and PDGFR-β show potential for diagnosis and targeted treatment in sarcomas and AGASAC, while OXTR represents an innovative area for further research. The observed heterogeneity of target expression underscores the need for tailored, molecularly guided therapies.","language":"eng","citation":"ASSESSMENT OF RELEVANT MOLECULAR TARGETS WITH THERAPEUTIC SIGNIFICANCE IN CANINE NEOPLASMS / S. Dell'aere ; tutor: P. Roccabianca ; coordinatore: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2026. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13706.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 06-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1205155"},"title":"THE LYSOSOMAL AMYLOID AGGREGATION OF B2-MICROGLOBULIN PROMOTES MULTIPLE MYELOMA PROGRESSION: A MOLECULAR FOCUS ON THIS PRO-CANCER MECHANISM","internalauthor":"RIZZI, GIULIA","type":"Tesi di dottorato","year":"2025","abstract":"Maintenance of native folding is crucial for ensuring protein biological activity. Despite cells have evolved several control mechanisms to preserve folding, when they fail, proteins undergo destabilization or partial unfolding, events that favor the onset of protein misfolding diseases. These conditions are characterized by formation of protein aggregates, which impair tissues and organ functionalities. A widely studied example is β2-microglobulin (β2m), whose aggregation into amyloid fibrils underlies dialysis-related amyloidosis. Beyond this role, β2m also serves as prognostic factor for several hematological malignancies, including multiple myeloma (MM). Recent studies demonstrated that β2m actively contributes to MM pathogenesis by aggregating inside the lysosomes of tumor-associated macrophages. The resulting lysosomal damage induces NLRP3 inflammasome activation which sustain inflammation and malignant plasma cell proliferation. This thesis investigates the link between β2m fold stability and aggregation propensity under lysosomal-like conditions, and the resulting inflammatory response in macrophage-like cells. Wild-type and four β2m variants, namely D76N, ΔN6, D59P, and W60G were expressed, purified, and biophysically characterized in terms of pH and temperature stability, flexibility and aggregation propensity under physiological and lysosomal-like pH. In parallel, cellular studies were performed on THP-1-derived macrophages to monitor the effect of β2m uptake on lysosomal integrity, inflammasome activation, cytokine release, and cell viability. The biophysical analysis revealed three stability groups: ΔN6 and D59P, strongly destabilized by lysosomal pH and highly aggregation-prone; wt and D76N, with intermediate stability; and W60G, remarkably resistant to pH destabilization and aggregation. In cells, aggregation-prone variants formed large intracellular foci that increased in number and size over time. Furthermore, a prolonged NLRP3 and caspase-1 activation, as well as elevated IL-1β release was detected. In contrast, W60G, by remaining stable under lysosomal conditions, did not lead to aggregate formation, and neither to inflammasome activation and inflammatory cytokine release. Taken together, these results establish a direct link between β2m structural stability and its capacity to modulate macrophage-driven inflammation, supporting the evidence that β2m is not only a biomarker but also an active pathogenic factor in MM. Additionally, two distinct side projects were developed. The first aiming at the characterization of affinity molecules designed to stabilize β2m fold under lysosomal-like conditions; in the second a site-directed mutagenesis was applied on reactive intermediate deaminase to characterize the remarkable stability and enzymatic potential of this enzyme.","language":"eng","citation":"THE LYSOSOMAL AMYLOID AGGREGATION OF B2-MICROGLOBULIN PROMOTES MULTIPLE MYELOMA PROGRESSION: A MOLECULAR FOCUS ON THIS PRO-CANCER MECHANISM / G. Rizzi ; supervisor: S. Ricagno ; phd coordinator: S. Ricagno. Dipartimento di Bioscienze, 2025 Dec 19. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13768_3.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1205155/3212953/phd_unimi_R13768_3.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1157335"},"title":"INTERFACE EVALUATION AND OPERATOR PERFORMANCE PREDICTION, APPLIED TO A TELEROBOTIC CASE-STUDY.","internalauthor":"FERNANDES RAMOS, INES FILIPA","type":"Tesi di dottorato","year":"2025","abstract":"With the increased use of automation in Industry, the role of the operator is shifting to a monitoring and supervising role. The design of the Human-Machine Interfaces has a critical impact on operator situational awareness and ability to manually control the system when facing automation failures. The current work investigates how human performance assessment methods can be leveraged to support the design of more effective, user-centered and intelligent Human-Machine Interfaces and Interactions (HMIIs) in Industry, that can keep the human in the loop.  This investigation is guided by a specific case-study, the use of a telerobotic system for a medical device manufacturing application. Teleoperation has gained traction, particularly for industrial use, with the fast development of new interaction modalities and extended reality technology. However, it is still challenging for non-expert users, as human performance is hindered by the lack of feedback, limited awareness of the remote environment and the control complexity. Literature on teleoperation interface design has focused mostly on solving technological challenges and typically employs subjective operator measures for its development.  As a result, two main research questions are established in this thesis: 1) identify what human performance measures are better suited to support the design and evaluation of telerobotic interfaces, 2) assess whether human performance can be reliably predicted with ML, to potentially inform the system and adapt the human-machine interface to the operator needs.  To address the former, a telerobotics user study was conducted, where 27 subjects performed a teleoperated cutting task, while performance, physiological and behavioral data was collected. Four telerobotic interfaces with different control and visual designs were developed and evaluated, aiming to advance our understanding of how the interface impacts the operator and how that impact can be assessed. To address the latter, traditional machine learning methods were employed for human performance prediction on the collected dataset. In alternative, the author also explores the use of deep learning techniques for the recognition of performance-related states, such as cognitive workload and task engagement, from raw multimodal physiological signals. Taking into consideration the industrial focus, the work provides in addition insights into the safety, ethical and regulatory requirements and challenges of applying these systems in Industry, as a guideline for the future research needs.","language":"eng","citation":"INTERFACE EVALUATION AND OPERATOR PERFORMANCE PREDICTION, APPLIED TO A TELEROBOTIC CASE-STUDY / I.f. Fernandes Ramos ; supervisor: G. Gianini ; co-supervisor: E. Damiani ; coordinator: R. Sassi. Università degli Studi di Milano, 2025 Apr 14. 36. ciclo","filename":"phd_unimi_R13250.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1157335/2745096/phd_unimi_R13250.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/888958"},"title":"A MULTIDISCIPLINARY APPROACH AGAINST ANTIMICROBIAL RESISTANCE: INTEGRATING IMMUNITY, MICROBIOLOGICAL FACTORS AND CLINICAL CARE TO FACE THE THREAT OF KLEBSIELLA PNEUMONIAE-CARBAPENEMASE (KPC)-PRODUCING KLEBSIELLA PNEUMONIAE","internalauthor":"MANGIONI, DAVIDE","type":"Tesi di dottorato","year":"2022","abstract":"BACKGROUND: Klebsiella pneumoniae-carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) accounts for a third of invasive strains of Kp in Italy and is responsible for increased morbidity and mortality. Host and bacterial factors involved in KPC-Kp colonization and/or infection are not yet clearly characterized.  METHODS: Observational, prospective, multicenter national study part of the project Ricerca Finalizzata 2016 (GR-2016-02362572). Patients were enrolled from 03/2019 to 08/2021. Patients enrolled in a previous study at one of the participating centers (09/2017-05/2018) were included in the analysis. Plasma, peripheral blood mononuclear cells (PBMC) and faecal samples were collected at the diagnosis of KPC-Kp colonization and/or infection. In a subgroup of patients, KPC-Kp strains were collected for genomic analyses. Soluble markers (pentraxin-3 and soluble IL-1R2) were measured by home-made sandwich ELISAs. Immunophenotyping was conducted on frozen PBMCs by multiparameter flow cytometry analysis. Microbiome was sequenced for V3–V4 region of 16S rRNA amplicons (Illumina MiSeq) and analyzed using QIIME2. KPC-Kp strains were analyzed by whole genome sequencing (Illumina Nextseq 550 System), virulence and resistance genes were characterized with Kleborate software.  RESULTS: Overall, 135 patients were included: 89/135 (65.9%) with KPC-Kp colonization (KPCcol), 46/135 (34.1%) with KPC-Kp infection (KPCinf). The two groups differed in time between hospital admittance and enrollment (KPCcol median 18.5 (Q1-Q3: 8-37) days, KPCinf 10 (5-24) days, p 0.004), invasive procedures in the 72 hours prior to KPC-Kp isolation (KPCcol 18%, KPCinf 36.4%, p 0.03), concomitant infection/colonization by multidrug-resistant bacteria other than KPC-Kp (KPCcol 45.2%, KPCinf 25.6%, p 0.038). Conversely, the number of patients with acute medical conditions and with ongoing antibiotic therapy at KPC-Kp isolation resulted similar in both groups at high percentages (KPCcol 85.9%, KPCinf 85.5%; KPCcol 70.6%, KPCinf 76.7%, respectively).  Whole genome sequencing was performed in 37 KPC-Kp strains. The most common sequence type (ST) was ST307 (32.4%) followed by ST512 (24.3%) and ST20 (21.7%). Two KPC variants were found, KPC-2 in 13/37 (35.1%) and KPC-3 in 24/37 (64.9%) isolates. For each KPC-Kp strain, major virulence and resistance genes were characterized and virulence and resistance scores were calculated. Core SNP phylogenetic tree analysis including KPC-Kp strains from European hospitals was obtained.  Soluble markers were evaluated in 79 KPCcol and 39 KPCinf. No differences between groups were observed (PTX3: KPCcol 14.63 (9.78-23.36), KPCinf 18.87 (10.58-39.51) ng/ml; sIL-1R2: KPCcol 16.01 (11.6-24.2), KPCinf 20.64 (13.63-25.04) ng/ml).  PBMCs were evaluated in 37 KPCcol and 21 KPCinf. The two groups differed in percentages of circulating Th1, Th2 and Th17, with higher values in KPCcol compared to KPCinf (Th1: KPCcol 8.48 (4.29-17.1), KPCinf 4.43 (1.16-9.01) % CD4+ T cells, p 0.017; Th2: KPCcol 9.38 (4.29-17.1), KPCinf 4.26 (2.40-9.73) % CD4+ T cells, p 0.037; Th17: KPCcol 16.6 (7.09- 38.8), KPCinf 7.89 (3.55-15.42) % CD4+ T cells, p 0.035 )  Gut microbiome was evaluated in 46 KPCcol and 23 KPCinf. Alpha diversity values differed between groups (Pielou’s eveness index: KPCcol 0.68 (0.6-0.74), KPCinf 0.56 (0.51-0.69), p 0.019) whereas beta diversity values did not. Alpha diversity values differed also comparing patients with and without broad-spectrum antibiotic therapy at KPC-Kp isolation (0.64 (Q1-Q3: 0.51-0.70) vs 0.68 (Q1-Q3: 0.60-0.75), p 0.021) and, within KPCINF, comparing those presenting with and without sepsis at presentation (0.50 (Q1-Q3: 0.48-0.54) vs 0.65 (Q1-Q3: 0.51-0.7), p 0.033).  CONCLUSION: In addition to different clinical characteristics, patients with KPC-Kp infection seem to display poorer gut microbiome richness and different circulating cellular immunity as compared to hospitalized subject with KPC-Kp colonization.  Although still partial, these results indicate that an integrated approach combining immunological and microbiological analyses could unravel important aspects of the complex host-pathogen interaction.","language":"eng","citation":"A MULTIDISCIPLINARY APPROACH AGAINST ANTIMICROBIAL RESISTANCE: INTEGRATING IMMUNITY, MICROBIOLOGICAL FACTORS AND CLINICAL CARE TO FACE THE THREAT OF KLEBSIELLA PNEUMONIAE-CARBAPENEMASE (KPC)-PRODUCING KLEBSIELLA PNEUMONIAE / D. Mangioni ; tutor: D. L. Trabattoni ; cotutor: A. Gori. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2022 Jan 14. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12335.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/888958/1936460/phd_unimi_R12335.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1224055"},"title":"TRACKING THE INVISIBLE. A SEARCH FOR SUPERSYMMETRIC HIGGSINOS WITH THE ATLAS DETECTOR.","internalauthor":"SALA, ALESSANDRO","type":"Tesi di dottorato","year":"2026","abstract":"This thesis presents two complementary searches for supersymmetric particles with compressed mass spectra using proton-proton collision data     collected by the ATLAS detector during the LHC Run 2 and Run 3. The analyses target the production of charginos and neutralinos near the electroweak scale and with mass splittings     in the range $0.3-1.5$ GeV. Owing to the small mass differences, the heavier neutralino and chargino are relatively long-lived and decay into low-momentum charged pions, which     are reconstructed as soft tracks displaced by a few millimeters from the proton-proton interaction point and characterised by unusually large impact parameters. The resulting final-state     signature is defined by the presence of an energetic jet, missing transverse momentum, and one or more than one soft, mildly displaced tracks. The first search    uses data collected at a center-of-mass energy of $\\sqrt{s} = 13$ TeV, corresponding to a total integrated luminosity of $140 \\ \\text{fb}^{-1}$. Dedicated event-level and track-level     selections are applied to define two Signal Regions maximising the overall signal-to-background ratio. No significant data excess above the Standard Model expectations     is observed, and 95\\% confidence level exclusion limits are set on the chargino and neutralino masses as a function of their mass splitting. In the mass splitting range $0.35-1$ GeV,     chargino masses are excluded up to about 170 GeV, significantly extending the reach beyond the legacy LEP results for the first time. The second search uses data collected at center-of-mass energies    of $\\sqrt{s} = 13$ and $\\sqrt{s} = 13.6$ TeV, corresponding to a total integrated luminosity of $299 \\ \\text{fb}^{-1}$. In this second analysis, an event-level binary neural network     and a track-level parameterised multi-class neural network are developed and employed in place of the cut-based approach used in the first analysis. The enhanced discriminating power     provided by the machine learning techniques, combined with the increased statistics of the Run 3 data set, is expected to further extend the LHC sensitivity into regions of parameter space     that are anticipated to remain inaccessible to future direct detection Dark Matter experiments.","language":"eng","citation":"TRACKING THE INVISIBLE. A SEARCH FOR SUPERSYMMETRIC HIGGSINOS WITH THE ATLAS DETECTOR / A. Sala ; supervisore: T. Lari; referees: M. D'Onofrio, M. Paganoni ; coordinator: A. Mennella. Dipartimento di Fisica Aldo Pontremoli, 2026 Mar 16. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13824.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1224055/3272489/phd_unimi_R13824.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1130977"},"title":"SPECIAL RIEMANNIAN STRUCTURES ON FOUR-MANIFOLDS: FROM TWISTOR SPACES TO UNOBSTRUCTED CONDITIONS","internalauthor":"DAMENO, DAVIDE","type":"Tesi di dottorato","year":"2025","abstract":"This thesis deals with special Riemannian metrics  on smooth manifolds: in particular, we study the  relations between the existence of metrics satisfying  curvature properties and the topology of the manifold  they are defined on. In the first part of the work,  we introduce Riemannian twistor spaces, which are   6-dimensional manifolds which can be associated to  any Riemannian four-manifold: these spaces can be  endowed with two natural almost Hermitian structures, which   are strictly linked to the geometry of the   underlying manifold. We prove rigidity and characterization results  for special metrics on four-manifolds in twistorial terms and  we study curvature conditions holding on the twistor spaces:  in particular, we show a non-existence result  regarding locally conformally flat twistor spaces,   we classify Bochner-parallel and Ricci-parallel  twistor spaces, we generalize the integrability condition of  the celebrated Atiyah-Hitchin-Singer almost complex structure,  which occurs if and only if the underlying manifold is half  conformally flat, and we characterize manifolds such that  the almost complex structures on their twistor spaces satisfy  a PDE in their first covariant derivatives. We also focus on  Einstein four-manifolds, finding two local characterizations  in terms of the Nijenhuis tensors defined on their twistor spaces;  moreover, we classify Einstein four-manifolds with positive  scalar curvature, under the assumption that the  scalar curvature of their twistor   spaces is constant on the fibers of the  twistor bundle.     In the second part of the thesis, we adapt a construction method  introduced by Aubin in order to produce Riemannian metrics which  are not obstructed by the topology of the manifold and which  satisfy non-vanishing curvature conditions involving the Weyl tensor and  the geometric quantities derived from it. In particular, we prove that,  on any compact four-manifold, there exists a Riemannian metric  whose (anti-)self-dual Weyl tensor has constant squared norm  equal to 1. We show that this result also implies the existence,  in a given conformal class of metrics, of   minimizers,  called weak half harmonic Weyl metrics, of the  L^2-norm of the divergence of this tensor; we also show that,  on any compact manifold of dimension at least 4, there exists  a Riemannian metric such that the Cotton tensor vanishes at  finitely many points. Finally, we prove the existence of Riemannian  metrics with nowhere vanishing Bach tensor on any compact four-manifold.","language":"eng","citation":"SPECIAL RIEMANNIAN STRUCTURES ON FOUR-MANIFOLDS: FROM TWISTOR SPACES TO UNOBSTRUCTED CONDITIONS / D. Dameno ; tutor: P. Mastrolia ; phd coordinator: D. P. Bambusi. Dipartimento di Matematica Federigo Enriques, 2025 Jan 21. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13256.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1130977/2623823/phd_unimi_R13256.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1040030"},"title":"PATIENT SIMILARITY NETWORKS-BASED METHODS FOR MULTIMODAL DATA INTEGRATION AND CLINICAL OUTCOME PREDICTION","internalauthor":"GLIOZZO, JESSICA","type":"Tesi di dottorato","year":"2024","abstract":"\"Artificial Intelligence is significantly contributing to the development of Precision Medicine, a revolutionary approach in healthcare. This new medical paradigm leverages heterogeneous patients' descriptions to enhance disease prevention, diagnosis, prognosis, and treatment.    The progress of Precision Medicine significantly relies on the ability to collect comprehensive data from each patient, covering various aspects of their disease. This includes gathering information at different levels to form a complete picture of the pathology, incorporating genomic, environmental, and lifestyle factors.     Recent technological advancements have facilitated the ongoing collection of a vast array of diverse health data. This includes clinical data, radiological and digital pathology images, molecular data, and information from wearable devices and smartphones. Such developments have ushered the field of biomedicine into the era of \"\"Big Data\"\", presenting unique challenges in data analysis.    Among these various data types, multi-omics data has become the gold standard for the in-depth molecular-level characterization of individuals. Multi-omics data involves measuring a comprehensive set of biomolecules that describe a specific biological layer. Examples include DNA sequencing, gene expression levels, DNA methylation, and protein expression. As a result, this data is both multimodal and high-dimensional, offering a more nuanced understanding of biological processes.    Network Medicine is an innovative and interdisciplinary field of bioinformatics research that applies the principles of network science to understand and treat diseases. It revolves around the concept that most diseases are not caused by individual genes, but rather by complex interactions within biological networks. In Network Medicine, diseases are viewed as the result of perturbations in these networks. By understanding these network interactions and their degradation, researchers can better understand the multifactorial nature of diseases, therefore providing crucial insights that enable Precision Medicine to develop more targeted and effective prevention, diagnosis, prognosis, and treatment strategies.    In the current landscape, Patient Similarity Networks (PSNs) are emerging as a powerful tool for representing patients' clinical and molecular profiles. These networks adapt the principles of Network Medicine, originally applied to biomolecular networks, to patient data. In a PSN, each node represents a patient, and the edges express the degree of similarity between patients' clinical or biomolecular profiles. PSNs have proven particularly effective in key Precision Medicine tasks such as patient subtyping and predicting clinical outcomes through clustering and classification techniques. They offer the benefits of being interpretable and privacy-preserving, and are capable of integrating multimodal data.  The growing availability of multi-omics data, combined with the impressive performance of PSN-based models, underscores the need for developing sophisticated methods to integrate multimodal data in constructing PSNs. This approach promises to enhance the effectiveness of PSNs in capturing the nuances of patient profiles, further advancing the capabilities of Precision Medicine.    The first contribution of this thesis is an extensive literature review that collects and critically analyses multimodal data fusion methods for the computation of PSNs. Firstly, recognizing that the development of PSNs is highly dependent on the selection of patient similarity measures, we conduct a comprehensive review of the most commonly used and effective similarity metrics, encompassing multiple data types, including categorical, discrete, continuous, and binary. Next, considering the wide and varied range of literature works about multimodal data fusion techniques with numerous taxonomies proposed over the years, we compiled and organized all of them to offer a clear starting point for exploring this field. The acquired knowledge allowed us to propose a novel taxonomy for multimodal data integration approaches that allows building and analyzing PSNs. In more detail, we grouped all the surveyed approaches into three categories (PSN-fusion methods, Input data-fusion methods, and Output-fusion methods) and identified their advantages and drawbacks.  To provide readers with comprehensive knowledge, we considered not only bioinformatics methods but also approaches proposed in the machine learning literature, that could be potentially leveraged to build PSN. For the same reason, we did not limit the discussion to methods for the integration of multi-omics data, as done by other reviews in this context, but we also considered approaches developed to fuse clinical data and medical images.    Besides the faceted semantics of multi-omics data, which requires proper integration approaches, -omics data is characterized by high-dimensionality opposed to a limited sample size (\"\"small-sample-size\"\" problem). The high level of sparsity in the resulting datasets often leads to high computational costs and to biased (supervised and unsupervised) analysis, mainly due to redundant and noisy features. These problems can be mitigated by the application of unsupervised feature selection and feature extraction approaches to reduce the dimensionality of individual views. However, dimensionality reduction is a challenging task; besides the choice of the reduction algorithm, the choice of the lower dimension is a critical task that should be properly chosen. Several bioinformatics works often neglect the importance of this pre-processing step and set the dimensionality of each view using some heuristic value that is the same for each view, thus ignoring that different views can bring different amount of information and that some of them might not even need reduction.    To deal with this issue, the second contribution of this thesis is a novel dimensionality reduction (DR) approach that exploits block-analysis to obtain an unbiased estimate of the intrinsic dimensionality (id) of individual data sources. Besides providing an unbiased  id estimate  that can be used to lower the dimension of the reduction space where the view under analysis should be projected, the analysis of the distribution of the id estimates for increasing block sizes provides hints about the amount of noise and redundancy affecting the view. Leveraging this analysis, we automatically tailored the DR method, so that views affected by higher amounts of noise and redundancy undergo two consecutive DR steps (feature selection followed by feature extraction), while views with negligible amount of noise and redundancy undergo a unique feature extraction step. We extensively validated our proposal by applying a supervised task (outcome prediction via Random Forest classifiers) on nine multi-omics cancer datasets. The experiments allowed the unbiased comparative evaluation of different state-of-the-art feature selection/extraction approaches, and data fusion methods. Experiments evidenced that: (I) the usage of the id estimate outperforms the use of common heuristics to set the dimension of the lower dimensional space; (II) the two-step DR approach we proposed is an effective solution that allows computing a robust representation of all the available -omics sources, avoiding the time and costs needed to assess and compare the usage of different -omics combinations; (III) we also showed that, in our problem, the integration of demographic and multi-omics data improves classification performance.    The last important contribution of this thesis is the proposal of a data integration method for \"\"partially missing data\"\". More precisely, one of the main problems hampering the application of many effective state-of-the-art multi-omics data fusion techniques is due to the frequent incompleteness of the -omics data sources, meaning that some patients have one or more completely missing data sources. Most data integration approaches are not able to handle these (partial) datasets, which are however frequent in medical research and in clinical practice. Moreover, they are often designed and/or evaluated to tackle specific learning tasks, where unsupervised clustering is the most common. To address these points we propose miss-SNF, a novel task-agnostic data fusion approach that, leveraging a nonlinear message-passing learning strategy, integrates incomplete datasets and partially reconstructs missing pairwise similarities by exploiting patients’ neighbourhoods. The computed integrated PSN can be used to perform unsupervised clustering and (semi-)supervised classification tasks. We evaluated miss-SNF on the integration of nine multi-omics datasets having increasing percentages of completely missing data sources in each view, considering the classification of two clinical outcomes and patients' clustering. We show that miss-SNF has a superior ability to recover missing pairwise similarities while maintaining network topology w.r.t. state-of-the-art data integration approaches (i.e. NEMO, MOFA+). It leads to clusters enriched for clinical variables and capturing differences in differential survival. The integrated PSN can be effectively exploited to perform classification leveraging both supervised and semi-supervised learning algorithms (i.e. Random Forests, label propagation and guilt-by-association), thus being potentially used to integrate datasets having unlabeled patients that are common in multi-omics datasets. To the best of our knowledge, this is the first time that a multimodal integration method for incomplete datasets is extensively evaluated for such different learning tasks.      The thesis is structured as follows. Chapter 1: introduces the context of the work, focusing on the use of Patient Similarity Network (PSN)-based methods for integrating multimodal data in Precision Medicine. Chapter 2: This chapter provides a thorough review and analysis of data integration approaches for constructing PSNs, highlighting existing challenges in the field, for which we provide our solution in the subsequent chapters. Chapter 3: presents the author's dimensionality reduction approach, including the experimental setup and results demonstrating its effectiveness. Chapter 4: details the miss-SNF algorithm and its evaluation in the reconstruction and integration of partial datasets. Experimental results in unsupervised and supervised analysis of multimodal PSNs show that miss-SNF is competitive with state-of-the-art methods. Chapter 5: summarizes the main contributions of the thesis and outlines potential future work in this area.\"","language":"eng","citation":"PATIENT SIMILARITY NETWORKS-BASED METHODS FOR MULTIMODAL DATA INTEGRATION AND CLINICAL OUTCOME PREDICTION / J. Gliozzo ; supervisor: G. Valentini ; co-supervisor: E. Casiraghi, A. Patak ; coordinator: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2024 Apr. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R13052.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1040030/2385158/phd_unimi_R13052.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1203337"},"title":"THE TRANSCRIPTIONAL PROGRAM OF GOLGI BIOGENESIS","internalauthor":"ABETE, DOMENICO","type":"Tesi di dottorato","year":"2025","abstract":"The Golgi apparatus is considered a fundamental organelle that regulates various physiological processes. Due to its plasticity, it can expand during differentiation and in response to high secretory demand. However, transcriptional contribution to Golgi biogenesis remains poorly understood because of the lack of a robust method to induce large-scale production of new Golgi units. In this study, we developed an enzyme-based approach to eliminate the Golgi apparatus, triggering the de novo formation of fully functional stacks in a substantial cohort of cells within 10-18 hours. The structural and functional recovery of the Golgi allowed us to study transcriptomic changes associated with Golgi regeneration. Indeed, Single-cell RNA-seq of cells rebuilding the Golgi revealed coordinated induction of a broad Golgi gene network, coinciding with structural and functional organelle maturation. The upregulated Golgi genes encode proteins belonging to different compartments (cis-, medial-, and trans-Golgi), which are involved in diverse functions such as glycosylation, membrane tethering, and ion/sugar transport. These findings suggest the existence of a master regulator that orchestrates the simultaneous expression of components required for the structural and functional integrity of the organelle. Through bioinformatic and in vitro analysis, we identified CREB3L1 as a key transcriptional regulator that activates a Golgi gene network and drives organelle rebuilding. Our findings demonstrate that CREB3L1 activation initiates a transcriptional program essential for complete Golgi biogenesis program, which may be critical for organelle regeneration and remodulation.","language":"eng","citation":"THE TRANSCRIPTIONAL PROGRAM OF GOLGI BIOGENESIS / D. Abete ; tutor: R.Polishchuk ; co-tutor: M.A De Matteis; internal examiner: Mirko Cortese ; external examiner: F. Campelo; external evaluator: T. Anelli ; coordinator: D. Pasini. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Dec 19. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13458.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1203337/3206659/phd_unimi_R13458.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/954243"},"title":"ELECTRO-OPTICAL AND ELECTRO-MECHANICAL RESPONSE OF FERROELECTRIC NEMATIC FLUIDS","internalauthor":"CAIMI, FEDERICO","type":"Tesi di dottorato","year":"2023","abstract":"The recent discovery of the ferroelectric nematic (NF) phase opened a brand-new field of explorations in liquid crystal science thanks to new physical effects, resulting from the polar nature of this novel mesophase. Indeed, the electrical and optical properties of NF phase, in which molecules share a common direction other than a common orientation, vastly differ from the ones of conventional liquid and liquid-crystalline materials, making it an optimal candidate for both basic research and the realization of next generation electro-optical devices.   The present thesis is mainly focused on three major topics, concerning various electro-optical and electro-mechanical properties of the NF phase of RM734, the first reported ferroelectric nematic mesogen.  First, the surface alignment of  RM734 has been explored upon confining it into flat cells, realized with various rubbed and unrubbed surfaces, proving the importance of the 2D confining surfaces on the 3D structuring and field response of NF materials.  Second, the instability events, occurring when a sessile ferroelectric liquid droplet is deposited onto a ferroelectric crystal, has been studied. These phenomena has been interpreted as a particular case of Rayleigh instability, happening when the electrostatic repulsion, caused by the accumulation of polarization charges on the droplet surface, overcomes the surface tension of the liquid.   Third, RM734 has been confined into microchannels connecting gold electrodes, demonstrating that the application of low electric fields forces the material to continuously follow the channels, even in sections designed to be directed against the applied field. This is caused by the elimination of the field component perpendicular to the channel surfaces, a phenomenon that has been called “ferroelectric superscreening”.  The main effects described in this work,  such as polar surface alignment, electrostatic droplet instability and ferroelectric superscreening, are indeed distinctive properties of the ferroelectric nematic phase, never observed in other liquid crystalline mesophases.","language":"eng","citation":"ELECTRO-OPTICAL AND ELECTRO-MECHANICAL RESPONSE OF FERROELECTRIC NEMATIC FLUIDS / F. Caimi ; tutor: T. Bellini ; revisori: F. Serra, R. Caputo. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2023 Feb 23. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12762.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/954243/2139160/phd_unimi_R12762.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/916665"},"title":"GAMMA-PROBE GUIDED SENTINEL LYMPH NODE EXTIRPATION TO ASSESS PATTERNS OF NODAL METASTASIS IN SPONTANEOUS HEAD AND NECK MALIGNANCIES OF THE DOG: A SECOND STEP BASED ON PREVIOUS EXPERIENCES ON MAST-CELL TUMORS","internalauthor":"CHITI, LAVINIA ELENA","type":"Tesi di dottorato","year":"2022","abstract":"Canine oncology has recently reported interest in the detection of occult nodal metastases, and efforts have been made to identify the best strategy for accurate nodal staging. In this scenario, the present PhD thesis was aimed to improve knowledge on the current understanding of the feasibility and impact of sentinel lymph node (SLN) mapping with radiopharmaceutical and blue dye in cancer-bearing dogs. Initially, we evaluated the technique in canine mast cell tumors (MCT), given the high prevalence of this tumor type, the propensity for lymphatic spread and recognized prognostic impact of nodal metastases. Thirty client-owned dogs with 34 MCT were included. At least one SLN was identified in all but 3 dogs that had a scar from previously excised MCT, and in 30 cases (63%) the SLN did not correspond to the regional lymph node (RLN). As a second step, we explored the impact of SLN mapping and extirpation in dogs with head and neck tumors, given the well-accepted unpredictability of patterns of nodal metastases. Twenty-three dogs with tumors of the head and neck and absence of clinically evident nodal disease (cN0 neck) were prospectively included and underwent tumor excision and SLN extirpation. Reported detection rate was 83%, with at least one SLN identified in all but 4 dogs with thyroid tumors. In 52% of dogs, the SLN did not correspond to the RLN and at histopathology 42% of dogs had nodal metastases, of which 4 differed from the RLN. As the last step of this PhD project, we conducted an explorative study to identify clinical or pathological characteristics that could allow for identification of dogs with MCT at lower risk of SLN metastases, that could be excluded a priori from the SLN mapping and extirpation. Surprisingly, tumor grade was not able to predict the risk of having HN2-3 or HN3 SLN and the only variables that correlated with nodal metastases were tumor size, number or SLN and subcutaneous MCT. Given low to moderate discriminant ability, however, none of these variables could safely determine the exclusion of patients from the procedure.   Results of the present project underscore the utility of implementation of SLN biopsy in the management of dogs with MCT and head and neck tumors, given the low correspondence between clinically expected RLN and SLN and the high rate of occult nodal metastases that could be detected with this procedure. Future research should be aimed at investigating the impact on long-term prognosis and disease free interval of the extirpation of metastatic SLN, and identify variables that could allow for exclusion of low-risk patients from the procedure.","language":"eng","citation":"GAMMA-PROBE GUIDED SENTINEL LYMPH NODE EXTIRPATION TO ASSESS PATTERNS OF NODAL METASTASIS IN SPONTANEOUS HEAD AND NECK MALIGNANCIES OF THE DOG: A SECOND STEP BASED ON PREVIOUS EXPERIENCES ON MAST-CELL TUMORS / L.e. Chiti ; tutor: D. Stefanello ; internal reviewer: D. D Zane, S. Romussi, A. Belloli ; external reviewer: M. Martano, M.C. Nolff ; coordinator: V. Grieco, F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2022 Mar 31. 34. ciclo, Anno Accademico 2021. [10.13130/chiti-lavinia-elena_phd2022-03-31].","filename":"phd_unimi_R12229.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/916665/2003306/phd_unimi_R12229.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/841555"},"title":"MOLECULAR DESIGN OF A NOVEL DUAL-PURPOSE BARLEY VARIETY","internalauthor":"ROTASPERTI, LISA","type":"Tesi di dottorato","year":"2021","abstract":"By mid-century the bio-based economy is expected to have grown significantly in Europe and all around the world. A pillar of this, both now and in the future, is the sustainable processing of biomass into a spectrum of marketable products and energy. That will depend largely on the availability of a reliable supply of appropriate quantities of biomass in a sustainable manner and at fair prices. Among the primary sources of agriculture-derived biomass, crop residues have a great potential to supply large, reliable, and sustainable quantities of biomass.  This Ph.D. thesis work was aimed to address this issue using barley as model crop, since its straw is characterized by the largest content of carbohydrates among cereals, thus a valuable product for its potential conversion into biofuels and other eco-friendly products. Especially, we tried to explore the possibility to increase barley biomass production, without penalty on grain yield, by improving the light phase of photosynthesis through:  i)   decreasing the light harvesting antenna size of photosystems, thus reducing the excess of light absorption on top of the canopy, together with the consequent decrease in photo-damage, and favoring a more uniform light absorption and photosynthesis throughout the canopy;  ii)   the fine-tuning of the photoprotective mechanism, known as Non-Photochemical Quenching mechanism (NPQ), with aim to have a more rapid induction/relaxation of this mechanism, hence a better photosynthetic performance.    Within this frame, we have characterised into details the hus1 (happy under the sun) barley mutant, isolated by a forward genetics approach within the HorTILLUS chemical mutagenize population. hus1 plants are characterised by pale-green leaves, a reduced antenna size of photosystems and an improved photosynthetic performance with respect to cv. Sebastian, used as control. Segregation analysis performed on the F2 population obtained by crossing hus1 with Morex indicates that the hus1 phenotype is caused by a monogenic recessive allele. Using exome capture sequencing of DNA pools from 50 WT and 50 hus1-like plants, the putative SNP mutation has been identified in the Arabidopsis thaliana homologous CHAOS gene, encoding the Chloroplast Signal Recognition Particle 43 (cpSRP43), a stromal chaperone that upload the antenna proteins into the thylakoid membranes. As a matter of fact, immune-blot analyses confirmed that barley hus1 and the Arabidopsis chaos mutants have a similar reduction in the levels of antenna protein accumulation. Furthermore, using an allele mining strategy, the natural genetic variability of HUS1 locus has been studied in the exome sequences of the Whealbi collection. 26 accessions with different polymorphisms have been identified in HUS1 locus. A preliminary screening led to the identification of few pale lines that seem to have a higher photosynthetic activity compared to the corresponding WT. These natural accessions have been collected from different regions of the planet and represent an invaluable genetic material to understand how photosynthesis adapt to the different growth conditions.   With respect to fine-tuning of NPQ, a reverse genetic approach has been used to identify allelic variants of Violaxanthin De-Epoxidase (VDE) and Zeaxanthin Epoxidase (ZEP) enzymes both involved in the xanthophyll cycle, an integral part of NPQ photoprotective mechanism. Five allelic variants of the VDE gene and one of ZEP gene have been found. Most of the mutant plants show a Sebastian-like phenotype under green-house growth conditions, but they show very different NPQ kinetics, thus representing the ideal genetic material to investigate the impact of NPQ alteration on photosynthetic performance and biomass accumulation.","language":"eng","citation":"MOLECULAR DESIGN OF A NOVEL DUAL-PURPOSE BARLEY VARIETY / L. Rotasperti ; tutor: L.Tadini ; supervisor: P. Pesaresi ; phd school coordinator: M. Kater. Dipartimento di Bioscienze, 2021 May 21. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11969.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/841555/1794445/phd_unimi_R11969.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/907414"},"title":"PATIENT-SPECIFIC MODELLING OF SYNDROMIC AUTISM: UNCOVERING THE ROLE OF ADNP IN CHROMATIN DYSREGULATION","internalauthor":"RIZZUTI, LUDOVICO","type":"Tesi di dottorato","year":"2022","abstract":"ADNP encodes Activity-Dependent Neuroprotective Protein, whose de novo heterozygous mutations cause Helsmoortel-Van der Aa Syndrome (HVDAS), a rare developmental syndrome affecting brain formation and neuronal functions, involving autism spectrum disorder and intellectual disability. Although ADNP is one of the single-gene most frequently mutated in ASD, its precise role in the syndrome onset has yet to be clarified. ADNP is the DNA-binding component of the newly identified chromatin remodeler complex ChAHP in mESC. It recognizes euchromatin regions to establish less accessible local chromatin domains and has also been recently identified as a new player in the regulation of genomic topology, competing with CTCF in the organization of chromatin architecture. Our aim is to understand the genetic and epigenetic implications of ADNP underlying this neurodevelopmental condition; we harnessed cell reprogramming to establish a highly informative cohort of patient-specific iPSCs and use it as a platform to develop meaningful model for the pathology, thus enabling the assessment of the ADNP pivotal relevance in both pluripotent and neuronally-patterned stages. We discovered an altered gene expression program associated with cell fate decision and neuronal lineage commitment, highlighting a neurodevelopmental disruption elicited by ADNP mutations already at the pluripotent stage. Employing CRISPR/Cas9-engineering, we FLAG-tagged the endogenous ADNP to assess its genomic occupancy and revealed a genome-wide distribution of ADNP at gene-regulatory elements and a predominant presence at transposable elements, Alu sequences in particular. We decoupled ADNP and CTCF interplay in our human iPSCs model, and found a global redistribution of active enhancer histone marks signature, which sustain upregulation with the intervention of EZH2-mediated derepression. Finally, HVDAS cortical organoid models show morpho-functional impairment in the early stages of neuronal differentiation, with decreased size and lower mitotic activity, coupled with accelerated maturation phenotype assessed through single-cell transcriptomic analysis. Altogether, with these results we delineate how ADNP deficiency affects pluripotent regulatory landscape and disease-relevant mechanisms that ultimately impact neuronal development and functionality.","language":"eng","citation":"PATIENT-SPECIFIC MODELLING OF SYNDROMIC AUTISM: UNCOVERING THE ROLE OF ADNP IN CHROMATIN DYSREGULATION / L. Rizzuti ; internal advisor: S. Casola ; external advisor: M. Bühler ; tutor: G. Testa ; coordinator: S. Minucci. Università degli Studi di Milano, 2022 Mar 14. 33. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12114.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/907414/1979792/phd_unimi_R12114.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1211196"},"title":"CANCERHUBS: A NETWORK-CENTRIC FRAMEWORK FOR CANCER GENE PRIORITISATION","internalauthor":"FERRARI, IVAN","type":"Tesi di dottorato","year":"2026","abstract":"\"Cancer is a complex disease that originates from genetic mutations, which represent the primary triggering events of neoplastic transformation. Nevertheless,  such lesions alone are not sufficient to account for the full complexity of tumour  development, which also arises from epigenetic and regulatory alterations that remodel cellular networks and molecular circuits. In this framework, conventional  single-gene approaches risk overlooking key elements that, although not frequently  mutated or differentially expressed, play a critical role as network hubs. In this thesis, \"\"CancerHubs\"\" is presented, a systematic data mining and integration pipeline  that combines mutational data, clinical outcome predictions (via PRECOG meta-Z  scores), and protein-protein interaction networks to identify cancer-related protein  hubs. The method computes a composite Network Score that integrates mutational  profiles, prognostic associations, and interactome connectivity, thereby prioritising  genes that may not be strongly mutated or differentially expressed, but are central to the cancer network structure. This approach moves beyond conventional  mutation-centric strategies and provides a network-informed perspective on cancer  gene discovery. Alongside the computational method, \"\"CancerHubs Data Explorer\"\",  a Shiny web application that allows users to interactively explore mutation-enriched  hubs across 11 tumour types was developed. The application provides ranked tables, global interactomes, and neighbourhood visualisations of user-defined genes,  with filtering options for mutational and prognostic data. This ensures that the  results of the pipeline are not only reproducible but also broadly accessible to researchers with varying computational expertise. As a proof of principle, predictions  generated by CancerHubs were validated both in silico and experimentally. These  analyses demonstrated that TGOLN2 displays tumour suppressor features in Multiple Myeloma, Breast, and Prostate Cancer, while EFTUD2 exhibits oncogene-like  behaviour specifically in Multiple Myeloma. This validation highlights the ability  of the framework to uncover genes of clinical and mechanistic relevance that may  be missed by mutation- or expression-centric approaches. Altogether, CancerHubs  provides a exible and extensible framework for interactome-based cancer gene prioritisation. By integrating heterogeneous data layers into a unied network-aware  metric, and by complementing predictions with functional validation and accessibility through the CancerHubs Data Explorer, this work contributes to the advancement of systems oncology. The tools and ndings described here aim to support  hypothesis generation, biomarker discovery, and the identification of novel therapeutic targets, ultimately bridging the gap between large-scale cancer genomics and  translational applications.\"","language":"eng","citation":"CANCERHUBS: A NETWORK-CENTRIC FRAMEWORK FOR CANCER GENE PRIORITISATION / I. Ferrari ; tutor: S. Biffo. Dipartimento di Bioscienze, 2026. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13707_4.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 11-FEB-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1202220"},"title":"STUDY OF THE EFFECT OF TUMOUR EDUCATED MACROPHAGES ON NEURAL CELLS","internalauthor":"PRUONTO, GIULIA","type":"Tesi di dottorato","year":"2026","abstract":"Background: Traumatic injuries to the brain and spinal cord, including spinal cord injury (SCI), represent devastating conditions that lead to permanent loss of function, mainly due to the poor intrinsic regenerative capacity of the central nervous system (CNS). At the lesion site, the hostile microenvironment which develops within the CNS prevents regeneration. Current therapeutic strategies for traumatic CNS injury aim at patient stabilization and symptoms management, however without promoting neural tissue regeneration. Ongoing studies focus on the development of both acellular and cell-based therapies to allow neuroprotection, improve cell survival, and modulate the pro-inflammatory microenvironment. However, they proved very poor functional improvement in clinical trials. Given the complexity of the lesion formed following a loss of neural tissue, effective treatments would require a multi-targeted strategy capable to both reprogram the hostile injured microenvironment and enhance CNS regeneration.   Hypothesis: We hypothesised that Tumour-associated macrophages (TAMs), a distinctive cell type within the tumour microenvironment, could represent an innovative therapeutic approach for neuro-regenerative medicine. Indeed, TAMs possess a unique set of properties, including immune suppression, extracellular matrix remodelling, and neoangiogenesis, that, while detrimental in cancer, could be harnessed for promoting tissue regeneration following neurotrauma. Moreover, studies conducted in our laboratory further identified that TAMs are endowed with a strong nerve growth property both in vitro and in vivo in a mouse model of severe contusive compressive SCI (scSCI). In the light of that, my PhD project aimed to characterize in vitro generated TAMs’ biological and functional properties as well as to study the key molecular mechanisms underlying such neuro-regenerative activities.   Methods: To achieve these goals, I performed a multi-level in vitro characterization, including transcriptomic, phenotypical and secretome analysis of in vitro generated TAMs, generated both from mouse (mTAMs) and humans (hTAMs). Moreover, functional assays were conducted to test TAMs chemotactic, immune modulatory, neuroprotective and neural regenerative activities. Furthermore, zebrafish model of axonal regeneration in combination with mechanistic studies using pharmacological and genetic modulations of TAMs were employed to validate the translational potential of our findings and to elucidate the molecular mechanisms of TAMs action.   Results: Our findings revealed that in vitro generated hTAMs exhibit a TAM-like phenotype, with the upregulation of genes involved in immune suppression, extracellular matrix remodelling and angiogenesis. Moreover, we confirmed that hTAMs display the peculiar neurogenic signature already observed in mTAMs. From in vitro characterization, we demonstrated that TAMs are endowed with chemotactic, immune modulatory, neuroprotective and neurite outgrowth properties. TAMs effectively promote axonal regeneration in a zebrafish model, suggesting its pro-regenerative capacity conserved throughout species. This PhD thesis work also revealed that secreted phosphoprotein 1 (SPP1) is as a required key mediator for TAMs neurogenic activities. TAM-derived SPP1 promote nerve growth by upregulating mTORC2/Rictor pathway in neural cells.  Conclusions: Our findings revealed that in vitro generated hTAMs can be exploited as a novel, multifaceted cell-based therapy for CNS injuries. TAMs integrate chemotactic, immune modulatory, metabolic and neurotrophic activities, allowing them to function in hostile environments where many other cellular therapies lose their efficacy. The identification of the SPP1-Rictor axis as a central component of TAM-induced neurotrophic effects provides the molecular framework for further investigations. Overall, these findings support the development of TAM-based autologous cell therapies as a promising strategy for neural repair and may pave the way for future translational applications.","language":"eng","citation":"STUDY OF THE EFFECT OF TUMOUR EDUCATED MACROPHAGES ON NEURAL CELLS / G. Pruonto ; tutor: F. Bifari ;  co-tutor: M. Locati ; coordinatore: N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2026 Jan 09. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13796.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 05-GIU-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1117975"},"title":"MODELING SEMANTIC CHANGE THROUGH LARGE LANGUAGE MODELS","internalauthor":"PERITI, FRANCESCO","type":"Tesi di dottorato","year":"2024","abstract":"This PhD thesis focuses on computational modeling of semantic change through large language models. It investigates the modeling of lexical semantic change, where words change in meaning over time, and extends this study to model text-level semantic change, specifically historical resonance. The thesis addresses three research questions: (1) how to model lexical semantic change using large language models, (2) how to extend the modeling from two time periods to multiple time periods, and (3) how to model historical resonance. The thesis reviews state-of-the-art approaches, proposes novel frameworks, and evaluates different methods across multiple languages. Findings suggest that word embeddings of BERT models can be used to accurately detect semantic change. The thesis also underscores the interpretability and effectiveness of lexical replacements and sense definitions generated by Llama and Flan-T5 models in modeling word meaning. By advancing methodologies and tools in Natural Language Processing and Computational Linguistics, this thesis contributes significantly to modeling the dynamic nature of text semantics over time.","language":"eng","citation":"MODELING SEMANTIC CHANGE THROUGH LARGE LANGUAGE MODELS / F. Periti ; supervisor: S. Montanelli ; Ph.D. coordinator: R. Sassi. - University of Milan. Dipartimento di Informatica Giovanni Degli Antoni, 2024 Dec. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13329.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1117975/2587365/phd_unimi_R13329.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/951469"},"title":"BREAST CANCER DURING PREGNANCY AS A SPECIAL TYPE OF EARLY-ONSET BREAST CANCER: INSIGHTS INTO THE TUMOR MICROENVIRONMENT AND IMMUNE TRANSCRIPTOME","internalauthor":"VENETIS, KONSTANTINOS","type":"Tesi di dottorato","year":"2023","abstract":"Breast cancer during pregnancy (PrBC) is a rare tumor with limited information on its immune landscape. Here, we sought to characterize the cellular composition of the tumor microenvironment (TME) and the immune transcriptome of PrBC to identify their differences from early-onset breast cancer (EOBC) in non-pregnant women. Eighty-three PrBC and 89 EOBC were selected and subjected to tumor-infiltrating lymphocytes (TILs) profiling and immunohistochemistry for CD4, CD8, forkhead box P3 (FOXP3), and programmed death-ligand 1 (PD-L1) (clone 22C3). A subset of 28 PrBC and 23 EOBC was selected for transcriptome profiling. RNA extracted from tumor (T) and corresponding normal (N) tissues was subjected to gene expression analysis using a next-generation sequencing assay (Oncomine™ Immune Response Research Assay) targeting 395 immune-related genes. A significantly lower frequency of hormone receptor (HR)-positive tumors was found in PrBC. The prevalence of low/null PD-L1 and CD8+TILs was higher in PrBC than in the controls, specifically in HR+/HER2– breast cancers. PrBC had a significantly higher risk of relapse and disease-related death, compared to EOBC. The presence of TILs and each TIL subpopulation were significantly associated with disease relapse. The death rate was higher in PrBC with CD8+ TILs. Twenty-three differentially expressed genes (DEGs) were found in the comparison between T (PrBC and EOBC), 3 (IFNA17, IFNB1, and PECAM1) upregulated and 20 downregulated. Compared to corresponding N, PrBCT had 46 upregulated and 18 downregulated genes. Four DEGs were PrBCT-specific, one (PECAM1) upregulated and 3 (CXCL1, CCL21, and HGF) downregulated. The TME and immune transcriptome of PrBC are characterized by specific patterns of TIL subpopulations and distinct gene expression patterns. Assessment of TILs and TILs subtyping in these patients might help to identify clinically relevant subsets of women with PrBC. Our findings suggest that immune regulation takes different genomic pathways in PrBC, and PrBCT has a unique immune transcriptome.","language":"eng","citation":"BREAST CANCER DURING PREGNANCY AS A SPECIAL TYPE OF EARLY-ONSET BREAST CANCER: INSIGHTS INTO THE TUMOR MICROENVIRONMENT AND IMMUNE TRANSCRIPTOME / K. Venetis ; tutor: N. Fusco ; phd coordinator: C. Sforza. Dipartimento di Oncologia ed Emato-Oncologia, 2023 Jan 27. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12671.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/951469/2123620/phd_unimi_R12671.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1231195"},"title":"HAMSTRING INJURIES IN FOOTBALL: A COMPLEX SYSTEMS APPROACH THROUGH VIDEO ANALYSIS","internalauthor":"PELLEGRINI, ALESSANDRO","type":"Tesi di dottorato","year":"2026","abstract":"Hamstring injuries remain the most frequent muscle injuries in football and continue to impose a substantial burden on player availability, performance, and club management. Despite the large body of literature on hamstring injury risk factors, recurrence, and rehabilitation, their incidence is still rising, suggesting that reductionist models do not fully capture the complexity of their etiology. This PhD thesis aimed to investigate hamstring injuries in football through a complex systems approach, using video analysis to integrate biomechanical, contextual, and perceptual-cognitive dimensions of the injury-inciting event. In doing so, the thesis contributes to the second step of the “sequence of prevention” by providing ecologically valid information on how injuries emerge within the dynamic and interactive environment of football.    The thesis is structured around a series of complementary studies. First, a systematic 2D video analysis of hamstring injuries in women’s football addressed the limited sex-specific evidence and showed that injuries do not occur exclusively during maximal sprinting, but also during football-specific actions such as passing, lunging, dueling, and ball-related movements. Second, a case report using Model-Based Image Matching reconstructed, for the first time in football, the full-body 3D kinematics of run-type and stretch-type hamstring injuries from uncalibrated broadcast footage, highlighting that different movement solutions may lead to a similar injury outcome. Third, a systematic review synthesized the methodological approaches used in video analysis studies of hamstring injuries in football and led to the development of a comprehensive methodological framework to guide future research and improve data quality, reproducibility, and integration with complementary sources such as MRI, GPS, and clinical information. The thesis also outlines a field-based markerless motion capture perspective for the analysis of stretch-type mechanisms in football-specific tasks.    Overall, this work supports video analysis as an ecological and multidimensional tool for understanding hamstring injury mechanisms in football. By bridging biomechanics, neurocognition, and environmental interaction, the thesis advances a more dynamic and sport-specific understanding of injury and provides a methodological foundation for future prevention and rehabilitation strategies.","language":"eng","citation":"HAMSTRING INJURIES IN FOOTBALL: A COMPLEX SYSTEMS APPROACH THROUGH VIDEO ANALYSIS / A. Pellegrini ; tutor: M. Zago coordinatore: C. Gozzoli. Dipartimento di Scienze Biomediche per la Salute, 2026 Apr 21. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13872.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1231195/3292781/phd_unimi_R13872.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/938246"},"title":"IN BATCH AND IN FLOW SYNTHESIS OF QUATERNARY AMINO ACIDS/AMINO DERIVATIVES","internalauthor":"KRSTIC, MILENA","type":"Tesi di dottorato","year":"2022","abstract":"In Batch and In Flow Synthesis of Quaternary Amino Acids/Amino Derivatives    (nel pdf n. 2 )","language":"eng","citation":"IN BATCH AND IN FLOW SYNTHESIS OF QUATERNARY AMINO ACIDS/AMINO DERIVATIVES / M. Krstic ; tutor: M. Benaglia ; co-tutor: M. Sanz ; phd coordinator: D. Roberto. Università degli Studi di Milano, 2022 Sep 20. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12466_1.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/938246/2092151/phd_unimi_R12466_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1028388"},"title":"IDENTIFICATION OF CANCER- AND METASTASIS-RELATED EPIGENETIC DYNAMICS USING PATIENT-DERIVED ORGANOIDS","internalauthor":"BORDO, ROBERTA","type":"Tesi di dottorato","year":"2024","abstract":"Tumor initiation and progression imply radical changes of cell identity that can’t be entirely explained by specific genetic mutations. This suggests that cells might be epigenetically reprogrammed to undergo those phenotypic alterations. Regarding this, enhancers are crucial since their activation is tightly cell-type-specific. Accordingly, we have recently identified a group of enhancers selectively activated in colorectal cancer (CRC) patient-derived organoids (PDOs) with respect to the normal counterpart that are also conserved among different CRC subtypes, suggesting the presence of shared epigenetic mechanisms that are activated despite heterogeneous mutational landscapes.   Aiming at investigating the role of epigenetic reprogramming in the context of the poorly understood process of metastasization, we generated PDOs from different types of metastases and characterized their histone mark profiling through chromatin immunoprecipitation followed by sequencing (ChIP-seq). In order to provide a global genome-wide annotation of chromatin regions, we evaluated the combinatorial distribution of five histone marks (H3K27ac, H3K4me1, H3K4me3, H3K36me3 and H3K27me3) through ChromHMM, modelling chromatin into 12 biologically distinct states. We then focused on active enhancers to perform a differential analysis between primary and metastatic CRC PDOs. Next, we annotated the enhancers gained in metastasis to their target genes and performed pathway analysis and motif binding analysis. Interestingly, pathways relative to tissue development and intermediate filaments organization were enriched. As trans modulators of these enhancers, we identified transcription factors belonging to the Wnt/β-catenin pathway and AP-1 complex. We also observed epigenomic and transcriptomic inter-metastases heterogeneity, that seemed to be mirrored by the different invasive capability of organoids in an in vitro 3D assay.  In parallel, in order to perform a more accurate annotation of enhancers to their target genes and to address the formation of hubs of interacting enhancers, we performed enhancer capture-HiC on CRC PDOs. As proof of concept, we identified a group of highly interconnected enhancers that established hubs of interactions with other enhancers and concomitantly regulated the expression of cancer-relevant genes. Promoter capture-HiC has also been performed to provide future insights into the global 3D chromatin organization in cancer and metastasis.","language":"eng","citation":"IDENTIFICATION OF CANCER- AND METASTASIS-RELATED EPIGENETIC DYNAMICS USING PATIENT-DERIVED ORGANOIDS / R. Bordo ; tutor: M. Pagani ; director: N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2024 Feb 12. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13107.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1028388/2359012/phd_unimi_R13107.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1018415"},"title":"THE CRISPRATOR: A FEEDBACK CONTROLLER IN MAMMALIAN CELLS FOR ROBUST PERFECT ADAPTATION","internalauthor":"MALLOZZI, ALESSIO","type":"Tesi di dottorato","year":"2023","abstract":"Synthetic Biology, merging genetic engineering with control theory, aims to achieve predictable behaviours in living systems, not relying on single components but rather on their interactions. Viewing DNA, RNA, and proteins as electronic circuit components, Synthetic Biology seeks to emulate circuit topologies to attain desired functionalities. Natural gene networks display robustness, the capacity of the cell to maintain its state despite perturbations, and more specifically Robust Perfect Adaptation (RPA), i.e. the ability to maintain a constant output level despite changes in the environment. In Control Engineering, RPA can be achieved by mechanisms like integral feedback control, a specific implementation of Negative Feedback loops. However, the engineering of synthetic biomolecular circuits implementing an integral controller able to confer RPA in living cells is still an open problem, which if solved could have a major impact in several applications. Gene networks implementing an Antithetic Integral Controller have only been presented very recently using mRNA pairs and inteins. In this thesis, I implemented the CRISPRaTOR, an Integral Controller based on the interaction between a CRISPR/Cas9-derived transcription factor and the recently discovered anti-CRISPR proteins, demonstrating its capability to achieve robust perfect adaptation in cell lines to various disturbances. I showcase precise, tunable, and robust control of a synthetic gene of interest and harness the programmable nature of the CRISPR/Cas9-derived transcription factor to apply this controller to an endogenous gene of interest. Additionally, I showcased an application of the CRISPRaTOR to enhance the linearity and robustness of a whole-cell biosensor of intracellular copper.","language":"eng","citation":"THE CRISPRATOR: A FEEDBACK CONTROLLER IN MAMMALIAN CELLS FOR ROBUST PERFECT ADAPTATION / A. Mallozzi ; internal advisor: M. A. de Matteis ; external advisor: R. Jerala ; supervisor: D. Di Bernardo. Università degli Studi di Milano, 2023 Dec 04. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12698.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1018415/2327912/phd_unimi_R12698.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1137055"},"title":"DISSECTING THE ROLE OF REACTIVE OXYGEN SPECIES IN EARLY MAMMALIAN EMBRYOGENESIS","internalauthor":"BONUMALLU, SAI KAMAL NAG","type":"Tesi di dottorato","year":"2025","abstract":"Reactive oxygen species (ROS) comprise a broad spectrum of molecules that are known to induce oxidative stress (OS) in both gametes and embryos. OS arises when ROS production exceeds a critical threshold, or when intracellular antioxidant systems are unable to neutralize them effectively. OS is a key factor impairing embryo quality during the processes of oocyte maturation, fertilization, and early embryonic development in vitro. However, ROS also play essential roles as regulators of physiological processes, leading to the widely accepted hypothesis that excessive suppression of ROS could negatively affect cellular function. This is particularly relevant in cattle, where assisted reproductive technologies increasingly depend on in vitro production (IVP). A deeper understanding of the specific roles of different ROS is required to optimize culture systems and enhance reproductive efficiency.     One major limitation in this research area is the absence of molecular tools to quantitatively monitor ROS levels over time. To address this issue, we utilized novel probe called HyPer7, an ultrasensitive fluorescent ratiometric sensor capable of tracking real-time H₂O₂ fluctuations within cellular sub-compartments, surpassing traditional methodologies. The HyPer7 sensor has been used in Xenopus models to demonstrate that fertilization-induced calcium signaling triggers mitochondrial H₂O₂ production, which subsequently activates the cell cycle (Han et al., 2018). In our study, we utilized HyPer7-MLS mRNA encoded to the mitochondrial matrix, which was microinjected into immature oocytes (GV) and in vitro matured oocytes (MII). These microinjected oocytes were then matured or fertilized in vitro. To assess the sensor’s ability to detect H₂O₂ with high spatial and temporal resolution, samples were imaged under control conditions and following exposure to a prooxidant challenge. Image acquisitions were conducted at the NOLIMITS UNITECH microscopy facility at the University of Milan, using a Nikon-Eclipse Ti2-E with Yokogawa W1- SoRa spinning disk confocal microscope equipped with a temperature-controlled CO₂ chamber and appropriate lasers and filters at 30-second intervals.     Our image analysis confirmed that HyPer7 successfully detects H₂O₂ in both oocytes and zygotes. However, under control conditions, a significant increase in signal was observed after 20 minutes imaging, suggesting that phototoxicity may contribute to this rise during the image acquisition procedure. Nevertheless, both oocytes and zygotes exposed to a prooxidant (tBOOH) exhibited higher H₂O₂ levels than the control group, validating the sensor's capacity to quantify increased H₂O₂ concentrations. When comparing H₂O₂ content between oocytes and zygotes our results showed no significant difference under standard culture conditions. However, upon exposure to the prooxidant, oocytes demonstrated nearly doubled H₂O₂ levels compared to zygotes. This result raises important biological questions regarding the distinct regulation of redox balance, particularly whether antioxidant mechanisms are more robust in zygotes than in oocytes.    We then explored the hypothesis that increasing concentrations of an antioxidant cocktail could serve as a model for suppressing mitochondrial H₂O₂, providing a tool to study the role of mt-H₂O₂ in zygotes. Fertilized zygotes were exposed for six hours to either standard culture conditions or an antioxidant mixture at concentrations 10, 100, and 1000 times higher than those previously shown to reduce oxidative stress (Truong et al., 2016; Truong & Gardner, 2017). The zygotes were then cultured for seven days. Our analysis revealed that higher concentrations of antioxidants impaired blastocyst development. However, Contrary to our hypothesis, increasing antioxidant levels did not reduce mt-H₂O₂ but instead increased its production, as assessed by means of the Hyper7 sensor. Therefore, the observed reduction in embryonic developmental competence is likely not due to mt-H₂O₂ suppression but rather their increased production due to the paradoxical effect of high antioxidant concentrations.    In conclusion, we established a method to quantitatively measure mitochondrial H₂O₂ in bovine oocytes and zygotes using the HyPer7 sensor, offering a valuable tool for further elucidating its role of mt-H₂O₂ during oocyte maturation and early embryogenesis. However, additional efforts are necessary to optimize methods and reduce phototoxicity, enabling longer acquisition times with the HyPer7 sensor to monitor ROS fluctuations throughout the critical stages of oocyte maturation and early embryo development and use of specific inhibitors or the genetic engineering techniques to suppress the mt-H₂O₂ levels and elucidate their role in the early embryogenesis and the oocyte maturation.","language":"eng","citation":"DISSECTING THE ROLE OF REACTIVE OXYGEN SPECIES IN EARLY MAMMALIAN EMBRYOGENESIS / S.k.n. Bonumallu ; supervisore : V. Lodde ;  coordinatore: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2025 Jan 30. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13371.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1137055/2640153/phd_unimi_R13371.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1151235"},"title":"NUTRITIONAL AND FUNCTIONAL CHARACTERISATION OF ALTERNATIVE FEED AND FOOD INGREDIENTS: EMPHASIS ON HEMP-BASED PRODUCTS, CO-PRODUCTS, MICROALGAE AND CULTURED MEAT","internalauthor":"LANZONI, DAVIDE","type":"Tesi di dottorato","year":"2025","abstract":"The growth of the world population has led to an increase in demand for food, particularly meat and dairy products, further intensifying livestock production, resulting in an enhanced use of grain for animal feed and competition with crops for direct human consumption. In parallel, over time, the livestock sector has exerted considerable pressure on resources, with large areas of arable land dedicated to food cultures and grazing, as well as high water use. This highlights the urgent need for action with multidisciplinary approaches. For this reason, the aims of this thesis were to evaluate the nutritional and functional potential of alternative plant-based products, including hemp, cardoon, and camelina, by analysing their antioxidant properties, bioactive peptide profiles, and their impact on the quality of animal-derived products. It also aimed to optimize the culture medium of microalgae, in particular for Euglena gracilis to enhance its functional profile while investigating the risks of nanoplastics and microplastics contamination during cultivation under heterotrophic conditions. Additionally, the research sought to address key challenges in cultured meat production by developing alternatives to fetal bovine serum, scalable biofabrication methods, and the integration of waste-derived components to support cell proliferation and differentiation. These objectives collectively aimed to advance sustainable, ethical, and innovative practices in the agri-food sector.  Hemp based-products and their co-products have demonstrated high nutritional and functional profiles, as observed following in vitro digestion and solvent extraction methods. In support of this, an in vivo trial, conducted on laying hens, showed how the inclusion of a hemp co-product of up to 9% (leaves, non-standard hemp seeds, hulls and stems) improved performance while increasing the functional and nutritional profile of the eggs. However, it is important to emphasise that their applicability in the livestock sector requires a multidisciplinary approach, evaluating not only the positive effects on animal health but also taking into account limiting factors such as availability, high cost and variability.  Among the various possible alternatives, microbial proteins, in particular microalgae, are strong candidates. In particular, as demonstrated in this thesis, the modulation of the culture medium of E. gracilis, cultivated under heterotrophic conditions, led to improvements in the nutritional and functional profile. This result represents a milestone in the formulation of a product that can be specifically designed for the needs of farm animals. However, the widespread use of plastic bioreactors for microalgae cultivation poses potential health challenges for the user. Indeed, plastics can release micro- and nanoplastics into the culture medium, which can accumulate in the biomass and enter the food chain, potentially impacting animal and human health.  Finally, a possible alternative of recent interest is the production of cellular foods. In this field, cultured meat is certainly the most discussed. Although scientific research has tried to find answers to the main questions concerning the production process and its sustainability, many open issues still remain. Among these, alternatives to foetal bovine serum that can guarantee the growth, proliferation and differentiation of muscle cells through an ethical and sustainable process deserve further and necessary investigation. As demonstrated in this thesis, possible alternatives involve co-products of food (e.g. whey proteins), which can support the viability, proliferation and differentiation of C2C12 murine muscle cells.  Although further studies are needed, all these alternatives represent fundamental steps towards the creation of resilient and environmentally friendly food systems. Despite promising results, further research is needed to standardise these approaches and address unresolved issues, ensuring their feasibility in the food, feed and livestock sectors. The exploration of these alternative proteins is in line with global efforts to create sustainable food systems and mitigate the environmental challenges posed by traditional agricultural practices.","language":"eng","citation":"NUTRITIONAL AND FUNCTIONAL CHARACTERISATION OF ALTERNATIVE FEED AND FOOD INGREDIENTS: EMPHASIS ON HEMP-BASED PRODUCTS, CO-PRODUCTS, MICROALGAE AND CULTURED MEAT / D. Lanzoni ; supervisor: C. Giromini ; co-supervisor: E. Pěchoučková ; coordinator: F. Cheli. - Lodi. Università degli Studi di Milano, Dipartimento di Medicina Veterinaria e Scienze Animali. Dipartimento di Medicina Veterinaria e Scienze Animali, 2025 Mar 21. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13628_2.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1151235/2705289/phd_unimi_R13628_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/940540"},"title":"LA SVOLTA AMOROSA DELLA FENOMENOLOGIA FRANCESE. LA POSSIBILITÀ DI UN'ETICA FENOMENOLOGIA","internalauthor":"BELLI, MANUEL","type":"Tesi di dottorato","year":"2022","abstract":"\"The question of ethics is as old as phenomenology. Husserl held numerous series of lectures on ethics throughout his academic career. When Heidegger wrote Sein und Zeit, some critics thought the book was a text on moral philosophy and ethics. According to Husserl, the task of phenomenology with regard to ethics is the clarification of the formal conditions of practical reason. Phenomenology (in accordance with its own method) must suspend judgment on moral values and must focus on the formal connections necessary for ethical reasoning. However, analyzing the texts, it is clear how Husserl gradually accords more space to circumstance: the study of moral judgment shows how singularity and historicity cannot be underestimated. When man has to choose what is right, the most universal thing is the importance of the singular. As far as Husserl is concerned, the main driving force of ethical actions is love, and love can only be understood within circumstance. From this point of view, Heidegger and Husserl show unprecedented proximity. According to Heidegger, there is no difference between ethics and ontology: being is what happens.  Ethics shows the potential and limits of phenomenology: the phenomenological investigation of ethics indicates the possibility of further avenues of investigation. The subject \"\"becomes himself\"\" in the exercise of ethical discernment. Levinas and Marion follow the path of the investigation of how the subject becomes such in relation to otherness. In their investigations they cross the question of love, which is fundamental for the constitution of the subject. The second part of the research evaluates the path of French phenomenology as an important theoretical attempt to investigate what Husserl only indicated by impacting, writing about the weight of singularity and history.\"","language":"ita","citation":"LA SVOLTA AMOROSA DELLA FENOMENOLOGIA FRANCESE. LA POSSIBILITÀ DI UN'ETICA FENOMENOLOGIA / M. Belli ; tutor: C. di Martino, L. Solignac ; supervisori: A. Caputo, E. Falque. Università degli Studi di Milano, 2022 Dec 12. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12793.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/940540/2077612/phd_unimi_R12793.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1172787"},"title":"PARADIGMS OF EVIDENCE. REFRAMING FORENSIC IMAGES THROUGH EXTENDED REALITY MEDIA","internalauthor":"CINELLI, ROSA","type":"Tesi di dottorato","year":"2025","abstract":"This research explores contemporary transformations of visual evidence in the context of an expanding visual culture shaped by hybridisations between photography and extended reality media. Starting from the historical centrality of photography as a medium of evidence, traditionally based on notions of transparency and mechanical objectivity, the thesis develops a reflection based on Carlo Ginzburg's evidential paradigm, which is reinterpreted in terms of a forensic gaze. This paradigm allows evidence to be conceived not simply in terms of the apparent absence of mediation, but as a clue to be interpreted and an operational tool for investigation.  Starting from this theoretical framework, the research examines the forensic uses of photography from the nineteenth century to the present day, identifying a genealogy of XR media in the cartographic and metric tradition of crime scene documentation. Through the analysis of contemporary investigative practices, in particular those developed by Forensic Architecture, it shows how virtual reconstructions do not mark a break with photographic images, inviting an intermedial reconceptualisation of visual evidence that goes beyond the specificity of the photographic medium.  This theoretical framework is then tested through archival research conducted at the Archives nationales in Paris, focusing on forensic images used in the so-called V13 trial, i.e. the legal trial following the 13 November 2015 attacks in Paris. The thesis analyses the institutional, archival and media conditions under which forensic images were presented in court, situating their presence in the courtroom through the semiopragmatic device of recontextualisation. The research highlights the tensions that arise when visual evidence of the attack scenes is shown in court: tensions between visibility and concealment, between testimonial function and control logic, between renunciation and remediation.  Finally, the thesis concludes with an art-based research experiment that explores the audiovisual archive of the V13 trial in light of its difficult accessibility through an immersive installation.  Developed from interviews with archivists and spatialised through a generative sound score and photogrammetric scans of archival working documents, the work evokes a documentary heritage by summoning it, without showing it, in terms of “missing pictures”.","language":"eng","citation":"PARADIGMS OF EVIDENCE. REFRAMING FORENSIC IMAGES THROUGH EXTENDED REALITY MEDIA / R. Cinelli ; supervised by: B. Grespi, M. Treleani, M. Sobieszsanski ; coordinator: N. Guicciardini Salviati. Dipartimento di Filosofia Piero Martinetti, 2025 Jun 30. 37. ciclo [10.13130/cinelli-rosa_phd2025-06-30].","filename":"phd_unimi_R13369.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1172787/3258871/phd_unimi_R13369.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/918909"},"title":"MUSIC INTERPRETATION ANALYSIS. A MULTIMODAL APPROACH TO SCORE-INFORMED RESYNTHESIS OF PIANO RECORDINGS","internalauthor":"SIMONETTA, FEDERICO","type":"Tesi di dottorato","year":"2022","abstract":"This Thesis discusses the development of technologies for the automatic resynthesis of music recordings using digital synthesizers. First, the main issue is identified in the understanding of  how Music Information Processing (MIP) methods can take into consideration the influence of the acoustic context on the music performance. For this, a novel conceptual and mathematical  framework named “Music Interpretation Analysis” (MIA) is presented. In the proposed framework, a distinction is made between the “performance” – the physical action of playing – and the  “interpretation” – the action that the performer wishes to achieve. Second, the Thesis describes further works aiming at the democratization of music production tools via automatic resynthesis: 1) it elaborates software and file formats for historical music archiving and multimodal machine-learning datasets; 2) it explores and extends MIP technologies; 3) it presents the mathematical foundations of the MIA framework and shows preliminary evaluations to demonstrate the effectiveness of the approach","language":"eng","citation":"MUSIC INTERPRETATION ANALYSIS. A MULTIMODAL APPROACH TO SCORE-INFORMED RESYNTHESIS OF PIANO RECORDINGS / F. Simonetta ; tutor: S. Ntalampiras ; co-tutor: F. Avanzini ; coordinatore: R. Sassi ; coordinatore: P. Boldi. Dipartimento di Informatica Giovanni Degli Antoni, 2022 Apr 22. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12272.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/918909/2009894/phd_unimi_R12272.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/838364"},"title":"CHARACTERISATION OF AUXIN RESPONSE FACTOR 5/MONOPTEROS POST-TRANSCRIPTIONAL AND POST-TRANSLATIONAL REGULATIONS DURING ARABIDOPSIS THALIANA DEVELOPMENT","internalauthor":"CAVALLERI, ALEX","type":"Tesi di dottorato","year":"2021","abstract":"Alternative splicing generates a MONOPTEROS isoform required for ovules development    Auxin is one of the main designers of plant development and organs differentiation and its function relies on its differential accumulation with the generation of points of high and low hormone content.   At cellular level, auxin signaling impacts on the transcriptomic landscape thought the modulation of the interplay between AUX/IAA repressor proteins and AUXIN RESPONSE FACTOR transcriptional factors. AUX/IAAs and ARFs compose a combinatory system in which AUX/IAAs binding to ARFs negatively regulates their ability to activate the transcription of downstream targets. Upon auxin sensing, AUX/IAAs stability is compromised thought their direct ubiquitination and degradation, allowing transcriptional activator ARFs to promote gene expression. Among transcriptional activator ARFs, ARF5/MONOPTEROS (MP) has been shown to be a key integrator of auxin signaling for many developmental events, thought the activation of the transcription of target genes above auxin threshold concentration. We show that in ovules, MP is expressed and functional in domains of low auxin content. We described that MP post-transcriptional regulations are involved in this process thought the generation of a biologically functional mRNA splicing variant, whose translation generates a protein isoform lacking the AUX/IAA interaction domain. Indeed, the alternative MPint11 isoform was able to partially complement mp mutants defects and ovule developmental process. Interestingly, also the canonical MP protein results partially functional for complementation of ovules formation, with a similar behavior to the one observed for MPint11. Our results suggest that MP functions relies on the combined activity of both its isoforms with the evidence that, during ovules development, MP domains involved in AUX/IAAs binding are not strictly required. These findings describe a novel scenario in which, not only MP is able to work uncoupled from the classical auxin signaling model, but also in which post-transcriptional regulation controls the formation of a functional isoform required for correct ovules development.","language":"eng","citation":"CHARACTERISATION OF AUXIN RESPONSE FACTOR 5/MONOPTEROS POST-TRANSCRIPTIONAL AND POST-TRANSLATIONAL REGULATIONS DURING ARABIDOPSIS THALIANA DEVELOPMENT / A. Cavalleri ; tutor: L.Colombo ; supervisore: M.Cucinotta ; phd director: M. Kater. Dipartimento di Bioscienze, 2021 Apr 14. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12105.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/838364/1784602/phd_unimi_R12105.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1233359"},"title":"IL FEMMINISMO PER IL SALARIO AL LAVORO DOMESTICO IN ITALIA: GENEALOGIE, PRATICHE E PROSPETTIVE INTERNAZIONALI","internalauthor":"GABRIELLI, MARTINA","type":"Tesi di dottorato","year":"2026","abstract":"This research examines the origins, development, and practices of the Italian Wages for Housework movement, which emerged in the early 1970s and soon acquired a transnational dimension. It investigates how activists within Lotta Femminista and, later, the Network of Committees and Groups for Wages for Housework redefined the notion of “domestic work” shifting it from an invisible, naturalized activity to a political category and a site of mobilization. Drawing on archival materials, printed sources, and oral testimonies, the study reconstructs both theoretical elaborations and political practices, highlighting internal tensions as well as connections with other feminist movements and with the left, particularly the extra-parliamentary. The analysis combines national and international perspectives, showing how Italian claims intersected with experiences in the United Kingdom and the United States. Situating the Wages for Housework movement within the broader historiography of contemporary feminisms, the research places it in the context of the political and cultural transformations of the late twentieth century.","language":"ita","citation":"\"IL FEMMINISMO PER IL SALARIO AL LAVORO DOMESTICO IN ITALIA: GENEALOGIE, PRATICHE E PROSPETTIVE INTERNAZIONALI / M. Gabrielli ; tutor: C. Baldoli ; cotutor: P. Willson ; coordinatore: P. Grillo. - Milano. Dipartimento di Studi Storici \"\"Federico Chabod\"\", 2026 Apr 10. 38. ciclo, Anno Accademico 2025/2026.\"","filename":"phd_unimi_R13879.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1233359/3299479/phd_unimi_R13879.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1254415"},"title":"RAP IN EXILE: SYRIAN DIASPORA, HYBRIDITY AND DIGITAL CULTURAL PRODUCTION IN GERMANY","internalauthor":"RABIO, ALIA","type":"Tesi di dottorato","year":"2026","abstract":"This dissertation examines Syrian rap as a locus of diasporic cultural production among displaced musicians, principally those residing in Germany, to expound how these artists construct and negotiate identity, belonging and political subjectivity through sonic and digital practices. Situated within scholarly debates on diaspora, transnationalism and cultural citizenship, the study contends that rap operates as a pivotal medium through which exiled creators articulate experiences of fragmentation, marginalisation and re‑anchoring within host societies.    Adopting a reflexive, digitally‑grounded ethnographic methodology, the research draws on qualitative data collected between 2022 and 2024. The corpus comprises semi‑structured interviews with a purposively selected sample of male and female Syrian rappers, close textual and visual analyses of lyrics and accompanying aesthetics, and digital ethnography of platformed activity on YouTube, Instagram and related social media. Methodological consistency is ensured through sustained attention to researcher positionality, access constraints and the ethics of studying precarious cultural scenes in exile.    Findings reveal that Syrian rap in Europe is embedded within fragmented networks shaped by forced‑migration trajectories, legal precarity, gendered hierarchies and platform governance regimes. While rap enables performers to voice narratives of displacement, loss and political disenchantment, it also surfaces intra‑community tensions of competition, mistrust and unequal resource distribution. The concept of digital de‑integration is introduced to describe strategic withdrawals from visibility regimes, linguistic assimilation anxieties and institutional co-optation, thereby resisting algorithmic commodification of refugee creativity.    A gender‑focused sub‑analysis demonstrates that female Syrian rappers navigate a predominantly masculinised rap field through selective visibility, linguistic modulation and curated digital self‑presentation, tactics that mitigate exposure to harassment and reputational risk. Their practices illuminate the intersection of gender, migratory status, class and language in structuring access to cultural participation.    Collectively, the study challenges reductive readings of Syrian rap as merely political resistance or integrationist discourse. Instead, the genre constitutes a complex arena of diasporic cultural production wherein belonging is continuously negotiated via aesthetic experimentation, digital labour and everyday survival strategies. By foregrounding the voices and practices of displaced artists, this research contributes to sociological debates on migration, musicology and digital culture, offering a nuanced account of how exilic musicians reconfigure cultural forms to assert presence, negotiate constraints and envisage possibilities within contemporary European contexts.","language":"eng","citation":"RAP IN EXILE: SYRIAN DIASPORA, HYBRIDITY AND DIGITAL CULTURAL PRODUCTION IN GERMANY / A. Rabio ; supervisor: C. Nardella ; co-supervisor: P. Rebughini ; director of doctoral program:  P. Rebughini. Dipartimento di Scienze Sociali e Politiche, 2026 Jun 16. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13675.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 11-DIC-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1175348"},"title":"DEVELOPMENT OF NEW  METHODOLOGIES AND PRACTICES TO REDUCE THE ENVIRONMENTAL IMPACT IN THE PRODUCTION OF CERAMIC MATERIALS","internalauthor":"MARCOLINI, ELEONORA","type":"Tesi di dottorato","year":"2025","abstract":"In response to the growing global challenges of energy security and water pollution, this thesis explores integrated electrochemical and photocatalytic approaches for sustainable hydrogen production and advanced wastewater treatment. By coupling the anodic oxidation of nitrogen- and pharmaceutical-based pollutants with cathodic hydrogen evolution, the research proposes a dual-purpose strategy that simultaneously enables pollutant removal and green energy generation.  A key innovation of this work is the development and electrochemical evaluation of non-noble metal electrodes, particularly cobalt phosphide-based systems, which operate efficiently under alkaline conditions. These materials were tested in both ideal and contaminated environments, including real-matrix simulations containing diclofenac and Rhodamine B. The hydrogen production was directly quantified, providing, for the first time, a scientific assessment of the faradaic efficiency of hydrogen generation from real wastewater containing organic contaminants using non-precious electrodes.  To overcome the limitations of electrochemical oxidation alone, a hybrid process integrating visible-light-active BiOCl photocatalysis was implemented, enhancing degradation kinetics and mineralization efficiency. This combined strategy offers a scalable and energy-efficient route for water remediation.  Beyond laboratory scale, the study includes a case analysis of the industrial implementation of green hydrogen at Iris Ceramica Group’s H₂ Factory, where hydrogen produced via photovoltaic-powered alkaline electrolysis is blended with methane to fuel ceramic kilns. Energy balances, emission monitoring (via GC–MS), and product quality evaluations were conducted to assess the technical feasibility and environmental benefits of hydrogen integration in ceramic manufacturing.  Overall, the thesis provides a multi-scale perspective—spanning materials design, process engineering, and industrial application—demonstrating how wastewater can serve as a valuable resource for both clean energy production and environmental protection. The findings contribute to advancing circular economy principles and accelerating the transition toward decarbonized, sustainable manufacturing.","language":"eng","citation":"DEVELOPMENT OF NEW  METHODOLOGIES AND PRACTICES TO REDUCE THE ENVIRONMENTAL IMPACT IN THE PRODUCTION OF CERAMIC MATERIALS / E. Marcolini ; tutor: C.. L. M. Bianchi ; co-tutor: R. Zini ; phd coordinator: L. Prati. - Dipartimento di Chimica, via C.Golgi 19. Dipartimento di Chimica, 2025 Jul 17. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13535.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 17-GEN-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1125897"},"title":"DEAD MEN TELL NO TALES: MEDICAL DIATRIBES IN EARLY MODERN DRAMA","internalauthor":"CATERINO, ANNA","type":"Tesi di dottorato","year":"2025","abstract":"Health, sickness, and death have always been concerns deeply embedded in society. Even more so in early modern England, at a time when people saw physicians as suspicious and vice-ridden individuals, medicine could easily turn into something grotesque, and kitchen physics was one step away from being labelled as witchcraft. The cultural terrors that emerged from the uneven and non-linear progression of medicine and the socio-political environment of Tudor and Stuart England led to the (re-)emergence of fruitful stereotypes: barbarous barbers, practising apothecaries, prescribing surgeons and, of course, quacks and mountebanks. After the foundation of the Royal College of Physicians (1518), they all seemed like stumbling blocks to physicians’ rise to eminence—aided by the population’s ignorance and foolishness. Vulgus vult decipi, as the saying went. However, the situation was more ambiguous, last but not least, because things were not as backward and unorthodox as they may seem to anyone who looks at the past searching for ignorance and deplorableness. The preheminence of these matters explains the abundance of references to disease and recovery featured in the works of William Shakespeare and his contemporaries. Nevertheless, this dissertation aims to go further and analyse if and how these struggles over authority can also be traced in the time’s dramatic production. By opening a dialogue between sixteenth- and seventeenth-century drama and anti-quack literature, this study suggests that the richness of medical practices onstage mirrors the richness of the ones in real life, often with consistent overlaps and variations at times of increased uncertainty and anxiety. By examining a wide and diversified range of primary texts and moving beyond England’s most famous and staged playwrights, this dissertation argues that playwrights actively participate in the vernacular debate on knowledge to the point that the incorporation of medical diatribes into their work becomes a testimony to early modern culture and doctor-patient relationships, all while providing a less grim outlook on life. Both then and now.","language":"eng","citation":"DEAD MEN TELL NO TALES: MEDICAL DIATRIBES IN EARLY MODERN DRAMA / A. Caterino ; tutor: P. Caponi; coordinatore: L. Pinnavaia. Dipartimento di Lingue, Letterature, Culture e Mediazioni, 2025 Jan 22. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13237.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1125897/2612589/phd_unimi_R13237.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/971241"},"title":"COLLECTIVE ACTION IN THE ENERGY SECTOR IN THE EUROPEAN UNION AND THE UNITED STATES: A COMPARISON BETWEEN THE EU AND THE US AND THE POTENTIAL FOR SCALING UP TO IMPACT THE ENERGY TRANSITION","internalauthor":"GILCREASE, GREGORY WINSTON","type":"Tesi di dottorato","year":"2023","abstract":"With energy-related carbon emissions at historic highs, and trends expected to rise, organizing a new energy future is crucial now more than ever. In the face of increasing threats of climate disruption and energy security, one positive outlook is the drive for innovative grassroots solutions towards a renewable-based energy transition. Collective Action Initiatives (CAIs) have been contributing to this approach, aiming to create more economically and socially inclusive communities, acting as an example for a sustainable future. CAIs are contributing to the evolution of a decentralized energy market with a large number of ‘prosumers’ (producing consumers) and moving away from a historically centralized energy market dominated by large utilities. The energy transition to renewables will be accelerated when citizens are engaged, helping to build trust and stronger cooperation among communities, as well as support more inclusive regulatory systems. While energy CAIs have potential to offer a number of advantages that address social and environmental problems, their development faces several barriers. In fact, they still represent a small share of the energy market in the European Union (EU) and the United States (US), emerging under different forms and influenced by distinctive factors. This doctorate research is a quantitative and qualitative comparative analysis, complemented by an in-depth data mining and analysis to explore the socioeconomic phenomena of these initiatives. This includes investigating how they are already influencing the EU and US energy systems, and their future roadmaps to potentially impact the energy transition to renewable sources.","language":"eng","citation":"COLLECTIVE ACTION IN THE ENERGY SECTOR IN THE EUROPEAN UNION AND THE UNITED STATES: A COMPARISON BETWEEN THE EU AND THE US AND THE POTENTIAL FOR SCALING UP TO IMPACT THE ENERGY TRANSITION / G.w. Gilcrease ; advisor: D. Padovan (University of Turin) ; tutor: L. Storti (University of Turin). Dipartimento di Scienze Sociali e Politiche, 2023 May 31. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12616.pdf","fileformat":"Adobe PDF","fileversion":"preprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/971241/2205279/phd_unimi_R12616.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1026148"},"title":"OBSERVATIONAL CONSTRAINTS OF THE INTERACTION BETWEEN PLANETS AND PROTOPLANETARY DISKS","internalauthor":"CURONE, PIETRO","type":"Tesi di dottorato","year":"2024","abstract":"Over the course of almost three decades, exoplanet research has unveiled thousands of planets orbiting stars beyond our Sun. Surprisingly, the majority of these exoplanetary systems exhibit significant differences from our own Solar System. To comprehend the reasons behind these distinctions, it is imperative to study how planets form. Planets take shape during the star formation process, emerging from the material within the protoplanetary disk surrounding the young protostar. Interactions between these newly formed planets and the disk create observable effects on the disk itself, which can be detected in the sub-millimeter to centimeter wavelength range through advanced interferometers like ALMA and VLA.  In this Thesis, I explore various protoplanetary disks, each possessing unique characteristics. They range from extended disks with noticeable substructures in dust emission to a disk surrounding a very low-mass star that may have undergone giant planet formation, as well as a compact, structureless disk exhibiting a peculiar behavior whose origin remains uncertain. The methodologies employed in these investigations are diverse, encompassing high-resolution ALMA observations, comprehensive numerical modeling involving hydrodynamical and radiative transfer simulations, and a multiwavelength analysis spanning from centimeter to sub-millimeter wavelengths, incorporating data from VLA, ALMA, and other interferometers. In all the systems under examination, the presence of planets could potentially play a role, whether giant planets shaping observed dust substructures at tens or hundreds of astronomical units or inner planets generating unresolved substructures, preventing radial drift and leading to the formation of a compact disk.","language":"eng","citation":"OBSERVATIONAL CONSTRAINTS OF THE INTERACTION BETWEEN PLANETS AND PROTOPLANETARY DISKS / P. Curone ; supervisore: L. Testi ; co-supervisori: M. Lombardi, F. Borsa ; coordinatore: R. Vecchi. - Dipartimento di Fisica Aldo Pontremoli. Università degli Studi di Milano, 2024 Feb 05. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12942.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1026148/2352613/phd_unimi_R12942.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1201435"},"title":"DISTRIBUTED AND DELAYED ONLINE LEARNING","internalauthor":"QIU, HAO","type":"Tesi di dottorato","year":"2025","abstract":"This thesis investigates the design and analysis of distributed and delayed online learning algorithms. First, we introduce delayed online learning, where model updates rely on feedback arriving with variable delays. We study the online learning problem with curved losses and delayed feedback, designing algorithms that exploit loss curvature to  achieve improved guarantees with delayed feedback. Furthermore, we demonstrate how intermediate observations can mitigate the deleterious effects of delayed feedback in settings with partial feedback (e.g., multi-armed bandits) by developing a meta-algorithm that achieves near-optimal regret with significantly reduced sensitivity to total delay. Second, we consider distributed online convex optimization over communication graphs, in which a network of agents cooperatively minimizes a global convex loss function expressed as the sum of local loss functions, using only neighbor-to-neighbor exchanges and local computation. We propose and rigorously analyze a distributed online convex optimization algorithm that accommodates both random communication and stochastic agent availability, where two agents communicate only when both are simultaneously active. We then present a unified algorithmic framework that simultaneously addresses network decentralization and delayed feedback in distributed online convex optimization. We design distributed online learning algorithms that adapt to unknown, time- and agent-varying delays while maintaining near-optimal regret guarantees. Finally, transitioning from adversarial to stochastic regimes, we extend this framework to distributed stochastic multi-armed bandit settings over random communication graphs. We derive improved regret bounds that combine the optimal centralized regret with a natural term depending on the graph's algebraic connectivity and edge probability.","language":"eng","citation":"DISTRIBUTED AND DELAYED ONLINE LEARNING / H. Qiu ; tutor: N. Cesa-Bianchi, W. M. Koolen coordinator: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2025 Dec 09. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13958.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1201435/3200830/phd_unimi_R13958.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1050419"},"title":"PREDICTING ANTIPSYCHOTIC TREATMENT OUTCOMES USING BRAIN CONNECTIVITY AND NEUROCOGNITION IN EARLY PHASES OF PSYCHOSIS","internalauthor":"DEL FABRO, LORENZO","type":"Tesi di dottorato","year":"2024","abstract":"Background: Prognostic biomarkers of clinical remission in individuals with psychotic disorders treated with antipsychotic drugs have been lacking. The development of biomarkers for prediction of clinical improvement may be helpful to guide treatment strategies. The aim of this study was to develop and validate machine learning models based on brain functional connectivity and neurocognition to predict clinical remissions in individuals at Recent Onset of Psychosis (ROP) treated with antipsychotics.  Methods: ROP patients treated with antipsychotics were classified as remitters or as non-remitters based on the adapted remission criteria of the Positive and Negative Syndrome (PANSS) Scale after a follow-up period of 3, 6 and 9 months. Baseline resting-state fMRI measures of brain connectivity and a neuropsychological test battery were evaluated on their ability to predict symptom remission using machine learning algorithms.   Results: Machine learning models using resting-state fMRI connectivity data predicted clinical remission in 51 ROP individuals treated with antipsychotics after 3 months with the best overall performances (BAC: 71.2%, AUC: 0.77). In order to evaluate the generalizability of our methods, we applied machine learning models to an independent replication sample of 41 ROP patients (BAC: 66.7%, AUC 0.77).  Conclusions: These results suggest that functional brain connectivity data at baseline could represent potential biomarkers of symptomatic improvement prediction in ROP individuals treated with antipsychotics. The methods and findings in this study could provide a critical step toward fMRI-based personalized patient treatment in early psychosis. Future work is needed to improve prediction performance to be clinically useful.","language":"eng","citation":"PREDICTING ANTIPSYCHOTIC TREATMENT OUTCOMES USING BRAIN CONNECTIVITY AND NEUROCOGNITION IN EARLY PHASES OF PSYCHOSIS / L. Del Fabro ; supervisor: P. Brambilla ; coordinator: C. Sforza. - Università di Milano. Università degli Studi di Milano, 2024 Jun 17. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13010.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1050419/2411608/phd_unimi_R13010.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1132775"},"title":"QUANTITATIVE EVALUATION OF THE CONSOLIDATING EFFECTS INDUCED BY INORGANIC MINERAL TREATMENTS APPLIED ON POROUS CARBONATE STONE SURFACES","internalauthor":"MASSINELLI, GIULIA","type":"Tesi di dottorato","year":"2025","abstract":"Carbonate stones have been extensively used in cultural heritage (CH) throughout history due to their abundance and workability for many historical monuments and artworks. However, these stone materials are decaying at a noticeable rate, particularly under the influence of pollutants like sulfur oxides and CO₂, compounded by climate change. The heterogeneity of carbonate stones, including texture and porosity, further complicates their conservation, often leading to unpredictable decay processes. Moreover, previous conservation efforts, frequently lacking in standardized diagnostic assessments, can create complex challenges for future interventions. This means that stone conservation research is of crucial importance.  This research focuses on two inorganic treatments for carbonate stone materials: ammonium oxalate (AmOx) and diammonium hydrogen phosphate (DAP) water solutions. AmOx generates a calcium oxalate (CaOx) layer on the stone surface, preventing further weathering. DAP forms calcium phosphate (CaP), addressing the loss of cohesion and increasing the strength of a decayed matrix by binding detached grains. Despite their efficacy, challenges remain in optimizing treatment penetration, unambiguous results, and long-term effectiveness. Given that the stone conservation field is constantly evolving, this dissertation explores a novel sequential treatment approach combining AmOx and DAP, aiming to harness the protective surface layer of CaOx and the deeper consolidation effects of CaP. While initial studies show promise, results are extremely variable. A comprehensive understanding of the single treatments' interactions with the stone’s substrate is crucial. Specifically, this research focuses on the kinetics, crystallization effects on porosity, and mineralogical transformations within the calcite matrix during and after the reaction with the single solutions. The second objective of this study is to identify advanced, high-resolution imaging techniques to characterize these conservation processes better. Emphasis is placed on synchrotron-based imaging, including synchrotron 4D X-ray computed microtomography (SR-µCT), micro-X-ray diffraction (SR-µXRD), and micro-X-ray fluorescence (SR-µXRF). These high-resolution techniques are complemented by laboratory methods for initial assessments.  The first manuscript published in the framework of this research activity investigates the crystallization kinetics of DAP-treated in porous Noto limestone using SR-µCT to track porosity changes over time, revealing the dynamic microstructural evolution during treatment. This time-resolved (4D) analysis unveils the complex nucleation processes and porosity evolution during treatment. The second paper introduces a combined SR-µXRD and SR-µXRF approach to map the spatial distribution and composition of new phases formed by AmOx and DAP treatments. This method overcomes challenges posed by the heterogeneous nature of the treated stone, allowing for precise localization and characterization of crystalline and poorly crystalline CaOx and CaP phases within the calcite matrix. Finally, the third paper extends the research described in Article #2, combining SR-µXRD and SR-µXRF mapping to visualize the direct effect of AmOx and DAP reaction with the matrix, providing insights into the reaction site of different macroareas, i.e., areas of unique phases crystallization as a function of depth in each treatment. The Rietveld method and Pearson VII peak analysis were used to study the microstructural changes in the calcite substrate in the reaction sites. The paper deals with the difficulty of understanding the effect of dissolution and precipitation processes. The third paper also extends these methods to sequential AmOx-DAP treatments, exploring and quantifying the macro- and microstructural changes across spatial and depth-dependent reaction sites. This study uncovers the impact of application methods, substrate composition, and the interaction of the two treatments on the effects of the consolidation.  This body of work offers valuable insights into the performance and properties of treated materials and the pros and cons of various imaging techniques used to examine these properties. The general discussion addresses the research implications of the study’s objectives, critically analyzing the data within the field context. Any unexpected or contradictory findings are explored and explained where possible, with suggestions for re-evaluating the results. This comprehensive discussion aims to raise awareness of the thesis topic's challenges, inspire new ideas, and provide a foundation for future X-ray imaging research. The experimental findings are expected to contribute to conservation practice, providing guidelines for restorers to perform treatments with improved performance, considering the specifics of each case study and the conservative history of the stone artwork.","language":"eng","citation":"Quantitative evaluation of the consolidating effects induced by inorganic mineral treatments applied on porous carbonate stone surfaces / G. Massinelli ; tutor: N. Marinoni, G. D. Gatta ; co-advisors: C. Colombo, E. Possenti. Dipartimento di Scienze della Terra Ardito Desio, 2025 Feb 28. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13350.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1132775/2629019/phd_unimi_R13350.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1142075"},"title":"IRON DEFICIT IN HEART FAILURE","internalauthor":"CAMPODONICO, JENESS SIMONA","type":"Tesi di dottorato","year":"2024","abstract":"IS RDW A VALID TOOL TO PREDICT IMPAIRED IRON TRANSPORT IN HEART FAILURE?    Abstract  Aims   Impaired iron transport (IIT) is a form of iron deficiency (ID) defined as transferrin saturation (TSAT) <20% irrespective of serum ferritin levels. It is frequently observed in heart failure (HF) where it negatively affects prognosis irrespective of anemia. In this retrospective study we searched for a surrogate biomarker of IIT.   Methods and Results   We tested the predictive power of red distribution width (RDW), mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC) to detect IIT in 797 non-anemic HF patients. At ROC analysis, RDW provided the best AUC (0.6928). An RDW cut-off value of 14.2% identified patients with IIT, with positive and negative predictive values of 48 and 80%, respectively. Comparison between the true and false negative groups showed that estimated glomerular filtration rate (eGFR) was significantly higher (p=0.0092) in the true negative vs. false negative group. Therefore, we divided the study population according to eGFR value: 109 patients with eGFR ≥ 90 mL/min/1.73m2, 318 patients with eGFR 60-89 mL/min/1.73m2, 308 patients with eGFR 30-59 mL/min/1.73m2 and 62 patients with eGFR < 30 mL/min/1.73m2. In the first group, positive and negative predictive values were 48 and 81% respectively, 51 and 85% in the second group, 48 and 73% in the third group and 43 and 67% in the fourth group.   Conclusion  RDW may be seen as a reliable IIT marker in non-anemic HF patients, particularly in subjects with eGFR ≥60 mL/min/1.73m2, and could be used to identify non-anemic non-low eGFR HF patients at high risk of IIT.","language":"eng","citation":"IRON DEFICIT IN HEART FAILURE / J.s. Campodonico ; tutor: P. AGOSTONI ;  coordinator: C. SFORZA. Dipartimento di Scienze Cliniche e di Comunità, 2024 Jun 03. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R13174.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1142075/2658109/phd_unimi_R13174.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1027770"},"title":"SEMISTABLE MODELS OF HYPERELLIPTIC CURVES IN THE WILD CASE & DIFFERENTIAL OPERATORS ON P-ADIC MODULAR FORMS","internalauthor":"FIORE, LEONARDO","type":"Tesi di dottorato","year":"2024","abstract":"This PhD thesis is divided into two parts, collecting two independent pieces of work I completed during my PhD, both in the realm of number theory and arithmetic geometry. The first part presents a joint work with J. Yelton, regarding semistable models of hyperelliptic curves in the wild case. To this subject, which was already the topic of my MSc. thesis, I devoted part of my research work during my PhD, until completing it during summer 2022. The second part of this thesis discusses some research findings related to a completely unrelated topic proposed to me by my PhD advisor Fabrizio Andreatta, namely the one of geometric constructions of differential operators on sheaves of p-adic modular forms.","language":"eng","citation":"SEMISTABLE MODELS OF HYPERELLIPTIC CURVES IN THE WILD CASE & DIFFERENTIAL OPERATORS ON P-ADIC MODULAR FORMS / L. Fiore ; tutor: F. Andreatta. Dipartimento di Matematica Federigo Enriques, 2023. 36. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R12801.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1027770/2357177/phd_unimi_R12801.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1151535"},"title":"CHARACTERIZATION OF AIR POLLUTION AND AIR QUALITY USING INNOVATIVE SAMPLING METHODS AND ANALYTICAL TECHNIQUES FOR REGULATED AND NON-REGULATED POLLUTANTS","internalauthor":"BERGOMI, ANDREA","type":"Tesi di dottorato","year":"2025","abstract":"Air pollution is a critical global health and environmental issue, with major health risks associated with pollutants such as particulate matter (PM), ozone (O3), carbon monoxide (CO), and nitrogen oxides (NOx). Despite advancements in air quality regulations, many pollutants remain unregulated, both outdoors and indoors. Additionally, several sources of air pollution continue to be unmonitored, with their impacts on air quality yet to be fully understood. This thesis addresses two key research areas aimed at improving air quality monitoring and mitigation efforts. The first investigates the emissions from pizza ovens, a largely overlooked source of pollution in urban areas. Using advanced sampling methodologies and analytical techniques, this study assesses the contribution of these ovens to air quality. Emission factors for major pollutants (NOx, CO, OGC, TSP, PM10, PM2.5, PAHs) were determined through experimental testing, and their impact on urban air quality was evaluated through a case study in Milan. The second explores air quality monitoring in indoor sites, specifically schools and places of worship, using innovative sensors and monitoring techniques to evaluate a wide range of pollutants. The results underscore the importance of continuous monitoring to better understand the nature and impact of indoor pollutant sources, as well as to identify critical air quality issues in these spaces. The dual focus on both outdoor and indoor air quality aims to provide comprehensive insights into the evolving challenges of air pollution and the need for effective, targeted measures to protect public health and the environment.","language":"eng","citation":"CHARACTERIZATION OF AIR POLLUTION AND AIR QUALITY USING INNOVATIVE SAMPLING METHODS AND ANALYTICAL TECHNIQUES FOR REGULATED AND NON-REGULATED POLLUTANTS / A. Bergomi ; tutor: P. Fermo ;  co-tutor: V. Comite, G. Migliavacca ;  coordinatore: D. Passarella. - Università degli Studi di Milano. Dipartimento di Chimica, 2025 Mar 05. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13589.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1151535/2706592/phd_unimi_R13589.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1201457"},"title":"THE IMPACT OF VASCULAR SMOOTH MUSCLE CELL SENESCENCE ON MITOCHONDRIA DYSFUNCTION AND ANGIOGENESIS","internalauthor":"ROSSI, CLARA","type":"Tesi di dottorato","year":"2025","abstract":"INTRODUCTION: Atherosclerosis, the principal underlying cause of most cardiovascular diseases, progresses from early fatty streaks to advanced unstable plaques that, if ruptured, cause life-threatening events. A hallmark of plaque instability is intraplaque angiogenesis, the formation of neovessels. These neovessels are often immature and leaky, facilitating intraplaque haemorrhage, which exacerbates inflammation, promotes plaque growth, and culminates in rupture and thrombotic complications. While hypoxia is a critical driver of this process, additional pro-angiogenic mechanisms within the plaque microenvironment remain incompletely defined. Atherosclerosis is also an age-associated disease characterized by the accumulation of senescent cells, particularly vascular smooth muscle cells (VSMCs), which remain metabolically active but exhibit significant morphological changes, mitochondrial dysfunction and adopt a senescence-associated secretory phenotype (SASP). Despite growing recognition of senescent VSMCs’ detrimental roles in atherosclerosis, like sustained local inflammation, matrix degradation, and tissue remodelling, their potential contribution to intraplaque angiogenesis through pro-angiogenic SASP has not yet been elucidated.   Moreover, while statin therapy, the most widely used drugs for the prevention and treatment of atherosclerosis, plays a crucial role in managing atherosclerosis by reducing cholesterol levels and promoting plaque stability, its impact on mitochondrial dysfunction and SASP in senescent VSMCs remains largely unexplored.     AIM: This study aimed to investigate the interplay between VSMC senescence, mitochondrial dysfunction, SASP, and angiogenesis, and to evaluate the effect of simvastatin on these processes, and to test whether targeting specific SASP-related pathways (VEGF/VEGFR2 and NF-κB) may represent more effective therapeutic strategies.     RESULTS: We demonstrated, using both single-cell RNA sequencing datasets and immunohistochemistry, that senescent VSMCs are significantly more abundant in human unstable carotid atherosclerotic plaques than in stable ones. Consequently, based on these premises and in order to study senescent VSMCs more thoroughly, we developed and characterized two in vitro models of VSMC senescence: replicative (or old cells) and doxorubicin-induced mimicking stress-induced premature senescence, by assessing key senescence features such as cell morphology, cell cycle arrest, SASP, and mitochondrial dysfunction. Interestingly, both senescent models displayed an accumulation of dysfunctional mitochondria characterized by reduced mitochondrial membrane potential (MMP) and respiration, accumulation of reactive oxygen species (ROS), and an altered mitochondria morphology when compared to their young cells control. Moreover, TFAM and TOM70 expression was found to be downregulated only in old cells suggesting a reduction of mitochondrial biogenesis. In addition, both models of senescent VSMCs showed a significant increase in the gene expression and protein production of pro-inflammatory cytokines, including IL-1β, IL-6, and IL-8, thereby validating the SASP profile.  Next, we investigated whether simvastatin could ameliorate age-associated phenotypes in senescent VSMCs. Simvastatin (0.1 μM) improved mitochondrial respiration and reduced ROS production and the inflammatory SASP in both doxorubicin-induced and old VSMCs.  Notably, when mevalonic acid, a downstream product of the HMG-CoA reductase pathway, was added, these beneficial effects of simvastatin on mitochondrial function and the SASP were no longer observed. This indicates that simvastatin's impact on mitochondrial respiration and SASP is specifically mediated through the inhibition of HMG-CoA reductase, the enzyme targeted by statins in the cholesterol biosynthesis pathway.  Multiplex analysis of the inflammatory SASP in the cell culture medium of the senescent VSMCs confirmed the appropriateness of our in vitro models as doxorubicin-treated and old cells produced significantly more pro-inflammatory proteins such as IL-1β, IFN-γ and TNF-α compared to young cells, as already reported in the literature. Surprisingly, we also found that doxorubicin and old VSMCs produced significantly more pro-angiogenic molecules like Angiopoietin 1 and 2, IL-6, IL-8 and VEGFa, compared to young control cells. Interestingly, VEGFa showed a 4-fold increased concentration in doxorubicin and old cells when compared to young control cells.  We next investigated the paracrine effect of the SASP derived from both our senescent VSMC models on angiogenesis, by exposing Human Umbilical Vein Endothelial Cells (HUVECs) to senescent VSMC-conditioned media. HUVECs treated with conditioned media from senescent cells showed enhanced endothelial cell proliferation, migration, and tube formation when compared the their control treated with conditioned medium from young cells.   Notably, simvastatin-treated senescent VSMCs secreted significantly lower levels of pro-angiogenic factors, especially VEGFa, compared to their untreated control. Consistently, conditioned media from simvastatin-treated senescent VSMCs led to a significant reduction in HUVECs proliferation, migration, and tube formation compared to untreated media from senescent VSMCs.   As VEGF stood out as the main pro-angiogenic factor in our multiplex analysis, we supplemented the conditioned media from senescent VSMCs with rivoceranib, a selective VEGFR2 inhibitor, and assessed its impact on angiogenesis. Interestingly, VEGFR2 inhibition completely abolished SASP induced HUVEC proliferation, migration, and tube formation, confirming the central role of VEGF and its receptor VEGFR2 in mediating the paracrine pro-angiogenic effects of the SASP produced by senescent VSMCs.   Since NF-κB is a well-known regulator of the SASP, we pharmacologically inhibited NF-κB activity and we found a significant reduction in VEGF production in senescent VSMCs, suggesting that targeting this pathway could reduce the angiogenic potential of senescent VSMCs.     CONCLUSIONS: Overall, our findings underscore the multifaceted role of VSMC senescence in promoting atherosclerotic plaque progression and vulnerability. By integrating transcriptomic, histological, and functional analyses, we identify cellular senescence not only as a passive hallmark of vascular aging but as an active driver of plaque destabilization, particularly through mitochondrial dysfunction and the pro-angiogenic secretory phenotype.","language":"eng","citation":"THE IMPACT OF VASCULAR SMOOTH MUSCLE CELL SENESCENCE ON MITOCHONDRIA DYSFUNCTION AND ANGIOGENESIS / C. Rossi ; tutor: A. Corsini ; co-tutor: S. Bellosta ; coordinatore: G.D. Norata. - Milano. Dipartimento di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti, 2025 Dec 16. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13829_1.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1201457/3200981/phd_unimi_R13829_1.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1041949"},"title":"PREDICTION AND CAUSAL ANALYSIS OF CHURN IN THE TELECOMMUNICATION DOMAIN","internalauthor":"BARSOTTI, ANNALISA","type":"Tesi di dottorato","year":"2024","abstract":"In the Telecom context, the problem of Customer Churn Prediction (CCP), (or customer defection prediction) can be addressed by using not only well- established domain expert knowledge, but also by exploiting the potential wealth represented by customer-related data and applying Machine Learning Techniques. In this work, we used a TIM S.p.A. real-world dataset to train models that could predict which customers can defect. We compared the outcomes of a considerable number of classification algorithms on our real-world dataset. Furthermore, we applied the causal reasoning on the real dataset identifying actionable features by indirect confirmation of the domain experts. Another need of the telecom stakeholders is to understand the reasons why a customer might defect. This calls for the use of Causal Analysis: thanks to Causal Analysis – and more specifically to Causal Calculus – one can try to extract the direct and indirect causes from observational data. For such an analysis to be possible, one needs beforehand to count on the availability of a Structural Causal Model, or to extract causal graph and other information from the data. Causal discovery can be performed using a number of algorithms, based on different principles, which, when reconstructing sufficiently large graphs, can produce discordant outcomes.  In this work, we contribute a causal discovery method that takes advantage of topology-related information generated by an ensemble of causal discovery algorithms to identify which topology is closest to the ground truth. The method relies on the results of the discovery algorithms, considered as a committee of experts, and on a supervised learning approach consisting of stacking of a multi-label classifier on the outcomes of the ensemble. Ideally, this discovery method could also be used on Telecom data;  however, since for our data the ground truth (GT) was not available, we limited ourselves to validating the method on synthetic data, generated by a specialized library. Applying our method to the synthetic data we found that we could considerably improve the accuracy of the discovery with respect to the use of individual discovery algorithms.","language":"eng","citation":"PREDICTION AND CAUSAL ANALYSIS OF CHURN IN THE TELECOMMUNICATION DOMAIN / A. Barsotti ; tutor: G. Gianini ; co-tutor: E. Damiani ; external tutor: L. Liverani ; PhD program coordinator: R. Sassi. - Milano. Università degli Studi di Milano, 2024 Apr 17. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12824.pdf","fileformat":"Adobe PDF","fileversion":"preprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1041949/2389590/phd_unimi_R12824.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/955257"},"title":"BANCA CENTRALE, FORMA DI GOVERNO ITALIANA E INTEGRAZIONE EUROPEA","internalauthor":"SORRENTINO, EDOARDO","type":"Tesi di dottorato","year":"2023","abstract":"Central bank, Italian form of government and European integration    Edoardo Sorrentino  PhD in Public, International and European Law  Università degli Studi di Milano    The purpose of my thesis is to highlight an aspect that could redefine today’s theory of forms of gov-ernment. It is well known that the latter has, as its object of study, the provisions governing the relations between the constitutional bodies that participate at the function of political orientation. And this func-tion, in contemporary states, almost entirely coincides with the public management of the economy. Sus-tained growth of national income has become the primary objective of contemporary States, both to en-sure high levels of employment and to find the necessary tax revenue to finance the services provided by the State itself. It is immediately appropriate to point out that the public government of the economy is not the exclusive prerogative of fiscal policy. Monetary policy has an equally fundamental function. We cannot ignore the role that central banks have played in the public management of the economy. Through its operations – such as the fixing of interest rates, credit facilities to the Treasury and the pur-chase and sale of public and private securities – central banks are able to influence the growth of nation-al income, the general level of prices and the evolution of external accounts. In other words, the results of the economic policies adopted by governments are conditioned by the choices made by the issuing institutions. Consequently, a complete theory of the forms of government cannot be separated from the analysis of the relationship that the central bank has with the Government and with the Parliament, in other words with the political orientation circuit.  The first chapter highlights the history of central banks and the evolution of their function, explaining how the position of the issuing institution is intimately linked to the purposes chosen by the State. A clear separation of roles has characterized nineteenth-century liberal democracies, dedicated to the safe-guard of markets. A government that had the monetary support of the central bank would, in fact, have interfered with the right of ownership and the freedom of economic initiative. An issuing institution in-dependent from the executive power and committed to maintaining price stability was therefore a means of making the Government to adopt a balanced economic policy. But in the substantial post-war democ-racies the government had to take an active role in order to correct the most intolerable inequalities produced by the market.  In this framework, the central bank had to operate in a manner that served the government’s economic policy draft by ensuring that it would be financed on more favourable terms than those determined by the market. Obviously, this worldwide phenomenon has involved the Italian Republic. The constituents outlined, in addition to a poorly rationalized parliamentarism, an “economic constitution” that lacked clear guidance on the management of fiscal and monetary policy. The original 1948 text allowed the use of public debt without substantive, but only procedural, limits and did not openly enshrine the principle of monetary stability. The action of public authorities had to be oriented towards achieving full employment and reducing inequalities.  The second chapter deals with the development of the Italian form of government during the first twen-ty years of the Republic. It is well known that the lack of rationalization of parliamentarism has led to the development of a political system with an extreme multi-party situation where the element of alter-nation of government has failed, due to the conventio ad excludendum of the anti-system forces. However, the ministerial instability do not affect the development of the country, which benefits from a particular international framework: the fixed exchange rate system designed at Bretton Woods in fact allows the acceding countries to modulate economic policy according to their growth goals, given that large capi-tals were not free to circulate internationally. Moreover, the expansionary economic policy of the United States – the center of the international monetary system – ensures high economic growth and low infla-tion levels in all western countries. In this period, the monetary policy of the Bank of Italy has been functional to the achievement of the economic policy goals of many governments. Despite the instability of the executives, in fact, the fundamental lines of development remain firm: an export-oriented econo-my in order to maintain the equilibrium of balance of trade of a country without raw materials and en-ergy sources. In other words, the monetary system built after the war allowed the development of a de-featist party system without this calling into question its constitutional assumptions.  The third chapter analyses the effects of the collapse of the monetary system devised at Bretton Woods and the subsequent “stagflation” on the Italian institutional system. In fact, ministerial instability does not make it possible to counter the rise of prices during the 1970’s caused by wage demands and the oil shock. In this decade, Italy has experienced the highest levels of inflation among the large Western coun-tries accompanied by severe trade deficits. Only thanks to the governments of national unity the country succeeds in embarking on a path of recovery, crowned by the entry of Italy into the European Monetary System. This is a new system of fixed exchange rates in which the objective of ensuring the free move-ment of capital is expressly pursued. The entry into the Ems is supposed to push Italy to reduce state in-tervention in the economy. The so-called “divorce” between the Treasury and the Bank of Italy in 1981 is, in this regard, the tool to reduce the central bank’s financial support for the State’s borrowing ma-noeuvres. However, the 1980’s see an inflation fall, but at the same time the explosion of public debt and the formation of a large trade deficit financed by foreign capital, especially German ones. The continuing ministerial instability does not allow any serious restructuring of public expenditure. Moreover, in the 1980,s the fragmentation of the party system increases due to the crisis of the two political parties pro-tagonists of the previous thirty years.  The fourth chapter focuses, in particular, on the crisis of the first half of the 1990’s, in which Italy leaves the Ems and faces the final crisis of the traditional parties, which give way to a new party system that re-volves on two opposite poles. At this stage there is a strengthening of the role of the President of the Republic in the resolution of government crises. The Head of State promotes the formation of technical governments that begin a serious work of fiscal consolidation, guaranteeing the commitments made by Italy at European level. In fact, the Maastricht Treaty, signed in 1992, will lead in 1999 to the creation of a single currency and a fixed exchange rate regime. The future currency will be managed by a central bank independent from member States of the monetary union and committed to the sole maintenance of price stability. The direct consequence of this priority objective is the prohibition of direct financial support to States which will be bound to finance themselves on the market under the conditions laid down for any private entity. In short, since 1992 the Italian “economic constitution” has entered a new phase: the democratically legitimized constitutional organs completely lose the levers of monetary policy. Price stability becomes an overarching value, to be pursued even when it goes against other objectives, such as a high level of employment. Fiscal policy itself is conditioned by quantitative parameters which the European institutions monitor. However, thanks to the consolidation work begun in the first half of the 1990’s, Italy also managed to join the single currency.  The fifth chapter analyses the effects of Italy’s entry into the single currency area on the form of gov-ernment. The 2008 financial crisis led to a tightening of European budgetary constraints, while the Eu-ropean Central Bank has launched monetary support programmes that have allowed States to finance themselves on better terms than market conditions. At this juncture there was a new intervention by the Head of State as guarantor of Italy’s European commitments. A new technical government was formed whose primary objective was to reduce the country’s trade deficit and introduce the principle of budget-ary balance in the Italian Constitution. With this step, the “economic constitution” completed the turn-ing point towards the depoliticization of the public law of the economy that began in 1992. The crisis has determined the end of the fragile Italian bipolarism with the emergence of political forces alien to the traditional camps. The renewed political instability has led to a further strengthening of the Presi-dent of the Republic in his role of guarantor of the permanence of Italy in the single currency area. In this regard, the events surrounding the formation of a eurosceptic government in 2018 are emblematic. Following the 2020 pandemic, it was decided to lift budgetary constraints, while the Ecb expanded its monetary support to member States. It seems that a new phase of monetary union has been reached, but the rise in prices due to the Ukrainian conflict could force European States to adopt deflationary measures even more stringent than those adopted in the previous decade, with perhaps even more evi-dent effects on the party system and on the Italian form of government.","language":"ita","citation":"BANCA CENTRALE, FORMA DI GOVERNO ITALIANA E INTEGRAZIONE EUROPEA / E. Sorrentino ; tutor: F. G. Pizzetti ; coordinatrice: F. Biondi. Dipartimento di Studi Internazionali, Giuridici e Storico - Politici, 2023 Feb 20. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12617.pdf","fileformat":"Adobe PDF","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/955257/2143797/phd_unimi_R12617.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/841278"},"title":"DRUG-MEDIATED NFIX INHIBITION AS A NEW THERAPY FOR MUSCULAR DYSTROPHIES","internalauthor":"ANGELINI, GIUSEPPE","type":"Tesi di dottorato","year":"2021","abstract":"Muscular Dystrophies (MDs) are still incurable monogenic myopathies characterized by progressive degeneration of skeletal muscle, respiratory and cardiac complications, and premature death. Dystrophic myofibers are highly fragile, due to mutations in the Dystrophin-Glycoprotein Complex (DGC), which provides a physical support to muscle contraction. In dystrophic muscles, chronic cycles of degeneration/regeneration of myofibers occur, progressively leading to an exhaustion of satellite cells, the skeletal muscle stem cells (MuSCs), and to the loss of skeletal muscle tissue.   Dystrophic mice lacking the transcription factor Nfix, crucial for the switch from embryonic to fetal myogenesis, display morphological and functional improvements of the disease, due to the slowing down of muscle regeneration and to a shift towards more oxidative myofibers.  Recently, we demonstrated that the MAPK (MEK/ERK) signaling pathway positively regulates the Nfix protein levels both in fetal myoblasts in vitro and in fetuses in vivo, bringing out the idea of an indirect pharmacological inhibition of Nfix in a dystrophic context.  In this research project, we demonstrate that this regulation is also conserved in postnatal myoblasts. Chronic treatment of adult Sgca null mice with two FDA-approved MEK-inhibitors, Trametinib and Selumetinib, every day for 14 days by oral gavage, causes a decrease of pERK and Nfix protein levels in dystrophic skeletal muscles. The Nfix gene expression in treated muscle does not change, indicating the involvement of post-translational rather than transcriptional mechanisms of regulation. This reduction of Nfix is nevertheless not sufficient to improve the histology of dystrophic muscles, which display smaller myofibers, higher necrosis, and, unexpectedly, calcification at high drugs dosages. However, Trametinib- and Selumetinib-treated muscles exhibit more myofibers with an oxidative metabolism, which is known to protect from dystrophic damage.  Our study provides a proof-of-concept that Nfix is modulated by the MEK/ERK pathway in postnatal dystrophic muscles in vivo, unraveling the regulatory network behind this crucial transcription factor in MDs. Combining the MEK-inhibitor administration with other drugs and/or a type of diet acting on calcifications might improve the treatment, setting the stage for a combined approach to face such heterogeneous diseases.","language":"eng","citation":"DRUG-MEDIATED NFIX INHIBITION AS A NEW THERAPY FOR MUSCULAR DYSTROPHIES / G. Angelini ; tutor: G. Messina ; coordinator: M. Kater. Dipartimento di Bioscienze, 2021 May 28. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11968.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/841278/1793163/phd_unimi_R11968.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1076889"},"title":"RICOSTRUZIONE STORICA DEL COLLEZIONISMO D'ARTE GIAPPONESE DI ERA MEIJI IN ITALIA SETTENTRIONALE. SVILUPPI DI UN MERCATO PARALLELO AGLI SCAMBI COMMERCIALI E DIPLOMATICI.","internalauthor":"LANZA, ELEONORA","type":"Tesi di dottorato","year":"2024","abstract":"This research delves into the experiences of Italian entrepreneurs, diplomats, and other notable figures who first developed a keen interest in Japanese art and significantly influenced the enthusiasm for collecting oriental manufacturing products in Italy. They explored Japan for diplomatic reasons or in search of healthy silkworm seeds following an epidemic disease of the worms in Europe during Japan's transition from the Edo period (1603-1868) to the Meiji era (1868-1912). These characters  have been examined in scientific studies from a historical perspective, but their contribution to fostering Italian enthusiasm for Japanese art has never been deepened. This study focuses on their collections and other aspects of their involvement with the artistic sphere. In fact, it is possible to perceive the foundation of Italian impressions of Japanese art and initial  demonstrations of interest in Japanese art and craft through diverse sources such as diplomatic reports, personal diaries, letters, and photographs. Many individuals were captivated by the beauty of the  prints, illustrated books, lacquers, bronzes, ivories, and porcelain, they collected avidly for personal pleasure driven by a strong desire to learn about a new culture. For example, Paolo Velini, Giacomo Bolmida, Giovanni Battista Imberti, and the Bertone brothers assembled collections that remained private and mostly unknown until this research. Some individuals transformed their passion into business activities, like Carlo Orio and Pietro Beretta who assisted the Duke of Genoa Tommaso di Savoia in acquiring artifacts in Japan. Others, like Enrico Andreossi, expanded their collecting  interests to include Western art. This fascination with Japanese art extended to diplomats, politicians, and members of the Italian navy, such as Cristoforo Robecchi, Camillo Candiani, Carlo Grillo who brought back works of Japanese art for themselves and on commission. Ultimately, these individuals played a crucial role in shaping the artistic tastes of their time, towards the end of the century, they also contributed to international exhibitions. Interest in Japanese art culminated in the opening of  specialised stores, such as the Tognacca and Giglio-Tos shop in Turin, aiming to satisfy the new tastes of Italians who were ready to collect all kinds of artifacts, including woodblock printed books that are kept in some public libraries in northern Italian cities.","language":"ita","citation":"RICOSTRUZIONE STORICA DEL COLLEZIONISMO D'ARTE GIAPPONESE DI ERA MEIJI IN ITALIA SETTENTRIONALE. SVILUPPI DI UN MERCATO PARALLELO AGLI SCAMBI COMMERCIALI E DIPLOMATICI / E. Lanza ; tutor: R. Menegazzo ; coordinator: F. Slavazzi. Università degli Studi di Milano, 2024 Jul 18. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12862.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1076889/2477699/phd_unimi_R12862.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1073948"},"title":"RICERCHE SULLA LEGISLAZIONE DI ONORIO","internalauthor":"LANTI, LORENZO","type":"Tesi di dottorato","year":"2024","abstract":"Emperor Honorius has not received much attention from historiography, which has often limited itself to emphasising his inadequacy and weakness in relation to the various problems that the western part of the empire was experiencing; indeed, barbarian incursions, complex religious issues, and the constant need for considerable economic resources were formally entrusted to the purple of a teenager, given that Honorius came to power in 395 when he was only eleven years old. In fact, it was others who influenced the political direction of Honorius' reign, among them Stilicho and Constantius III: the former as regent appointed by Theodosius I on his deathbed, the latter also appointed emperor in 421. This does not detract from the fact that the figure and reign of Honorius nevertheless deserves to be framed in the light of both the few literary testimonies we have (e.g. Zosimus, Claudian and the chronological sources) and, above all, through the more than four hundred and fifty constitutions issued by his chancellery in the twenty-eight years of his reign. In particular, the biography of the young emperor will be traced, highlighting the most salient and most debated moments in the literature, with particular reference to his childhood and the role of Stilicho.   It has been decided to provide a list of all constitutions attributed to Honorius that are known from the Theodosian Codex and the Codex Iustinianus, giving their respective correspondences, a summary of their content and data on their addressee and dating.  Two Appendices, dedicated respectively to the addressees of the constitutions and the places of promulgation, data that can be deduced from the inscriptiones and subscriptiones, conclude this section, to offer hints for prosopographical research and to assess the movements of the imperial comitatus.  Then, a number of thematic in-depth studies were carried out: the first encompasses some interventions by Honorius' chancellery on African issues, both from an anti-heretical and anti-pagan perspective, as well as disciplining public order (discipline against raids by nomadic peoples and the case of Heraclianus). Finally, we wanted to identify some of Honorius' constitutions on the subject of succession in order to verify how the institutions and classical law were transposed and possibly adapted to new situations.  Many of the major questions concerning late antique legislation stand out when dealing with Honorius' legacy of legislation: from the relationship between the West and the East to the choices of legislative technique oscillating between a concrete case and a tension towards generalisation, from the effects of the textual manipulations carried out by Theodosius II's commissioners to the manuscript tradition of the two Codices.","language":"ita","citation":"RICERCHE SULLA LEGISLAZIONE DI ONORIO / L. Lanti ; tutor: I. Fargnoli ; coordinatrice: F. Poggi. Dipartimento di Diritto Privato e Storia del Diritto, 2024 Jul 04. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13041.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1073948/2470183/phd_unimi_R13041.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/829369"},"title":"CONTROLLING FACTORS ON THE DEPOSITIONAL ARCHITECTURE OF CARBONATE SYSTEMS: SEDIMENTOLOGY, FACIES, GEOMETRY, DIAGENESIS AND GEOCHEMISTRY OF EASTERN SARDINIA JURASSIC CARBONATES","internalauthor":"NEMBRINI, MATTIA","type":"Tesi di dottorato","year":"2021","abstract":"The evolution through time and space of carbonate platforms and reefs is controlled by the interplay of global (climate, eustasy), regional (tectonic) and local environmental (nutrient levels, light penetration) factors affecting changes in accommodation and in the nature of the carbonate factories.  Major tectonic plate reorganizations related to the opening of the Alpine Tethys and climatic fluctuations affected Jurassic carbonate successions, which recorded one of the major peaks in the Phanerozoic for the abundance of coral, sponge and microbialite reefs.  This study focuses on the eastern Sardinia well-exposed Middle-Upper Jurassic carbonate depositional system that evolved in time and space in terms of facies composition and architecture, characters of the carbonate factory and geometry of the depositional profile encompassing four depositional phases. Detailed facies and microfacies analyses, diagenetic and geochemical investigations and new biostratigraphic data and strontium isotope analyses allowed to better constrain the distinctive sedimentological characteristics and age of these depositional phases, building upon the lithostratigraphic framework published in previous studies on eastern Sardinia carbonate succession.  Phase 1 (Callovian-middle Oxfordian) was characterized by the development of a coated-grain dominated carbonate ramp with inner ramp ooidal shoals and peloidal packstone in middle to outer ramp.  Phase 2 (late Oxfordian-late Kimmeridgian) recorded the evolution of a reef-bearing carbonate ramp characterized by three types of build-ups laterally distributed along the depositional profile, reflecting water depth increase and the interplay of water energy and light penetration. Type 1 build-ups (45 m thick, 100 m wide) consisted of coral-stromatoporoid boundstone and coral-stromatoporoid rudstone-grainstone and colonized proximal middle ramp settings. Type 2 build-ups (1-2 m thick, 3-4 m wide) were lens-shaped build-ups made of coral-calcareous sponge-diceratid boundstone, including stromatoporoids and chaetetid sponges associated with bioclastic packstone-grainstone developed in deeper, distal middle ramp settings. Type 3 build-ups (1 m thick and few metres wide) consisted of calcareous and siliceous sponge-coral-microbialite boundstone associated with bioclastic packstone-grainstone colonizing distal middle to outer ramp settings. The evolution from phase 1 to phase 2 was related to the global expansion of coral, stromatoporoid, calcareous and siliceous sponge and microbialite reefs during the middle Oxfordian-late Kimmeridgian due to eustatic sea-level rise and climatic fluctuations.  Phase 3 (late Kimmeridgian) followed a sea-level fall likely driven by regional extensional tectonics recorded by a subaerial exposure surface at the top of phase 2 likely due to fault block uplift. During  phase 3 peritidal facies accumulated in the proximal inner platform setting, whereas coated grain dominated facies (ooids and oncoids) were deposited as reworked grains in the more distal middle ramp domains. Differently from previous studies, the age of phase 3 was assigned to late Kimmeridgian according to strontium isotope and biostratigraphic data based on the occurrence of the foraminifer Alveosepta jaccardi rather than to the Tithonian. The top of phase 3 is marked by another event of subaerial exposure, also recorded in coeval Tethyan depositional settings as a regional unconformity attributed to extensional tectonics.  The beginning of phase 4 (Tithonian) is characterized by transgressive basinal deposits followed by the recovery of a reefal carbonate factory. Phase 4 recorded a change in depositional geometry from a carbonate ramp to a higher-relief platform with a slope (about 70 m high and 3-15º steep). Basinal deposits consisted of mudstone, wackestone and siltstone and lithoclastic breccia with resedimented clasts from shallower environments through debris-flow mechanisms. Bio-intraclastic grainstone, wackestone with Clypeina jurassica, wackestone to floatstone with oncoids and peloidal intraclastic packstone to grainstone were resedimented from inner platform depositional environments. Debris-flow breccias include also lithoclasts of boundstone facies representing Tithonian bioconstructions developed during phase 4, different from the upper Oxfordian-upper Kimmeridgian phase 2 build-up types. Coral-calcareous sponge-microbialite boundstone and Bacinella boundstone constituted build-ups in well-illuminated shallow-water settings at the margin of phase 4 platform. Calcareous sponge-Crescentiella-coral boundstone and calcareous and siliceous sponge boundstone formed build-ups in the deeper upper slope and were resedimented into the adjacent basinal setting.  The transgression and recovery of the reefal carbonate factory at the beginning of phase 4 were dated to the early Tithonian due to ammonite biostratigraphic data from the basinal deposits. These depositional events were coeval and possibly triggered by tectonic instability during the eustatic sea-level rise that promoted optimal conditions for reef growth during phase 4.  The evolution of eastern Sardinia Callovian-Tithonian carbonate succession was controlled by global changes in the dominant carbonate factory with the onset of reef-building biota (late Oxfordian), regional extensional tectonics affecting the European margin of the Alpine Tethys that controlled relative sea-level changes and accommodation (late Kimmeridgian) and global eustatic rises in sea-level (late Oxfordian and early Tithonian).  Petrographic, cathodoluminescence and carbon and oxygen stable isotope analyses allowed reconstructing the diagenetic evolution of each depositional phase. Phase 1 facies were characterized by replacive burial dolomitization of zoned luminescent dolomite close to the Hercynian basement and precipitation of blocky calcite cement and microsparite in burial environment and during meteoric telogenesis. Phase 2 facies were characterized by isopachous fibrous cement during early marine  diagenesis, burial dolomitization and precipitation of equant blocky calcite and microsparite cement in burial and meteoric telogenetic diagenetic environments. Facies deposited during phase 3 were affected by early marine isopachous fibrous cement (middle ramp facies) or early meteoric vadose cementation by micritic meniscus and pendant cement (inner platform facies). The upper part of phase 3 succession, close to the subaerial exposure surface at the top, is characterized by fabric replacive dolomitization due to evaporitic brines in supratidal settings as inferred from the carbon and oxygen stable isotope signature. Precipitation of equant blocky calcite, fine-grained equant calcite and microsparite took place during burial diagenesis and telogenesis. Phase 4 facies are characterized by early marine (isopachous fibrous cement) and meteoric vadose (micritic meniscus) cementation. Fabric replacive dolomitization took place in the lower part of phase 4 facies close to the subaerial exposure surface due to possibly evaporitic brines. Blocky calcite cement and microsparite precipitated in burial environment and during meteoric telogenesis.  This study, integrating field data, petrographic, biostratigraphic, diagenetic and geochemical stable isotope analyses, highlights how regional tectonics, eustasy and carbonate factory changes affected the evolution of a Jurassic carbonate depositional system and reef growth. These findings have implications for the understanding of the responses of carbonate platforms and reef-building biota to environmental, climate and accommodation changes in the geological record.","language":"eng","citation":"CONTROLLING FACTORS ON THE DEPOSITIONAL ARCHITECTURE OF CARBONATE SYSTEMS: SEDIMENTOLOGY, FACIES, GEOMETRY, DIAGENESIS AND GEOCHEMISTRY OF EASTERN SARDINIA JURASSIC CARBONATES / M. Nembrini ; tutor: G.  Della Porta ; co-tutor: F. Berra ; coordinatore: F. Camara Artigas. Università degli Studi di Milano, 2021 Mar 25. 33. ciclo, Anno Accademico 2020. [10.13130/nembrini-mattia_phd2021-03-25].","filename":"phd_unimi_R11949.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/829369/1751570/phd_unimi_R11949.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1215655"},"title":"IL DIRITTO DELL'UNIONE EUROPEA NEGLI APPALTI PUBBLICI SOTTO LE SOGLIE DI RILEVANZA COMUNITARIA","internalauthor":"PAGLIERANI, LINDA","type":"Tesi di dottorato","year":"2026","abstract":"The thesis examines the impact of European Union law on the national regulation of public procurement contracts whose value falls below the thresholds established for the application of Directive 2014/24/EU. Although such contracts are excluded from the harmonised regime, they nevertheless fall within the scope of the Treaties and of the general principles of EU law where they are capable of attracting the interest of economic operators established in other Member States (so-called certain cross-border interest). They are therefore subject, in particular, to the freedoms of movement and to the principles of equal treatment, non-discrimination, transparency and proportionality.  In the absence of uniform criteria for assessing the existence of cross-border interest and of guidance on the modalities for implementing these obligations at national level, the legal framework applicable to below-threshold contracts is currently characterised by a high degree of uncertainty and by significant divergences among Member States’ legal systems.  Building on an analysis of the Italian framework introduced by Article 48(2) of Legislative Decree No. 36 of 2023, the thesis proposes an evolution of EU legislation through the insertion, within the relevant directive, of a provision specifically devoted to below-threshold contracts with certain cross-border interest. Such a provision would, on the one hand, establish harmonised criteria for assessing the existence of such interest and, on the other, prescribe the selective application of only those rules governing above-threshold contracts that are necessary to ensure the effectiveness of EU law principles.    The proposal aims to overcome the fragmentation of the current regulatory framework by promoting a more balanced relationship between the need for procedural simplification — which characterises such contracts — and the effective application of EU freedoms and principles, with a view to strengthening legal certainty and achieving greater uniformity among the national systems of the Member States.","language":"ita","citation":"Il diritto dell'Unione europea negli appalti pubblici sotto le soglie di rilevanza comunitaria / L. Paglierani ; tutor: L. Bertonazzi ;   cotutor: M. Condinanzi, F. Picod  coordinatrice: F. Biondi. - Milano. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2026 Feb 04. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13942.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 17-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1151355"},"title":"IMPROVEMENT OF METAGENOMIC TECHNIQUES TO BETTER UNDERSTAND THE ROLE OF CANDIDATE PHYLA RADIATION IN FOOD ALLERGIES","internalauthor":"PAPALEO, STELLA","type":"Tesi di dottorato","year":"2025","abstract":"\"Food allergies are local or systemic reactions that occur after the ingestion of normally innocuous food antigens (allergens) and can be triggered by various factors. The oral microbiota plays a critical role in the development of immune tolerance and is one of the factors involved. During my PhD I participated in a study in which the oral microbiota of food-allergic children was compared to healthy controls, in order to identify a microbial “signature” that characterizes this pathological state. The results of this study led us to continuing the investigation by focusing on a specific group of bacteria which we found  to be enriched in the oral microbiota of allergic children: “Candidatus Saccharibacteria”. This group belongs to the Candidate Phyla Radiation (CPR), a category of peculiar bacteria that accounts for at least 25% of the whole bacterial domain. Several researches indicate that, within the human microbiota, CPR bacteria play a role in immune modulation and consequently they might too in food allergy development. However, the detection of CPR is challenging due to their unique characteristics: small size, almost unculturable, unusual aminoacidic code, peculiar 16S rRNA gene with introns and indels. Therefore, molecular methods currently used, such as 16S rRNA amplicon metagenomics, often underestimate CPR and prevent a fully understanding of their role in human physio-pathology. This led us to evaluate other existing methods to quantify CPR: we performed a comparative study between currently available qPCRs protocols targeting 16S rRNA and 23S rRNA genes for the quantification of “Candidatus Saccharibacteria”. Furthermore, we performed an in silico study to identify a novel target for amplicon metagenomics studies, capable of adequately quantifying CPR bacteria as well, which identified RecA as a novel gene target for pan-bacterial metagenomics studies. Finally, we compared different protocols for DNA extraction from human saliva to obtain an extract enriched in CPR DNA. This study led us to obtain an efficient laboratory protocol for enriching \"\"Candidatus Saccharibacteria\"\" in human saliva samples. This method will be necessary to perform genomic studies on these difficult-to-culture bacteria, in order to deepen our knowledge of their genomic features and better understand their involvement in human health and disease states.\"","language":"eng","citation":"IMPROVEMENT OF METAGENOMIC TECHNIQUES TO BETTER UNDERSTAND THE ROLE OF CANDIDATE PHYLA RADIATION IN FOOD ALLERGIES / S. Papaleo ; relatrice: C. Mameli ; correlatore: F. Comandatore ; coordinatrice di dottorato: F. Cheli. Dipartimento di Scienze Biomediche e Cliniche, 2025 Mar 26. 37. ciclo, Anno Accademico 2024. [10.13130/papaleo-stella_phd2025-03-26].","filename":"phd_unimi_R13409_2.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1151355/2706108/phd_unimi_R13409_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/820119"},"title":"ROLE OF P21 IN THE IMMUNE RESPONSE AGAINST BREAST CANCER","internalauthor":"PREDOLINI, FEDERICA","type":"Tesi di dottorato","year":"2021","abstract":"Abstract    The immune system plays a major role in the surveillance against tumors. Tumor cells develop different strategies to escape immune surveillance, while immune therapies are designed to overcome mechanisms that mediate tolerance to tumor cells.The cell-cycle inhibitor p21 regulates immune tolerance, as revealed by the susceptibility of p21-deficient (p21-/-) mice to develop mild autoimmune diseases. My host-lab has reported that p21-/- myeloid leukemias are unable to transplant into syngeneic mice. I demonstrated that the same phenotype applies to p21-/- breast cancers, and that p21-/- tumors reacquire transplantability when injected into immunodeficient mice. Thus, I investigated cellular and molecular mechanisms underlying the effect of p21 in evading the immune surveillance against breast cancer. I showed that depletion of p21 selectively in CD11b+c+ antigen presenting cells (APCs) induces a robust MHCII-dependent and antigen-independent proliferation of CD4+ lymphocytes endowed with effector/memory phenotype and potent anti-tumor activities, mimicking homeostatic proliferation of T cells. Single-cell RNA sequencing of WT and p21-/- CD11b+c+ APCs showed differential expression of genes encoding antigen-processing and -presentation membrane proteins. Notably, I showed that p21-/- CD11b+ APC cells (comprising ~50% of the CD11b+c+ subpopulation) can be used in vitro to generate T cells with potent anti-cancer effect in vivo, thus paving the way to novel anti-cancer immunotherapeutic approaches in humans.","language":"eng","citation":"ROLE OF P21 IN THE IMMUNE RESPONSE AGAINST BREAST CANCER / F. Predolini ; supervisor: P. G. Pelicci ; co-supervisor: A. Insinga ; coordinator: G. Viale. Dipartimento di Oncologia ed Emato-Oncologia, 2021 Mar 30. 32. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11756.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/820119/1720517/phd_unimi_R11756.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1046330"},"title":"CELLULAR AND MOLECULAR PATHWAYS CONTROLLING SARS-COV2 ASSEMBLY AND EGRESS","internalauthor":"SERGIO, MARIA CONCETTA","type":"Tesi di dottorato","year":"2024","abstract":"SARS-CoV-2 is an enveloped, single-stranded, positive-sense RNA virus belonging to the family of Coronaviridae. Coronaviruses assemble on intracellular membranes, differently from many other RNA viruses that assemble and egress directly at the plasma membrane. This feature adds an additional layer of complexity to the study of the coronavirus life cycle as, once assembled, virions have to traffic through host intracellular membranes to reach the plasma membrane to be released.   The assembly of SARS-CoV-2 virions occurs at the ER-Golgi intermediate compartment (ERGIC), also named vesicular-tubular cluster (VTC). Here, the structural proteins Spike (S), Membrane (M) and Envelope (E), after being translocated from the endoplasmic reticulum (ER) to the ERGIC, interact with the complex formed by viral RNA and the Nucleocapsid (N) protein (ribonucleocapsid) on the cytosolic side of the membrane and form the viral particle by budding into the lumen of the ERGIC. From here, newly formed virions would be expected to enter the Golgi complex and reach the plasma membrane to egress but the intermediate stations traversed by the virus and the molecular machineries that host cells put in place to counteract viral propagation have not been clearly established.   Many genetic screens have been performed to find host factors involved in SARS-CoV-2 infection. We filtered the results of these screens to select the host proteins involved in membrane trafficking and focused our attention on the Endosomal Complex Required for Transport (ESCRT) machinery that appears to behave as an anti-viral factor. To address the mechanism by which this molecular machinery acts as a restriction factor, we first used a reductionist approach based on transfection of single viral structural proteins, and then progressed to viral infection experiments.  We found that the SARS-CoV-2 E protein is able to recruit the ESCRT complex via syntenin and Alix, thus defining the chain of molecular interactions that leads to the binding of this complex by a viral protein. Using immunofluorescence analysis, we found that this interaction occurs at late endosomes, where the ESCRT complex mediates the budding of the E protein into the lumen of the inner vesicles of multivesicular bodies. To study the role of ESCRT in viral infection, we took advantage of a cell line in which the ESCRT function can be impaired in an inducible manner through the expression of the dominant negative mutant of VPS4, the ATPase responsible for ESCRT disassembly. We found an increase in viral spread upon ESCRT machinery impairment, thus confirming the anti-viral role of this complex.   Importantly, we found that viral structural proteins are degraded in lysosomes in infected cells, and also in transfected cells but only when the E protein is exogenously expressed. Our evidence led us to hypothesize that the ESCRT complex, through the interaction with the E protein, could be responsible for the degradation of single structural proteins and/or intact virions inside lysosomes.   We then addressed the role of the secretory pathway in SARS-CoV-2 egress, which has been recently questioned. We found that the release of infectious viral particles is strongly impaired by Brefeldin A, a fungal toxin which inhibits anterograde transport, without affecting viral replication. Our data point to a pivotal role of the Golgi complex and secretory pathway for the release of viral particles and we found the ESCRT machinery as a restriction factor for viral infection.","language":"eng","citation":"CELLULAR AND MOLECULAR PATHWAYS CONTROLLING SARS-COV2 ASSEMBLY AND EGRESS / M.c. Sergio ; supervisore: M. A. De Matteis ; phd coordinator: S. Minucci. - Telethon Institute of Genetics and Medicine (TIGEM). Dipartimento di Oncologia ed Emato-Oncologia, 2024 Apr 22. 35. ciclo","filename":"phd_unimi_R12712.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1046330/2401152/phd_unimi_R12712.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1149636"},"title":"GREEN SENSORS AND SMART SERVICES FOR THE OPTIMIZATION OF AGRI-FOOD SUPPLY CHAINS IN A VIEW OF INDUSTRY 4.0: GREATER SUSTAINABILITY OF PRODUCTION, BUSINESS COMPETITIVENESS AND REDUCTION OF FOOD WASTE","internalauthor":"VIGNATI, SARA","type":"Tesi di dottorato","year":"2025","abstract":"The 12th Sustainable Development Goal (SDG) focuses on the concept of sustainable consumption and production, with a particular focus on reducing food loss and waste (Goal 12.3) by 2030. In order to achieve this in the fresh-cut chain, it is necessary to implement systemic improvements, including advanced agronomic practices, optimised harvest timing, effective post-harvest storage and innovative packaging. Green technologies such as optical sensing have the potential to enhance quality, extend shelf life and reduce environmental impact. However, their high costs present a significant barrier to adoption, as multiple devices are often required to address the complexities of supply chains. Research is addressing this challenge by developing compact, and low-cost imaging solutions for both pre- and post-harvest monitoring.  This doctoral research project concerns the application of non-destructive imaging techniques to assess the quality of some fresh and fresh-cut products, in terms of freshness and shelf life. Additionally, it involves the development of customized optical devices in a view of Industry 4.0, with the objective of enhancing the sustainability of the supply chain and reducing food loss and food waste. Two distinct measurement configurations were employed at laboratory scale, each with a different application objective. The first configuration concerned a cost-effective IoT hyperspectral prototype, that has been designed and successfully tested. The prototype operated within the spectral range of 400 nm to 1000 nm and has been developed using commercial equipment and a 3D-printer. It has reached satisfactory results for the current stage of technology development, which is estimated to be at a TRL (Technology Readiness Level) of 2. The prototype exhibited the capacity to differentiate between healthy and damaged tissue and to be sensible to variations in leafy vegetables over time, thereby demonstrating the capability to detect changes in the product as it undergoes decay. The prototype was designed for future integration at critical points in the production chain. Instead, the second configuration was proposed with the aim of monitoring the quality level of packaged products, thereby improving their management at the sales point and providing consumers with information on the true quality level of the products. This study demonstrated the potential of multispectral imaging for non-destructive monitoring of fresh-cut lettuce deterioration through packaging. The application of chemometric methods enabled effective identification and classification of fresh samples. However, the classification accuracy for subsequent days was found to be variable due to differences in decay rates between sample groups and light reflections from packaging.   In conclusion, this PhD project has demonstrated the benefits and potential of imaging systems as an effective and sophisticated tool for quality assessment in the food industry throughout the production chain, as well as one of the key tools for reducing food loss and waste. However, continued research and development is essential to refine these technologies and make them accessible and adaptable for wider applications. By integrating these tools into sustainable practices, the agri-food sector can make significant progress towards achieving global sustainability goals.      Keywords: Green technology, food quality, imaging, industry 4.0, sensor design, cost-effective, chemometrics.","language":"eng","citation":"GREEN SENSORS AND SMART SERVICES FOR THE OPTIMIZATION OF AGRI-FOOD SUPPLY CHAINS IN A VIEW OF INDUSTRY 4.0: GREATER SUSTAINABILITY OF PRODUCTION, BUSINESS COMPETITIVENESS AND REDUCTION OF FOOD WASTE / S. Vignati ; tutor: R. Guidetti ; co-tutor: R. Beghi ; coordinatore: D. Mora. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2025 Mar 04. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13616_2.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1149636/2693482/phd_unimi_R13616_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1219178"},"title":"VIRAL SAFETY EVALUATION OF BIOTECHNOLOGY PRODUCTS: DEVELOPMENT AND OPTIMIZATIONOF RELIABLE VIRAL CLEARANCE STRATEGIES","internalauthor":"SONI, DHRUVKUMAR HARIHARBHAI","type":"Tesi di dottorato","year":"2026","abstract":"This manuscript brings together the research activities carried out throughout my doctoral program and  reflects the dual nature of the project, which developed at the interface between academic research and  industrial application. The thesis is part of a broader framework dedicated to the study, optimization, and  validation of viral clearance strategies within downstream processing for monoclonal antibody (mAb)  production, with the overarching goal of establishing procedures that are effective, reproducible, and fully  transferable to the biopharmaceutical industry.  During the first year, thanks to a structured training period at the Department of Pharmaceutical Sciences  (DISFARM), University of Milan, I consolidated essential skills in preparative chromatography and conducted  an extensive literature analysis on viral clearance approaches. This effort culminated in a review article,  entitled ‘Viral Clearance in Biopharmaceutical Manufacturing: Current Strategies, Challenges, and Future  Directions’, prepared in collaboration with Prof. Altomare and recently submitted, and positively revised, for  publication in Biotechnology Advances (Elsevier). Presented here as the first part of the thesis, the review  provides the reader with an up-to-date overview of the principles, technologies, and challenges associated  with viral removal within DSP, offering the conceptual foundation necessary to contextualize the  experimental core of the project.  The second part of the thesis is dedicated to the experimental work conducted jointly at DISFARM and  Eurofins Biolab Srl., where I established, optimized, and subsequently transferred to an industrial setting a  purification protocol based on Protein A chromatography and Ion Exchange Chromatography (IEX) for mAb  manufacturing. This workflow was integrated with viral removal and inactivation studies performed at the  Virology Unit of Eurofins, employing model viruses such as X-MuLV and MVM and combining  chromatographic systems, filtration technologies, and advanced biological assays. This section provides an  in-depth description of the methodologies adopted, the rationale behind the operational strategies, and a  critical discussion of the results, with particular focus on process scalability, robustness, and industrial  transferability.  Overall, the thesis aims to guide the reader through a coherent path that begins with the current state of viral  clearance technologies, progresses through the optimization of a laboratory-scale purification process, and  culminates in its validation under industrial conditions. The overarching objective is to provide a  comprehensive, structured, and forward-looking perspective on viral removal strategies for therapeutic  antibody production, highlighting the scientific and technical contributions developed over the course of the  PhD program.","language":"eng","citation":"VIRAL SAFETY EVALUATION OF BIOTECHNOLOGY PRODUCTS: DEVELOPMENT AND OPTIMIZATION OF RELIABLE VIRAL CLEARANCE STRATEGIES / D.h. Soni ; tutor: P. Minghetti; co-tutor: A. Altomare ; coordinatore: E. Damiani. Dipartimento di Scienze Farmaceutiche, 2026. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14046.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1219178/3259860/phd_unimi_R14046.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/945376"},"title":"INTEGRATION OF NUTRITIONAL SUPPORT IN ORTHOPEDICS: DIETARY AND NUTRITIONAL ASPECTS OF SURGICAL PATIENTS","internalauthor":"BRIGUGLIO, MATTEO","type":"Tesi di dottorato","year":"2022","abstract":"The nutritional support in orthopedic surgery is an unclear idea to date. In these years, the goal of this project has been to clarify what is meant by nutritional support in patients undergoing hip or knee replacement and spine surgery, demonstrating its value in relation to the perioperative path. This aim was pursued by applying a methodology of first studying the literature, then analyzing the setting, evidencing shortcomings, proposing management protocols, and verifying the effectiveness of nutritional strategies. The literature search highlighted the multiple phases that should be coordinated, including prehabilitation, perioperative, and postdischarge management. When applying optimization strategies, such as anemia correction, it may be necessary to examine the eating behavior and anticipate the metabolic responses according to the patient’s state of health. The predictive potential of hemoglobin on the clinical outcome in spine surgery has been investigated through retrospective analysis of existing data, suggesting the need to refine decision-making algorithms that identify the patients to be treated, underlining the importance of having high hemoglobin values in the preoperative period to have more chances of clinical success. Prospective observational studies confirmed that patients either after spine surgery or arthroplasty do not meet their needs for what concerns energy and proteins. It seems to be vital to redefine the tactics to promote early oral nutrition, counteract the depletion of body reserves, and acknowledge the impairment of the olfactory stimulus caused by anesthetic drugs. More transparent information on diet and nutrition should be conveyed to patients. The nutritional support program might include a healthy eating education that teaches the concepts of nutritional value, quantity, quality, and timing. Clear information on what to eat or not to eat before surgery must be accompanied by dietary advice also for postoperative recovery. New management proposals can integrate aspects of healthy eating education into a multimodal approach that includes advice on increasing physical activity and promoting night sleep. A risk management system inspired by the hazard analysis and critical control points system can be effectively applied before orthopedic surgery to manage malnutrition. The interventional trials proved that nutrient deficiencies, including those of vitamin D and iron, are common in the surgical population. Dietary supplements should be carefully selected for what concerns the pharmaceutical formula, as well as for the content of important cofactors that may be necessary to boost the metabolic response. Early cardiovascular effects can derive from correcting hypovitaminosis D with a liquid form of vitamin D, and promising data on enhancing preoperative hemoglobin values can derive from using a supplement containing iron and B vitamins. The future of perioperative medicine in orthopedic surgery should choose a pragmatic integration of dietary and nutritional aspects in orthopedics, thus possibly improving health performance and patient experience.","language":"eng","citation":"INTEGRATION OF NUTRITIONAL SUPPORT IN ORTHOPEDICS: DIETARY AND NUTRITIONAL ASPECTS OF SURGICAL PATIENTS / M. Briguglio ; tutor: M. Porrini : coordinator: L. Pinotti. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2022 Dec 05. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12734.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/945376/2095441/phd_unimi_R12734.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1157055"},"title":"ARTIFICIAL INTELLIGENCE AVAILABLE TO THE DEVELOPMENT OF A VIRTUAL REALITY SOFTWARE FOR AN AUTOMATED CEPHALOMETRIC ANALYSIS OF ULTRA-REDUCED CBCT FOV","internalauthor":"SERAFIN, MARCO","type":"Tesi di dottorato","year":"2025","abstract":"This thesis investigates the integration of artificial intelligence (AI), virtual reality (VR), and ultra-reduced cone-beam computed tomography (CBCT) fields of view (FOV) to develop a novel approach for automated cephalometric analysis in orthodontics. The study addresses key challenges such as enhancing diagnostic precision, ensuring radioprotection, and optimizing clinical workflows through innovative technological solutions.  Cephalometric analysis, a cornerstone of orthodontic diagnosis and treatment planning, has traditionally relied on manual or semi-automated methods using 2D radiographs. However, these methods face limitations, including superimposition of structures and the inability to assess depth. While 3D CBCT imaging offers significant advantages, its associated higher radiation exposure raises safety concerns, particularly for pediatric patients and cases requiring multiple imaging sessions. This research responds to the need for safer, more efficient imaging solutions by focusing on AI-driven automation and ultra-reduced FOVs in CBCT imaging.  The project developed an AI system based on the V-Net deep learning architecture to automate the detection of anatomical landmarks critical for cephalometric analysis. Using a robust training and validation process with expert-annotated CBCT datasets, the system achieved high accuracy, with a mean Euclidean distance error of less than 2 mm. Preprocessing techniques, such as intensity thresholding and data augmentation, enhanced the model’s reliability and robustness. The introduction of ultra-reduced FOV CBCT scans further minimized radiation exposure by up to 70% compared to conventional protocols, without compromising diagnostic quality. The integration of intraoral scans with CBCT data provided a comprehensive and accurate anatomical representation, enhancing the precision of automated analyses.  The use of VR technology added a transformative dimension to the system, offering an immersive platform for clinicians to interact with 3D cephalometric data. Through dynamic manipulation and visualization of craniofacial structures, the VR interface enhanced diagnostic confidence and facilitated a more intuitive understanding of patient anatomy. This approach streamlined the diagnostic workflow, reducing the time required for cephalometric measurements by over 50%, allowing clinicians to focus more on treatment planning and patient care.  Validation studies demonstrated the system's superior efficiency and reproducibility compared to traditional methods. Clinicians highlighted the VR platform’s user-friendly interface and its potential to revolutionize diagnostic workflows. By combining AI automation, VR interactivity, and radioprotection-focused imaging, the research provides a comprehensive diagnostic tool tailored to modern orthodontic needs.  This thesis concludes that the integration of AI, VR, and ultra-reduced FOV CBCT imaging represents a significant advancement in orthodontic diagnostics. The proposed system offers a safer, faster, and more precise alternative to conventional methods, aligning with the principles of patient-centered care and radioprotection. Future research should aim to expand the dataset to ensure broader applicability and explore predictive modeling for personalized treatment strategies. The findings underscore the transformative potential of combining cutting-edge technologies to address the evolving challenges of orthodontics, setting a new standard for diagnostic excellence and patient safety.","language":"eng","citation":"ARTIFICIAL INTELLIGENCE AVAILABLE TO THE DEVELOPMENT OF A VIRTUAL REALITY SOFTWARE FOR AN AUTOMATED CEPHALOMETRIC ANALYSIS OF ULTRA-REDUCED CBCT FOV / M. Serafin ; tutor: C. Sforza ;  cotutor: G. M. Tartaglia ;  coordinatore corso PhD: M. Clerici. Dipartimento di Scienze Biomediche per la Salute, 2025 Mar 24. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13593.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1157055/2742937/phd_unimi_R13593.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/821739"},"title":"CARDIORESPIRATORY AND METABOLIC RESPONSE TO DIFFERENT SINUSOIDAL WORK RATES","internalauthor":"SHOKOHYAR, SHEIDA","type":"Tesi di dottorato","year":"2021","abstract":"ABSTRACT  Cardiorespiratory and Metabolic Response to Different Sinusoidal Work Rates   Cardiorespiratory fitness is one of the most important health criteria in seemingly healthy individuals and nearly all patient populations. Alongside the traditional tests for cardiorespiratory functional evaluation, a test protocol was proposed based on the intensity of the exercise that varies according to a sine wave model. This approach engenders an incessantly fluctuating response in which the response to one cycle is repeated. Indeed, by the periodic occurrence of increasing and decreasing phases, an evaluation of the physiological response kinetic to similar work rate perturbations can be obtained in a single testing session. Sinusoidal protocol pattern depends on several factors: period (T), amplitude (AMP) and midpoint (MP), therefore, modulating one or all of these factors yield various responses of the heart-lung-muscle integrated system. So far, previous studies administered sine wave protocols to investigate changes in the physiological responses induced by changes in T, pedal frequency, or exercise intensity (below and above the lactate threshold). In particular, those studies focused on changes in the temporal responsiveness of the cardiorespiratory and metabolic parameters, measured as the time delay (TD, the latency between mechanical work rate and physiological responses). To date, no study has investigated the possible differences in the cardiorespiratory and metabolic kinetic induced by different sine waves AMP in two protocols sustained by the aerobic metabolism (exercise intensity below the critical power (CP)). Additionally, given that none of the previous studies has ever explored the influence of fatigue on sinusoidal responses, and considering that all the previously reported results were obtained by overlapping, rather than averaging, the analysis of each cycle, it is worth investigating if a cycle-by-cycle analysis may reveal any sign of fatigue with the cycle’s number progresses. Therefore, the aim of this study was two-folds: i) to assess the cardiorespiratory and metabolic response kinetic between two exhausting sinusoidal protocols differing in MP and AMP: 30CP-30 and 50CP-50, and ii) to compare the traditional data analysis approach with a cycle-by-cycle evaluation. In this latter, the possible impact of fatigue on the kinetics characteristics of cardiorespiratory and metabolic parameters will be explored. Ten active male (age: 25.7 ± 1.5 yrs; stature: 1.80 ± 0.06 m; body mass: 75.0 ± 2.7 kg; maximum oxygen uptake (V ̇_(O_2  max)): 3905±182 ml·min−1, CP: 216 ± 10 W) contributed to the study that was conducted in accordance with the Basic Principles of the Declaration of Helsinki. After determining individual V ̇_(O_2  max) and CP on a cycle ergometer, they randomly underwent two sinusoidal work rates (50CP-50: AMP= 50W, MP =CP-50W; 30CP-30: AMP= 30W, MP =CP-30W) with a period of 4 minutes, until exhaustion. Expiratory ventilation (V ̇_E), oxygen uptake (V ̇_(O_2 )), carbon dioxide output (V ̇_(CO_2 )), and heart rate (fH) responses were fitted by the sinewave function that minimized the residuals. AMP, MP and TD were assessed for all the physiological variables. The TD was determined for: i) peak (TD_MAX); ii) down-ward MP crossing (TD_DOWN); iii) nadir (TD_MIN); and iv) up-ward MP crossing (TD_UP) of all parameters for each cycle in 50CP-50 and 30CP-30. After examining the normality with Shapiro-Walk test, a two‐way ANOVA for repeated measures was applied to test the presence of differences between the two protocols and among cycles, taking the first cycle as the reference condition. To determine the presence of fatigue a regression analysis was also applied for exploring possible relationship between each variables and time. Lastly, a paired samples t-test also evaluated the differences between the traditional approach and the cycle-by-cycle analysis. Despite the lower AMP and higher MP values obtained on all the physiological parameters during 30CP-30 compared to 50CP-50, no difference was found in the TDs values in both protocols, regardless of which TD was considered. In some investigated variables, the impact of fatigue on AMP was dissimilar between the two protocols. Indeed, none of the physiological parameters showed any sign of fatigue in 30CP-30, while a significant increase in V ̇_E and V ̇_(CO_2 )was observed in 50CP-50. In regards to a possible impact of fatigue on MP, the V ̇_E, V ̇_(O_2 ) and V ̇_(CO_2 )responses remained steady, whereas a significant rise was observed in fH in both protocols.  Refer to a possible effect of fatigue on TDs, no difference was found among cycles in both protocols.Taken together, these findings indicated that the respiratory and metabolic parameters responded similarly among all the cycles and were not influenced by the onset of fatigue. On the contrary, the fH showed a different response in the MP since the beginning of the protocol therefore, the traditional analysis ventures the lack of possible alterations in cardiac response.  In conclusion, TDs of the cardiorespiratory and metabolic variables are not affected by the work rate intensity and oscillation AMP when the exercise is mostly aerobic (below CP). Additionally, a cycle-by-cycle analysis is recommended especially when the steadiness of all the cardiorespiratory and metabolic parameters cannot be ensured.","language":"eng","citation":"CARDIORESPIRATORY AND METABOLIC RESPONSE TO DIFFERENT SINUSOIDAL WORK RATES / S. Shokohyar ; supervisor: F. Esposito. Università degli Studi di Milano, 2021 Feb 23. 33. ciclo, Anno Accademico 2020. [10.13130/shokohyar-sheida_phd2021-02-23].","filename":"phd_unimi_R11898.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/821739/1726093/phd_unimi_R11898.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1199755"},"title":"OBESITY AND SEX IN CANCER IMMUNOTHERAPY","internalauthor":"VICINI, FRANCESCO","type":"Tesi di dottorato","year":"2025","abstract":"Obesity is a multifaceted condition often associated with poor outcomes in cancer, yet clinical evidence suggests that obese patients may benefit disproportionately from immunotherapy respect to the lean population. The mechanisms underlying this phenomenon, particularly in relation to sex, remain unclear.    In this thesis, I investigated the impact of obesity and sex on tumor progression and response to anti–PD-1 therapy. Using the MC38 murine colorectal cancer model, we observed that high-fat diet (HFD) feeding accelerated tumor growth in both sexes, but more prominently in males. Nevertheless, the therapeutic benefit of anti–PD-1 was greatest in obese males, whose tumors exhibited markedly reduced progression compared to lean counterparts. These results align with clinical trends indicating improved outcomes in obese male patients, while highlighting sexually dimorphic effects of obesity on tumor immunity.    To strengthen the robustness of our preclinical platform, we optimized the in vivo tumor model and applied a novel computational anti-clustering algorithm for animal randomization, which reduced baseline imbalances and enhanced reproducibility. My results revealed that macrophages, rather than CD8⁺ T cells alone, were the most consistently remodeled population in the tumor microenvironment, showing sex- and obesity-dependent infiltration. In vitro studies further demonstrated that lipid excess and estrogen differentially shaped macrophage inflammatory and antigen-presenting functions across sexes, with IL-6 emerging as a candidate mediator linking metabolic stress and immune regulation.    Our findings provide mechanistic insight into how sex and obesity interact to modulate cancer immunotherapy, highlighting macrophages as central regulators of these effects, and underscore the importance of considering host-intrinsic factors in both preclinical modeling and the design of personalized immunotherapeutic strategies.","language":"eng","citation":"OBESITY AND SEX IN CANCER IMMUNOTHERAPY / F. Vicini ; tutor: L. Mazzarella ; co-tutor: P.G. Pelicci ; coordinator: D. Pasini. Università degli Studi di Milano, 2025 Oct 09. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13506.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1199755/3194778/phd_unimi_R13506.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/958776"},"title":"INVESTIGATION OF ALPHA-SYNUCLEIN/TUBULIN INTERACTION IN PRESYNAPTIC MICROTUBULE DYNAMICS IN DOPAMINERGIC NEURONS","internalauthor":"COMINCINI, ALESSANDRO","type":"Tesi di dottorato","year":"2023","abstract":"The pathological mechanism underlying the degeneration and loss of the dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc) in Parkinson’s disease (PD) are still unknown. Among them, α-synuclein aggregation, mitochondrial impairment, increase oxidative stress and synaptic dysfunction are often indicated as culprits, although it is unclear whether these events are primary or secondary insults in PD neurodegeneration. Unlike other neurodegenerative diseases where cytoskeletal alterations are linked with mutations in key proteins involved in the progression of the pathology, PD lacks these findings. Nonetheless, microtubule (MT) dysfunction has recently emerged as a putative cause of the selective damage of the striatal DA synapses and consequent reduction in dopamine release that characterize PD clinical symptoms.   It was only recently when dynamic MTs were shown to enter the pre- and post-synapse as regulatory elements required for proper neurotransmitter release and synaptic plasticity. In pyramidal neurons, excitatory presynaptic sites are hotspots for MT nucleation, a process that regulates neurotransmission by providing the tracks for targeted bidirectional delivery of a rate-limiting supply of synaptic vesicles (SVs) to sites of stimulated release. Notably, α-synuclein, a small synaptic protein that aggregates in PD becoming the main component of Lewy bodies (LBs) and Lewy neurites (LNs), was recently discovered to promote MT assembly in vitro. α-synuclein-mutated PD forms lose this ability, suggesting a possible new connection between synaptic dysfunction and α-synuclein pathology through a tubulin-mediated mechanism.   Here, I investigated whether the α-synuclein/tubulin interaction is a feature of brain synapses and whether α-synuclein is a regulator of MT dynamics in primary DA neurons. I also reported a novel role for α-synuclein in activity-evoked presynaptic MT nucleation at en passant boutons, suggesting that α-synuclein may sustain synaptic transmission also by regulating MT nucleation at sites of release.  Overall, these data point to α-synuclein as a novel regulator of MT dynamics in primary neurons and reinforce the idea that MT dysfunction may represent an early insult in the sequence of events leading to DA synapse impairment.","language":"eng","citation":"INVESTIGATION OF ALPHA-SYNUCLEIN/TUBULIN INTERACTION IN PRESYNAPTIC MICROTUBULE DYNAMICS IN DOPAMINERGIC NEURONS / A. Comincini ; supervisore: F. Bartolini (Columbia University), D. Sulzer (Columbia University) ; scientific tutor: G. Cappelletti. Dipartimento di Bioscienze, 2023 Mar 30. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12564.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/958776/2160467/phd_unimi_R12564.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1055472"},"title":"AMIDYL RADICALS IN LIGHT PROMOTED REACTIONS","internalauthor":"BOSELLI, MONICA FIORENZA","type":"Tesi di dottorato","year":"2024","abstract":"The present thesis work is devoted to the study of four different topics as depicted in Figure 1, the enantioselective addition of amidyl radicals in α position to aldehydes, (Figure 1A), the addition of N lactam radicals to nucleophiles such as heteroarenes, arenes and aldehydes (Figure 1B), the preliminary investigation of the enantioselective addition of N-acetyl radicals to olefins (Figure 1C) and the development of the enantioselective α-SCF3 addition to β-ketoesters (Figure 1D).   Figure 1 Research outline.   In particular, Chapter 1 provides an overall introduction to the main topics encountered in this PhD thesis: Chapter 1.1 deals with a general definition of photocatalysis, the main photocatalytic activation pathway and same selected literature example to compare light catalysed reactions with and non-light catalysed reactions. The nitrogen radicals are introduced and classified in Chapter 1.2 with an historical overview of the previous literature work, while Chapter 1.3 reports the main advantages to perform a photochemical transformation exploiting the flow technology.  Chapter 2 is focused on the results obtained and it is divided in four main topics plus an appendix (illustrated in Figure 1): Chapter 2.1 deals with the enantioselective addition of amidyl radicals to aldehydes employing an imidazolidinone organocatalyst to promote the selectivity of the transformation. Moreover, we report also the development of the flow process for this transformation. Chapter 2.2 concerns the development and the study of a new class of amidyl radicals: the N lactam radicals. We are able to synthetize suitable nitrogen radical precursors and employ them in the photocatalytic addition of γ, δ, ε lactam radicals to heteroarenes, arenes and aldehydes. Moreover, we perform a wide reaction scope and a deepen mechanism investigation. After having deeply studied the employment of these new radicals, we selected a pharmaceutical target to applied the N lactam radicals and the results are reported in Chapter 2.3. A new photocatalytic synthesis of Levetiracetam, an antiepileptic drug, was developed. Chapter 2.4 reports the idea and the initial attempts done to develop the enantioselective addition of N-acetyl radicals to electronrich olefins. The experiments reported in the Appendix concerned the enantioselective addition of the enantioselective α-SCF3 addition to β-ketoesters were executed at the beginning of the PhD period before starting work on amidyl radicals in light promoted reactions.   Chapter 3 provides all the experimental part of the PhD thesis including the synthetic procedures, 1H-NMR, 19F-NMR and 13C-NMR of the unknown compounds and the HPLC traces of the enantiomeric excess of the asymmetric transformations.","language":"eng","citation":"AMIDYL RADICALS IN LIGHT PROMOTED REACTIONS / M.f. Boselli ; tutor: A. Puglisi ; co-tutor: M. Benaglia ; coordinatore: D. Passarella. - Milano. Dipartimento di Chimica, 2024 Jun 14. 36. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R12960_2.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1055472/2424013/phd_unimi_R12960_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1035850"},"title":"FEED & FOOD SAFETY: FROM ENVIRONMENTAL CHEMICAL CONTAMINANTS TO POTENTIAL EMERGING RISKS","internalauthor":"FERRARI, LUCA","type":"Tesi di dottorato","year":"2024","abstract":"The carry-over of chemical contaminants from feed to food products is a major concern in the animal production chain. For a proper containment, limits for feed as well as food products are fixed for a series of chemicals, e.g. dioxins and dioxin-like PCBs, heavy metals, some chlorinated pesticides, and some mycotoxins. Food and feed safety monitoring programs exist worldwide in order to protect consumers and animal health. Demand for animal products is expected to increase by up to 50% by 2050. Animal nutrition is the most challenging sector due to the limited availability of natural resources, climate change and food-feed-fuel competition. Due to the resource costs of conventional feeds, such as soybean meal, fishmeal, and standard grains such as maize, alternative sources (e.g. cereal processing by-products/co-products, former food products, seaweeds, insects) are increasingly being studied and used in animal diets. As new ingredients enter the food chain, new and potential risks are emerging on the feed and food security scene. At the same time, climate change can vary (and therefore increase) the risk for already widely known contaminants such as mycotoxins. An ideal goal is to assure that compliance to feed limits automatically results in compliance to food limits.  The focus of this dissertation comprises two distinct parts: 1) in the first part (6 chapters), it focuses on the monitoring of different chemical contaminants (mycotoxins and antibiotics) in feed and food ingredients. Various subjects will be addressed concerning the multi-annual monitoring programs of several mycotoxins in northern Italy and the determination and monitoring of antibiotic residues in both feed and food, throughout different analytical techniques. Still on the subject of food safety, 2) the second part of this dissertation (3 chapters) deals with the issue of selenium supplementation in insects as an alternative means to compensate for selenium deficiency, taking into account, however, that Se represents a risk factor due to the narrow range between deficiency and toxicity.","language":"eng","citation":"FEED & FOOD SAFETY: FROM ENVIRONMENTAL CHEMICAL CONTAMINANTS TO POTENTIAL EMERGING RISKS / L. Ferrari ; tutor: L. Pinotti ; co-tutor: U. Vincent ; coordinator: F. Cheli. Dipartimento di Medicina Veterinaria e Scienze Animali, 2024 Mar 13. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13166.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1035850/2376437/phd_unimi_R13166.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1023132"},"title":"MICROSCOPIC THEORY OF INFINITE NUCLEAR MATTER AND NON-EMPIRICAL ENERGY FUNCTIONALS","internalauthor":"MARINO, FRANCESCO","type":"Tesi di dottorato","year":"2023","abstract":"Nuclear density functional theory (DFT) and ab initio theory are complementary approaches to nuclear  structure. DFT can be applied to the whole nuclear chart, but relies on empirical energy density functionals  (EDFs). As a consequence, predictions in regions where experimental data are lacking, e.g. in neutron-rich  nuclei close to the driplines, are subject to significant uncertainties. In contrast, ab initio theory allows to draw  predictions with controlled uncertainties, but there are difficulties in extending these methods to heavy nuclei  or e.g. far from magic numbers. The purpose of this thesis is to combine DFT and ab initio by grounding the  nuclear EDFs into ab initio theoretical predictions, specifically on infinite nuclear matter calculations.  The ab initio Quantum Monte Carlo (QMC) and Self-consistent Green’s functions (SCGF) methods are employed  to study nuclear matter. An extension of SCGF based on the algebraic diagrammatic construction  (ADC-SCGF) is developed to include Gorkov pairing correlations. The ab initio equations of state (EOS) are  used to construct EDFs based on the local density approximation and gradient approximation, which are applied  to magic nuclei. Then, the static response of nuclear matter is tackled with both DFT and QMC, and a  study of the constraints that can be set on the EDF surface terms from ab initio is reported.  This thesis outlines a new strategy to ground nuclear EDFs into ab initio and implements some of its pillars.  A critical discussion of the difficulties encountered is given. Future developments include the study of  nuclear matter from a microscopic perspective, e.g. extending ADC-SCGF to tackle the dynamic response and  superfluid matter.","language":"eng","citation":"MICROSCOPIC THEORY OF INFINITE NUCLEAR MATTER AND NON-EMPIRICAL ENERGY FUNCTIONALS / F. Marino ; supervisor: G. Colò ; cosupervisor: F. Pederiva :  coordinatore: R. Vecchi. Dipartimento di Fisica Aldo Pontremoli, 2023. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12812.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1023132/2342424/phd_unimi_R12812.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1203690"},"title":"PROOF-OF-PRINCIPLE TEST FOR AN EXPERIMENT FOR SHORT-LIVED PARTICLE DIPOLE MOMENTS AT LHC","internalauthor":"CESARE, SARA","type":"Tesi di dottorato","year":"2025","abstract":"The magnetic (MDM) and electric (EDM) dipole moments of fundamental particles serve as powerful probes of the Standard Model and of possible extensions that introduce new sources of CP violation. A permanent EDM would constitute clear evidence of physics beyond the Standard Model, while magnetic moments offer insight into the internal structure of baryons and the dynamics of the strong interaction. Although the magnetic moments of light baryons are precisely known, those of charm baryons remain unmeasured due to their extremely short lifetimes. A direct measurement at the 10% level would enable discrimination among competing theoretical models.  This thesis summarises the physics motivations and preparatory work for a proposed fixed-target programme at the LHC aimed at performing the first direct measurements of charm baryon dipole moments. Central to this effort is the ALADDIN concept, which exploits bent-crystal channelling to produce forward charm baryons and measure their spin precession. The thesis reports simulation studies supporting the optimisation of the ALADDIN tracking system and assessing detector performance.  A significant portion of the document discusses the TWOCRYST proof-of-principle experiment, which is installed in LHC Interaction Region 3. This experiment is designed to demonstrate double channelling with multi-TeV protons. The thesis describes the development and commissioning of the PIXEL detector, which is based on the LHCb VELO technology. It describes the detector's integration into the LHC environment and its operation during Machine Development sessions. Additionally, it presents complementary crystal-channelling measurements at the CERN SPS and contributions to the LHCb Upstream Tracker during Run 3. Together, these studies lay the groundwork for a future program dedicated to measuring charm baryon dipole moments.","language":"eng","citation":"PROOF-OF-PRINCIPLE TEST FOR AN EXPERIMENT FOR SHORT-LIVED PARTICLE DIPOLE MOMENTS AT LHC / S. Cesare ; supervisor: N. Neri ; coordinatore: A. Mennella. Dipartimento di Fisica Aldo Pontremoli, 2025 Dec 16. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14019.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1203690/3207909/phd_unimi_R14019.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1045429"},"title":"THE ROLE OF BETA-KLOTHO PROTEIN IN NAFLD PATHOGENESIS","internalauthor":"PICIOTTI, ROBERTO","type":"Tesi di dottorato","year":"2024","abstract":"Non-Alcoholic Fatty Liver Disease (NAFLD) is the most prevalent and progressive liver condition characterized by the accumulation of fat in more than 5% of hepatocytes in the absence of excessive alcohol consumption. Considered a spectrum of liver disorders, NAFLD ranges from simple steatosis, where fat buildup is the primary feature, to Non-Alcoholic Steatohepatitis (NASH), a more severe form associated with inflammation and liver cell damage. As a burgeoning public health concern, NAFLD poses risks of progression to advanced liver diseases, including fibrosis, cirrhosis, and hepatocellular carcinoma and its evolution is closely linked to metabolic risk factors such as obesity, insulin resistance, and dyslipidemia. In addition, a genetic burden strongly underpins NAFLD pathogenesis, and several at-risk genetic variations have been found to predispose patients to the onset of liver disease. In this concern, our group previously reported that the rs17618244 G>A variant in the β-Klotho (KLB) gene dampened the KLB hepatic/plasma levels, leading to inflammation, ballooning, and fibrosis in NAFLD patients. KLB protein, functioning as coreceptor for fibroblast growth factor receptors 4 (FGFR4), mediates in the liver the hormonal activity of FGF19 and plays a central role in the regulation of lipid metabolism and in bile acids’ biosynthesis. Thus, a stable KLB full knock-out model in HepG2 hepatoma cells (KLB-/-) has been generated by using Crispr/Cas9 technology, with the aim to reproduce in in vitro the effects of the KLB rs17618244 variant. Then, in a cohort of 1311 NAFLD patients, among which 261 were children, the new intronic KLB rs12152703 T>G variant was associated with NAFLD traits and the hepatic/plasma levels of KLB were determined.  Our results outlined that KLB-/- cells have altered cell homeostasis and reported the impairment of several hepatocyte typical features. Indeed, KLB-/- cells showed the downregulation of important genes involved in lipid metabolism and in cholesterol production and uptake. Furthermore, an increase in the endoplasmic reticulum (ER) and oxidative stress were observed in KLB-/- cells. Cell homeostasis was further affected by the enhancement of cell apoptosis and by the impairment of the autophagic flux, mirroring in in vitro the progression to severe liver damage. Accordingly, in our model the release of pro-inflammatory cytokines was increased and a panel of of 586 genes associated to inflammation revealed the upregulation of important mediators related to the inflammatory response. Additionally, tumorigenic features were acquired after KLB depletion, resulting in increased cell growth, proliferation and invasiveness. Interestingly, in KLB depleted cells a reduction in the response to anti-cancer therapy was observed, along with the establishment of a pro-tumorigenic environment, supported by the upregulation of several oncogenes and by the increasing of cell self-renewal activity. We further reported that the absence of KLB in in vitro may mediate the transition to a mesenchymal phenotype through the downregulation of important epithelial markers and the upregulation of mesenchymal mediators. Finally, in patients we evaluated a new variant, the KLB rs12152703, showing its possible protective action against advanced liver disease in term of reduction of transaminases levels, NAFLD activity score (NAS) and predisposition to developing NASH. This action may be mediated by an increase in circulating and hepatic KLB mutated protein, as demonstrated in a pediatric patient with the rs12152703 TT homozygous genotype we evaluated.   In conclusion, our results outlined that KLB KO induced in HepG2 cells may drive important changes in liver cells metabolism and homeostasis, as consequence of the altered KLB signaling. In these cells, lipid and cholesterol metabolism were the mainly affected, thus possibly speculating that KLB depletion may lead to the loss of important hepatocyte-specific proprieties. Moreover, KLB-/- cells showed features resembling the switching towards progressive forms of liver damage observed in patients, pinpointing the possible involvement of KLB in NAFLD progression. Moreover, the acquisition of several pro-carcinogenic traits, such as enhanced proliferation, invasiveness and acquisition of stemness features may indicate that the absence of KLB further contributes to the shift towards a more aggressive cancerous phenotype.   As for the translational approach, we determined for the first time the potential protective role of another variant of KLB, the rs12152703, on liver disease which is correlated to an increase in KLB levels, observed in those patients carrying the TT mutation. These evidence highlights the potentiality of KLB as novel clinical targets to refine the NAFLD prognosis. Moreover, the recombinant isoforms of KLB could be used for the treatment of NASH and might have stronger effects in those patients reporting KLB downregulation.","language":"eng","citation":"THE ROLE OF BETA-KLOTHO PROTEIN IN NAFLD PATHOGENESIS / R. Piciotti ; tutor: R. Lombardi ; co-tutor. V. La Mura ; coordinatore: C. Sforza. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2024. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R13168.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1045429/2398844/phd_unimi_R13168.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1221300"},"title":"INTEGRATED TRANSCRIPTOMIC AND TRANSLATIONAL PROFILING OF EIF6-SBDS IN SHWACHMAN-DIAMOND SYNDROM REVEALS DIFFERENT CELLULAR STATES SHAPED BY RIBOSOME COMPOSITION AND FIDELITY","internalauthor":"D'ANDREA, GIACOMO","type":"Tesi di dottorato","year":"2026","abstract":"Ribosome biogenesis is an essential and tightly regulated process that underpins cellular growth, proteostasis, and metabolic homeostasis. Disruptions in its final cytoplasmic maturation steps can profoundly alter translational output and lead to human disease. Shwachman–Diamond syndrome (SDS) exemplifies this class of disorders. Caused by biallelic loss-of-function mutations in SBDS, SDS is characterised by exocrine pancreatic dysfunction, growth impairment, bone-marrow failure, and a markedly increased risk of myelodysplastic syndrome and acute myeloid leukaemia. SBDS is required for release of the anti-association factor eIF6 from nascent 60S subunits, a prerequisite for productive 80S assembly and translational initiation. Consequently, SBDS deficiency limits the pool of functional ribosomes and constrains global protein synthesis. Recent sequencing of SDS bone marrow has revealed a striking and recurrent event: the acquisition of somatic mutations in eIF6, most frequently the missense variant N106S, arising exclusively in individuals with germline SBDS mutations. Their selective occurrence in SDS haematopoiesis has led to the hypothesis that these mutations act as a rescue event, although the underlying mechanism has remained unclear.  Here, we investigate how the eIF6 N106S mutation modifies ribosome function and interacts with SBDS depletion. Using Prime Editing, we generated isogenic HEK293T lines carrying a N106S allele in heterozygosis and established matched SBDS-depleted models via shRNAi. Polysome profiling, RNA-seq, and Ribo-seq were used to assess how each perturbation influences translational output, decoding fidelity, and stress-response pathways. Additional analyses of rRNA fragments, snoRNA dynamics, and inferred ribosomal-protein association provided complementary insight into consequences on ribosome assembly. Translation assays showed that both SBDS depletion and the N106S mutation reduce global protein synthesis. Unexpectedly, their combination further repressed translation rather than restoring it, contradicting the view that N106S simply alleviates the SBDS-dependent anti-association defect. Transcriptome profiling revealed that the double-mutant state does not recapitulate either single perturbation but instead produces a coordinated shift in stress signalling and cellular metabolism. Rather than approximating wild-type behaviour, this condition establishes a distinct regulatory environment characterised by reduced inflammatory signalling and dampened anabolic activity.  Taken together, these findings indicate that the N106S mutation does not restore the translational output impaired by SBDS deficiency but instead gives rise to a modified cellular state in which ribosome function is altered: decoding fidelity appears improved, proteotoxic stress is diminished, and transcriptional and metabolic programs diverge from both wild-type and single-mutant cells. These observations offer a plausible explanation for the selective retention of EIF6 mutations in SDS haematopoiesis and provide a foundation for future studies evaluating how modulation of the eIF6–60Scould be exploited in therapeutic treatment for SDS patients.","language":"eng","citation":"INTEGRATED TRANSCRIPTOMIC AND TRANSLATIONAL PROFILING OF EIF6-SBDS IN SHWACHMAN-DIAMOND SYNDROM REVEALS DIFFERENT CELLULAR STATES SHAPED BY RIBOSOME COMPOSITION AND FIDELITY / G. D'andrea ; tutor: S. Biffo. Dipartimento di Bioscienze, 2026 Feb 23. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14011.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 03-MAR-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/927159"},"title":"ASYLUM-SEEKING AND REFUGEE WOMEN: A NORMATIVE FRAMEWORK","internalauthor":"ZUCCARELLI, GLORIA","type":"Tesi di dottorato","year":"2022","abstract":"The refugee crisis enduring from 2015 is conceptually and politically addressed as a gender-neutral phenomenon. However, there is increasing acknowledgment of the necessity to take a gender perspective on forced migration and refugeehood. The aim of this research is precisely to shed light on the vulnerabilities and injustices that these refugee and asylum-seeking women experience, and it does so by adopting an intersectional and bottom-up approach.   For this work begins theorizing upon an empirical and descriptive basis, engaging with the voices of these women and their lived experiences. Given the intersectional nature of this group of women, this research analyzes its particular positionality within the groups of women and asylum seekers and recognizes that they experience vulnerabilities and injustices that are not effectively  conceptualizable neither by gender studies’ theories nor by research and studies on forced migration and asylum.   Thus, the research questions are the following: What happens when different layers of vulnerability intersect? Do these intersectional vulnerabilities translate into injustice? If so, what kind of injustice is it? Where are these injustices grounded and what are their specificities? More generally, how can we conceptualize the experience of refugeehood and asylum of these women and what is missing in this sense in the existing academic normative literature?   After a first descriptive part based on empirical research, where I describe the journey throughout refugeehood of the women, from the reasons to flee from the country of origin to the outcome of the claim for international protection, the second part addresses the intersectional nature of this group. More precisely, this chapter justifies the conceptual salience of this group in the intersection of   gender and refugeehood.   A first answer will be found in the third chapter of this work, where the concept of vulnerability is studied and problematized, also in the light of possible downsides in adopting it. For these women suffer from intersectional layers and loops of vulnerability. Moreover, it will be argued that the structurality of these vulnerabilities grounds the injustices they suffer. In this regard, in the fourth   chapter the research will analyze asylum-seeking and refugee women experiences in the light of different forms of injustice and oppression – namely, Iris Marion Young’s five faces of oppression, Andrea Sangiovanni’s modes of inferiorizing treatments, and the line of thought of epistemic injustice.   The final part will treat how all these injustices interact in epistemic and non-epistemic directions to create vicious cycles of injustice and efface the peculiarity of their compound injustice. This process of interaction produces a specific form of injustice that I name effacement, which has theoretical, political, and practical consequences that call for urgent actions to break these cycles of injustice.","language":"eng","citation":"ASYLUM-SEEKING AND REFUGEE WOMEN: A NORMATIVE FRAMEWORK / G. Zuccarelli ; tutor:  A. Facchi ; coordinatore: M. Jessoula. Dipartimento di Scienze Sociali e Politiche, 2022 Jun 07. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12167.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/927159/2031651/phd_unimi_R12167.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1212378"},"title":"STRONG GRAVITATIONAL LENSING MODELLING OF GALAXY CLUSTERS IN THE ERA OF BIG DATA","internalauthor":"ABRIOLA, DAVIDE","type":"Tesi di dottorato","year":"2026","abstract":"Current observational facilities and surveys are revolutionizing the field of strong lensing (SL) by galaxy clusters. Remarkably, the Euclid Survey will cover approximately 15,000 square degrees of the sky, detecting SL features in thousands of massive clusters. Complementarily, the James Webb Space Telescope (JWST) is providing extremely deep and high-resolution observations, revealing a number of multiple images and substructures greater than previously unknown, and thus enabling lens models of unprecedented accuracy. The synergy between these observatories will drastically improve the number of currently known SL systems and significantly enhance the quality of SL studies. In order to deal with large sets of galaxy clusters and/or characterized by a huge number of observables, a modeling code capable of reconciling speed and accuracy is mandatory. The SL parametric modeling code Gravity.jl addresses this challenge directly, having been specifically developed for cluster-scale lensing analyses. Its high-performance architecture makes it ideally suited for processing the large and complex datasets from these and next-generation observatories.   In this Thesis, we present the SL Gravity.jl-based study of the galaxy cluster Abell 2390 combining, for the first time, Euclid ERO imaging and archival MUSE spectroscopy. Gravity.jl's computational efficiency enabled comparison of over 10 distinct total mass parameterizations within approximately just two hours per model. We then further explore what future SL studies of galaxy clusters based on Euclid imaging will look like by investigating how the expected limited number of identifiable multiple images affects the measurements of the lens parameters and of other quantities of interest, such as the cluster total mass. Finally, we push the limits of SL analyses by presenting the study of the galaxy cluster MACS J0416, an interesting complex system for which recent JWST observations have helped in the identification of nearly 500 spectroscopically-confirmed multiple images – the highest number ever recorded for a galaxy cluster. We will present the preliminary results of the first fully multi-plane lensing studies of this system carried on with Gravity.jl.","language":"eng","citation":"STRONG GRAVITATIONAL LENSING MODELLING OF GALAXY CLUSTERS IN THE ERA OF BIG DATA / D. Abriola ; supervisor: M. Lombardi ; co-supervisor: C. Grillo ; coordinator: D. Mennella. Dipartimento di Fisica Aldo Pontremoli, 2026 Jan 26. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13783.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1212378/3240876/phd_unimi_R13783.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/926974"},"title":"DEVELOPMENT OF COMBINED ANALYTICAL TECHNIQUES TO DETECT QUALITY AND AUTHENTICITY ATTRIBUTES IN ANIMAL PRODUCTS","internalauthor":"LOPEZ, ANNALAURA","type":"Tesi di dottorato","year":"2022","abstract":"Nowadays, consumers are reorienting themselves more and more toward the consumption of food products characterized by additional quality traits. Since consumers cannot always personally verify the attributes of foodstuffs, these have to be guaranteed by a robust quality assurance process acting along the whole supply chain. An important worldwide increase of the demand for animal source foods is occurring, leading to the arising of a phenomenon known as the “livestock revolution”. However, animal food products are considered among the most frequently adulterated edible goods.  Many compounds naturally present in animal products may represent important biomarkers related to considerable authenticity and quality issues. In the experimental part of this PhD thesis, chromatographic analytical techniques were developed and employed with the aim to identify and characterize chemical markers of integrity in animal products. This approach was employed on two levels: on a farm-scale, collecting raw material directly in the farms, and on a manufactory-scale, collecting transformed products, in order to relate their quality to the production process. Research was conducted on two different animal products: a) dairy products and b) fish products, particularly sturgeon meat and fish roes.  a) Dairy products  In Trial 1, the fatty acid (FA) composition of goat milk yielded in three Italian farms, chategorized based on the production system employed, was investigated by means of gas-chromatography and flame ionization detection (GC-FID). Results allowed to detect significant differences among milk collected in the three farms, particularly enhanced for many fatty acids, which amount varied in relation to the livestock system. Odd and branched chain fatty acids (OBCFA), linoleic acid (LA), α-linolneic acid (ALA), elaidic acid (EA), total n3 and n6 series FA were identified as the most significant factors in the characterization of samples coming from low- or high-input livestock systems in goat milk.  In Trial 2, nutritional quality of goat cheese obtained by GC-FID analysis of the acidic profile was supplemented with animal welfare measurements performed in the farms involved in Trial 1 by means of a standardized protocol. The so-called extrinsic quality of goat cheese samples analysed, represented by the chemical profile determined by laboratory analysis, showed a significant higher quality in cheese collected from low-input farms, confirming the results obtained in Trial 1. On the contrary, welfare parameters (referred to as intrinsic quality) showed that no clear relationship was observable between the level of the animal welfare and the livestock systems analysed. The results of this trial indicated that the extrinsic and the intrinsic quality of low-input farms did not always match, suggesting that the information on the livestock system is not always enough in order to provide consumers with complete awareness of the total product quality.  In Trial 3, fat quality in Alpine cow milk was characterized by means of GC-FID and related to the seasonal variations of diets. Two different feeding strategies were compared in two small mountain farms in Piedmont Alpine region, Italy. Particularly, during the summer season, one of the two farms was distinguished by the exclusive employment of Alpine pasture, assumed as the best way to improve the quality of FA profile in milk.   Milk samples obtained by the exclusive employment of alpine grazing during summer (farm A) were represented by a FA profile of higher quality. However, during the summer season, milk obtained by the integrated strategy (farm B) resulted in a more homogeneous composition, with higher concentration of polyunsaturated FA (PUFA). These outcomes confirmed that the integrated strategy, even if related to a slightly lower ability in improving milk FA profile, could represent a valid and cost-effective alternative for mountain farmers to obtain an overall superior quality of milk, being not strictly linked to the grazing practice.  b) Fish products – sturgeon meat and fish eggs  In Trial 4, sturgeon raw eggs, caviar and meat obtained from different species reared in an Italian production plant were evaluated for their chemical composition, in order to improve their appreciation on the market and to detect any eventual distinctness related to the species. Fatty acids profile was investigated by GC-FID and multivariate statistics. Important differences in the deposition of individual fatty acids in sturgeon meat and ovas were detected, principally based on their different biological role. Particularly, interesting differences were observed in the different FA profile that characterized the phospholipid and the neutral lipid fractions in sturgeon roes. Finally, colour parameters were measured on sturgeon fillets, characterizing the species-specific properties of sturgeon meat.  In Trial 5, quality, traceability and safety issues related to processed fish roe products from different species were investigated. FA was performed by GC-FID. Results showed a differentiation among eggs harvested from different fish species. Then, a discriminant model was applied including an external set of sturgeon roes samples, coming from Trial 4, that enabled a good discrimination among roes from sturgeon or other spescies. Additionally, food safety of fish roes products was investigated, proving a general good hygienic level for the products analysed. On the overall, results obtained by this trial suggested fish roes as safe food products, which can also provide human nutrition a valuable content of essential fatty acids.  In Trial 6, a multiple headspace solid phase microextraction (MHS-SPME) followed by GC and mass spectrometry detection (MS) was firstly developed and subsequently employed to identify and quantitatively estimate the presence of volatile compounds (VOCs) in white sturgeon caviar during 4 months of ripening. The method allowed the detection and the quantitative estimation of twenty-five VOCs, mainly represented by aldehydes and alcohols, already know as main representative of fish and seafood volatilome, without any severe alteration of the matrix before the analysis and in a short time. Mainly, an increase of the amount of total aldehydes was observed in 4 months of ripening; moreover, the arise of 3-hydroxy-2-butanone was observed at the last sampling time.  In Trial 7, a HS-SPME-GC-MS method was applied to evaluate the evolution of the volatile profile in white sturgeon caviar treated with different preservative mixtures in an extended storage time (up to 14 months). Results obtained for the VOCs profile were matched with microbiological analysis. Multivariate statistics allowed the identification of different clusters based on the time of ripening and the preservative treatment used.  Particularly, samples added just with salt were characterized by the highest viable counts and the greatest presence of VOCs driven by spoilage processes, strongly enhanced by the prolonged ripening time, pushed beyond the optimal maturation time generally considered in caviar production plants.  In Trial 8, a ultra high performance liquid chromatography and high resolution mass spectrometry (UHPLC-HRMS) method was developed and optimized in order to characterize the non volatile metabolome of white sturgeon caviar during the ripening. Both the optimization of the method and data analysis were performed by chemometrics techniques. Results showed a strong evolution of the non volatile compounds present in the aqueous phase of sturgeon eggs during the first 4 months of ripening and then a partial stabilization. Most of the compound tentatively identified were associated to a high nutritional value, comprising protein and non protein amino acids, phospholipids species made of long chain and unsaturated fatty acids and vitamins. Moreover, the presence of chemical species related to fundamental impact on the characteristic umami taste in food, such as glutamic acid and nucleotides, were detected.","language":"eng","citation":"DEVELOPMENT OF COMBINED ANALYTICAL TECHNIQUES TO DETECT QUALITY AND AUTHENTICITY ATTRIBUTES IN ANIMAL PRODUCTS / A. Lopez ; tutor: V. M. Moretti ; coordinatore: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2022 May 12. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12163.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/926974/2031114/phd_unimi_R12163.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1152695"},"title":"FROM MICRONUCLEI TO EMT: MOLECULAR MECHANISMS OF GENOMIC INSTABILITY AND CELLULAR PLASTICITY","internalauthor":"SCORZONI, SIMONE","type":"Tesi di dottorato","year":"2025","abstract":"Chromosomal instability and its cellular consequences represent critical aspects of cancer progression and genomic instability. The research presented in this thesis encompasses two complementary projects, focusing on distinct yet interconnected molecular pathways. The first project investigates the role of the autophagic receptor p62 in regulating micronuclear integrity. Utilizing advanced methodologies, including proximity labeling and mass spectrometry, this study reveals how p62 recognizes micronuclei through ubiquitination and proximity to mitochondria, with ROS-induced homo-oligomerization of p62 driving micronuclear envelope rupture. These findings uncover a critical mechanism by which p62 modulates nuclear membrane stability, influencing chromosomal rearrangements and genomic instability through its interaction with ESCRT components.  The second project explores the impact of chromosomal mis-segregation on cellular behavior, specifically its role in inducing Epithelial-to-Mesenchymal Transition, a pivotal process in cancer metastasis. By employing transcriptomic analysis, cellular migration assays, and intercellular signaling studies, my work demonstrates how aneuploidy influences cellular plasticity and activates key pathways such as NF-κB and TGF-β. Notably, this study emphasizes the influence of aneuploid cells on the plasticity of neighboring cells and also highlight the importance of late-stage events often overlooked in genomic instability research.  Together, these projects elucidate the intricate molecular relationships between chromosomal instability, autophagic pathways, and EMT, providing insights into the mechanisms that drive tumorigenesis and metastasis.","language":"eng","citation":"FROM MICRONUCLEI TO EMT: MOLECULAR MECHANISMS OF GENOMIC INSTABILITY AND CELLULAR PLASTICITY / S. Scorzoni ; tutor: S. Santaguida ; pha coordinator: D. Pasini. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Apr 03. 36. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13145_1.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1152695/2709408/phd_unimi_R13145_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/812809"},"title":"ON THE AXIOMATISABILITY OF THE DUAL OF COMPACT ORDERED SPACES","internalauthor":"ABBADINI, MARCO","type":"Tesi di dottorato","year":"2021","abstract":"We prove that the category of Nachbin's compact ordered spaces and order-preserving continuous maps between them is dually equivalent to a variety of algebras, with operations of at most countable arity.  Furthermore, we show that the countable bound on the arity is the best possible: the category of compact ordered spaces is not dually equivalent to any variety of finitary algebras.  Indeed, the following stronger results hold: the category of compact ordered spaces is not dually equivalent to (i) any finitely accessible category, (ii) any first-order definable class of structures, (iii) any class of finitary algebras closed under products and subalgebras.  An explicit equational axiomatisation of the dual of the category of compact ordered spaces is obtained; in fact, we provide a finite one, meaning that our description uses only finitely many function symbols and finitely many equational axioms.  In preparation for the latter result, we establish a generalisation of a celebrated theorem by D. Mundici: our result asserts that the category of unital commutative distributive lattice-ordered monoids is equivalent to the category of what we call MV-monoidal algebras.  Our proof is independent of Mundici's theorem.","language":"eng","citation":"ON THE AXIOMATISABILITY OF THE DUAL OF COMPACT ORDERED SPACES / M. Abbadini ; relator: V. Marra ; coordinator: V. Mastropietro. Dipartimento di Matematica Federigo Enriques, 2021 Apr 09. 33. ciclo, Anno Accademico 2020. [10.13130/abbadini-marco_phd2021-04-09].","filename":"phd_unimi_R11882.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/812809/1698986/phd_unimi_R11882.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/815634"},"title":"HYDROXYAPATITE-BASED MATERIALS FOR ENVIRONMENTAL PROCESSES","internalauthor":"FERRI, MICHELE","type":"Tesi di dottorato","year":"2021","abstract":"In this dissertation, hydroxyapatite-based and hydroxyapatite with carbon composite materials have been rationally designed, synthesized, characterized and applied to processes of environmental concern, namely wastewater remediation (as sorbents) and electrochemical CO2 reduction reaction, CO2RR (as electrocatalysts).  Pristine hydroxyapatite (HAP, Ca10(PO4)6(OH)2) and composite HAP/carbon materials have been synthesized according to a simple wet co-precipitation route. Composition, structure and morphology of samples have been investigated by a plethora of physical-chemical techniques (i.e. ICP/OES elemental analyses, N2 adsorption/desorption isotherms, XRD, TEM (and STEM) imaging, TEM/EDX mapping, transmittance FT-IR and Raman spectroscopies, and XPS). Since adsorption onto materials’ surface is crucial in both sorption and catalytic applications, a special attention has been devoted to surface properties, determined by means of zeta potential measurements, gas-solid calorimetric/volumetric titrations, and liquid-solid volumetric titrations, thus assessing the amphoteric nature of HAP-based surfaces.  At first, pristine pristine HAP has been studied as sorbent for the remediation of inorganic pollution in wastewater (i.e. heavy metal cations such as Cu(II), Pb(II), Cr(III), Ni(II) and Co(II)). Stirred batch adsorption tests and collection of adsorption isotherms in solutions containing both individual and mixtures of heavy metal cations allowed to quantitatively assess HAP sorption ability. Ad-hoc experiments (i.e. microcalorimetric adsorption isotherms) and physical-chemical investigation of metal-loaded samples shed light on the adsorption mechanisms of several polluting species onto HAP surface.   Eco-friendly HAP/carbon composites from renewable resources have been instead applied to the remediation of more complex effluents, where simultaneous organic and inorganic pollution may occur. Thanks to their dual nature, HAP/carbon composites exerted outstanding adsorption performances towards both class of polluting species. Both in the form of pristine HAP and HAP/carbon composites, the sorbents exhibited a strict retention of adsorbed pollutants when undergoing leach testing, therefore ensuring no secondary pollution issues.  In an exploratory study, HAP/carbon composites have been also implemented as modifiers in self-standing and mechanically stable electrodes for the electrochemical detection of heavy metal cations traces in waterbodies. Benefitting from the pronounced HAP affinity towards such species, encouraging results have been obtained on the detection of some benchmark pollutants, although the registered limits of detection (ca. one order of magnitude improvement to match legislative requirements) and linearity ranges currently limit HAP/carbon modified electrodes applications.  Finally, during a 6-months stay at University of California Irvine (UCI), hosted by Prof. Plamen Atanassov group, HAP has been applied as dopant in CO2RR electrocatalysts. The peculiar ability of HAP amphoteric surface to adsorb and destabilize CO2 (i.e. breakage of its linearity) has been exploited in composite electrocatalysts, composed by copper nanoparticles (active phase) and HAP (dopant), supported on N-doped 3D assembly of graphene nanosheets (3D-GNS, carbonaceous support). When tested in a lab scale CO2 electrolyzer, HAP-doped electrocatalysts displayed a faradic efficiency (FE) towards CO2RR ≥ 80% throughout the whole potential range under investigation, minimizing parasitic Hydrogen Evolution Reaction (HER). Interestingly, HAP doping actually altered CO2RR product distribution: in particular, small quantities of C2+ products were produced under low applied overpotential while at higher voltage formate production was boosted. Product distribution alteration has been rationalized taking into account the ability of HAP acid-basic surface groups to stabilize CO2 reduction intermediate species, directing the the selectivity of electrochemical CO2RR processes.  Overall, the present study demonstrates that the unique features of HAP make it a versatile material which may be applied for the protection of the environment at 360 degrees, from water to air remediation, as pristine and/or composite material, as sorbent and/or catalysts’ dopant.","language":"eng","citation":"HYDROXYAPATITE-BASED MATERIALS FOR ENVIRONMENTAL PROCESSES / M. Ferri ; tutor: Prof. A. Gervasini ; co-tutor: S. Trasatti, P. Cristiani ; coordinator: D. Roberto. Dipartimento di Chimica, 2021 Mar 22. 33. ciclo, Anno Accademico 2020. [10.13130/ferri-michele_phd2021-03-22].","filename":"phd_unimi_R11863.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/815634/1707148/phd_unimi_R11863.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1156996"},"title":"RETURN TO SPORT AFTER ACHILLES TENDON RUPTURE","internalauthor":"BUSA', MATTIA FERNANDO","type":"Tesi di dottorato","year":"2025","abstract":"Background: Achilles tendon (AT) rupture is a common injury, particularly among physically active individuals, with a 30% growth rate in the most affected age group (30–39 years). Among professional athletes, 25% fail to return to sport (RTS), and those who do typically require 8–11 months of recovery. Furthermore, their performance can decline by up to 50% during the two years following RTS, and their career length is shorter compared to non-injured players or those with anterior cruciate ligament (ACL) injuries. Long-term deficits after AT repair have been documented up to 10 years post-injury, including tendon elongation, reduced calf circumference, atrophy of type-1 muscle fibers, decreased heel-raise test performance, and reduced ability to generate force in a plantar-flexed position. Additionally, low psychological readiness to RTS, or high levels of kinesiophobia at six months may influence RTS outcomes. Given these suboptimal RTS outcomes and the lack of consensus on optimal treatment strategies for AT rupture, there is a need to explore potential areas for improvement in the RTS process. Aims: These considerations have inspired my PhD research project, which aims to identify gaps in the current AT RTS process and provide insights to optimize outcomes for patients recovering from AT rupture. The specific aims of the three research projects are as follows: 1. To map the literature regarding which criteria are used to clear athletes for RTS after AT repair. Understanding the criteria defined in the literature allows for clarity on the standards required for RTS and the identification of potential gaps area in the RTS process that lack clear guidelines. 2. To observe and analyze the impact of AT rupture in ankle movement quality during the mid-stage of rehabilitation. The comparison between the repaired and unrepaired limbs aims to identify potential differences in movement quality between the two ankles. 3. To describe the on-field rehabilitation (OFR) workload of football players returning to sport after AT repair. Global Positioning System (GPS) monitoring workloads during the late-stage of rehabilitation may be a key factor to lead load progression during the late-stage of rehabilitation, providing insights to prepare football players for the demands of the return to training (RTT).  Methods: 1) Project one involved a Scoping Review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. A combination of search terms and Boolean operators, regarding AT rupture and RTS criteria, was used to search the literature from 1995 to 2022 across three databases: Web of Science, Scopus, and MEDLINE. Papers inclusion and exclusion criteria were defined. A data charting was create to collect criteria, and the insights regarding AT rehabilitation outcome. 2) Project two was a case series involving 23 sportive patients who underwent AT repair. The inclusion criteria for participants were: being treated at one of the Isokinetic Medical Group Clinics, having undergone Achilles tendon (AT) repair surgery, and performing a bilateral depth jump. To observe the ankle movement quality the ankle joint angle (γ angle), and peak vertical ground reaction force (peak VGFR), in both repaired and unrepaired limbs during the eccentric and concentric phase of a bilateral depth jump where assessed. To test for differences between the repaired and unrepaired sides, variables were analyzed collectively using a multivariate Mixed Linear Model with repeated measures. Effect sizes and confidence intervals were also computed. 3) Project three was a pilot study with a small cohort including 5 male football players who underwent AT repair and were monitored during the OFR. Workload data for each OFR session were collected using GPS and heart rate tracking. Variables measured and reported were: PL, Player load (Arbitrary Unit-AU); TD, total distance (km); MSR, moderate speed running distance (defined as 15-20 km/h); HSR, high speed running distance (defined as 20-25 km/h); SRT, sprint distance (>25 km/h); MS, max-speed (km/h); ACC, Number of accelerations (>2m/s2); DEC, Number of decelerations (>2m/s2); time in Aerobic zone (70-85% HRmax); time in Anaerobic zone (>85% HRmax). Variations in GPS metrics were calculated as percentages between stages and from stage 1 to stage 5 to identify notable changes. As a follow-up, the ankle ligament reconstruction-return to sport injury (ALR-RSI) score was used to evaluate the footballers psychological readiness to RTS.  Main results: 1. In project one, the main result was that none of the 34 included studies explicitly defined any RTS criteria to clear athletes after AT rupture. The literature primarily focused on provide measurements related to the early stage of rehabilitation, while no specific measurements for the mid- and late-stages of rehabilitation were identified. These findings highlight the need to investigate appropriate measurements for evaluating progress during the mid-and late- stage of the rehabilitation process in the context of RTS after AT rupture. 2. In project two, the main findings were: an average ankle joint angle 8 degrees smaller for the limb that underwent AT repair compared to the unrepaired one at IC during the depth jump (p<0.001), and a mean peak VGRF 3.6 N/kg higher for the unrepaired limb at IC (p<0.001). These results suggest changes in ankle movement quality, with a more dorsiflexed repaired ankle and a body weight shift (BWS) towards the unrepaired limb during the landing phase of the jump, while no differences were observed during the concentric phase. Integrating ankle movement quality assessments in the mid-stage of rehabilitation may be a key factor in evaluating ankle impairments and potential shifts in ankle movement patterns with higher peak knee loads in the same limb. 3. In project three the main result was that a notable increase was found for RPE, MSR, HSR, ACC, DEC, aerobic and anaerobic zone from the start to the end of the OFR. These metrics may correlate with improved RTS outcomes and risk of re-injury. Thus, GPS load monitoring data plays a key role in the progress of the football player between OFR stages following AT repair. Additionally, suboptimal outcomes in psychological readiness for RTS may occur post- AT repair. Therefore, although RTS is achievable after AT repair, further research is required to optimize OFR load management and enhance psychological readiness for RTS.","language":"eng","citation":"RETURN TO SPORT AFTER ACHILLES TENDON RUPTURE / M.f. Busa' ; supervisor: F. Esposito ; co-supervisor: M. Zago ; executive supervisor: F. Della Villa ; chairs of the program: F. Esposito, C. Gozzoli. Dipartimento di Scienze Biomediche per la Salute, 2025 Mar 26. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13519.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1156996/2739220/phd_unimi_R13519.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1130756"},"title":"MULTIPLE MYELOMA PLASMA CELL PROFILING: INTEGRATED SINGLE-CELL RNA AND VDJ SEQUENCING APPROACHES UNCOVER NOVEL CLINICAL INSIGHTS","internalauthor":"MATERA, ANTONIO","type":"Tesi di dottorato","year":"2025","abstract":"\"Multiple Myeloma (MM) is a hematological malignancy characterized by the proliferation of antibody-secreting bone marrow (BM) plasma cells (PCs). It is preceded by asymptomatic stages defined as Monoclonal Gammopathy of Undetermined Significance (MGUS) or Smoldering MM (SMM). MM is characterized by complex clonal architectures and crucial tumor microenvironment (TME) interactions. As a matter of fact, disease progression is driven by the dysregulated interaction of the PC population with the tumor microenvironment (TME). The PC population comprises clonal PCs (cPCs) and polyclonal PCs (pPCs). Although the roles of immune and non-immune cells have been extensively studied, the disruption of pPCs and their role in TME dysregulation have not been deeply studied.   This thesis presents a cutting-edge investigation into the clonal and polyclonal landscape of MM, leveraging the power of single-cell RNA and VDJ sequencing (scRNAseq and scVDJseq) to provide a detailed exploration of both the genetic and transcriptomic landscapes of MM at single-cell resolution, with particular emphasis on pPCs, TME interactions and clonal evolution.  The first major outcome of this work is the validation of scVDJseq as an effective tool for identifying MM-specific VDJ rearrangements, enabling detailed clonal tracking with higher precision. Our results demonstrate that single-cell analysis could reach a better resolution, uncovering key VDJ rearrangements in cPCs compared with traditional bulk DNA sequencing. Specifically, scVDJseq identified clonotypes and new subclonal populations, providing a comprehensive view of clonal diversity within the BM of MM patients. This technology also enabled precise identification of pPCs at various disease stages, offering a new framework for understanding clonal evolution from early asymptomatic to advanced symptomatic disease.  Integrating with transcriptome data, we obtained crucial insights about pPCs. These exhibited distinct phenotypic changes, particularly in their interaction with the TME. Interestingly, we identified a progressive loss of key immune markers in pPCs across disease stages. This suggests that these cells may be underestimated in immune surveillance and the immune system's ability to recognize and respond to malignant cells. Moreover, the data showed that pPCs from MM patients undergo significant transcriptomic dysregulation, marked by increased expression of autophagy-related and inflammatory pathways, a pattern not observed in healthy donors (HDs). These findings suggest that pPCs may be actively reshaped by the TME, potentially contributing to immune evasion and disease progression.  The dissertation also explores the phenomenon of immunoparesis, a hallmark of PC dyscrasia, in greater detail. Using scRNAseq data, we uncovered a unique gene signature in pPCs associated with immunoparesis, characterized by the upregulation of inflammatory and stress-related pathways. These findings point to a mechanistic link between the disruption of pPCs function and the failure of the immune system to surveil the tumor adequately, highlighting the complex interplay between pPCs, cPCs, and the TME. Additionally, our analysis revealed a significant depletion of pPCs in patients with immunoparesis, correlating with a reduction in immunoglobulin production and a more pro-inflammatory TME environment.  The key result is the identification of a \"\"healthy plasma cell\"\" (hPC) signature. This novel signature, derived from PCs in HDs, was progressively lost across MM disease stages, correlating with poorer clinical outcomes. Patients whose polyclonal cells retained this hPC signature had significantly better progression-free survival (PFS) and overall survival (OS), suggesting that the preservation of functional pPCs may serve as a protective factor against disease progression.   Building on these findings, a groundbreaking analysis of clonal evolution was conducted using the Dandelion tool for VDJ tracking. This tool allowed for precise mapping of clonal complexity and diversity as the disease progressed from asymptomatic to symptomatic stages. Suggesting that as MM progresses, clonal diversity expands, potentially contributing to treatment resistance.  In conclusion, this dissertation advances our understanding of MM by leveraging cutting-edge single-cell technologies to dissect the clonal architecture and the role of the polyclonal counterpart, which is often overlooked. The research not only provides a refined picture of MM clonal dynamics but also underscores the potential clinical value of tracking pPCs signatures. These findings open the door to new research directions, including the development of targeted therapies aimed at restoring immune surveillance and normal PC function, with the ultimate goal of improving patient outcomes in MM.\"","language":"eng","citation":"MULTIPLE MYELOMA PLASMA CELL PROFILING: INTEGRATED SINGLE-CELL RNA AND VDJ SEQUENCING APPROACHES UNCOVER NOVEL CLINICAL INSIGHTS / A. Matera ; tutor: N. Bolli; supervisori: M. C. Da Vià, F. Lazzaroni; reviewer: Z. K. Tuong; coordinatore: C. Sforza. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Jan 23. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13292.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1130756/2623357/phd_unimi_R13292.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/823976"},"title":"STUDIO DELL¿EFFETTO DELLA SUPPLEMENTAZIONE DI CURCUMINA IN PAZIENTI AFFETTI DA INSUFFICIENZA RENALE CRONICA","internalauthor":"DE SIMONE, PAOLA","type":"Tesi di dottorato","year":"2021","abstract":"Introduction.The definition of Chronic Kidney Disease (CKD) was developed in 2012 by Kidney Disease: Improving Global Outcomes (KDIGO) and is associated with the presence of abnormalities in the structure and function of the kidney that persist for at least 3 months with implications for health of thepatient. The identification of the first alterations in renal function, changes in body composition and nutritional status in renal patients, are the basis for the correct diagnosis of Chronic Kidney Disease.    Aim.The aim of the study was to understand the interaction between nutritional and inflammatory status in CKD patients. In particular, the study aims to investigate the action of curcumin supplementation for 3 or 6 months with particular attention to inflammation markers and changes in the intestinal microbiome.    Population and Methods.An intervention study was carried out at the San Paolo Hospital in Milan on a population of 24 patients with CKD in conservative therapy who were administered curcumin for 3 and 6 months of treatment. The blood chemistry tests for the evaluation of renal function were evaluated, the nutritional status was evaluated through the analysis of the body composition (BMI, waist circumference and bioimpedance analysis), while, the insertion of the 3-day food diaries were analyzed by means of the EphoodTM software, in order to carry out the bromatological analysis of food intake. Blood samples were collected and inflammatory cytokines analyzed (ELISA) to assess the patients' inflammatory status. Patient feces were also collected in order to analyze the patients' microbiome during the progression of the disease and the administration of curcumin.    Results.Body composition analysis showed a reduction in fat mass (p-value <0.0001), and an improvement in lean mass and a slight decrease in BMI from time T0 to time T1, and also between time T1 and time T2. The blood chemistry parameters remain within the normal range for the entire duration of the study, this is an indication of a good compensation of the disease, both from a pharmacological and dietary point of view. From the analysis of pro-inflammatory cytokines at serum level, it emerged that the levels of CCL2 were statistically significantly reduced and after six months of treatment the IFN-γ and IL-4 values also decreased, confirming the anti-inflammatory effect of curcumin supplementation, also described extensively in the scientific literature. From the analysis of the intestinal microbiota there were no statistically significant data. From the α-diversity analysis, the control group showed a higher dysbiosis condition than the group with CKD, probably linked to pathologies related to the age of our control group.    Conclusions.The increase in the incidence of CKD is mainly linked to the general aging of the population and the consequent aging of the kidney, together with the presence of other diseases: cardiovascular diseases, obesity and metabolic syndrome. The high average age of our population (71 years) highlighted the limitations of the study that would have helped to determine the low compliance found in the intake of curcumin and the low motivation in continuing the study for the entire duration of the study. To better understand the data obtained from the taxonomic analysis of the intestinal microbiota, studies are underway that aim to relate the nutritional intake with the characteristics of the microbiota composition of the patient with CKD.","language":"ita","citation":"STUDIO DELL¿EFFETTO DELLA SUPPLEMENTAZIONE DI CURCUMINA IN PAZIENTI AFFETTI DA INSUFFICIENZA RENALE CRONICA / P. De Simone ; tutore: P. Signorelli ; co-tutore: L. Soldati ; coordinatore del dottorato: M. Samaja. Dipartimento di Scienze della Salute, 2021 Mar 26. 33. ciclo, Anno Accademico 2020. [10.13130/de-simone-paola_phd2021-03-26].","filename":"phd_unimi_R11927.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/823976/1733836/phd_unimi_R11927.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/935533"},"title":"GENETIC MODULATION OF NOTCH SIGNALING AND LYSOSOMAL FUNCTION IN DROSOPHILA MELANOGASTER","internalauthor":"GENCHI, CHINA","type":"Tesi di dottorato","year":"2022","abstract":"In the first part of my thesis, I study novel genes that might regulate the Notch signaling pathway. The evolutionarily conserved Notch signaling pathway controls cell proliferation and differentiation decisions that shape development and homeostasis of multiple tissues in metazoans. Notch mutants were discovered in the fruit fly Drosophila melanogaster more than one century ago. Since then, extensive investigation in flies led to a superior understanding of how Notch regulates signaling, and how core cellular processes such as endo-lysosomal trafficking might control Notch signaling. The study of Notch during wing development in Drosophila pioneered the uncovering of an ever-increasing Notch interaction network, that is far from being fully elucidated. My work started by downregulating a set of previously identified putative Notch regulators in the developing Drosophila wing. We identified RNAi against Cam and Trpm, encoding the fly calmodulin homolog and a channel permeable to divalent ions, respectively, as regulators of wing vein patterning, a process controlled by Notch. Further genetic and tissue biology analysis indicated that while RNAi against Cam might prevent Notch activation, RNAi against Trpm might increase it. Indeed, RNAi against Trpm during Drosophila wing development correlates with strong alterations that phenocopy Notch gain of function mutations. Moreover, we found that well-known Notch signaling components genetically interact with RNAi against Trpm. Finally, we observed that RNAi against Trpm could reduce Notch cis-inhibition, a phenomenon that restricts signaling, and strongly interacted with mutants of genes that control endo-lysosomal trafficking of Notch. Altogether, our results could provide new entryways into modulation of the Notch signaling pathway.  In the second part of my thesis, I investigate the function of Cathepsin F (CtsF), encoding a lysosomal cysteine protease, in Drosophila. Homozygous inactivating mutations in human CTSF cause Type B Kufs disease, an ultra-rare adult-onset neuronal ceroid lipofuscinosis (NCL) characterized by premature accumulation of lipopigments, neurodegeneration, cognitive decline, dementia, motor dysfunction, ataxia and premature death. I characterized a novel Drosophila model of Type B Kufs disease by taking advantage of CRISPR/Cas9 knock-out CtsF mutants previously generated in the lab. In particular, I assessed whether CtsF mutants could recapitulate features of the disease. I have found that CtsF mutant flies present a very strong motoneuron impairment, which manifests early during adulthood. Motoneuron dysfunction correlated with a trend towards increased brain autofluorescence, an established readout of the accumulation of lipopigments. In addition, CtsF mutant flies displayed increased brain vacuolization, a sign of neurodegeneration in flies. Finally, we observe that CtsF mutants present an alteration of autophagy, which is often associated with accumulation of toxic lysosomal storage or alterations of lysosomal function. Overall, our work indicates that fly CtsF mutants could be a promising model to study type B Kufs disease, thus allowing to clarify pathogenesis in humans.","language":"eng","citation":"GENETIC MODULATION OF NOTCH SIGNALING AND LYSOSOMAL FUNCTION IN DROSOPHILA MELANOGASTER / C. Genchi ; tutor: T. Vaccari ; coordinator: M. Kater. Dipartimento di Bioscienze, 2022 Jul 27. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12278.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/935533/2058469/phd_unimi_R12278.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1151755"},"title":"TIES OF POWER: A NETWORK ANALYSIS OF CONTRACTUAL AND KINSHIP RELATIONS BETWEEN MERCENARIES AND REGIONAL STATES IN THE WARFARE MARKET OF RENAISSANCE ITALY.","internalauthor":"CRIVELLER, MARGHERITA","type":"Tesi di dottorato","year":"2025","abstract":"This dissertation examines contractual relations between mercenaries (condottieri ) and Italian regional states and kinship relations among mercenaries between the late 14th to the beginning of the 17th centuries. In line with Granovetter’s theory of embeddedness (1985), this research emphasises that mercenary contracts in Renaissance Italy were not simply market-driven transactions, but were deeply embedded in kinship networks and wider social structures that significantly influenced their nego tiation, implementation and evolution. Indeed, these enduring social ties - rather than a simple cost-benefit logic - served as a form of social capital that enabled mercenary families to become part of the ruling elite and led states to rehire mercenaries even after a breach of contract.  The case of Italian Renaissance warfare adds an original context of study: the establishment of centralised armies and the modernisation of states. This process took place through a complex web  of contracts between mercenaries and states, in a context of competition and cooperation involving  families, elites and organisations whose boundaries were often blurred. This research contributes with an original dataset that includes time-stamped information on contractual relationships between states and mercenaries, and kinship ties among mercenaries. The creation of this dataset allows for the detailed tracking of both economic and kinship relationships in a longitudinal framework, allowing for the study of network dynamics over time.  By examining the relationship between network centrality and mercenaries’ contract compliance  behaviour, the study aims to test whether there is a positive association between a mercenary’s position within military networks (i.e. states’ ego-networks) and the likelihood of breaching a contract or being rehired by a previously betrayed state. It is hypothesised that mercenaries with higher centrality in the military networks of the states they served were better able to use these connections to be rehired by the same states despite past betrayals, due to their social capital and strategic influence. Logistic cross-classified multilevel models are used to assess how centrality measures affect the likelihood of betrayal and reinstatement.  Furthermore, this research focuses on kinship formation and contractual relationships among  condottieri in the Duchy of Milan. The aim is to determine whether mercenaries served the Duchy  of Milan as a result of the social influence of affinal family ties - suggesting that once they joined a  family already serving the Duchy, they were inclined to follow suit - or whether they actively selected their acquired family ties from those already serving the Duchy, reflecting social selection processes. A temporal analysis of the ego-networks of the mercenaries who served the Duchy was conducted, comparing the composition of the ego-networks before and after the date of the first contract with the Duchy, in order to verify which mechanism led to the establishment of affinal and contractual ties.","language":"eng","citation":"TIES OF POWER: A NETWORK ANALYSIS OF CONTRACTUAL AND KINSHIP RELATIONS BETWEEN MERCENARIES AND REGIONAL STATES IN THE WARFARE MARKET OF RENAISSANCE ITALY / M. Criveller ; supervisor: F. Squazzoni ;  co-supervisor: F. Bianchi ;  coordinatore di Dottorato: M. Guerci. - Facoltà di Scienze Politiche, Economiche e Sociali - Università degli Studi di Milano. Dipartimento di Scienze Sociali e Politiche, 2025 Mar 13. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13471.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1151755/2707212/phd_unimi_R13471.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1153596"},"title":"ROLE OF IL-10 PRODUCING EOMES+ TR1-LIKE CELLS IN MELANOMA","internalauthor":"CARELLI, ELENA","type":"Tesi di dottorato","year":"2025","abstract":"The regulatory mechanisms that prevent the adaptive immune system’s ability to  eradicate tumors are crucial for the development of effective cancer  immunotherapies. In particular, the immunosuppressive functions of FOXP3+ T  regulatory cells (Tregs) and EOMES+ type 1 regulatory T (Tr1) cells, which produce  the anti-inflammatory cytokine IL-10, have been identified as key modulators of  anti-tumor immunity. IL-10 plays a dual role in cancer, functioning as a checkpoint  receptor agonist during cytotoxic T cell priming and potentially enhancing  established CD8+ T cell responses. We demonstrated that EOMES+ Tr1-like cells  are not only enriched and clonally expanded in human tumors, but they also suppress  CD8+ T cell activity. Elevated levels of an EOMES+ Tr1-like gene signature  correlate with poor patient survival and predict responses to anti-PD1  immunotherapy in melanoma patients. Moreover, in vitro studies have demonstrated  that human EOMES+ Tr1-like cells exhibit a reduced capacity to suppress antigen-  experienced CD8+ T cells in the presence of anti-PD1 antibodies.  In this study, we employed the C57Bl/6 mouse model of B16-OVA melanoma to  investigate the molecular mechanisms by which EOMES+ Tr1-like cells modulate  anti-tumor T cell responses in vivo. Our findings reveal that EOMES+ Tr1 cells  producing IL-10 are significantly enriched in tumors and contribute to promote  tumor growth by suppressing cytotoxic T cell activity. Thus, adoptive transfer  experiments with IL-10-deficient FOXP3-CD4+ T cells confirmed the critical role  7  of Tr1-derived IL-10 in promoting tumor progression and impairing anti-tumor  immunity. Furthermore, therapeutic treatment with anti-PD-L1 antibodies reduced  T cell IL-10 production and inhibited tumor growth, a phenomenon that was absent  in the absence of Tr1-derived IL-10. Using MHC tetramer staining, we showed that  a subset of tumor-infiltrating EOMES+ Tr1-like cells were specific for the  neoantigen Ovalbumin (OVA). Single-cell RNA sequencing of purified OVA-  specific CD4+ T cells revealed two major clusters: FOXP3+ Tregs and FOXP3-  CD4+T-cells containing a Tr1-like population expressing granzyme K (GzmK).  Performing a Differential Gene Expression (DEG) analysis on Tr1 cells, we  observed no significant differences between OVA− and OVA+ cells. However, we  identified differentially expressed genes between untreated and anti-PD-L1-treated  mice, suggesting a heightened stress response and increased exhaustion in  intratumoral Tr1 cells following treatment.  In melanoma patients, Tr1 cells were significantly enriched within tumors,  exhibiting a high proliferation rate. Circulating EOMES+ Tr1 cells in immune  checkpoint blockade (ICB) treated patients showed an increased IFNg production,  as well as for CD4+ T helper cells and CD8+ T cells, while Tregs have a significant  reduction in IL-10 production, suggesting an enhancement of cytotoxic  differentiation following treatment. When stimulated with melanoma-associated  antigens, they produced both IFN-γ and IL-10, particularly in response to MelanA,  while healthy donors did not respond to any tumor antigens. Moreover, circulating  Tr1 cells from patients harbouring V600E mutation in the BRAF gene respond to  the mutated peptide, suggesting the neo antigen specificity of these cells. Notably,  melanoma patients treated with ICB exhibited a diminished capacity for IL-10  production in circulating tumor antigen-specific Tr1 cells, mirroring the effects  observed in intratumoral CD4+ T cells in the mouse model, while CD4+ CTL and  CD8+ T cells showed upregulation of IFNg response to tumor antigens in ICB  treated patients.  In summary, these data suggest a pivotal role of IL-10-producing EOMES+ Tr1 cells  in modulating anti-tumor immunity. This study also provides the first evidence that  a fraction of circulating Tr1 cells in melanoma patients are tumor antigen specific.  Our findings suggest that immune checkpoint blockade therapy may be particularly  effective when Tr1 cells are abundant in the tumor microenvironment, providing new  insights for optimizing immunotherapeutic strategies.","language":"eng","citation":"ROLE OF IL-10 PRODUCING EOMES+ TR1-LIKE CELLS IN MELANOMA / E. Carelli ; supervisors: J. E. A. GEGINAT, F. M. GRASSI. - Milano. Dipartimento di Scienze Cliniche e di Comunità, 2025 Apr 03. 36. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13162.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1153596/2712273/phd_unimi_R13162.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/943292"},"title":"CLINICAL APPLICATIONS OF PARAOXONASE-1 IN DOMESTIC ANIMALS: BEYOND CONVENTIONAL INFLAMMATORY MARKERS","internalauthor":"SCAVONE, DONATELLA","type":"Tesi di dottorato","year":"2022","abstract":"Inflammation and oxidative stress frequently occur in domestic animals. The diagnosis and monitoring of inflammatory and oxidative conditions are based on markers that are so far considered accurate but may lack specificity and prognostic utility. In the last years’ research, interest has grown about the role of Paraoxonase-1 (PON-1) in the pathogenesis and diagnosis of many diseases characterized by inflammation and/or oxidative stress, both in human and veterinary medicine. In veterinary species, PON-1 measurement is to date primarily restricted to the research field and has not been yet undertaken in the routine clinical field. However, recent research has highlighted promising utility in many clinical contexts. Since accurate and precise spectrophotometrical assays validated in many species are now available and proved to be cheap, rapid and automated, its measurement could easily be included in routine chemistry panel in the near future. Therefore, the aim of my research was focused on the evaluation of the usefulness of PON-1 as a diagnostic and prognostic marker in different conditions characterized by inflammation and/or oxidative stress in different veterinary species.  The results collected in the different studies described in this thesis provided further insights about the possible utility of PON-1 as a biomarker in veterinary clinical pathology. We confirmed the role of PON-1 as a marker of systemic inflammatory response syndrome, possibly associated with sepsis in horses and dogs, and its usefulness as a prognostic marker in these contexts. Furthermore, in dogs we confirmed its usefulness as a marker of disease severity and its possible applications as a tool for clinical decision or detection of subclinical disease. As regards cats and pigs, results about its usefulness are still preliminary and deserve further investigation with a wider and more standardized caseload. On the contrary, we demonstrated the usefulness of PON-1 as an ancillary test for clinical decisions or to address further testing in cattle with bovine respiratory disease.","language":"eng","citation":"CLINICAL APPLICATIONS OF PARAOXONASE-1 IN DOMESTIC ANIMALS: BEYOND CONVENTIONAL INFLAMMATORY MARKERS / D. Scavone ; tutor: S. Paltrinieri ; coordinator: F. Ceciliani. Università degli Studi di Milano, 2022 Sep 06. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12373.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/943292/2087822/phd_unimi_R12373.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1222035"},"title":"SYNTHESIS AND STRUCTURAL DESIGN OF CARBOHYDRATE-BASED ARCHITECTURES: FROM VACCINE ADJUVANTS TO GLYCAN FOLDAMERS","internalauthor":"SCHIVARDI, SIMONE","type":"Tesi di dottorato","year":"2026","abstract":"Carbohydrates are complex molecules currently under deep investigation for the multiple roles they have in Nature: from source of energy, bricks of cell surface to several biological processes1. In the past years carbohydrates have been used in many applications: in the pharmaceutical field they are found in drug discovery2, design and synthesis of glycomimetics structures3, vaccine adjuvants4. Polyglycan structures have been used both for biology and for material chemistry purpose5.  The first chapter of this PhD thesis focus the attention on vaccine adjuvant semi-synthesis. Vaccines are one of the oldest treatments in medicine prevention, since the first vaccination was performed in the 1790s by Edward Jenner for the cowpox prevention6. Science has made great strides over the last two centuries however, for many years vaccination relied on whole-pathogen approach exploiting: viral vector, live-attenuated vector or inactivated/killed vector to generate immunological response7. Although whole-pathogen vaccines elicit long-lasting immunity, safety issues related to administering these complex mixtures, prevent their universal application8; therefore, in the early 2000s, modern subunit vaccination were deeply investigated due to their improved safety and more precise targeting compared to whole-pathogen vaccination, as possible alternative9. Nevertheless, immunization with purified protein antigen (subunit) are inherently less immunogenic, typically resulting in a modest antibody response with little or no T cell response10.  Adjuvants, in the context of vaccines, are defined as substances capable to enhance antigen-specific immune responses by triggering and modulating both the innate and acquired immunity: memory of long-lasting10. However, despite many years of improvements and developments, only few adjuvants are currently included in vaccination approved for human use: aluminium salts, emulsions (e.g. squalene), liposomes/virosomes and microparticles just to mention a few11. In this scenario, new classes of adjuvants are currently under investigation to offer an alternative and overcome this issue. Among them QS-21, an immunostimulatory saponin natural product extracted form Quillja Saponaria tree bark9, has emerged as a noteworthy alternative. The semi-synthesis of QS-21 and its main components will be faced in the first chapter of this thesis.","language":"eng","citation":"SYNTHESIS AND STRUCTURAL DESIGN OF CARBOHYDRATE-BASED ARCHITECTURES: FROM VACCINE ADJUVANTS TO GLYCAN FOLDAMERS / S. Schivardi ; tutor: A. Bernardi (UNIMI) ;  co-tutor: L. Senaldi  (INDENA S.p.A.) coordinator: D. Passarella (UNIMI). Dipartimento di Chimica, 2026 Mar 02. 38. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R13921_2.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 04-SET-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/962096"},"title":"DIABETIC ENCEPHALOPATHY AND NEUROACTIVE STEROIDS: OBSERVATIONS IN FEMALE RATS","internalauthor":"FALVO, EVA","type":"Tesi di dottorato","year":"2023","abstract":"Diabetes mellitus (DM), a chronic metabolic disorder, may induce neurophysiological and structural changes in the central nervous system (i.e.,diabetic encephalopathy). Diabetic encephalopathy (DE) is one of the most common and severe chronic complications of DM, characterized by impaired cognitive and memory functions, and structural, neurochemical, and electrophysiological abnormalities. These alterations are associated with decline in cognitive processes, increased risk of cerebrovascular and Alzheimer’s disease, dementia, and psychiatric disorders.  Memory and cognitive impairments are associated with hippocampal dysfunction, but the mechanisms behind these alterations are not fully known. Based on data collected in literature, the development of cognitive deficit seems to be the result of the concomitant presence of different processes such as mitochondrial dysfunction, oxidative stress, neuroinflammation and aberrant synaptogenesis in several brain areas of male rat model of type 1 DM (T1DM). Another important factor involved in the development of DE are steroid molecules because it is widely known that these molecules are regulators of the nervous function. Indeed, our previous data have shown that levels of many neuroactive steroids (i.e., steroids affecting the nervous system functionality) are decreased by three months (long-term) of DM but also by one month (short-term) in male streptozotocin (STZ)- induced rats. Moreover, DE presents differences, between two sexes, in term of incidence, progression and severity of the pathology. However, despite DE shows many sex dimorphic features, no observations in female rats have been so far reported in literature.  On this basis, in the present study, firstly, we have explored the impact of one month of diabetes on memory abilities by Novel Object Recognition (NOR) test, on mitochondrial functionality, oxidative stress, synaptogenesis and neuroactive steroids levels in hippocampus and cerebral cortex of female STZ-rats in order to understand whether short-term DM affects these parameters also in females and whether possible changes are different in the two sexes.  Data reported in this thesis indicate that short term of T1DM is able to significantly decrease memory abilities. This result is associated with aberrant synaptogenesis (i.e., decrease in the levels of synaptophysin, synapsin and syntaxin) and neuroinflammation (i.e., increased levels of IL-1b and IL-6) in hippocampus of female STZ-rats. Oxidative stress and mitochondrial functionality are not affected in this brain area, possibly due to protective effect of dihydroprogesterone (DHP) and allopregnanolone (ALLO), whose hippocampal levels are significantly increased. These effects are specific for hippocampus since the cerebral cortex does not present a similar increase in steroid levels and consequently shows increased neuroinflammation and oxidative stress possibly due to mitochondria dysfunction.  T1DM induced not only a diabetic encephalopathy but also dysbiosis. On this basis, we focused our attention on the possible role of gut microbiota on the development of memory deficits in female STZ-rats in the contest of gut-brain axis. In particular, we explored, whether DM can affect the composition of gut microbiota, the levels of steroids in colon and gut permeability markers. In  addition, we also evaluated whether correlations may occur among these parameters in female STZ-rats. Results obtained demonstrated that T1DM alters gut β-, but not α-diversity. The pathology is also associated with a significant decrease in pregnenolone (PREG) and increase in ALLO levels in the colon of female STZ-rats. In addition, T1DM altered gut permeability (i.e., decreased of zonulin-1 and claudin-1). Interestingly, we reported a significant correlation of PREG with Blautia, claudin-1 and the NOR index and of ALLO with Parasutterella, Gammaproteobacteria and claudin-1.  Altogether, data obtained in this thesis suggest a pivotal role of neuroactive steroids and gut steroids in the development of memory disfunctions. In the central nervous system, increased levels of DHP and ALLO seem to be an attempt to counteract the negative effects of T1DM particularly in hippocampus. In periphery, the positive correlation between decreased level of PREG in colon and behavioural results, support the hypothesis that this steroid has an important role in the development of cognitive deficit observed in the CNS across the gut-brain-axis.","language":"eng","citation":"DIABETIC ENCEPHALOPATHY AND NEUROACTIVE STEROIDS: OBSERVATIONS IN FEMALE RATS / E. Falvo ; tutor: C. Melcangi ; coordinatore: G. D. Norata. Dipartimento di Scienze Farmacologiche e Biomolecolari, 2023 Apr 05. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12560.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/962096/2170969/phd_unimi_R12560.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1211196"},"title":"CANCERHUBS: A NETWORK-CENTRIC FRAMEWORK FOR CANCER GENE PRIORITISATION","internalauthor":"FERRARI, IVAN","type":"Tesi di dottorato","year":"2026","abstract":"\"Cancer is a complex disease that originates from genetic mutations, which represent the primary triggering events of neoplastic transformation. Nevertheless,  such lesions alone are not sufficient to account for the full complexity of tumour  development, which also arises from epigenetic and regulatory alterations that remodel cellular networks and molecular circuits. In this framework, conventional  single-gene approaches risk overlooking key elements that, although not frequently  mutated or differentially expressed, play a critical role as network hubs. In this thesis, \"\"CancerHubs\"\" is presented, a systematic data mining and integration pipeline  that combines mutational data, clinical outcome predictions (via PRECOG meta-Z  scores), and protein-protein interaction networks to identify cancer-related protein  hubs. The method computes a composite Network Score that integrates mutational  profiles, prognostic associations, and interactome connectivity, thereby prioritising  genes that may not be strongly mutated or differentially expressed, but are central to the cancer network structure. This approach moves beyond conventional  mutation-centric strategies and provides a network-informed perspective on cancer  gene discovery. Alongside the computational method, \"\"CancerHubs Data Explorer\"\",  a Shiny web application that allows users to interactively explore mutation-enriched  hubs across 11 tumour types was developed. The application provides ranked tables, global interactomes, and neighbourhood visualisations of user-defined genes,  with filtering options for mutational and prognostic data. This ensures that the  results of the pipeline are not only reproducible but also broadly accessible to researchers with varying computational expertise. As a proof of principle, predictions  generated by CancerHubs were validated both in silico and experimentally. These  analyses demonstrated that TGOLN2 displays tumour suppressor features in Multiple Myeloma, Breast, and Prostate Cancer, while EFTUD2 exhibits oncogene-like  behaviour specifically in Multiple Myeloma. This validation highlights the ability  of the framework to uncover genes of clinical and mechanistic relevance that may  be missed by mutation- or expression-centric approaches. Altogether, CancerHubs  provides a exible and extensible framework for interactome-based cancer gene prioritisation. By integrating heterogeneous data layers into a unied network-aware  metric, and by complementing predictions with functional validation and accessibility through the CancerHubs Data Explorer, this work contributes to the advancement of systems oncology. The tools and ndings described here aim to support  hypothesis generation, biomarker discovery, and the identification of novel therapeutic targets, ultimately bridging the gap between large-scale cancer genomics and  translational applications.\"","language":"eng","citation":"CANCERHUBS: A NETWORK-CENTRIC FRAMEWORK FOR CANCER GENE PRIORITISATION / I. Ferrari ; tutor: S. Biffo. Dipartimento di Bioscienze, 2026. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13707_1.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 11-FEB-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1272860"},"title":"LE CONFISCHE NEL DIRITTO VIVENTE. PROFILI SOSTANZIALI DEL POLIEDRICO PANORAMA ABLATIVO ITALIANO E SOVRANAZIONALE","internalauthor":"FROVA, GUILLEM","type":"Tesi di dottorato","year":"2026","abstract":"\"The thesis reconstructs the institution of confiscation as it operates in \"\"living law\"\" (diritto vivente), with the aim of offering a systematic reading of the main forms of asset deprivation currently in force in the Italian legal system and of their interplay with the supranational framework. The starting point is that confiscation is a \"\"plural\"\" institution. It comprises numerous provisions scattered across different areas of the legal order (the Criminal Code, special legislation, the Anti-Mafia Code, Legislative Decree No. 231/2001, and forms of administrative confiscation), all of which are shaped by intense case-law developments and by the growing influence of the European Union. This plurality makes the subject fascinating for scholars but complex for practitioners, since layers of legislation and interpretive fluctuations undermine the predictability of outcomes.    The research proposes a reading of the institution built around a number of recurring key issues: the qualified link with criminal conduct, the object subject to confiscation, the relationship between the person and the asset, and the protection of third parties. The core of the thesis is preventive confiscation under Legislative Decree No. 159/2011. This is currently the most extensively (though by no means exhaustively) regulated area, and it is frequently relied upon to fill the regulatory gaps that emerge in other fields. Indeed, the analysis shows that many issues recur across the different forms of confiscation, leading the system to reason by analogy and cross-reference, not always with consistent results.    Alongside the substantive dimension, the thesis emphasises the management and allocation of assets (Title III of the Anti-Mafia Code) as a key factor in effectiveness. Asset recovery does not end with the confiscation order. It depends on the entire chain of identification, administration, preservation of value and allocation of confiscated assets.    Finally, the thesis assesses the impact of the recent Directive (EU) 2024/1260. It highlights how its transposition may provide an opportunity to coordinate and simplify the Italian system, reducing inconsistencies and strengthening definitions and management tools, without sacrificing safeguards.\"","language":"ita","citation":"LE CONFISCHE NEL DIRITTO VIVENTE. PROFILI SOSTANZIALI DEL POLIEDRICO PANORAMA ABLATIVO ITALIANO E SOVRANAZIONALE / G. Frova ; tutor: F. Basile; cotutor: L. Musselli ; coordinatore: E. Damiani. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2026 Sep 21. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14029.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1272860/3407012/phd_unimi_R14029.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/828515"},"title":"«ICH BIN EIN REGISSEUR DES WORTS UND NICHT DER DEKORATION»:L¿ESTETICA TEATRALE DI LEOPOLD JESSNER: QUASI UN ÓRGANON","internalauthor":"D'ORAZIO, SILVIA VINCENZA","type":"Tesi di dottorato","year":"2021","abstract":"This dissertation aims at reconstruing Leopold Jessner’s theatre aesthetics through the  analysis of his theatrical essays. Jessner was one of the most influential German theatre  directors during the Weimar Republic. His figure came along in the cultural landscape in the  same years the director’s theatre emerged in both Europe and Germany. Through the  analysis, this dissertation also aims at rethinking Jessner’s theatre aesthetics in the artistic and  cultural landscape of the Weimar Republic.  The second chapter of the dissertation presents Jessner as a theatre director and focusses  on the obstacles and labels that prevented a scientific evaluation of his work.  The third chapter proposes an analysis of the author’s corpus. In order to shed light on the  key aspects of Jessner’s aesthetics, the investigation is organised in four macro-sections: Der  Theaterleiter, Zeittheater und Theaterpolitik, Regie und Schauspielkunst and Betrachtungen und  Bekenntnisse.  The fourth chapter summarises the results of the analysis and presents Jessner’s Stil des  Wesentlichen, focussing on its key elements: the dramaturgical method, the role of scenic  design, and of the actor and the relationship with the audience. The last section of the chapter  investigates the correlation between Jessners’ Stil des Wesentlichen, Expressionism and New  Objectivity.","language":"ita","citation":"«ICH BIN EIN REGISSEUR DES WORTS UND NICHT DER DEKORATION»:L¿ESTETICA TEATRALE DI LEOPOLD JESSNER: QUASI UN ÓRGANON / S.v. D'orazio ; tutor: M. Castellari ; coordinatrice: M. V. Calvi. Dipartimento di Lingue e Letterature Straniere, 2021 Apr 09. 32. ciclo, Anno Accademico 2020. [10.13130/d-orazio-silvia-vincenza_phd2021-04-09].","filename":"phd_unimi_R11582.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/828515/1748919/phd_unimi_R11582.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/918362"},"title":"HETEROCYCLIC Β-AMINO ACIDS AS MOLECULAR TOOLS FOR PEPTIDOMIMETIC SYNTHESIS AND ORGANOCATALYSIS","internalauthor":"VAGHI, FRANCESCO","type":"Tesi di dottorato","year":"2022","abstract":"β-Amino acid( AAs) are analogues of α-AAs with a difference: an additional carbon atom between the carboxylic and amine groups. β-AAs are commonly considered not natural amino acids, although there are some examples of this class in nature as secondary metabolites or as components of complex natural products.  Being not natural AAs, when they are inserted in a peptide structure they can confer major proteolytic stability to the system compered to natural AAs. In fact, human peptidases do not recognize beta-amino acids and are not able to hydrolyze peptide bond. Moreover β-peptides and α/β hybrid peptides can induce a predictable and well-defined secondary structure, such as helices, strands and loops that may be residue-controlled and biologically active.   During the PhD activity the synthesis of non-natural cyclic β-amino acids has been performed. Each of these has been used for different applications as described below:  - Synthesis of non-natural 3-Arylmorpholino-β-amino Acid as a PPII Helix Inducer    - Synthesis of electrospun fibers using model peptide containing morpholino-β-amino acid scaffolds    - Synthesis of nucleobase morpholino β amino acids from ribonucleosides as molecular chimeras for the preparation of photoluminescent materials     - Synthesis of non-natural amino acids with Morpholine core as organocatalysts for enantioselective Aldol-condensation reactions     - Synthesis of non-natural amino acid with isoxazoline core as β-turn inducer for the preparation of peptidomimetics     - Photochemistry cyclization peptide. This part of my thesis was performed during my visiting period at University of Manchester (UK) in Leonori Group.","language":"eng","citation":"HETEROCYCLIC Β-AMINO ACIDS AS MOLECULAR TOOLS FOR PEPTIDOMIMETIC SYNTHESIS AND ORGANOCATALYSIS / F. Vaghi ; tutor:  M. L. GELMI ; coordinator: G. ALDINI. Dipartimento di Scienze Farmaceutiche, 2022 Apr 04. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12318.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/918362/2007857/phd_unimi_R12318.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/858048"},"title":"FARBPHRASEOLOGISMEN ALBANISCH-DEUTSCH KONTRASTIV","internalauthor":"MUCO, ALBANA","type":"Tesi di dottorato","year":"2021","abstract":"This research project aimed to study the metaphorical meaning of colour (conceptualizations and categorizations) within phraseological units in Albanian and German from a pluricentric perspective (inter- and intralinguistic variety). The work consisted of three phases: 1) identification of linguistic units containing colour terms in both languages and creation of an inventory (more than 400 units; basis for bilingual and bi-directional Albanian-German/German-Albanian vocabulary); 2) identification of diatopic variants and analysis of the ‘knowledge’ and ‘use’ of colour phraseology through interviews in Albania, Kosovo, Germany and Austria (a total of 298 interviews), taking into consideration social variables such as interviewees’ ‘origin’, ‘age’, ‘gender’ and ‘education’ (ages 15 and up); 3) contrastive analysis according to the Construction Grammar (GxC) – grammatical model of Cognitive Linguistics – of a specific type of phraseologisms, namely one with a fixed schema structure: [[X] (verb) like/as [Y]]. These analysed linguistic units were collected from the interviews.","language":"ger","citation":"FARBPHRASEOLOGISMEN ALBANISCH-DEUTSCH KONTRASTIV / A. Muco ; tutor: P. Katelhoen ; coordinatrice: M. V. Calvi. Dipartimento di Lingue e Letterature Straniere, 2021 Jul 16. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11996.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/858048/1841888/phd_unimi_R11996.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/892466"},"title":"BREAST CANCER, FOCUS ON SELECTED EPIDEMIOLOGICAL ASPECTS","internalauthor":"PIZZATO, MARGHERITA","type":"Tesi di dottorato","year":"2022","abstract":"In this final report I described the main phases on my PhD period, collecting my main research work of the last three years. I have had the possibility to explore different epidemiological themes and to collaborate with leading researchers in this field. I mainly focused on breast cancer, through Piedmont Registry data, but I had also the possibility to address epidemiological aspects of other cancers. The added value was the chance to work in an international context in Lyon at the International Agency for Research on Cancer. My career in cancer epidemiology is only at the beginning. I will be able to continue my research in the next three years, thanks to a postgraduate scholarship in health statistics.","language":"eng","citation":"BREAST CANCER, FOCUS ON SELECTED EPIDEMIOLOGICAL ASPECTS / M. Pizzato ; tutor: C. La vecchia. Universita' degli Studi di MILANO, 2022 Jan 11. 34. ciclo, Anno Accademico 2021. [10.13130/pizzato-margherita_phd2022-01-11].","filename":"phd_unimi_R12208.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/892466/1939245/phd_unimi_R12208.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1196911"},"title":"ZSCAN4 AND REPLICATION STRESS: SAFEGUARDING GENOME STABILITY IN MOUSE EMBRYONIC STEM CELLS","internalauthor":"CASTELLAN, CRISTINA","type":"Tesi di dottorato","year":"2025","abstract":"The accuracy of DNA replication is essential for maintaining genome stability. However, replication can be disrupted by both endogenous and exogenous factors, leading to a condition known as replication stress (RS). RS slows down and eventually stalls replication forks. If stalled forks are not resolved, they can give rise to DNA double-strand breaks, thereby promoting genomic instability—a hallmark of cancer.  Our laboratory discovered that exposure of mouse embryonic stem cells (mESC) to RS induces the expression of Zscan4, a marker of the 2C stage in mouse embryo development. Depletion of Zscan4 in mouse zygotes reduces the number of blastocysts formed, which eventually fail to grow and implant. ZSCAN4 also plays a crucial role in mESC by contributing to telomere maintenance and genomic stability. Its prolonged knockdown leads to cell death, accompanied by karyotype abnormalities and telomere shortening. Moreover, deregulation of Zscan4 has been implicated in cancer development and maintenance.  Despite this, the mechanisms through which Zscan4 promotes genome maintenance in mESC, particularly within the context of RS, remain poorly understood. We analyzed the effect of Zscan4 expression modulation on DNA replication in mESC using DNA fiber assays and electron microscopy. We found that ZSCAN4 accelerates fork progression while concomitantly reducing single-stranded DNA gaps at fork junction. In addition, whole genome bisulfite sequencing revealed that Zscan4 overexpression induces global DNA demethylation in mESC, whereas RS increases global DNA methylation. Finally, short nascent strand sequencing analysis showed that RS leads to increased origin usage, while Zscan4 overexpression decreases origin usage.  Together, these findings reveal a novel function of ZSCAN4 in promoting replication fork progression and remodeling in mESC. Furthermore, Zscan4-induced genome-wide demethylation appears to facilitate DNA accessibility, for instance to DNA repair factors, while RS-induced hypermethylation has the opposite effect. Strikingly, the DNA methylation status correlates with the profile of origin usage: Zscan4 overexpression decreases origin usage, whereas RS increases it. These results suggest the existence of an underexplored connection between DNA methylation and DNA replication.","language":"eng","citation":"ZSCAN4 AND REPLICATION STRESS: SAFEGUARDING GENOME STABILITY IN MOUSE EMBRYONIC STEM CELLS / C. Castellan ; tutor: V. Costanzo ;  coordinatore del dottorato: D. Pasini. Dipartimento di Oncologia ed Emato-Oncologia, 2025. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13470.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 20-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/843597"},"title":"THE PHYSIOLOGICAL IMPACT OF CAPTURE: STRATEGIES FOR IMPROVING IMMOBILIZATION OF WILD EAST AFRICAN MESO- AND MEGA-HERBIVORES","internalauthor":"VITALI, FRANCESCA","type":"Tesi di dottorato","year":"2021","abstract":"East African meso- and mega-herbivores have been a key part of the Earth’s ecosystem for millions of years, but are now at risk of disappearing. To ensure their conservation, operations that involve veterinary immobilization are becoming essential for wild populations. However, capture morbidity remains high, with both short- and longer-term physiological alterations that can result in acute or delayed death. In large-sized herbivores, the size and unique anatomy and physiology contribute to the high susceptibility to capture stress, drugs adverse effects and alterations due to recumbency. On top of this, the limited knowledge in the species-specific physiological response to immobilization and, as a result, the obliged practice of extrapolating drug doses and protocols from similar species, enhances the risk of complications. Improvement in capture methods and drug protocols are advocated, and as such, in order to develop targeted strategies, it is essential to gain a better understanding of the species-specific physiological impact of capture.  The general objective of this thesis is to advance the knowledge of the physiological mechanism of capture morbidity, and evaluate strategies for the prevention, detection and treatment of complications arising from opioid-based immobilization of selected species of East African megaherbivores, the giraffe (Giraffa camelopardalis ssp. tippelskirchi and reticulata) and the black rhinoceros (Diceros bicornis ssp. michaeli), and in a large mesoherbivore, the African buffalo (Syncerus caffer). A key factor of this study was the collection of data through an opportunistic approach, whereas the research design was shaped for each of the study species based on targeted needs, thus different specific objectives were pursued for each species.    In free-ranging Masai giraffes that were immobilized for a translocation, a combination of etorphine and azaperone was evaluated for physiological and handling safety. Early opioid antagonization – a common procedure performed to reduce etorphine’s respiratory depression – was performed at low doses to assess if it would result in smoother restraint and transport. The protocol produced safe inductions, but variable opioid-related excitement occurred and accounted for metabolic derangement. On the other hand, early antagonization with low dose naltrexone allowed calm restraints, a stable physiological function during the recumbency, and enabled smooth recoveries and loading into the chariot with resulting uneventful transport. No delayed complications or resedation were observed during a two-week post-capture boma monitoring. Although the protocol allowed safe immobilization and transport, the study highlighted that further research on techniques that reduce induction-induced excitement, which poses severe health risks in giraffe capture, is advocated.  Building up on the study performed in Masai giraffe, the physiological mechanism of capture morbidity occurring in both vehicle and helicopter darted reticulated giraffes, immobilized with an etorphine-azaperone combination, was investigated in order to detect the predisposing factors for homeostatic alterations and to define and guide prevention strategies. Trends over time in blood gases, selected biochemistry variables and cardio-respiratory function were analyzed following early opioid antagonization, and the use of a non-invasive nasal capnometer was investigated. In the helicopter  darted giraffes, severe metabolic alterations were observed as a result of an intense startle response,     whereas in vehicle darted giraffes, these were moderate and mainly a result of etorphine-induced excitement. Intense excitement occurred when lower doses of etorphine were administered, whereas higher doses resulted in respiratory depression, severe respiratory acidosis and hypoxemia. Early antagonization produced an improvement over time of gas exchanges, but not of the acid-base status, and resulted in poor immobilization quality. Nasal capnometry proved to be a useful non-invasive monitoring tool for field ventilatory function in giraffes. The severe alterations observed suggest that advances in giraffe immobilization should focus on reducing both opioid-respiratory depression and excitement, and onto providing adequate sedation and analgesia during field immobilizations.  In Eastern black rhinoceroses, two intra-anesthetic treatments, butorphanol and oxygen, or doxapram, butorphanol and oxygen - which are routinely administered to improve gas exchanges, but which efficacy has not been investigated yet in the species - were evaluated. The mechanism of physiological alterations resulting from capture was investigated, and nasal capnometry was evaluated for its accuracy in monitoring carbon dioxide. Hypoxemia and severe lactic acidosis, proportional to more intense pre-dart chase, occurred. After the administration of doxapram and butorphanol, the initial hypoxemia and acidosis improved, presumably as a result of increase in ventilation mediated by doxapram; whereas the same values worsened when butorphanol only was administered. This might suggest that, different to other rhinoceroses, increased oxygen consumption is not the primary mechanism of hypoxemia in black rhinoceros. Nasal capnometry was efficient in monitoring carbon dioxide trends, but not accurate in predicting absolute values. Although intra-anesthetic treatment with doxapram partially improved gas exchanges, and post-capture complications did not occur for at least nine months, the severe metabolic and respiratory alterations observed highlight the need of advances in black rhinoceros capture methods that focus on preventing the origin of physiological alterations.  The physiological safety of two immobilization protocols, etorphine-azaperone and etorphine- medetomidine-azaperone combinations, was compared in free-ranging African buffalos. The aim was to evaluate if medetomidine’s sparing effect would have allowed to safely decrease etorphine doses, and its adverse respiratory effects, without increasing the risk of excitement or poor immobilization quality. The addition of a low dose of medetomidine allowed to decrease etorphine dose by 30 %, and resulted in quicker and smoother inductions, and significantly improved immobilization quality. Medetomidine reduced the occurrence of tachycardia and respiratory acidosis, but not of hypoxemia. Etorphine-medetomidine-azaperone combination is recommended for buffalo immobilization as it provides greater physiological and handling safety, and can help to reduce the onset of capture stress.    The new knowledge acquired within the different studies of this thesis has allowed to detect and evaluate species-specific strategies for the prevention (through knowledge of factors influencing capture morbidity, and improved immobilization protocols), detection (through clinical monitoring) or treatment (intra-anesthetic drugs) of capture and drug complications in large-sized herbivores. Species- specific and intra-specific variation of physiological response to capture stress and drugs were individuated, and hence a species-specific approach needs to be endorsed when capturing large-sized herbivores. Furthermore, based on the new information gained in this thesis, further studies can now specifically focus towards targeting solutions for the specific detected physiological alterations. The advances on immobilization methods resulting from this thesis represents a first step towards the improvement of the safety of immobilization of giraffes, black rhinoceroses and buffalos, and by reducing the risk of occurrence of delayed morbidity, it also contributes to the conservation of these East African large-sized herbivores.","language":"eng","citation":"THE PHYSIOLOGICAL IMPACT OF CAPTURE: STRATEGIES FOR IMPROVING IMMOBILIZATION OF WILD EAST AFRICAN MESO- AND MEGA-HERBIVORES / F. Vitali ; tutor: M. Faustini, G. Ravasio ; coordinatore: V. Grieco. Università degli Studi di Milano, 2021 May 17. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12000.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/843597/1800111/phd_unimi_R12000.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/814664"},"title":"GAIN OF TOXIC FUNCTION OF CHAPERONE ASSISTED SELECTIVE AUTOPHAGY MEMBERS IN NEUROMUSCULAR DISEASES: A CHARACTERIZATION OF DISEASE-RELATED MUTANTS","internalauthor":"TEDESCO, BARBARA","type":"Tesi di dottorato","year":"2021","abstract":"Proteostasis alteration characterizes several diseases affecting muscle and neuronal cells and can be caused by protein misfolding and aggregation and/or mutations in Protein Quality Control system members. For instance, mutations in the Chaperone Assisted Selective Autophagy (CASA) members are causative of neuropathies/myopathies. The CASA complex mainly acts in muscles and neurons, by facilitating the disposal of misfolding and aggregating proteins. This occurs through substrate recognition by the chaperone HSPB8, which interacts with the HSP70 co-chaperone BAG3. If substrates cannot be refolded by HSP70, they are ubiquitinated by the E3 ubiquitin ligase CHIP. Substrates are then routed and compartmentalized into perinuclear deposits of aggregates, or aggresomes, for subsequent autophagic-lysosomal disposal.  In the first part of my studies, I showed results on neuropathies/myopathies related P209S/L/Q BAG3 mutants. By overexpressing BAG3 mutants in cells, I observed that all BAG3-P209 mutants are characterized by decreased solubility. The decreased solubility determines BAG3-P209 mutants aggregation and relocation with the other CASA members at the aggresome, resulting in an impairment of CASA activity against misfolded clients. In addition, I demonstrated that BAG3-P209 mutants are preferentially degraded through autophagy. Thus, I showed that boosting autophagy using trehalose, proven to favour the clearance of aggregating proteins related to neurodegenerative diseases, determined BAG3-P209 aggregates disposal, representing a valuable therapeutic approach in BAG3-P209 diseases.  In the second part, I firstly showed results on HSPB8 variants S9P, P41S and S181C found in Amyotrophic Lateral Sclerosis (ALS) patients. Using a motoneuron-like cell model overexpressing HSPB8 variants, I observed no differences in HSPB8 variants biochemical behaviour with respect to HSPB8 wildtype (WT), except for the S181C variant, characterized by a structural alteration. However, no differences in HSPB8 variants activity were observed. Instead, I obtained promising results on myopathies/neuropathies-related frameshift mutants pPro173Serfs*43, pGln170Glyfs*45, and pThr194Serfs*23. I found that these mutants present the same C-terminal modification and/or an identical elongated C-terminal tail, predicted to affect protein solubility. Indeed, I observed insolubility and aggregation of these mutants, when overexpressed in cells. Similar to BAG3-P209 mutants, HSPB8 mutants co-segregate with CASA members and associate to an increase in ubiquitinated proteins, suggesting CASA impairment. Again, trehalose-mediated autophagic enhancement favoured the clearance of these aggregating HSPB8 mutants.  In the third part, I characterized isogenic iPSCs-derived motoneurons as new cell models to study TDP-43-related proteinopathies. These cell lines were previously gene-edited, to express WT or the ALS-A315T mutated TDP-43, tagged with the DENDRA2 reporter. Using a small molecules-based protocol, I differentiated these iPSCs obtaining a mixed population of neurons and motoneurons. Model validation showed that under untreated conditions all WT and A315T-mutated cell lines are not characterized by TDP-43 misbehaviour, since no hallmark of pathogenic TDP-43 was observed; instead, upon proteasome inhibition, all cell lines showed TDP-43 cleavage, phosphorylation, and aggregation, correlating with activated cleaved caspase-3, in line with the current literature.  With my work, I determined shared biochemical and functional alterations between BAG3 and HSPB8 mutants, suggesting that a common therapeutic strategy might be beneficial in the related neuromuscular diseases. In addition, I defined TDP-43-DENDRA2-derived motoneurons as a valuable tool to study TDP-43-related proteinopathies.","language":"eng","citation":"GAIN OF TOXIC FUNCTION OF CHAPERONE ASSISTED SELECTIVE AUTOPHAGY MEMBERS IN NEUROMUSCULAR DISEASES: A CHARACTERIZATION OF DISEASE-RELATED MUTANTS / B. Tedesco ; supervisor: A. Poletti ; co-supervisor: V. Crippa ; coordinator: C. Sforza. Dipartimento di Scienze Farmacologiche e Biomolecolari, 2021 Feb 23. 33. ciclo, Anno Accademico 2020. [10.13130/tedesco-barbara_phd2021-02-23].","filename":"phd_unimi_R11989.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/814664/1704386/phd_unimi_R11989.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1240896"},"title":"ELT IN CHINESE GENERAL SENIOR HIGH SCHOOL: AN ANALYSIS OF CONTEMPORARY CHINESE ELT TEXTBOOKS","internalauthor":"SCARINGELLA, FRANCESCO MICHAEL","type":"Tesi di dottorato","year":"2026","abstract":"This study explores the teaching of the English language in general senior high schools in China, using the textbooks currently in use as its main research tool. The relevance of the topic stems from the importance attributed to foreign language teaching (which in most cases coincides with the teaching of English) in Chinese primary and secondary education, as it constitutes one of the three core subjects of the national education system, alongside Chinese and mathematics. A direct consequence of this is that these three subjects also form the compulsory component of the gaokao 高考, short for putong gaodeng xuexiao zhaosheng quanguo tongyi kaoshi 普通高等学校招生全国统一考试 (“Nationwide Unified Examination for Admissions to General Universities and Colleges”), China’s national university entrance examination.  Specifically, this study is divided into four chapters. The first chapter traces the history of English language teaching in China, proposing a periodization into seven historical phases, ranging from the imperial era (up to 1912) to the present day, identified as the “Xi Jinping Era” (2012–present). This classification, developed by the author, is based on the function attributed to English language teaching in different periods – a function closely intertwined with political considerations, to the extent that English language teaching in China has been described as a true “barometer” of the country’s diplomatic relations (Vickers & Zeng, 2018: 140).  The second chapter analyzes the historical development of both the English curriculum for general senior high schools and the corresponding textbooks. Conceived as complementary to the first chapter (whose periodization it follows), it aims to provide a more comprehensive picture of the state of English language teaching at this level of education and of the structure of the textbooks currently in use. It also seeks to achieve a deeper understanding of the process through which an “official” form of English is constructed in China, as well as what is considered acceptable in terms of content (Adamson, 2004).  The third chapter constitutes the core of the study and presents the author’s analysis of the English language textbooks currently in use in general senior high schools in China. The analysis covers the eight sets officially approved by the Chinese Ministry of Education (MOE, 2023) and was conducted using an evaluation framework for foreign language teaching textbooks, developed by the author on the basis of that proposed by Cortés Velásquez et al. (2017). This instrument includes 37 questions designed to examine textbook structure, the organization of volumes, input characteristics, graphic design, and theoretical and cultural references.  The fourth and final chapter presents the results of the author’s field research, consisting of semi-structured interviews – both oral and written – with English language teachers from both general senior high schools and international senior high schools, the latter serving as a control group. The primary motivation behind this investigation was to gain a deeper understanding of how English language textbooks are actually used, as well as of teachers’ beliefs and opinions regarding English language teaching in China.  Overall, this study aims to highlight the close relationship in China between the English curriculum, the English component of the gaokao, and textbooks.","language":"eng","citation":"ELT IN CHINESE GENERAL SENIOR HIGH SCHOOL: AN ANALYSIS OF CONTEMPORARY CHINESE ELT TEXTBOOKS / F.m. Scaringella ; tutor: B. Mottura ; co-tutor: A. Nava ; coordinatore: L. Pinnavaia. Dipartimento di Lingue, Letterature, Culture e Mediazioni, 2026 May 08. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13791.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 05-NOV-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1019210"},"title":"UN ESTATUTO COMÚN DE DERECHOS PARA LOS SOLICITANTES DE PROTECCIÓN INTERNACIONAL EN LA UNIÓN EUROPEA","internalauthor":"REQUENA DE TORRE, MARIA DOLORES","type":"Tesi di dottorato","year":"2023","abstract":"For decades the European Union has developed a regulatory system that has no equal on the international scene: the Common European Asylum System ( hereinafter CEAS) in order to achieve the objective enshrined in Article 78 of the TFEU: to grant an adequate protection status to any third-country national in need of protection. However, despite its many achievements, the CEAS remains far from being perfect. Following the massive migratory influx that reached Europe between 2015 and 2016, it became evident that the EU's international protection policy was deficient; and the consequence of its failures was a succession of grave violations of the international protection seekers' rights. Many used the collapse of overburdened national systems to justify the mistreatment of thousands of applicants for protection. This served the EU and its states to justify a controversial policy of externalization of migration controls and the adoption of dissuasive measures as varied as they were questionable. However, such violations of the rights of applicants were already occurring years before, when the number of arrivals was much lower.  Following a study of the CEAS, it has been observed that it suffers from shortcomings that make it an inefficient and non-solidarity-based system, which provides an insufficient degree of harmonization of international protection procedures and conditions related to the reception of applicants. Thus, due to a plurality of procedures, deadlines, guarantees and rights, the recognition rates and reception conditions granted by one State or the other can make a transcendental difference for the applicant. For all these reasons, the legal status of the applicant for protection is affected by great legal uncertainty, which undoubtedly weakens their protection.  Consequently, the incorporation of a new regulation to the CEAS is proposed: A regulation concerning the common statute of rights of the applicant for international protection in the European Union. It is argued that it can constitute a normative tool against the systematic violations suffered by a particularly vulnerable group, favouring the efficacy of the system. Thus, this study analyses the current state of the CEAS, the reasons that support the proposal, and its objectives, concluding with an explanation of the guidelines that should be developed in the regulation.","language":"spa","citation":"UN ESTATUTO COMÚN DE DERECHOS PARA LOS SOLICITANTES DE PROTECCIÓN INTERNACIONAL EN LA UNIÓN EUROPEA / M.d. Requena De Torre ; tutor: F. Scuto ;  tutor: J.M. Porras Ramírez (Granada) ; coordinatore del Dottorato: F. Biondi ; coordinadora del doctorado (Granada): F. Villalba Pérez   coordinadora del doctorado (Granada): F. Villalba Pérez. Dipartimento di Studi Internazionali, Giuridici e Storico - Politici, 2023 Oct 25. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R13122.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1019210/2330206/phd_unimi_R13122.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/816946"},"title":"OXYTOCIN RECEPTORS IN NEURODEVELOPMENTAL DISORDERS: INNOVATIVE APPROACHES FOR THE QUANTIFICATION OF SOPRAMOLECULAR RECEPTOR COMPLEXES","internalauthor":"SANTINI, FRANCESCA","type":"Tesi di dottorato","year":"2021","abstract":"In the brain, the oxytocinergic system is a key regulator of social behaviour. Oxytocin could therefore become a promising therapeutic molecule to treat behavioural alterations in neurodevelopmental disorders; however, in order to define its translational potential we need to understand more about the localization and signaling properties of its receptor (OTR) in the brain. The OTR is a G protein coupled receptor (GPCR) able to form homo or heterodimeric complexes with distinct pharmacological properties. Targeting GPCRs dimers in endogenous environments is often problematic: the techniques currently used to study them in native tissues can only prove molecular proximity between two protomers, not their actual dimerization. For these reasons, in my project I worked to develop new tools to study dimeric and monomeric OTRs in endogenous tissues. I characterized a series of bivalent ligands designed to pharmacologically target OTR homodimers, and started to develop an innovative “Nanoruler” technique to label OTR homodimers in native tissues. In parallel I also run an extensive autoradiographic mapping of the OTR in mouse brains, looking for changes of OTR levels in a mouse model of neurodevelopmental disorder (Magel2-KO). Through my work I already found important sex and genotype-induced effects on OTR expression in Magel2-KO mice, and I showed that in some cases a neonatal OT treatment (that can rescue some autistic traits of this model) modifies OTR levels in several regions. Once the Nanoruler technique is fully optimized we will compare its results with this mapping, to gather new important information about the dynamics of OTR distribution in mouse brain.","language":"eng","citation":"OXYTOCIN RECEPTORS IN NEURODEVELOPMENTAL DISORDERS: INNOVATIVE APPROACHES FOR THE QUANTIFICATION OF SOPRAMOLECULAR RECEPTOR COMPLEXES / F. Santini ; tutor: M. Locati ; supervisor: B. Chini, F. Muscatelli ; phd coordinator: M. Locati. Università degli Studi di Milano, 2021 Mar 22. 33. ciclo, Anno Accademico 2020. [10.13130/santini-francesca_phd2021-03-22].","filename":"phd_unimi_R12120.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/816946/1710831/phd_unimi_R12120.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1235595"},"title":"DESIGN, IMPLEMENTATION, AND EVALUATION OF AN ACCESSIBLE DIGITAL MUSICAL INSTRUMENTS FOR MUSIC INCLUSION","internalauthor":"FASCHI, VANESSA","type":"Tesi di dottorato","year":"2026","abstract":"This Ph.D. thesis investigates accessibility in music from both a theoretical–design perspective and a technological–practical one. The research is structured into two main parts. The first explores accessibility in music as a cultural, social, and design challenge, addressing how musical practices, materials, and technologies are often shaped around normative assumptions that exclude a wide range of bodies, abilities,  and forms of interaction. Furthermore, this part explores how advanced digital formats, specifically IEEE 1599 multilayered representations, and the MIDI 2.0 expandend protocol can serve as transformative tools to foster autonomy and unlock music archives for users with diverse needs. The second part documents the core original contribution of this research: the design, implementation, and evaluation of an inclusive MIDI controller, a type of Accessible Digital Musical Instrument, developed within an industrial Ph.D. framework in collaboration with Audio Modeling S.r.l.. Conceived as a flexible hardware/software ecosystem, it aims to adapt to different motor, sensory, and cognitive abilities. The instrument is designed to foster musical expression, learning, and collaboration, while reducing barriers imposed by conventional musical interfaces and production environments. The proposed system is validated through initial observational studies and usability tests, demonstrating its potential as an enabling tool for music inclusion in educational, creative, and professional contexts.","language":"eng","citation":"DESIGN, IMPLEMENTATION, AND EVALUATION OF AN ACCESSIBLE DIGITAL MUSICAL INSTRUMENTS FOR MUSIC INCLUSION / V. Faschi ; tutor: F. Avanzini ; co-tutor: L. A. Ludovico ; coordinatore: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2026 Apr 29. 38. ciclo, Anno Accademico 2026/2027.","filename":"phd_unimi_R13911_2.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1235595/3304463/phd_unimi_R13911_2.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/858357"},"title":"IMPACTS OF ABRUPT CLIMATE CHANGE ON NATIONAL SECURITY: THE UNITED STATES PERSPECTIVE ON HOMELAND DEFENSE IN THE NORTH AMERICAN ARCTIC","internalauthor":"LAVORIO, AGATA","type":"Tesi di dottorato","year":"2021","abstract":"The purpose of this research is to assess whether abrupt climate change (intended   as a major change in physical geography) can be a driver for national security planning.   To demonstrate that geography still affects national security planning, this research   retrieves the concept of environmental causality applied to an empirical case – that of US adaptation   to climate change for homeland defense in an area called “The North American Arctic.”   Consequently,  the research  frames  the  adaptation  process  into  a  causal  mechanism  where   proximity  to  climate  change  effects (experienced  by  some  actors  of  the  defense   domain)  is  the  cause  explaining  the  change  of  the  United  States  (US)  geostrategic   posture in the Arctic.    Indeed, one of the most severe impacts climate change is having on US national   security regards its homeland defense in the Arctic. Traditionally, the US was granted   continental defense thanks to its invulnerability in the Northern hemisphere. Still, with   the Arctic gatekeeper's collapse caused by climate change, US homeland defense may   be at stake. According to the environmental probabilistic perspective (here adopted),   the fact that climate change is shaping the physical conformation of the Arctic is not   necessarily acknowledged by policy-makers or military leaders since geography does   not dictate predetermined outcomes. It follows that to consider climate change as a   driver, it must be found consistent evidence that actors are including climate change   in national security planning and reacting to its impacts.    To do so, the research reconstructs the process of adaptation to climate change   in the North American Arctic from the point of view of the actors involved in homeland   defense and looks for the cause and the contextual factors of the process. The   research  then  provides  systematic  qualitative  data  (e.g.,  strategies,  reports,  grey   literature,  journal  articles,  newspaper  interviews)  triangulated  with  some  élite   interviews with climate security experts and government officials.   Through  the  framing  of  evidence  into  a  causal  mechanism  supporting  the   hypothesis  of  conscious  adaptation,  it  is  demonstrated  that  1)  proximity  to   geographical change can account for a revitalization of the US Arctic posture with a   growing concern over homeland defense itself and 2) that climate change can act, in   the presence of some contextual factors, as a driver for national security planning at   all levels of strategy.","language":"eng","citation":"IMPACTS OF ABRUPT CLIMATE CHANGE ON NATIONAL SECURITY: THE UNITED STATES PERSPECTIVE ON HOMELAND DEFENSE IN THE NORTH AMERICAN ARCTIC / A. Lavorio ; supervisor: M. Clementi ; phd director: M. Jessoula. Dipartimento di Scienze Sociali e Politiche, 2021 Jul 21. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11881.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/858357/1842876/phd_unimi_R11881.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/909362"},"title":"WORD USE AND LANGUAGE STYLE MATCHING IN PATIENT-DOCTOR COMMUNICATION IN ONCOLOGY: PRESENT AND FUTURE","internalauthor":"VERGANI, LAURA","type":"Tesi di dottorato","year":"2022","abstract":"Patient-doctor communication is a central process in healthcare. It is related to various beneficial effects, as patient satisfaction with consultation and the implementation of a shared decision-making process. It has specific characteristics in the oncological context, and in new online-related contexts. Due to its importance, patient-doctor communication has been widely studied, with the majority of these studies focused on broad themes and content of the communication process. Less studied are the more-granular characteristics, as word use and verbal mimicry. With the diffusion of computerized text analysis methods, a growing literature is showing that the words people use daily have various relationships with psychological variables, while verbal mimicry, established between two people talking or writing to each other, is related to various relationship outcomes. LIWC, a computerized text analysis program, allows the analysis of word use and verbal mimicry, through LSM measure. This thesis work had the aim to analyze patient-doctor communication in its granular components. I aimed to analyze word use and LSM, established in the dyad patient- physician and in association with patient satisfaction with the consultation, in an online Italian, oncological setting. Moreover, the second aim was to lay the foundations to explore these constructs, and the shared decision-making process, in a real, face-to-face, Italian oncological setting.  First, I started focusing on a more general context (Study 1). I analyzed the characteristics of word use and LSM in patient-healthcare professional communication in an English language “Ask-the-Expert” website. In this context, patients (i.e., users) can post a question that will be answered by a healthcare professional. I found different patterns of words used by patient and healthcare professionals, and medical doctors. Moreover, I found healthcare professionals’ and websites’ characteristics related to LSM. After these initial insights, I moved on a preparatory step, translating into Italian language the function word categories of the LIWC 2015 English Dictionary, and developing the Italian Function Words Dictionary (Study 2a). This instrument allowed to calculate LSM with Italian samples. I implemented it in a case study (Study 2b). Then, in Study 3, I analyzed word use, LSM, and the relationship between LSM and patient satisfaction with the consultation in an Italian, oncological “Ask-the-Expert” websites. I found specific patterns of word use in patients and oncologists, and an association between LSM, established between patients and oncologists, and patient satisfaction with the consultation. In Study 4, a general population study focused on a dyadic collaborative negotiation task. I found that LSM, established during this task, had a relationship with the perception of a shared decision-making process happened during the task, but only for some participants. These results laid the foundations to develop a study assessing these constructs – use of words, LSM, patient satisfaction with the consultation and shared decision-making process – in patient-doctor communication happening in real, oncological consultations. Moreover, these results are initial insights on these themes, that can have potential practical implication and shed new light on patient-doctor communication process.","language":"eng","citation":"WORD USE AND LANGUAGE STYLE MATCHING IN PATIENT-DOCTOR COMMUNICATION IN ONCOLOGY: PRESENT AND FUTURE / L. Vergani ; internal advisor: D. Monzani ; tutor: K. Mazzocco ; phd coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2022 Mar 14. 33. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12074.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/909362/1984321/phd_unimi_R12074.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/818834"},"title":"STUDIO PILOTA SULL'ACCURATEZZA DELLA METODICA DI IMPLANTOLOGIA ZIGOMATICA GUIDATA","internalauthor":"BOLZONI, ALESSANDRO","type":"Tesi di dottorato","year":"2021","abstract":"In cases when the residual maxillary bone is not appropriate for insertion of standard implants, the treatment of full dental arch rehabilitation can be performed with zygomatic (ZIs) and pterygoid implants (PI). Although, ZI/PI rehabilitations are well established treatment modalities, these kinds of surgeries are difficult to perform and need a highly experienced operator. One of the major operational challenge is to perform accurate presurgical diagnostics to plan ZI/PI receptor sites. Further research on guided  ZI/PI surgery is highly encouraged, in order to reduce errors and complications in free hand surgeries.The purpose of this study is to introduce a novel protocol for the placement of ZI/PI utilizing presurgical planning with 3-D (3-dimensional) CB-CT (cone beam- computed tomography) diagnostic technologies and 3-D printing through the development of a custom made surgical guide.   For this purpose, CBCT-derived surgical guides and an exact replica of the entire maxilla and zygomatic bone were fabricated in actual scale model size using 3D printing technology. A total of 4 zygomatic and 2 pterygoid implants were inserted.   According to the results, the novel surgical guide design afforded the surgeon direct visual control and support. Positioning the guide in close proximity to the entry point of the zygomatic body aided the control of drills up to the vicinity of the exit point, significantly limiting problems associated with angular deviation. There was no damage to adjacent vital anatomical structures. Provisional  prosthesis was delivered a week after the surgery and clinical follow-ups of 3 months  showed  good healing with no complications. As a conclusion, the use of “inverted supports guided technique” for ZI/PI placement is a safe protocol with successful results.","language":"ita","citation":"STUDIO PILOTA SULL'ACCURATEZZA DELLA METODICA DI IMPLANTOLOGIA ZIGOMATICA GUIDATA / A. Bolzoni ; tutor: A. B. Giannì ; coordinatore: M. Del Fabbro. Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, 2021 Mar 01. 33. ciclo, Anno Accademico 2020. [10.13130/bolzoni-alessandro_phd2021-03-01].","filename":"phd_unimi_R11835.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/818834/1716354/phd_unimi_R11835.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1247730"},"title":"AN INTEGRATED APPROACH TO THE DEVELOPMENT OF RESISTANCE TO COMMON BACTERIAL BLIGHT IN COMMON BEAN (PHASEOLUS VULGARIS)","internalauthor":"GAITI, ANGELO","type":"Tesi di dottorato","year":"2026","abstract":"Common bean (Phaseolus vulgaris L.) is a globally important legume, providing proteins, fibres and micronutrients to hundreds of millions of people. This legume plays a central role in food and nutrition security, but yields are threatened by biotic stresses, such as common bacterial blight (CBB) disease. CBB, caused by Xanthomonas phaseoli pv. phaseoli (Xpp) and Xanthomonas citri pv. fuscans, can reduce yields by up to 45 %. Breeding for resistance is the most sustainable control strategy, yet resistance is quantitative and influenced by pathogen diversity. Most known quantitative trait loci (QTLs) derive from Mesoamerican germplasm, leaving Andean market classes such as cranberry bean understudied.  This thesis uses a multi‑scale approach, combining QTL mapping, transcriptomics and CBB pathogens comparative genomics, to clarify the genetic basis of CBB resistance and to provide practical tools for breeding.  In Chapter 1, two mapping populations in the cranberry bean market class (a recombinant inbred line population and an F₂ population) were analysed using QTL mapping and QTL-seq approaches. Three resistance loci were detected. Major QTLs on chromosomes Pv06 and Pv08 explained most of the phenotypic variance, while a minor QTL on Pv11 was identified only in the RIL population. The Pv08 QTL corresponds to the known SU91 region, whereas the Pv06 QTL does not coincide with the classical BC420 locus, suggesting a novel resistance source. QTL interaction was assessed and confirmed strong epistatic behaviour between the two major loci, expanding our understanding of the CBB resistance genetics in the cranberry market class.  Chapter 2 examines host responses to isolates with different virulence features. Four Italian isolates causing CBB were screened on 2 common bean genotypes (one resistant and one susceptible). The screening underlined virulence differences in the susceptible genotype infection, but most importantly two Xpp isolates with contrasting behaviour on the intermediate cultivar Vaillant were identified. USB771 induced resistance response while DEF699 caused a significant infection in Vaillant. RNA‑seq of Vaillant leaves at 48 h post‑inoculation showed that the resistant interaction elicited extensive transcriptional regulation. 1,256 genes were differentially expressed and defence‑related pathways such as plant-pathogen interaction, MAPK signalling and secondary metabolism were enriched. By contrast, the susceptible interaction induced only 269 differentially expressed genes and lacked enrichment in plant-defence related pathways. However, the DEF699 interaction caused upregulation of a Lateral Organ Boundaries (LOB) domain gene, known to be linked to Xanthomonas susceptibility in citrus canker disease. This study provides for the first time a transcriptomic analysis focused on isolate-driven responses within a common genetic background. The chapter 2 analysis highlights: (i) activation of defence mechanism in the resistant interaction; (ii) the repression of the defence response and the concomitant activation of putative susceptibility genes in the susceptible interaction.  In Chapter 3, the pathogen perspective is addressed by sequencing two Italian Xpp strains using Nanopore long‑read technology. Comparative analysis based on genome similarity show that USB771 clusters with Canadian strains, while DEF699 groups with a strain isolated in the USA. A key finding is the variation in transcription activator‑like (TAL) effector presence: USB771 contains a single chromosomal tal gene (tal19B) and lacks plasmid‑borne TALs, whereas DEF699 carries chromosomal (tal18A) and plasmid‑encoded tal (tal20B) genes. Because TAL effectors bind host promoters and activate susceptibility genes, such variation might contribute to the observed differences in host responses.  Overall, this thesis provided new insights into the genetic and molecular basis of CBB resistance. Identification of novel QTLs provides breeders with additional markers for pyramiding resistance. Transcriptomic analyses reveal that effective resistance involves robust activation of immune signalling and secondary metabolism pathways, whereas the isolate overcoming resistance represses host-defence responses, while exploiting host susceptibility genes. Comparative genomics extends knowledge of pathogen diversity and TAL effectors repertoires and underscores the value of long‑read sequencing for complete genome assembly. By integrating quantitative genetics, gene expression and pathogen genomics, this research advances knowledge for developing durable, broad‑spectrum resistance to common bacterial blight in common bean and illustrates the benefits of cross‑disciplinary approaches for crop protection and food security.","language":"eng","citation":"AN INTEGRATED APPROACH TO THE DEVELOPMENT OF RESISTANCE TO COMMON BACTERIAL BLIGHT IN COMMON BEAN (PHASEOLUS VULGARIS) / A. Gaiti ; tutor: A. Kunova ; co-tutor: C. M. Pozzi; coordinatore: D. Mora. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2026 May 22. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13794.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 21-NOV-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1221297"},"title":"INNOVATIVE APPROACHES TO PLANT PROTECTION AND PRODUCE SAFETY THROUGH HIGH-PRECISION PLANT MANAGEMENT SYSTEMS","internalauthor":"FOLLADOR, ALESSIA REGINA VERA","type":"Tesi di dottorato","year":"2026","abstract":"In recent years, the growing need to minimize the environmental impact of agriculture has encouraged the development of sustainable crop protection strategies that combine biological efficacy, food safety, and the preservation of microbial biodiversity. Within this framework, the use of biocontrol agents (BCAs), ultraviolet (UV) radiation, and advanced diagnostic technologies have emerged as an innovative toolkit for integrated pest management, reducing reliance on conventional agrochemicals. In these studies, we have explored these approaches in economically relevant crops such as lettuce, cucumber, tomato, bell pepper, and wild rocket, assessing their effectiveness against fungal and viral pathogens, as well as their impact on plant physiology and microbial community dynamics.  In the first study, six bacterial strains were evaluated as BCAs against Rhizoctonia solani, a major soilborne pathogen. Among them, Bacillus sp. B04A33 and Psychrobacillus sp. B04A42, isolated from maize embryos, together with Lactiplantibacillus plantarum S61, showed significant antagonistic activity, comparable or superior to a commercial Trichoderma-based product. Treatments applied to the soil with B04A33, B04A42, and S61 enhanced germination rates and seedling vigor of lettuce, increasing both root and epigeal biomass. Root imaging and analysis using MATLAB confirmed the promotion of root system development, and a better wellness of plants grown in soils treated with those isolates. MinION sequencing revealed a dominance of Pseudomonadota, Actinomycetota, and Bacillota, with enrichment of Bacillaceae and Lactobacillaceae in treated soils, suggesting a positive reshaping of the soil microbiota. These results highlight both the potential of selected bacterial strains as effective BCAs and the usefulness of automated imaging systems for germination and growth-parameters collection and analysis. Ultraviolet radiation has gained attention as a promising physical tool for pathogen suppression and the activation of plant defense mechanisms. In Diplotaxis tenuifolia, short-term exposure to UV-B radiation (43.2 kJ m⁻²) induced only moderate physiological stress and shifts in the composition of epiphytic and endophytic bacterial communities. 16S rDNA profiling through Nanopore sequencing of both DNA (epiphytic part) and cDNA (endophytic part) templates revealed that microbial localization (epiphytic vs. endophytic) and time of sampling were the main structuring factors, whereas UV-B treatment exerted a secondary influence. Nevertheless, a slight enrichment of Burkholderiaceae and Lactobacillaceae was detected in epiphytic and endophytic niches respectively after the second UVC treatment, suggesting a selective adaptation toward radiation-resistant microorganisms. These findings indicate that short-term UV-B exposure can subtly modulate the leaf-associated microbiota while maintaining its overall resilience.  Further applications of UV technology, especially UV-C radiation, were evaluated for the management of major fungal diseases in greenhouse-grown vegetables. In cucumber (Cucumis sativus L.), UV-C radiation at 254 nm proved highly effective in suppressing Podosphaera xanthii, the causal agent of powdery mildew. Treatments with doses 250 and 400 J·m⁻² delayed fungal development, and the application of a 400 J·m⁻² dose within six hours post-inoculation completely prevented disease onset without visible leaf damage, unlike 222 nm exposures, which caused severe tissue injury. Biochemical analyses revealed increased lipid peroxidation (TBARS) following 254 nm UV-C exposure, indicative of oxidative stress, though no significant alterations in photosynthetic pigments were observed. Microbiota profiling showed that disease presence had a stronger effect on bacterial community composition than UV-C treatment, though moderate shifts occurred in UV-C-treated healthy leaves. Gene expression analysis indicated early upregulation of PAL and PR1, pointing to activation of salicylic acid–dependent defense and phenylpropanoid pathways in response to both UV-C and fungal application. Moreover, hyperspectral imaging enabled partial discrimination between healthy and infected tissues, supporting its potential as a non-destructive monitoring tool for disease detection.  Similarly, studies on lettuce (Lactuca sativa L.) assessed the antifungal potential of various UV-C wavelengths (254 nm, 222 nm, and 250–280 nm LEDs) against Botrytis cinerea, the agent of grey mold. Conidial germination was completely inhibited by UV-C doses above 0.87 kJ/m² with the 222 nm lamp, while higher doses were required with the classical 254 nm lamp. Mycelial growth inhibition demanded even greater energy input, and in vivo applications often failed to prevent infection due to the leaf surface morphology and the fungus’ DNA repair mechanisms. Leaf damage occurred at doses above 0.5 kJ/m² for both 254 and 222 nm sources, underlining the need to balance antifungal efficacy with plant tolerance. Gene expression analyses revealed limited transcriptional responses, possibly linked to low replication and delayed sampling times. Only one treatment showed upregulation in UV-damage endonuclease and photolyase related genes, compared to the others: 222W Low dose (UVC treatment using a 222 nm lamp with dose 0.056 kJ/m²).  Beyond fungal diseases, viral infections remain a major constraint to the productivity of solanaceous crops. In tomato (Solanum lycopersicum L.) and bell pepper (Capsicum annuum L.), Tobamovirus tabaci (Tobacco mosaic virus, TMV) and Orthotospovirus tomatomaculae (Tomato spotted wilt virus, TSWV) cause severe yield losses, emphasizing the importance of early and accurate detection to prevent the spread of diseases. A comparative evaluation of visual inspection, real-time PCR, chlorophyll fluorescence, and hyperspectral imaging (HSI) demonstrated that real-time PCR was the most sensitive and specific method, detecting viral RNA as early as two days post-inoculation. However, its destructive nature, high cost, and limited scalability restrict field applicability. HSI coupled with supervised machine learning achieved classification accuracies up to 95.6%, enabling early, non-destructive detection of infection with performance comparable to real-time PCR. This highlights the promise of HSI as a scalable and sustainable diagnostic tool for real-time monitoring of viral diseases in precision agriculture systems.  Overall, these studies collectively demonstrate that the integration of biological and physical control methods, supported by advanced imaging technologies, can provide effective and environmentally sustainable solutions for crop protection. The combined use of biological control agents (BCAs), controlled UV irradiation, and optical diagnostic tools could not only reduce chemical inputs and enable earlier pathogen detection but also enhance plant resilience. This multidisciplinary approach, bridging microbiology, plant physiology, and sensor technology, forms the foundation for the next generation of sustainable agricultural practices aimed at environmental preservation, food security, and the long-term health of agroecosystems.","language":"eng","citation":"INNOVATIVE APPROACHES TO PLANT PROTECTION AND PRODUCE SAFETY THROUGH HIGH-PRECISION PLANT MANAGEMENT SYSTEMS / A.r.v. Follador ; tutor: P. Casati; co-tutor: R. Oberti; coordinatore: E. Damiani. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2026 Feb 26. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14104.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 02-SET-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1196714"},"title":"DISSECTION OF HOST-VIRUS INTERACTIONS IN THE HUMAN CENTRAL NERVOUS SYSTEM","internalauthor":"PALAZZI, NICOLA","type":"Tesi di dottorato","year":"2025","abstract":"Viral encephalitis is an inflammatory brain that can lead to severe neurological  deficits, despite antiviral treatment. Neurotropic viruses cause viral encephalitis due  to their ability to invade the central nervous system (CNS), and the most common  cause is HSV-1. Inborn errors of immunity (IEIs) have demonstrated that neuron,  cell type-specific, antiviral immunity is essential to prevent viral infection and  encephalitis. However, despite these key advances in human genetics, relatively  little is known about what regulates neuron-specific antiviral immunity and how this  may differ against specific neurotropic viruses. Human pluripotent stem cells  (hPSCs) can, theoretically, be differentiated into any given cell type of the human  body. Here, we leverage hPSC technology by differentiating cortical neurons at  scale to study the neurotropism of Herpes simplex virus-1 (HSV-1), Monkeypox  virus (MPXV), Varicella zoster virus (VZV) and Influenza A viruses (IAV). Our  comparative virology approach demonstrated a susceptibility and permissiveness to  herpesvirus infection, while in contrast neurons did not show any productive  infection to either IAV or MPXV. By developing a genome-wide CRISPR/Cas9  screening platform in human neurons, we were able to identify several candidate  host factors that regulate neuronal anti-HSV-1 immunity, such as MTBP, SIRT7,  GNAI3, NPPA, POLR3E and RNGTT. In a complementary approach, we performed  high temporal resolution transcriptional profiling of human cortical neurons upon  infection with herpesviruses. This allowed us to dissect neuronal responses from 30  minutes to 48 hours post infection (hpi) to HSV-1 and VZV infections, identifying a  delayed antiviral response in neurons compared to fibroblasts. Interestingly, both  human cortical neurons and fibroblasts showed the upregulation of cilium-related  genes starting from 24hpi onwards. We validated several cilia-related genes, such  as ARL13b and DNAH5 by immunostaining, demonstrating both an increased  expression and mislocalisation of these proteins upon HSV-1 infection. siRNA-  mediated knockdown experiments of ARL13b show reduced intracellular replication  in fibroblasts, identifying a potential proviral role for cilia-related proteins during  herpesvirus infection. To conclude, through our genome-wide screens and  transcriptional profiling we identified candidate neuronal anti- and proviral host  factors of HSV-1 infection, providing a better understanding of intrinsic neuronal  antiviral immunity. Our datasets yield a unique resource to the virology and neuroscience fields and, especially, in the context of viral encephalitis. Moreover,  our candidate anti- and proviral factors may provide therapeutic targets for viral  encephalitis.","language":"eng","citation":"DISSECTION OF HOST-VIRUS INTERACTIONS IN THE HUMAN CENTRAL NERVOUS SYSTEM / N. Palazzi ; tutor: O. Harschnitz, D. Pasini ; co-tutor: G. Testa ;  curatori: B.Soskic, C. M. Rice. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Nov 07. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13492.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 19-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1023852"},"title":"BIO-ELECTRORECYCLING OF CARBON DIOXIDE INTO VALUABLE PRODUCTS","internalauthor":"CARRARA, ARIANNA","type":"Tesi di dottorato","year":"2024","abstract":"Carbon dioxide (CO2) is largely emitted during the combustion of fossil fuels for transportation,  electricity generation, and other industrial processes. CO2 is an inorganic compound that naturally  exists on Earth, but its concentration has increased exponentially since the industrial revolution,  leading to the acceleration of global warming and, consequently, the climate change.  Bioelectrochemical systems (BES) are among several platforms that have been proposed to capture  and convert CO2. The primary system widely applied for this purpose is microbial electrosynthesis  (MES), in which microorganisms serve as catalysts in the reduction of CO2 to target compounds,  without the need for expensive and precious materials.  In this regard, this PhD thesis addresses the challenges of improving microbial electrosynthesis of  acetate (HA) from CO2 by testing different sources of inoculum in various reactor setups. Biocharbased electrodes were fabricated through the pyrolysis of waste feedstocks (woody chips (WC) and  organic wastes (OW)). Their performances, after being applied to a carbon cloth cathode, were tested  in MES systems. Additionally, a review of the state of the art of carbon capture technologies will  provide an initial understanding of the context.  My PhD project was divided into four different work packages: 1) selection and enrichment of  bacterial consortia, 2) production of biochar-based electrodes, 3) production of HA by testing  different MES setups, while modulating the applied potential and changing cathode materials, 4)  analysis of possible applications in a pilot-scale scenario.  In MES reactors equipped with a carbon cloth electrode (CC) and an inoculum from brewery  wastewater, the best applied potential was -1.0 V with a conversion of 60.37% of CO2 in HA with a  daily production rate of 97.05 mg HA L-1  d  -1  . Considering these results, it has been calculated that,  8  using all the CO2 produced by the biogas plants in Italy after upgrading of biogas could approximately  recycled 6.1·106  tons of CO2 in HA.  Regarding the comparison of biochar-based electrodes, MES reactors equipped with WC-cathodes  achieved better performance in all considered parameters than the OW-based ones. Moreover, the HA  produced by WC-cathodes was ten times higher than in OW reactors (0.3 g L-1  d  -1  ), and the moles of  CO2 converted into acetic acid every day reached 65%. In the last MES experiment, the WC electrode  was compared to the CC one in terms of energy demand, and it proved to be a better alternative than  carbon-based electrodes in terms of Coulombic efficiency (57%), specific energy consumption (21.5  kWh kg-1HA), and HA surface production rate (13 g HA m-2  d  -1  ). It was also demonstrated that its  three-dimensional spatial distribution enhanced microbial growth, leading to a higher number of  microorganisms adhering to its surface.","language":"eng","citation":"BIO-ELECTRORECYCLING OF CARBON DIOXIDE INTO VALUABLE PRODUCTS / A. Carrara ; tutor: F. Adani ; co-tutor: A. Goglio ; cordinatore: P. A. Bianco. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2024 Jan 22. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13032.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1023852/2343612/phd_unimi_R13032.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1166883"},"title":"THE EMERGING MARKET OF MEME-NEWS: HOW POLITICAL INTERNET MEMES INFORM YOUNG ADULTS AND SHAPE THEIR POLITICAL OPINIONS","internalauthor":"SACCOMANNO, PIETRO","type":"Tesi di dottorato","year":"2025","abstract":"\"In the digital age, Internet memes have emerged as a pervasive mode of online communication, significantly impacting how political information is disseminated and consumed. This dissertation explores the multifaceted role of political Internet memes in informing younger generations and provides early insights on the emergence of a meme-news market on social media. Despite the growing \"\"memeification of politics,\"\" there remains a paucity of empirical research on how meme-based communication influences individual political behaviors and opinions. This study seeks to fill this gap by providing a comprehensive theoretical framework, developing an operational definition of Internet memes, and empirically investigating their effects on users’ political engagement, opinions formation, and knowledge acquisition.  The first part of the dissertation delves into the complex relationship between political Internet memes and public opinion. By integrating insights from sociology, media and communication studies, cultural studies, and humor research, it offers a theoretical framework that elucidates the phenomenon of political meme sharing on social media. This framework addresses the mechanisms through which memes can influence users' political knowledge and opinions, considering most recent empirical findings in light of traditional media effects theories. A critical review of existing experimental studies highlights significant gaps in the literature, particularly the lack of a standardized definition of Internet memes, which hampers empirical investigation and, especially, the use of experimental methodologies.  To address this definitional challenge, the second part of the dissertation proposes a parsimonious operational definition of Internet memes. Through a logical examination of necessary and sufficient conditions, it identifies the essential attributes that constitute an Internet meme. The study presents a set of three essential indicators to guide scholars in selecting and creating memes for experimental research. This operationalization provides a methodological tool that enables the quantification and empirical analysis of memes, thereby advancing the study of this digital phenomenon within the social sciences.  The third part examines whether political Internet memes satisfy the news consumption’ s habits and preferences of younger generations, who increasingly favor passive and incidental exposure to information on social media. By conducting an ethnographic observation within the newsroom of \"\"AQTR\"\"—Italy's largest political meme page—and surveying its followers, the study analyzes both the supply and demand sides of this emerging meme market. Findings reveal that political meme pages play a significant role in informing younger audiences, often exerting more influence on their news consumption than traditional journalists or news outlets. The research also uncovers a trend toward the professionalization of political meme-making, with content creators recognizing the potential for monetization and seeking to establish themselves as legitimate media actors.  Building on these insights, the fourth part investigates whether political Internet memes can make hard news more attractive and engaging to young adults compared to traditional journalistic content. Utilizing an experimental approach on Instagram through Meta Ads' parallel randomized A/B tests, the study engages approximately 350,000 users in a large-scale online field experiment. Results  indicate that political Internet memes outperform traditional informative posts across all measured behavioral metrics, including views, screen time, and likes. The study also finds that familiarity with the content source moderates user preference, with memes being more appealing when the source is unfamiliar. Interestingly, older cohorts displayed a higher responsiveness to memes than millennials and genZ, suggesting specific generational audience dynamics. Overall, findings indicate that political Internet memes have a greater potential to reach and engage younger generations with news and political content than traditional formats.  The final part of the dissertation explores the impact of political Internet memes on political knowledge acquisition and opinion formation. Through an online factorial experiment with 1,781 participants, the study examines whether memes encourage a subsequent or deeper information-seeking behavior, or it limits to induce a superficial consumption, and the extent to which memes can shape users' opinions through priming and framing effects. The results show that while the fast-paced environment of social media may discourage extensive information-seeking, political Internet memes still contribute to improving users' political knowledge on par with traditional informative posts. However, the knowledge gained is not substantial and tends to fade quickly. Additionally, although memes can establish framing and priming effects, their influence on users' interpretations of news is mild and unlikely to result in radicalization or increased polarization.  In conclusion, this dissertation advances the understanding of meme-news as a new mediatic phenomenon in contemporary political communication. It demonstrates that memes are not only tools for entertainment but also serve as important vehicles for political information dissemination among younger audiences. Compared to traditional journalistic content shared on social media, memes have a greater potential to enhance users’ reach and engagement with hard news and political events. However, their impact on deepening political knowledge and significantly altering opinions is limited. The research underscores the necessity for further studies to explore the informative effects of political Internet memes within the digital media ecosystem and their implications for democratic discourse.\"","language":"eng","citation":"THE EMERGING MARKET OF MEME-NEWS: HOW POLITICAL INTERNET MEMES INFORM YOUNG ADULTS AND SHAPE THEIR POLITICAL OPINIONS / P. Saccomanno ; supervisor: F. Squazzoni ; co-supervisor: K. Krakowski ; phd program director: M. Guerci. Dipartimento di Scienze Sociali e Politiche, 2025 Jun 11. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13216.pdf","fileformat":"Adobe PDF","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1166883/3069169/phd_unimi_R13216.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1127296"},"title":"FROM CHEMO-RESISTANCE PREDICTION TO THE IDENTIFICATION OF NEW POTENTIAL THERAPEUTIC STRATEGIES FOR CHEMO-RESISTANT MICROSATELLITE STABLE METASTATIC COLORECTAL CANCER: THE OCEANUS STUDY","internalauthor":"MAURI, GIANLUCA","type":"Tesi di dottorato","year":"2025","abstract":"Colorectal cancer (CRC) is one of the most common and deadly cancer worldwide. More than half of patients diagnosed with CRC will develop metastases over time, even after primary tumor resection. Despite recent immunotherapy and targeted treatment advancements, doublet or triplet chemotherapy regimens are still the most effective therapeutic opportunity to treat microsatellite stable (MSS) metastatic CRC (mCRC) patients. However, around 20% of mCRC patients are primary refractory to chemotherapy and do not benefit at all from this active but also toxic therapeutic approach. Despite that, no predictive biomarkers are available to predict resistance to chemotherapy. Accordingly, since standard of care treatments for chemo-refractory patients are scarcely effective, new therapeutic approaches are warranted to treat these patients.  In this context, we designed the OCEANUS translational project with the aim to predict resistance to chemotherapy and to identify new therapeutic opportunities for chemo-refractory MSS mCRC patients. In this thesis, we first demonstrated that radio-pathomics can predict chemoresistance with a promising negative predictive value (NPV) of 75% (95%CI = 41-93%) in a population of chemo-response outliers MSS mCRC patients who had primary tumor resection ahead of first line chemotherapy. These findings stand as the first promising step to design a first-in-kind artificial intelligence (AI)-based biomarker to predict chemoresistance in MSS mCRC patients. Further validation steps, as well as the implementation of these results by immunohistochemistry and RNA sequencing profiling, are ongoing. Second, we identified a subset of MSS CRC cell lines which were proven resistant to standard chemotherapy. Here, by performing a High Throughput Screening (HTS), we found that inhibiting the enzyme nicotinamide phosphoribosyl-transferase (NAMPT) synergizes with SN-38, the active metabolite of irinotecan, to treat chemo-resistant MSS RAS/BRAF mutant CRC cell lines. Subsequently, in-vitro findings were validated in-vivo in NOD-SCID mice.  All together these promising findings represent the initial and crucial step of the OCEANUS translational study ultimately aiming at predicting chemo-response and tailoring first line treatment in MSS mCRC patients.","language":"eng","citation":"FROM CHEMO-RESISTANCE PREDICTION TO THE IDENTIFICATION OF NEW POTENTIAL THERAPEUTIC STRATEGIES FOR CHEMO-RESISTANT MICROSATELLITE STABLE METASTATIC COLORECTAL CANCER: THE OCEANUS STUDY / G. Mauri ; tutor: S. Minucci ; supervisor (co-tutor): A. Bardelli ; PhD Coordinator: D. Pasini. - IFOM-ETS - The AIRC Institute of Molecular Oncology. Università degli Studi di Milano, 2025 Jan 21. 36. ciclo","filename":"phd_unimi_R13137.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1127296/2615808/phd_unimi_R13137.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/932670"},"title":"FREE-BASE PORPHYRIN FOR CO2 ACTIVATION","internalauthor":"SONZINI, PAOLO","type":"Tesi di dottorato","year":"2022","abstract":"Chapter I: Introduction  The human influence in the raise of the atmospheric concentration of carbon dioxide registered in the last decades up to the actual alarming situation is clear. The most evident consequence is the global warming, but this is only one of the problems correlated to emissions of greenhouse gases. Unfortunately, almost all the economic sectors play a role in the CO2 production and the complete elimination of the anthropogenic emissions of carbon dioxide is not possible in the short term. Thus, one of the major scientific challenges of this century is to find a solution to this problem. In addition to the reduction of the emissions, three ways has emerged as the most promising and interesting tools to face the carbon dioxide problem: Carbon Capture and Storage (CCS), Bioenergy from Carbon Capture and Storage (BECCS) and Carbon Capture and Usage (CCU).   The carbon dioxide cycloaddition to three membered heterocycles is an example of CCU that can be exploited to mitigate the human influence on the climate change. Moreover, this reaction is very promising because makes possible the synthesis of very useful fine chemicals such as cyclic carbonates and oxazolidinones from a waste -as CO2- with a 100% of atom economy. However, carbon dioxide is a very stable molecule and an efficient catalytic species is needed to make the reaction proceeds by avoiding drastic conditions.  Even if the reaction between epoxides and CO2 has been deeply studied in the last 20 years, the analogous carbon dioxide cycloaddition to aziridines has been much less studied and the conversion of N aryl aziridines into corresponding oxazolidinones resulted challenging and only few examples of efficient catalysts have been reported up to now. This work is devoted to the study of porphyrins as organic catalysts of the carbon dioxide cycloaddition both under homogeneous and heterogeneous conditions with the final the goal to improve the sustainability of the production of cyclic carbonates and oxazolidinones.    Chapter II: Homogeneous catalysts for the CO2 cycloaddition reaction  In this chapter the full organic catalytic meso-tetraphenyl porphyrin (TPPH2)/TBACl combination has been studied in the synthesis of oxazolidinones and cyclic carbonates from CO2 and aziridines or epoxides, respectively. After the initial optimization of the experimental conditions, this catalytic system was applied for converting a plethora of different substrates into corresponding five-membered products. The gathered data made possible to present the first general methodology for the conversion of N-aryl aziridines and CO2 into N-aryl oxazolidinones. Then, a tandem methodology for the production of these useful molecules from aryl azides, styrenes and carbon dioxide has been presented. This methodology resulted effective also in the synthesis of the pharmacologically active oxazalidin-2-one 41.  Encouraged by the good results obtained in these studies, the proposed catalytic procedure was successfully extended to the reaction of CO2 with N alkyl aziridines and epoxides. Moreover, different catalysts have been tested in combination with TBACl in order to shed some light on the influences of the steric and electronic characteristic of the porphyrins on the reaction productivity. Moreover, a first mechanistic study has been presented in collaboration with Dr. Gabriele Manca of the ICCCOM-CNR of Sesto Fiorentino.  Chapter III: Heterogeneous catalysts for the CO2 cycloaddition reaction  The heterogenization of the porphyrin onto a SBA-15 silica material has been proposed in this chapter. To improve the reaction sustainability, the synthesis of an active heterogeneous catalyst represents a crucial step to simplify the catalyst recovery and the product purification. The possibility to combine the characteristics of a heterogeneous catalyst with the high activity demonstrated by the TPPH2/TBACl homogeneous catalytic system propelled the preparation of a hybrid material by supporting a free porphyrin onto mesoporous SBA-15 silica trough covalent bondings. This solid support was selected because it is easy to functionalize and the presence of silanols group onto its surface foster the reactivity of epoxides towards CO2.   The so-prepared catalyst, in combination with tetrabutyl ammonium iodide (TBAI) resulted very active in the preparation of cyclic carbonates from the reaction of epoxides with CO2. Then, the same catalytic system was successfully tested for the carbon dioxide cycloaddition to N alkyl aziridines. Finally, the supported porphyrin, in combination with TBACl, represents the first heterogeneous catalyst active in the conversion of N-aryl aziridines into N-aryl oxazolidinones.  The good results obtained with the three different classes of substrates, in combination with the recyclability of the heterogeneous catalyst and the possibility to use it with up to 1.00 g of substrate, make this hybrid material an interesting candidate for further industrial applications.","language":"eng","citation":"FREE-BASE PORPHYRIN FOR CO2 ACTIVATION / P. Sonzini ; tutor: E. Gallo ; co-tutor: C. Damiano ; coordinator: D. Passarella. Dipartimento di Chimica, 2022 Jul 28. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12430.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/932670/2047984/phd_unimi_R12430.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/901444"},"title":"INDUSTRIAL DISTRICTS AND THE FOURTH INDUSTRIAL REVOLUTION, RECENT CHANGES AND THE INDUSTRY 4.0 CHALLENGE","internalauthor":"PESSINA, GIANMARIA LUIGI","type":"Tesi di dottorato","year":"2022","abstract":"Industrial districts represent the past and the future of the Italian production landscape. Nowadays, they are one of the few examples of economic dynamism in extra-urban areas. In recent years, these socioeconomic agglomerations have been facing huge challenges, including international competition, financial crises and servitization of the manufacturing industry. However, it is the technological change of the Fourth Industrial Revolution that represents the greatest challenge and at the same time, the greatest opportunity for industrial districts. Thus, observing how these places are facing this technological revolution is of particular interest. This thesis is based on a mix-method approach and is organised into six main chapters. Chapter 1 is dedicated to describing the theoretical backgrounds at the base of local development studies, focusing particularly on endogenous factors. More precisely, this chapter is divided into three sections. Firstly, we discuss the notion of economic embeddedness. Secondly, we provide an outline of the so-called local development ‘Italian school’ centred on the industrial district concept. Finally, we present a more recent contribution to the field from the emerging approach of new evolutionary economic geography. Chapter 2 is based on descriptive analyses aiming to grasp the current role of industrial districts in the Italian economy and how they have changed in recent years. Chapter 3 introduces the theoretical notion of territorial manufacturing servitization and tests the hypothesis connected to it, alongside the ones that emerged in the first chapter, through a multilevel regression. Chapter 4 is more theoretical; it presents a detailed discussion of the Industry 4.0 concept and reflects on the relationship between technological changes, economic organisation and places. Chapter 5 empirically investigates the sectorial and territorial articulation of the Italian 4.0 policy by using an original dataset. It also performs a quantitative counterfactual analysis to understand if industrial district firms show a higher propensity in adopting 4.0 technologies. Lastly, Chapter 6 utilises qualitative methods to compare two metalworking industrial districts. These last empirical steps allow for investigating the hypothesis that emerged in the previous chapter and the role of local governances in fostering Industry 4.0 adoption.","language":"eng","citation":"INDUSTRIAL DISTRICTS AND THE FOURTH INDUSTRIAL REVOLUTION, RECENT CHANGES AND THE INDUSTRY 4.0 CHALLENGE / G.l. Pessina ; tutor: F. Ramella, A. Gherardini, M. Guerci ; coordinatore G. Ballarino. Università degli Studi di Milano, 2022 Feb 02. 33. ciclo, Anno Accademico 2020. [10.13130/pessina-gianmaria-luigi_phd2022-02-02].","filename":"phd_unimi_R11985.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/901444/1964622/phd_unimi_R11985.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1069009"},"title":"LA MAFIA 'OLTRE' LA MAFIA: L'ART.416-BIS IN UNA PROSPETTIVA 'DE JURE CONDENDO'","internalauthor":"CIPANI, EDOARDO","type":"Tesi di dottorato","year":"2024","abstract":"The thesis concerns a proposal for normative modification of Article 416-bis of the Criminal Code,  with a focus on the normative technique of normative indices. The structure of the work is composed  as follows. The first chapter aims to provide a comprehensive overview of the most recent  jurisprudential applications of art. 416-bis to the phenomenon of “new mafias,” highlighting its  peculiarities and the degree of deviation from the traditional approach of mafia-type association  introduced in 1982. The second chapter starts from a reconnaissance about the profiles of  constitutional criticality of art. 416-bis, under the twofold profile of determinacy and offensiveness,  highlighted by the jurisprudential application mentioned above. It also investigates two phenomena  that are in some ways contiguous (the terrorist phenomenon and the phenomenon of labor  exploitation), to highlight how the legislator has intervened normatively in order to go along with  their profound sociological evolution. In conclusion, the third chapter deals with the “de jure  condendo” perspective, verifying the extendibility of the solutions adopted to the phenomena  assimilated to mafia and proposing the formulation of some normative indices, which appear to the  author to be the only ones capable of overcoming the criticism in terms of determinacy and  offensiveness. Thereby we ensure an adaptation of the normative instrument to new protection needs  connected to the constant change of the criminal phenomenon.","language":"ita","citation":"LA MAFIA 'OLTRE' LA MAFIA: L'ART.416-BIS IN UNA PROSPETTIVA 'DE JURE CONDENDO' / E. Cipani ; tutor: A. P. A. Della Bella ; co-tutor: L. Masera ; coordinatrice: F. Poggi. - Milano. Università degli Studi di Milano, 2024 Jul 12. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12884.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1069009/2471732/phd_unimi_R12884.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1197195"},"title":"A FULL-STACK SOFTWARE ARCHITECTURE FOR THE CONTROL AND CALIBRATION OF QUANTUM HARDWARE","internalauthor":"PEDICILLO, EDOARDO","type":"Tesi di dottorato","year":"2025","abstract":"Over the last 20 years, thanks to the development of quantum technologies, it has been possible to deploy quantum algorithms and applications  that before were only accessible through simulation on real quantum  hardware. The current devices available are often referred to as noisy  intermediate-scale quantum (NISQ) computers, and they require calibration routines in order to obtain consistent results.  In this context, we present Qibo, an open-source framework for quantum computing. Qibo was initially born as a tool for simulating quantum  circuits. Through its modular layout for backend abstraction, it is possible  to change effortlessly between different backends, including a simulator  based on just-in-time compilation, Qibojit.  In order to enable the execution and calibration of self-hosted quantum  hardware we have developed two open-source libraries integrated with  the Qibo framework: Qibolab and Qibocal. Qibolab provides the software layer required to automatically execute circuit-based algorithms  on custom self-hosted quantum hardware platforms. It enables experimentalists and developers to delegate all complex aspects of hardware  implementation to the library so they can standardize the deployment of  quantum computing algorithms in a hardware-agnostic way.  Qibocal is based on a modular QPU (Quantum Processor Unit) platform agnostic approach and introduces tools that support the calibration  and characterization of QPUs on three different levels: development,  deployment and distribution. Qibocal provides a code library to rapidly  develop protocols for different hardware abstraction layers. The integration with Qibo allows one to easily switch between hardware execution  and high-perfomance simulation.  Finally, to showcase the capabilities of the framework, we present the  calibration of a superconducting qubit pair with Qibocal and applications  developed with Qibo, including a novel method for improving ground  state preparation through Variational Quantum Eigensolvers and Double  Bracket algorithms.","language":"eng","citation":"A FULL-STACK SOFTWARE ARCHITECTURE FOR THE CONTROL AND CALIBRATION OF QUANTUM HARDWARE / E. Pedicillo ; supervisor: S. Carrazza ; coordinator: A. Mennella. - Università degli Studi di Milano. Dipartimento di Fisica Aldo Pontremoli, 2025 Nov 28. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13831.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1197195/3186744/phd_unimi_R13831.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/991608"},"title":"USING B-STRAND AND B-HAIRPIN PEPTIDOMIMETICS INDUCED BY CONSTRAINED AMINO ACIDS TO MODULATE  THE AGGREGATION OF THE MICROTUBULE ASSOCIATED PROTEIN TAU: DESIGN, SYNTHESIS AND  EVALUATION","internalauthor":"DI LORENZO, DAVIDE","type":"Tesi di dottorato","year":"2023","abstract":"Tauopathies refer to neurodegenerative disorders characterized by the presence of abnormal aggregates of Tau protein, leading to the formation of neurofibrillary tangles (NFTs) within neuronal cells. Tau, a protein associated with microtubules (MTs), plays a crucial role in regulating the dynamics of MTs and facilitating proper axonal transport in neurons. Alzheimer's disease (AD) is characterized by abnormal protein-protein interactions (PPIs) which lead to the accumulation of β-amyloid plaques and hyperphosphorylated Tau (P-tau) NFTs. Multiple evidence has suggested that the interplay between Tau and Aβ contribute to worsening the disease since the aggregation of one protein can trigger the aggregation of the other.   Within this thesis, we have explored, for the first time, the possibility of creating peptidomimetics capable of stabilizing either a β-hairpin or an extended structure to modulate Tau protein aggregation. This work focuses on three distinct peptidomimetic units with the goal of highlighting the significant role of secondary structure in the selective regulation of both physiological and pathological PPIs of Tau.   The utilization of a previously developed piperidine-pyrroline β-turn mimic has led to highly effective peptidomimetics that act as dual inhibitors targeting both Tau and Aβ1-42 proteins but show no activity on the other amyloid protein hIAPP. These compounds were designed either on Tau PPIs, by mimicking its self-interaction in NFTs or its physiological interaction with MTs; or on small sequences of the chaperone protein Hsp90, which is a physiological Tau aggregation inhibitor: Through various analyses, including proteolytic stability, ThT fluorescence, cell viability (LDH and MTT), and live cell imaging FDAP assays, we have demonstrated the critical role of pre-organized hairpin structures in achieving potent activity, selectivity, and stability. Among the designed compounds, the one mimicking Hsp90-Tau- interaction showed the highest potency, and NMR titration with 15N-Tau protein provided valuable insights into the possible mechanism of action of Hsp90 on Tau.  Then, the employment of the non-natural β2,2-isoxazoline unit into a peptide sequence was used to stabilize two different secondary structures, either in β-hairpin or extended. These structures were confirmed through a combination of CD, IR, and NMR analyses in aqueous solvents. The stabilized hairpin structure was used to develop our most potent inhibitor of Tau aggregation by mimicking Hsp90 protein. The extended structure bearing the PHF6 and PHF6* sequences (both involved in the physiological and pathological processes of Tau), was used to prove that it is the exposure of these sequences on Tau protein the event triggering its aggregation. As a counter-test, the hairpin conformation with the same sequences, did not induce any pathological aggregation.   Finally, the development of new difluorinated triazoles and their incorporation into existing peptide inhibitors of Tau, led to enhance their effectiveness, as demonstrated by ThT and live cell FDAP imaging, possibly because of their increased pharmacokinetic properties driven by the presence of the fluorine atoms.  In summary, the findings presented in this thesis provide a proof of concept that pre-structured hairpin mimics serve as a solid foundation for the development of innovative inhibitors of Tau and Aβ aggregation. The chaperone mimicry strategy has demonstrated its remarkable efficacy being the most potent dual inhibitor and, providing at the same time a new probe to simplify and study Tau-Hsp90 physiological interactions. The inclusion of the β2,2-isoxazoline amino acid into the peptide sequence allowed to demonstrate that the conversion of Tau toward an extended conformation, with the consequent exposure of PHF6* and PHF6, is the triggering event leading to Tau self-assembly.","language":"eng","citation":"USING B-STRAND AND B-HAIRPIN PEPTIDOMIMETICS INDUCED BY CONSTRAINED AMINO ACIDS TO MODULATE  THE AGGREGATION OF THE MICROTUBULE ASSOCIATED PROTEIN TAU: DESIGN, SYNTHESIS AND  EVALUATION / D. Di Lorenzo ; supervisor: S. Ongeri, M. L. Gelmi ; co-supervisor: N. Tonali. Università degli Studi di Milano, 2023 Jul 04. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R13186.pdf","fileformat":"Adobe PDF","fileversion":"preprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/991608/2264217/phd_unimi_R13186.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/819943"},"title":"INVESTIGATION OF CELL-MICROENVIRONMENT INTERACTIONS BY ATOMIC FORCE MICROSCOPY TECHNIQUES","internalauthor":"CHIGHIZOLA, MATTEO","type":"Tesi di dottorato","year":"2021","abstract":"The role of forces is fundamental in a wide variety of biological processes, such as cell adhesion, migration, proliferation and differentiation. The ability of cells to perceive the nanotopographical features of the surrounding microenvironment (i.e. the extracellular matrix, ECM), called mechanotransduction, is mediated by specific trans-membrane proteins, called integrins, clustered together in Integrin Adhesion Complexes (IAC). Unraveling which mechanical and nanoscale morphological properties of the ECM determine the IAC composition and tune specific cellular response, is particularly challenging.  Works have shown that biocompatible nanostructured thin films, grown by assembling zirconia nanoparticles (ns-ZrO2) on a substrate by Supersonic Cluster Beam Deposition technique, possess a morphological disorder on nanometer scale with structural features that mimic topographical properties of the ECM. Experiments performed with the neuron-like cell line PC12 demonstrated a link between the nanotopography of the ns-ZrO2 films and mechanotransductive events, which eventually foster neuronal differentiation.  During my three years of PhD, I have developed novel approach based on Atomic Force Microscopy (AFM) to quantify cell sensing of nanotopographical features of the microenvironment, represented by ns-ZrO2 films reproducing the nanostructured surface of the ECM. Using custom ns-ZrO2–coated colloidal probes, we have carried out a quantitative analysis of adhesion strength and distribution of IACs by AFM-based adhesive force spectroscopy.   We deposited ns-ZrO2 on custom AFM colloidal probes5. Bringing these nanostructured colloidal probes into contact with the body of living PC12 cells, it was possible to measure the strength, number and distribution of the IAC bonds by AFM force spectroscopy6, for different morphological properties of the interface. Furthermore, I used these functionalized probes to characterize the role of the surface pericellular layer, known as the Glycocalyx, in relation to the cell capability to react to external stimuli.  Eventually, along with my personal research project, I had the opportunity to participate to two external collaboration with the Istituto Nazionale dei Tumori and with Istitute of Nuclear Physiscs from the Polish academy of Science. These collaborations aimed to exploit the knowledge in the mechanobiolgy field to study the mechanical implications of cells and tissues in cancer development and survival.","language":"eng","citation":"INVESTIGATION OF CELL-MICROENVIRONMENT INTERACTIONS BY ATOMIC FORCE MICROSCOPY TECHNIQUES / M. Chighizola ; director of the School: M.Paris; supervisor of the Thesis: A. Podestà. Dipartimento di Fisica Aldo Pontremoli, 2021 Feb 25. 33. ciclo, Anno Accademico 2020. [10.13130/chighizola-matteo_phd2021-02-25].","filename":"phd_unimi_R11891.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/819943/1719897/phd_unimi_R11891.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1156155"},"title":"ELECTROCHEMICAL IODINATION AND DEIODINATION PROCESSES FOR GREEN SYNTHESIS AND WATER REMEDIATION","internalauthor":"SORTI, LETIZIA","type":"Tesi di dottorato","year":"2025","abstract":"This project is devoted to highlight the importance and the great innovation that the application of electrochemistry could bring in the protection of the environment. The aim was to develop cost-effective and eco-friendly methods in both environmental remediation and green chemistry fields, to make electrochemistry considered as a valid alternative to classical methods in the contrast media industry. The first part of the thesis is focused on the study of the electrochemical iodination of N,N’-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (idroamide, IA), an important intermediate for the synthesis of iomeprol (IMP). It has been demonstrated that the use of a carbonaceous anode can successfully transform I-/I2 in iodinating species, leading to a complete iodination of the reagent and almost no by-products. The experimental conditions have been optimized and the potentiostatic electrolysis in a recirculating divided cell (cation exchange membrane) has been successfully scaled for the treatment of 0.8 L of IA 23.5% w/w. A pre-pilot system has been designed and installed and the first tests showed the way forward from here. Parameters related to increasing volumes will be studied, also optimising them for flow chemistry. The success of the scale-up of this study will provide a concrete, as well as green, alternative to the current use of ICl, a highly corrosive iodinating agent that must be handled with great caution. The second part of this work is instead focus on iodinated contrast media (ICM) electrochemical degradation, and, in particular, on reductive processes. Gold was found to be a powerful electrocatalyst in the case of C-I bond breaking and a preliminary study on sputtered 10 nm bilayer films showed promising results about a powerful synergy between gold and silver. The reductive mechanism was also investigated for IMP deiodination, allowing the optimization of the experimental parameters in conditions similar to those of real polluted matrices. Iodine was almost completely recovered as iodides in this case, while in simulated urine and industrial wastewater, where an undivided cell was chosen to promote mineralization, it was accumulated as iodates. Further development will be focused on iodides separation from the polluted matrix, in a iodine circular economy perspective.","language":"eng","citation":"ELECTROCHEMICAL IODINATION AND DEIODINATION PROCESSES FOR GREEN SYNTHESIS AND WATER REMEDIATION / L. Sorti ; tutor: A. Minguzzi ; supervisori: A. Vertova, F. Uggeri ; coordinatore: L. Prati. Università degli Studi di Milano, 2025 Apr 11. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13361_3.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1156155/2730421/phd_unimi_R13361_3.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/986648"},"title":"CLAUSOLE SULL¿INVALIDITÀ CONTRATTUALE","internalauthor":"BUSSI, PAOLO","type":"Tesi di dottorato","year":"2023","abstract":"International contracts frequently adopt clauses on contractual invalidity: waiver of avoidance clauses and severability and inseverability clauses. This work focuses on the issue of validity of such covenants under Italian law, together with some additional profiles. The first chapter analysis the origin of these agreements: tailor-made international contracts and standard contracts, intended to regulate a plurality of identical relationships. Parties to contracts of the first type need their agreement to be stable and, therefore, they are willing to waive remedies that may cause its avoidance. This explains the provision of clauses that exclude claims for avoidance. In standard contracts, on the other hand, the predisposing party feels the need to bargain on uniform terms to decrease transaction costs. To do so, it is necessary to reduce interferences of the applicable law. The adoption of severability and inseverability clauses predetermine the extension of a clause’s invalidity and serves this purpose. The second chapter focuses on the waiver of avoidance clause. Scholars deem the clause invalid, as Article 1462 Civil Code prohibits waiver of the objection of avoidance and Article 1444 Civil Code prevents prior confirmation. However, it is maintained that these arguments apply only to the waiver of the objection of avoidance, but not to the waiver of the claim for avoidance. Next, we argue in favour of the clause’s validity as to avoidance for mistake, based on the possibility of excluding the warranty for lack of quality of the goods purchased. Lastly, agreements to waive a claim for avoidance on the ground of fraud, threat and incapacity are deemed null and void under Article 1322(2) of the Civil Code. The same tends to apply as far as conflict of interests is concerned. The clause is unfair and, therefore, invalid when adopted in consumer contracts. The third chapter focuses on severability and inseverability clauses. These terms are void as they infringe the mandatory rule of Art. 1419 of the Civil Code. However, they must be considered to verify whether other possible void terms, included in the same agreement, are essential under Art. 1419(1) of the Civil Code. Next, automatic adjustment or renegotiation mechanisms provided for by the parties are analysed. Finally, the thesis verifies the influence that these clauses can have on a possible judgement as to the determinative nature of fraud under Article 1439 Civil Code or the seriousness of the non-performance  pursuant to Art. 1455 of the Civil Code. It is concluded that severability and inseverability clauses will make it more difficult – or easier - for the aggrieved party to prove the fundamental nature of the breach or to show that, should the fraud did not occur, it would have nonetheless signed the agreement. We then examine the interference between these covenants and termination clauses or exclusive remedy  clauses.","language":"ita","citation":"CLAUSOLE SULL¿INVALIDITÀ CONTRATTUALE / P. Bussi ; tutor: G. Villa ; coordinatore: G. Ludovico. Dipartimento di Diritto Privato e Storia del Diritto, 2023 Jul 18. 35. ciclo","filename":"phd_unimi_R12622.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/986648/2250212/phd_unimi_R12622.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/960940"},"title":"ABUSO D'UFFICIO: PROBLEMI GIURIDICI ATTUALI E PROSPETTIVE DI RIFORMA","internalauthor":"PAGELLA, CECILIA","type":"Tesi di dottorato","year":"2023","abstract":"The object of this thesis is article 323 of the Italian penal code (Abuso d’ufficio), which, after the reform approved in 2020, sanctions the public agent who, in carrying out his/her functions, violates a law being specific and binding or fails to abstain in presence of conflict of interests and intentionally obtains an undue patrimonial advantage for himself, attributes an undue patrimonial advantage to others or causes an unjust damage to others. The provision of article 323 c.p. has always – since its introduction in 1889 – been controversial. The principal reason is that the legislator, sanctioning the wrongful use of public power, allows Prosecutors and Judges to syndicate how administrative discretion has been used and therefore puts the principle of separation of powers at risk; the other reason why article 323 c.p. has been discussed over times is that its previous formulations were considered vague. The thesis is divided in two sections. In the first section, around 500 judgements of the Italian Supreme Court are analysed from a double perspective: criminological, to understand the role of public officials who normally commit abuse of office, the sector in which they operate, the objective they pursue (attribute ad advantage to others, obtain an advantage for themselves, cause a damage to others); and legal, to understand the interpretative problems and the practical difficulties that the disposition poses when it has to be applied. The first part of the present work has the scope to help lawyers and Courts to apply the disposition correctly and equally. The second section of the thesis is about recent proposals to amend the disposition, a ruling by the Constitutional court defining the limit of a possible legislative intervention on art. 323 and the effectiveness of non-criminal instruments in the repression of Abuso d’ufficio. The scope of this second section is to understand whether the provision in force after 2020 reform is necessary and sufficient to sanctions all the behaviours (and only the behaviours) which can be considered serious and that do not fall within the scope of application of different provisions, and, if necessary, formulate a proposal for the reformulation of art. 323 c.p.","language":"ita","citation":"ABUSO D'UFFICIO: PROBLEMI GIURIDICI ATTUALI E PROSPETTIVE DI RIFORMA / C. Pagella ; tutor: G. Gatta ; coordinatore: F. Poggi. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2023 Apr 03. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12542.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/960940/2166973/phd_unimi_R12542.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1025738"},"title":"TIME RESOLVED PROBING OF MAGNETO-ELASTIC EXCITATIONS IN MAGNETIC MATERIALS","internalauthor":"CARRARA, PIETRO","type":"Tesi di dottorato","year":"2024","abstract":"This booklet collects the results of my work as a doctoral student of the Ph.D. School in Physics, Astrophysics and Applied Physics at Universita degli Studi di Milano, that has been carried out since November 2020 at Istituto Officina dei Materiali of Consiglio Nazionale delle Ricerche (IOM-CNR) and within the framework of Nanoscale Foundries and Fine Analysis (NFFA) consortium.  My experimental activity addressed the coupling of magnetic and acoustic degrees of freedom in transition-metal ferromagnetic systems. Within the NFFA-SPRINT laboratory, hosted in the premises of the facility FERMI@Elettra (Elettra-Sincrotrone Trieste), I developed a setup to perform optical Transient-Grating spectroscopy, and correlative time-resolved optical spectroscopies (time-resolved reflectivity and polarimetry). Via sub-picosecond optical pulses, acoustic and magnetic transients are impulsively generated: their intertwined evolution and decay are monitored via time-resolved optical probing.  In a first experiment, a Ni thin film was investigated via Transient-Grating spectroscopy. Acoustically-driven magnetization precession was observed at the condition of crossing of phononic and magnonic dispersions, at finite wavevector. With the aid of correlative ferromagnetic resonance measurements the boundary of applicability of the proposed experimental approach was established.  In a second experiment, time-resolved magneto-optical polarimetry was employed to investigate magneto-acoustic waves excited in a ferromagnetic nanostructured array. The details of the magnon-phonon mode crossing allowed to identify experimental features which qualify the degree of coherence in the coupling; a Hamiltonian model was proposed to account for the observations.","language":"eng","citation":"TIME-RESOLVED PROBING OF MAGNETO-ELASTIC EXCITATIONS IN MAGNETIC MATERIALS / P. Carrara ; supervisore: G. Rossi ; co-supervisore: R. Cucini ; director of the school: M. Paris. Dipartimento di Fisica Aldo Pontremoli, 2024 Jan 22. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R12807.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1025738/2351653/phd_unimi_R12807.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/848956"},"title":"POLITICAL CONFIDENCE AND PUBLIC CONTESTATION: A MULTILEVEL ANALYSIS OF INSTITUTIONAL CONFIDENCE IN EAST ASIA","internalauthor":"CARTENY, GIUSEPPE","type":"Tesi di dottorato","year":"2021","abstract":"This dissertation consists in an empirical study of the relationship between democracy and political confidence in East Asia, a region of our globe that goes from Mongolia to Indonesia, as Northern and Southern limits, and from Myanmar to Japan, as Western and Eastern borders. The study of individuals’ confidence in public institutions, often linked with the more general discussion about political legitimacy, arguably represents one of the most analysed and debated topics of political science. Nonetheless, the almost entirety of our knowledge about this relationship derives from theoretical discussion and empirical investigations about the impact, or potential impact, of citizens’ confidence in institutions on democratic viability. Although during the last two decades a burgeoning number of studies about the the interplay between institutions and individuals’ political confidence has been produced, studies investigating this relationship from the opposite perspective, namely the extent to which democracy impacts on individual confidence in institutions, has been seldom investigated.     Institutional studies of political confidence have been increasingly focusing on the extent to which the economic or political performance of state institutions and authorities, or other features of the political system, such as the fairness, responsiveness, and honesty of political process, affect citizens’ confidence in institutions. In those few cases in which the essential features of a democratic system have been considered as potential antecedents of individual confidence in institutions these effects have been investigated in and across democratic regimes, especially in the European and North American contexts. As a consequence, what it is contended is that our knowledge of this relationship, and the largely positive view about said relationship, is to a large extent contingent on the contexts in which it has been studied. For this reason, this work steps out from the usual yard of normative debates and empirical studies about this topic, and focuses on East Asia, a region of our globe providing several opportunities (and challenges) to empirically investigate individual confidence in institutions and its interplay with political institutions.     East Asia nowadays represents one of the most heterogeneous regions of our world on a plethora of structural and systemic features. Among these, East Asia presents a remarkable variety of political systems, ranging from single-party autocratic regimes to pluralistic liberal-democracies, and including several types of ‘hybrid’ regimes, fitting in neither categories. Since the late 1990s and early 2000s data about individual attitudes and behavior across this variety of regimes have been collected, allowing scholars and researchers to reassess, and in some cases challenge, issues and assumptions about a long list of political phenomena, including political confidence. In- deed, while individual-level studies of political confidence in this region have shown that the dynamics generating different degrees of confidence across individuals overlap with those seen in other regions of our globe, descriptive studies of cross-national variations of political confidence in this region have shown that individual confidence in institutions, during the last two decades, has been invariably higher in non-democratic regimes as compared to democratic countries. Several hypotheses and arguments, although scarcely investigated, have been developed in order to explain these aggregate regularities. Some authors attempted to explain these variations following socio-deterministic theories about an increasing mismatch between individual basic orientations to politics and the reality of their political systems determined by socioeconomic modernization, that is the so-called ‘critical citizens’ theory, or enduring cultural traditions, the so-called ‘Asian Values’ argument. Others have pointed their attention on differences in terms of (especially economic) performance of East Asian governments. Still others have called into question the reliability and validity of individual confidence measures in non-democratic settings. Few scholars have considered the idea that these differences may be related to structural characteristics of the political processes that differentiate democratic regimes from non-democratic ones. In this work, although accounting for alternative explanations both theoretically and empirically, this latter perspective is developed and investigated.      Building on arguments and evidence concerning the effects of political competition outputs (namely, election results) on individual-level variations of confidence in institutions, and relying on the renowned theoretical and analytical comparative framework developed by Robert Dahl (1971) in its seminal study on political participation and opposition, this thesis aims to investigate how an essential characteristic of any political system, namely the extent to which a regime provides institutional guarantees for public contestation to a more or less broad share of its population, affects individuals’ confidence in institutions. In order to provide a rigorous, specific, but also comprehensive empirical assessment of this topic, this dissertation is structured as follows.  Chapter 1 is dedicated to a theoretical and conceptual discussion about the notion of political confidence and the main explanations of its origins, starting from which the broad research question inspiring this dissertation is presented. About the former topic, building on relatively recent theoretical and conceptual developments, what it is contended is that the notion of confidence is conceptually distinct to the notion of trust, and the former should be preferred to the latter in order to conceptualize the relationship between individuals and public institutions (Ch. 1, Sect. 1.2.1). Furthermore, the relationship between this notion and the related concepts of regime legitimacy and political support is critically assessed in order to define the peculiar nature of the individual attitude under investigation (Ch. 1, Sect. 1.2.2). The chapter, then, continues with a reassessments of the second topic mentioned above, namely a review of theories and explanations of political confidence, based on the ubiquitous categorization of theories of political phenomena distinguishing between culturalist and institutionalist arguments (Ch. 1, Sect. 1.3). Building on these two sections the chapter ends with a discussion concerning the scope of these explanations, and briefly reviewing the debate about the relationship between democracy and political confidence (Ch. 1, Sect. 1.4). In particular, what is claimed is that, while providing opposite and to some extent irreconcilable perspectives about the determinants of political confidence, current theories and explanations of this phenomenon lack arguments assessing the systemic impact of democracy on individual confidence in institutions, for both theoretical reasons and the already mentioned focus of theoretical discussions and empirical investigation on democratic settings, driving to a contingent understanding of the relationship between democracy and political confidence. What it is contended, thus, is that for assessing this issue a different analytical strategy is needed.     Chapter 2 is, thus, dedicated to developing the specific argument of this thesis (Ch. 2, Sect. 2.2), discussing the state of art of the empirical research dedicated to political confidence in East Asia, thus introducing the geopolitical context in which this work is situated (Ch. 2, Sect. 2.3), and finally presenting the research design adopted to investigate the main puzzle and related research questions of this research effort (Sect. 2.4). The first section (Sect. 2.2.1) clarifies which is the notion of democracy adopted in this study, that consists in Dahl’s (1971, 1989, 1998) notion of polyarchy and the theoretical and analytical framework that has been produced around this notion (e.g. Coppedge and Reinicke 1990; Coppedge et al. 2008; Teorell et al. 2019). The section then continues (Sect. 2.2.2) with an explanation of why varying levels of democracy are interpreted as variations of levels of public contestation, one of the two dimensions informing the notion of democracy used in this work. The following pages are then dedicated to a discussion about why and how variations of institutional features and dimensions identified by the notion of democracy used in this thesis can be related to varying levels of individuals’ confidence in institutions (Sect. 2.2.3). What it is contended is that variations of these attributes shape the structure of incentives and constraints affecting individuals assessments of institutions and authorities trustworthiness, and that higher degrees of public contestation are likely to produce both positive and negative incentives for individuals’ confidence in public institutions. The following section is then dedicated to the state of art of the study of political confidence in this region, that highlights the main findings and gaps about aggregate- level and individual-level studies of political confidence in this region. By doing so, in this section the East Asian context is presented and the opportunities and challenges given by the structural heterogeneity of this region are discussed, and the necessity of a study able to fill the the lack of contextual analyses of political confidence in this region is underlined. Then, Finally, the chapter ends presenting the specific research questions investigated in the following chapters and the research strategy employed to address these questions (Sect. 2.4.1), as well as the main individual-level and contextual-level data bases of this empirical study (Sect. 2.4.2).     The following three chapters of the thesis (Chs. 3, 4, and 5) consist in the three sets of empirical analyses used to address the research questions and the main hypothesis grounding this work. Chapter 3 presents a dimensionality analysis of political confidence in East Asia. What it is claimed is that in order to properly analyse the relationship between democracy and political confidence, what is needed is a prior assessment of whether East Asians confidence in institutions represent a single and general assessment of public institutions, or rather a multidimensional attitude (an assessment seldom performed in previous research). Consequently, this chapter, building on the ongoing debate about political confidence dimensionality in Europe (Ch. 3, Sect. 3.2), and after presenting the main expectations derived by translating this debate in investigates this issue through the means of exploratory and (multi-group) confirmatory factor analyses (EFA and CFA), applied to (almost) all the studies composing the first four rounds of the ABS (Ch. 3, Sect. 3.3). The main finding of this chapter is that, despite the crucial diversities of the countries included in this study on a series of structural factors potentially affecting the way in which East Asians organize their attitudes toward public institutions, a common factor structure of political confidence in this region can be found, and that this configuration consists in a two-dimensional conception distinguishing between confidence in political institutions (e.g. national governments and national assemblies) and confidence in implementative institutions (e.g. civil services and police forces).     Chapter 4 is then dedicated to an analysis of these two types of political confidence in the aggregate. In the first part of the chapter, a descriptive analysis of East Asians’ confidence in both political and implementative institutions is provided (Ch. 4, Sect. 4.2). In this part the cross-national variations of political confidence already highlighted by previous research are presented, although in a broader picture, spanning across approximately fifteen years of evidence provided by the ABS data. The stable differences between East Asian countries are then assessed through a bivariate and multivariate correlational analyses, performed in order to test alternative explanations of these cross-national patterns (Ch. 4, Sect. 4.4 and Sect. 4.5). What it is shown is that the selected indicator of political contestation levels consistently negatively correlates with the index dedicated to ABS respondents’ political confidence, representing the best predictor of cross-national variations of aggregate levels of these attitudes, outperforming all the alternative explanations. What the chapter shows, however, is that the impact of contestation on aggregate levels of political confidence is much stronger for confidence in political institutions as compared to confidence in implementative ones.    Chapter 5 then represents the last empirical chapter of this dissertation, and presents a multilevel analysis of political confidence, spanning across the second, third, and fourth rounds of the ABS, and providing an assessment of both individual-level and contextual-level determinants of political confidence, and their interplay. After providing hypotheses concerning the relationship between relevant individual-level antecedents of political confidence as identified by previous research, and expectations concerning the direct and indirect effect of the contextual variable of interest (Ch. 5, Sect. 5.2), a series of hierarchical linear regression models (HLMs) are performed in order to account for both individual-level and contextual-level variation of political confidence (Ch. 5, Sect. 5.4). What these models provide is, first, a reassessment of previous findings about the direct effect of political contestation on confidence in political institutions and confidence in implementative institutions, partially confirming previous results, but also highlighting even more the different impact of political contestation on the two indices of political confidence, strong and statistically significant for average levels of confidence in political institutions, while much weaker and even not significant in affecting confidence in implementative ones. Second, the HLMs return a clear picture about the individual-level determinants of political confidence in this region, showing how institutional performance indicators represent the best individual-level predictors of confidence across all the contexts considered, and how their effects vary according to the type of political confidence taken into account. Third, these models show how the indirect effect of political contestation, considered as a moderating factor of the effect of some individual-level determinants, operates differently according to the type of political confidence considered, moderating the effect of individual-level variables when considering confidence in implementative institutions but not in the case of the other type investigated in this work. The chapter, hence, returns a rather puzzling scenario that is further discussed in the last section of this chapter (Ch. 5, Sect. 5.5). The dissertation, then, concludes with a reassessment of the main findings proposed in previous chapters, the limitations of the study, and the main implications for the empirical study of political confidence in East Asia and beyond.","language":"eng","citation":"POLITICAL CONFIDENCE AND PUBLIC CONTESTATION: A MULTILEVEL ANALYSIS OF INSTITUTIONAL CONFIDENCE IN EAST ASIA / G. Carteny ; supervisor: P. Segatti, C. Vezzoni ; phd director: M. Jessoula. Università degli Studi di Milano, 2021 Jun 07. 33. ciclo, Anno Accademico 2020. [10.13130/carteny-giuseppe_phd2021-06-07].","filename":"phd_unimi_R11998.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/848956/1817450/phd_unimi_R11998.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/923825"},"title":"HEDGEHOG/HDAC6 INHIBITION AND CHEMOTHERAPY: ASSESSMENT OF NEW DRUG COMBINATION IN ACUTE MYELOID LEUKEMIA","internalauthor":"PEZZOTTA, ALEX","type":"Tesi di dottorato","year":"2022","abstract":"In Acute Myeloid Leukemia (AML), the dysregulation of the Hh signaling is involved in the development and expansion of leukemic cancer cells and influences the response to therapeutic agents. Notably, the FDA approved only one Hh inhibitor (glasdegib) as a therapeutic strategy for AML treatment, and the majority of patients eventually relapse, underlying the urgency of discovering new therapeutic targets. One characteristic of the Hh pathway is its localization on the primary cilium membrane (PC), a microtubule-based organelle expressed by almost all non-proliferating mammalian cells. Indeed, centrosomes participate in a mutually exclusive manner in the formation of PC or mitotic spindle. Cancer cells, including AML cell lines, are characterized by a high rate of proliferation and fail to present the PC on their surface. Novel approaches to restore the PC on the surface of cancer cells are emerging, and most of them target the histone deacetylase HDAC6. Indeed, HDAC6 inhibition prevents the reabsorption of the PC and blocks cell proliferation. Since HDAC6 inhibitors (i.e., TubastatinA) are already used to treat other tumors, they might also be promising in AML treatment. In this work, analyzing the blood samples of 36 adult AML patients, we demonstrated that Hh target genes (GLI1, PTCH1), HDAC6, and the Multi- Drug-Resistant genes (MDRs) ABCC1 and ASXL1 were more expressed than in healthy donors (HD). In addition, through in silico analyses, we verified that in AML patients the expression of Hh/HDAC6 and MDRs genes were positively correlated. We also detected the same genetic regulation in in vitro models of AML, as cell lines with higher Hh expression (U937 and THP-1) showed higher levels of HDAC6 and MDRs than cell lines with low Hh expression (NB-4 and OCI-AML2). We generated a zebrafish model with Hh hyperactivation through the injection of the shh mRNA to functionally investigate the effect of Hh/HDAC6 dysregulation, and we confirmed the increased expression of hdac6 and MDRs.  Moreover, in the zebrafish reporter line for the hematopoietic stem precursor cells (HSPCs) the Tg(CD41:GFP) line, we found that Hh hyperactivation induces the hyperproliferation and expansion of the HSPCs in the caudal hematopoietic tissue, a phenotype that resembles the expansion of leukemic blast of AML patients. Interestingly, we rescued this hematopoietic defect by treating the embryos with the HDAC6 inhibitor TubastatinA but not with the Hh inhibitor cyclopamine. By the generation of a zebrafish model carrying the overexpression of the human HDAC6 mRNA, we demonstrated that HDAC6 alone can induce the hyperproliferation of the HSPCs population and that this phenotype is specific as, through its inhibition, we rescued the hematopoietic defect. Since we observed that an increased proliferation rate elicited the expansion of HSPCs, we hypothesized an implication  of the PC. Indeed, we demonstrated that zebrafish HSPCs present the PC, therefore suggesting that HDAC6 controls HSPCs proliferation, through PC's stabilization on their surface. For the first time, we described a role for HDAC6 in HSPCs expansion and identified it as a promising target for AML patients. Indeed, HDAC6 inhibition was also efficient in reducing the viability of leukemic cell lines and HSPCs expansion in well-established AML zebrafish models, carrying the overexpression of genes frequently mutated in AML patients: NPMc+ and FLT3-ITD. Moreover, in these zebrafish models, we demonstrated the efficacy of combination therapy with the standard chemotherapeutic agent cytarabine and HDAC6 inhibition.  In conclusion, we identified a positive correlation between the Hh signaling, HDAC6 and the MDR genes in AML patients. In the zebrafish model, we reported that both Hh or HDAC6 overexpression drive the hyperproliferation of the HSPCs population, a phenotype that is rescued only through HDAC6 inhibition. HSPCs hyperproliferation and the rescue through the specific HDAC6 inhibition, might be explained by alteration in the PC, that we described to present in the HSPCs. As reporter for Hh inhibition, we demonstrated that also HDAC6 inhibition efficiently reduces the expression of MDR genes. Therefore, we hypothesize the use of HDAC6 inhibitor to counteract AML resistance mechanisms. Finally, we described that HDAC6 inhibition shows high potency in specific AML condition, and that can be a suitable target for the assessment of new combination therapies with standard chemotherapic agents.","language":"eng","citation":"HEDGEHOG/HDAC6 INHIBITION AND CHEMOTHERAPY: ASSESSMENT OF NEW DRUG COMBINATION IN ACUTE MYELOID LEUKEMIA / A. Pezzotta ; supervisor: A. Rissone ; tutor: A. Pistocchi ; director: N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2022 May 18. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12198.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/923825/2023149/phd_unimi_R12198.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1121096"},"title":"TIME-DOMAIN INVESTIGATION OF ACOUSTICALLY AND THERMALLY DRIVEN MAGNONS","internalauthor":"BRIOSCHI, MARTA","type":"Tesi di dottorato","year":"2024","abstract":"This thesis is the result of the research program carried out as Ph.D. student of the School in Physics, Astrophysics and Applied Physics at Università degli Studi di Milano, which was performed from October 2021 at the Istituto Officina dei Materiali of Consiglio Nazionale delle Ricerche (CNR-IOM) within the Nanoscale Foundries and Fine Analysis (NFFA) facility. My experimental activity led to the implementation of a novel experimental setup within the NFFA-SPRINT laboratory in the premises of the FERMI@Elettra facility (Elettra-Sincrotrone Trieste), and to the establishment of new methodologies for the study of the dynamical properties of matter. In a first experiment, acoustically driven spin wave resonance in polycrystalline Ni thin films was investigated using the Transient Grating (TG) technique. The focus was on examining how the acoustic waves generated in the substrate influence and drive the magnetization dynamics of the Ni thin films via magnetoelastic coupling. In a second experiment, the TG approach has been exploited to drive coherent magnons at a selected wavevector non-relying on the magnetoelastic coupling but rather on the spatially modulated temperature profile generated by the TG excitation mechanism itself. The approach was successfully tested on ferrimagnetic Co78Gd22 alloy. This measurement campaign was conducted as part of an international collaboration aimed at extending this methodology to the Extreme Ultra Violet range, where magnons with wavelengths as short as a few tens of nm can be selectively triggered. Finally, I studied systematically the laser-driven ferromagnetic resonance in Fe5GeTe2 employing tr-Magneto-Optical Kerr Effect (MOKE), implemented in the same setup, as a function of both the external magnetic field and the temperature. The presented results provide insights into the dynamic magnetic properties of the systems studied and highlight promising opportunities for advancing research on coherent magnetization dynamics in the time domain.","language":"eng","citation":"TIME-DOMAIN INVESTIGATION OF ACOUSTICALLY AND THERMALLY DRIVEN MAGNONS / M. Brioschi ; supervisor: G. Rossi ; co-supervisor: R. Cucini ; director of the School: A. Mennella. Dipartimento di Fisica Aldo Pontremoli, 2024 Dec 16. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13263.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1121096/2597196/phd_unimi_R13263.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1142915"},"title":"ROLE OF A SPECIFIC NANOG SUPER-ENHANCER ERNA IN EPIGENETIC REMODELING AND ENHANCER-PROMOTER INTERACTION","internalauthor":"COSTABILE, DAVIDE","type":"Tesi di dottorato","year":"2025","abstract":"During last years, the role of enhancer RNAs has been in part explored; however, it’s still not clear the exact role these transcripts carry out concerning gene regulation.  In this work, the role of eRNAs transcribed from the region 5kb upper the TSS of Nanog gene in mESCs has been investigated. In particular, a specific eRNA transcript, here defined as antisense eRNA, resulted actively involved in the maintenance of Nanog gene in an active epigenetic state. After the antisense eRNA silencing, Nanog was turned-off and the cell underwent differentiation. This process was achieved through the involvement of the three layers of epigenetic regulation: the hypermethylation of the Nanog promoter and the SE region; the chromatin switch between activation and repression markers; the disruption of the SE-promoter loop responsible of the Nanog gene activation in stemness conditions. Thus, results suggested that the expression of the antisense eRNA has a key role in preserving the pluripotency in mESCs. Futhermore, preliminary experiments were performed on human cancer stem cells models to investigate the presence of eRNAs in a putative enhancer region 3kb upper the NANOG TSS.","language":"eng","citation":"ROLE OF A SPECIFIC NANOG SUPER-ENHANCER ERNA IN EPIGENETIC REMODELING AND ENHANCER-PROMOTER INTERACTION / D. Costabile ; supervisor: L. Chiariotti ;  additional supervisor: M Cuomo. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Feb 21. 36. ciclo","filename":"phd_unimi_R13155.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1142915/2663950/phd_unimi_R13155.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1123335"},"title":"EXTENDING MALAT1 ACTIVITY TO THE MODULATION OF LSD1 SPLICING: A NOVEL MECHANISM DEVOTED TO STRESS RESILIENCY","internalauthor":"ROMITO, ELENA","type":"Tesi di dottorato","year":"2025","abstract":"The brain acts as the key central hub for detecting of environmental stress and triggering adaptive responses to manage threats. Among these mechanisms, the epigenetic spatiotemporal regulation of gene expression plays a pivotal role maintaining homeostasis by functionally restraining excessive neuronal excitability. Among the players, Lysine Specific Demethylase 1 (LSD1ub) plays a crucial role in repressing the expression of plasticity genes as a secondary stress response. Notably, its increased expression and activity in response to stimulation, are mediated by a transient reduction in the inclusion of its alternative exon E8a, leading to decreased levels of its dominant-negative splicing isoform, neuroLSD1. Understanding the mechanisms of LSD1 alternative splicing is essential, given the importance of the LSD1ub/neuroLSD1 ratio in stress responses and neuroplasticity.   During my PhD research, I investigated the role of the lncRNA MALAT1 as an activity-dependent modulator of LSD1 splicing. Our data demonstrate that MALAT1 expression is increased in response to neuronal depolarization, both in vitro and in vivo, particularly upon stress exposure and developmental periods characterized by intense neuroplasticity. Through experiments involving MALAT1 overexpression and pharmacological inhibition, I observed that MALAT1 activity reduces the expression of neuroLSD1 in favor of LSD1ub upon depolarization. Additionally, cross-linking immunoprecipitation (CLIP) experiments suggest that MALAT1 interact with nSR100, the master splicing regulator of LSD1, potentially mediating its sequestration in inactive nuclear compartments.   The correct functioning of homeostatic mechanisms, possibly including the splicing modulation of LSD1, is necessary for effectively terminating stress responses and establishing of adaptive behaviors. Chronic stress challenges these mechanism, creating potential hotspots for maladaptive behaviors and for the onset of psychiatric conditions. In this context, we propose LSD1ub and MALAT1 as novel stress-vulnerability genes. Our findings reveal that in the hippocampus of stress-susceptible mice, MALAT1 is downregulated alongside a deficiency in LSD1ub upregulation. Remarkably, this molecular signature is also observed in the hippocampus of individuals who died by suicide, an extreme manifestation of the stress response spectrum and depressive phenotype. Here, we identified reduced MALAT1 levels, which correlates with reduced LSD1ub expression compared to control individuals. Taken together, this research highlights the role of the novel MALAT1-nSR100-LSD1 pathway in the homeostatic control of stress responses, influencing resilient and adaptive behaviors, and suggesting that these genes are promising candidates involved in genetic stress vulnerability.","language":"eng","citation":"EXTENDING MALAT1 ACTIVITY TO THE MODULATION OF LSD1 SPLICING: A NOVEL MECHANISM DEVOTED TO STRESS RESILIENCY / E. Romito ; tutor: E. Battaglioli ; supervisore: F. S. Rusconi ; coordinatore: N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2025 Jan 28. 37. ciclo","filename":"phd_unimi_R13426.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1123335/2605008/phd_unimi_R13426.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1222755"},"title":"THE ADAPTIVE POTENTIAL OF A MULTIDOMAIN SYSTEM: FUNCTIONAL, COGNITIVE AND PHYSIOLOGICAL INSIGHTS FROM AN INTERVENTION STUDY ON PRE-FRAIL OLDER ADULTS.","internalauthor":"PUPPO, LUCIA","type":"Tesi di dottorato","year":"2026","abstract":"Background: Frailty and Intrinsic Capacity (IC) are often conceptualized as distinct constructs in ageing research, yet both likely emerge from interactions among cognitive, physiological, psychological, and functional domains. This thesis examined Frailty and IC as features of a dynamic, multi-domain system and tested whether a personalized dual-task exergame intervention could strengthen adaptive reserves in pre-frail older adults.  Methods: PRAISE is a monocentric, randomized, two-arm pilot trial enrolling community-dwelling older adults in the pre-frailty range. Participants were randomized to a 12-month personalized dual-task exergame intervention or to a control group receiving good-practice advice. Assessments at baseline and follow-up included Frailty Index, IC composites, dual-task neuropsychological measures, actigraphy registration, and heart rate variability (HRV) measures. Correlation, clustering, and network analyses characterized system organization, while longitudinal mixed-effects models tested group × time effects.  Results: Frailty and IC emerged as embedded nodes within a dynamic multi-domain architecture whose topology varied according to physiological and functional states. The intervention significantly reduced Frailty (primary outcome), improved global cognition and dual-task inhibitory control, and enhanced lower-limb function. Clustering and subject-level analyses on a restricted HRV sample further identified a distinct community linking cognitive and dual-task measures with ΔHRV reactivity parameters, which functioned as central bridging nodes. Greater gains in ΔLFnu were associated with poorer cognitive and dual-task performance. Inspection of spectral components demonstrated that this index reflected parasympathetic withdrawal rather than increased absolute low-frequency power. Expressed as a relative shift in high-frequency power (ΔHF%), this parameter may capture a “neurovegetative cost” of cognitive challenge, an autonomic analogue of dual-task cost, highlighting how adaptive resources are allocated under load.   Conclusions: This work provides empirical evidence that a personalized dual-task intervention can induce coherent multi-domain improvements and offers a conceptual systems-based framework for ageing. Preserving independence in later life appears to depend not on isolated domains, but on strengthening adaptive interactions across cognitive, autonomic, and functional subsystems.","language":"eng","citation":"THE ADAPTIVE POTENTIAL OF A MULTIDOMAIN SYSTEM: FUNCTIONAL, COGNITIVE AND PHYSIOLOGICAL INSIGHTS FROM AN INTERVENTION STUDY ON PRE-FRAIL OLDER ADULTS / L. Puppo ; supervisor: G. Cerri, L. Bello ; coordinator: A. Sereni. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2026 Feb 27. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13265.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1222755/3269661/phd_unimi_R13265.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1048815"},"title":"UNDERSTANDING THE FACTORS INFLUENCING FUNCTIONAL TASKS FOR THE ASSESSMENT OF MUSCULOSKELETAL INJURY-RELATED BIOMECHANICS","internalauthor":"RABELLO DA SILVA, RODRIGO","type":"Tesi di dottorato","year":"2024","abstract":"Background: The evaluation of lower limb biomechanics during functional tasks is extremely common and relevant in the current sports and exercise medicine literature. The choice of which task to use, which variation to adopt and which metric to extract is dependent on the research question and on the population investigated. However, each of those factors (in combination with many others) may affect the findings obtained by functional task, which, in turn, may lead to inadequate planning of rehabilitation and injury prevention protocols in clinical and sports practice.   Aims: To evaluate how distinct factors influence biomechanical assessment during functional tasks using different tasks, metrics, and populations.  Thesis structure: Four experimental studies were conducted in order to address five specific aims that will contribute to the current knowledge on the use of functional tasks.  Study 1: This study compared kinematics when executing three squat-based tasks (single-leg squat, anterior step-down, and lateral step-down) at three different speeds (slow, fast and self-selected. The study found that both task type and movement speed can influence several metrics commonly used to assess movement kinematics, albeit with small absolute difference in degrees.  Study 2: This study investigated if there were relationships between two metrics of muscle activation of lower limb and core muscles during single-leg squats and anterior step-downs. The findings show that, although present, this relationship is muscle, metric and task dependent.  Study 3: This study compared the differences between people with different running experience levels on linear and angular stiffness during running gait, finding that these metrics were not different between groups, suggesting that the increased injury rate in less-experienced runners is likely not explained by different gait patterns.  Study 4: This study measured the test-retest reliability of force measurements during the execution of functional tasks with progressive difficulty in a healthy and pathological population. The results show that these metrics is dependent on the task, the metric and the participants’ injury status and that several metrics were not sufficiently reliable.  Conclusion: The thesis findings support the idea that results are highly dependent on many components that need to be taken into account when using functional tasks for the evaluation of healthy and clinical populations. Furthermore, it supports the necessity for the sports and exercise medicine literature to provide as many details as possible when describing these tasks and that care should be taken when comparing research findings with other studies that might have used different task variations, metrics and populations.","language":"eng","citation":"UNDERSTANDING THE FACTORS INFLUENCING FUNCTIONAL TASKS FOR THE ASSESSMENT OF MUSCULOSKELETAL INJURY-RELATED BIOMECHANICS / R. Rabello Da Silva ; tutor: C. Sforza ; coordinatore: C. Sforza. Dipartimento di Scienze Biomediche per la Salute, 2024 May. 36. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R12828.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1048815/2407872/phd_unimi_R12828.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1228455"},"title":"IL CONTROLLO GIURISDIZIONALE SULL¿ACCUSA: GLI SVILUPPI DELL¿UDIENZA PRELIMINARE E DEI MODELLI DI COMMON LAW","internalauthor":"LAZZARINI, FRANCESCO","type":"Tesi di dottorato","year":"2026","abstract":"Despite repeated attempts at revitalization, including the most recent reform of criminal justice, the preliminary hearing continues to show its limitations in performing its fundamental functions of safeguarding the defendant’s rights and ensuring the efficiency of the system. Even repeated efforts to strengthen the preliminary hearing have proven insufficient, even though this control has been profoundly changed in its defining features since its introduction in 1988, modeled on analogous English and American proceedings as an emblem of adherence to the adversarial system. Starting from these premises, the thesis first traces the evolution of the Italian preliminary hearing, analyzing its main trajectories and, in particular, the evidentiary basis of the decision, the control   over the indictment, and the applicable standard. The analysis then focuses on England and the United States, where preliminary proceedings originated and came to characterize the adversarial system, albeit undergoing radical transformations over the centuries and now appearing significantly reduced in scope and in a state of serious crisis. Considering the evolutionary paths of the three legal systems, the study investigates the relationship between the Italian preliminary hearing and its reference models, exploring whether the latter may offer useful insights into the deeper causes of its failure, the adequacy of the current regulatory framework, and possible directions for the future.","language":"ita","citation":"IL CONTROLLO GIURISDIZIONALE SULL'ACCUSA: GLI SVILUPPI DELL'UDIENZA PRELIMINARE E DEI MODELLI DI COMMON LAW / F. Lazzarini ; tutor: D. Vigoni ; co-tutor: G. Caneschi ;  coordinatore del dottorato: F. Poggi. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2026 Apr 24. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13730.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 24-SET-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1238276"},"title":"ARTIFICIAL INTELLIGENCE IN PUBLIC WELFARE POLICIES: ADOPTIONS, PERCEPTIONS AND TRUST","internalauthor":"PRELLE, GINEVRA","type":"Tesi di dottorato","year":"2026","abstract":"What consequences will the widespread adoption of Artificial Intelligence (AI) in the public sector have on society? I was inspired by this question to conduct five studies using multidisciplinary and multi-methods research designs. While most research focuses on the private sector or pioneering countries in digitalization and public services, this work examines automated decision-making tools (ADM) and AI in Italian public welfare policies. Firstly, using qualitative methods, I explore how public employees perceive that AI adoption in public welfare policies can affect organizational and social factors such as administrative discretion and social inclusion. Secondly, relying on quantitative and experimental methods I examine two further social consequences: trust in AI applications and trust in institutions adopting AI. Besides advancing knowledge about this specific topic in Italy, the overall theoretical contribution highlights the role of social factors— including public values, social norms, and prior experience with institutions— in shaping the consequences of AI adoption rather than the technical characteristics of algorithms. Methodologically, this thesis generates a new dataset that combines survey items with experimental measures of trust in institutions and attitudes toward AI in Italy. Results from the qualitative study indicate that in Italy a fragmented and heterogenous AI adoption is occurring in the provision of welfare benefits and to detect fraudulent behaviours. These adoptions already imply relevant organizational and social consequences, reinforcing public employees’ narratives of efficiency in terms of redistribution, social inclusion and the relation between the state and citizens. Survey items reveal balance between AI attitudes such as perceived benefits and risks, but contradictory patterns concern AI knowledge and awareness. Moreover, perceived benefits and social norms consistently predict higher trust in AI applications. Instead, perceived risks play a more heterogeneous role, particularly for high-stake domains such as healthcare or human resources compared to Chat-GPT like applications. Finally, a vignette experiment indicates that institutional trust is still shaped more by performance and prior experience than the decision-maker— whether a public administrator, a hybrid system or an AI. However, context-dependent dynamics emerge, particularly between welfare-related and justice-related decisions.","language":"eng","citation":"ARTIFICIAL INTELLIGENCE IN PUBLIC WELFARE POLICIES: ADOPTIONS, PERCEPTIONS AND TRUST / G. Prelle ; tutor: E. Pavolini, Á. Székely ; coordinatore: M. Guerci. - Milano. Università degli Studi di Milano, 2026 May 12. 38. ciclo, Anno Accademico 2025.","filename":"phd_unimi_R13777.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1238276/3311756/phd_unimi_R13777.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/895694"},"title":"ADDITIVE MICRO- AND NANOPATTERNING FOR THE FABRICATION OF BRAIN CELL NETWORKS","internalauthor":"PREVIDI, ANITA","type":"Tesi di dottorato","year":"2022","abstract":"The challenges in creating cell cultures with controlled topology and in which cells maintain their in vivo-like phenotype are manifold. Engineering physiologically relevant brain cell networks requires the precise placement of cell bodies in an organized manner while providing the appropriate biophysical cues typical of the native extracellular matrix.  In this work, an additive nanofabrication and micropatterning technique is employed to produce nanostructured substrates with complex micropatterns for cell culture aiming at this goal.  The strength of this approach resides in the fact that the control on the nanoscale properties of the films, mimicking the native environment of the cells, is combined with the possibility to limit cell adhesion to predetermined substrate areas arranged in patterns. This enables the reproduction of in vitro cell networks with anatomically or functionally relevant geometrical shapes.  This thesis provides the details of the method for the fabrication of nanostructured micropatterned films, analysing the advantages and limitations of the technique and providing solutions for obtaining stable and reproducible results.  The nanostructured micropatterned substrates were used to characterize the combined effect of the nanoscale topography and cell confinement on astrocytic ensembles. The nanostructure is demonstrated to impact on proliferation, cell morphology, cytoskeletal structure, and calcium activity. It favours the development of astrocytes with morphological features like those found in vivo. Also, the micrometric architecture of the cultures was shown to affect cell morphology and behaviour. Calcium wave signaling was more effective in cells forming elongated clusters with dimension in the same range of blood vessels or axon fibers.  The findings of this thesis provide novel insights on the mechanotransductive interaction between astrocytes and the nano- and micro-topographic cues of the cellular microenvironment, while highlighting the crucial role of the biophysical properties of the growth scaffolds to direct brain cell behaviour.","language":"eng","citation":"ADDITIVE MICRO- AND NANOPATTERNING FOR THE FABRICATION OF BRAIN CELL NETWORKS / A. Previdi ; supervisor: P. MILANI ; coordinatore: M. PARIS. Dipartimento di Fisica Aldo Pontremoli, 2022 Jan 20. 34. ciclo, Anno Accademico 2021. [10.13130/previdi-anita_phd2022-01-20].","filename":"phd_unimi_R12346.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/895694/1948254/phd_unimi_R12346.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/957717"},"title":"DISSECTING MELANOMA-TUMOUR MICROENVIRONMENT INTERACTIONS DURING TUMOUR PROGRESSION","internalauthor":"LOVATI, GIULIA","type":"Tesi di dottorato","year":"2023","abstract":"Despite the latest advances in melanoma management, patients frequently experience relapse and die of metastases. The development of new approaches to better mimic the metastatic process and test novel combination therapies are therefore urgently required. It was recently shown that not transformed cells in the tumour ecosystem could act as key players in driving cancer development, progression, spreading and metastatic niche formation. To deepen the current knowledge of how melanoma reacts to a changing microenvironment and how the cross-talk between melanoma and the surrounding cells impacts on therapy response, we established an innovative, flexible and highly reproducible three-dimensional (3D) model.   Making use of our platform of PDXs and primary patient cultures, we proved that patient-derived cells, and not human cell lines, allow us to closer recapitulate the cellular organization of the melanoma tissue. Besides, we determine that the addition of microenvironmental components in the culture, such as fibroblasts and endothelial cells, fosters melanoma invasion of collagen matrix in vitro. Furthermore, we show that 3D cultures are not only tumorigenic in immunodeficient mice (NSG), but that we could also score differences in the metastatic potential of melanomas exposed to fibroblasts and endothelium in hetero-cultures, compared to homo-culture controls, further supporting the in vitro data.   In order to dissect the mechanism behind melanoma phenotypical alterations induced by fibroblasts and/or endothelial cells, we inspected the transcriptional and phenotypic profiles of our 3D cultures. We, therefore, assess the upregulation of pathways related to invasion, EMT and ECM remodelling during organotypic culture growth. Notably, L1 cell adhesion molecule (L1CAM/CD171) expression results highly increased in melanoma cells' interaction with either fibroblasts and/or endothelial cells. L1CAM overexpression on melanoma cells proved to be necessary, but not sufficient, to mimic environmental interactions in in vitro invasion assays, still highly prompting melanoma aggressiveness in in vivo experimental models of metastasis. These data imply a fundamental role of TME in driving L1CAM activation. Accordingly, its depletion reduces melanoma cells invasion capability in vitro, while strikingly abolishing the melanoma metastatic properties in NSG mice, even when transplanted with hetero-organotypic cultures. Indeed, all the mice transplanted with L1CAM silenced cells displayed lower metastatic burden and prolonged overall survival. Transcriptional analyses also evidence melanoma transcriptional reprogramming upon L1CAM variation, particularly involving epithelial-to-mesenchymal transition.  Plasminogen Activator Inhibitor 1 (PAI1) or SERPINE1, one of the prominent members of the serpins superfamily, is among the secreted factors mostly altered in the hetero-cultures and its production is strictly dictated by melanoma/stroma cross-talk. Interestingly, the increase in L1CAM levels is able to sensitize melanoma to anti-PAI-1 agent cytotoxic effects, while it is only partially effective on L1CAM low expressing cells. Even if further studies are required to determine the reciprocal role of the two proteins in the context of the organotypic culture to then translate it to the tumour niche, our results suggest the existence of an L1CAM/SERPINE1 axis involved in melanoma TME-driven acquisition of invasive and metastatic phenotype, possibly exploitable as a novel vulnerability of highly aggressive cancer cell.    Taken together our data indicate that fibroblasts and endothelial cells are able to reprogram melanoma cells' transcriptome and phenotype in our organotypic cultures. Thus, our model is a powerful tool to unveil the mechanisms behind melanoma and surrounding ecosystem relationships during tumour progression, as well as to identify new targetable vulnerabilities during tumour evolution, finally allowing to test of innovative combination treatments in a complex and relevant system.","language":"eng","citation":"DISSECTING MELANOMA-TUMOUR MICROENVIRONMENT INTERACTIONS DURING TUMOUR PROGRESSION / G. Lovati ; tutor: L. Lanfrancone ; co-tutor: P. G. Pelicci ; phd coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2023 Apr 13. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12437.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/957717/2157090/phd_unimi_R12437.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/938229"},"title":"(ASYMMETRIC) PHOTOCATALYSIS UNDER HOMOGENEOUS AND HETEROGENEOUS CONDITIONS - OPTIMIZATION IN CONTINUO, NOVEL CATALYTIC REACTORS AND MATERIALS","internalauthor":"HERBRIK, FABIAN","type":"Tesi di dottorato","year":"2022","abstract":"Solid supported catalysts exhibit several advantages over the homogenous ones – to name only a few: ease of catalyst separation and low catalyst loadings under continuous operation. This work shows how careful fine-tuning of solid supported material, transmission-based considerations (photocatalyst choice, concentration, and other methodologies) allowed to overcome the difficulties with the inefficient irradiation of reaction mixtures. Generally, the herein described solid supported catalyst shows higher degrees of enantioinduction than its homogeneous counterpart often even higher degrees than previously reported in literature by MacMillan et al and Melchiorre et al. By building a homemade chiral reactor for continuous flow operations productivity was greatly increased when comparing to the batch process, with significantly decreased catalysts loading. Ultimately the applicability of the material was proven by employing it in the telescoped synthesis of an approved antidiabetic drug – Mitiglinide in high yield and satisfactory enantioselectivity.","language":"eng","citation":"(ASYMMETRIC) PHOTOCATALYSIS UNDER HOMOGENEOUS AND HETEROGENEOUS CONDITIONS - OPTIMIZATION IN CONTINUO, NOVEL CATALYTIC REACTORS AND MATERIALS / F. Herbrik ; tutor: M. Benaglia ; co-tutor: A. Puglisi ; coordinator: D. Roberto. Università degli Studi di Milano, 2022 Sep 20. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12465.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/938229/2068359/phd_unimi_R12465.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1217755"},"title":"LITISPENDENZA E CONNESSIONE NEL REGOLAMENTO BRUXELLES I-BIS","internalauthor":"GANEA, DIANA RAMONA","type":"Tesi di dottorato","year":"2026","abstract":"The present dissertation aims to examine the European lis pendens in civil and commercial disputes as governed by the Brussels I-bis Regulation. In order to provide a deeper understanding of the legal framework in which the lis pendens rule operate, the study begins by tracing the development of  European procedural law, starting with the founding treaties of the European Community and the European Union. A more detailed analysis of the specific procedural matters follows outlining the historical evolution that led to the 1968 Brussels Convention on Jurisdiction and the Enforcement of Judgments, its subsequent recast in the Brussels I Regulation (Regulation No. 44/2001), and its further recast in the Brussels I-bis Regulation (Regulation No. 1215/2012). The evolution of the provision on lis pendens is then examined, with a focus on the changes introduced in the transition from the Brussels Convention to the Brussels I-bis Regulation.  With the regulatory framework thus established, the dissertation proceeds to the specific analysis of lis pendens rule. It begins by addressing the issue of the autonomous nature of the rule. Then it addresses the subjective and objective prerequisites of the lis pendens. In light of the fact that, within the European legal system, the Court of Justice holds exclusive authority to interpret European regulations on procedural matters pursuant to Articles 81 and 267 TFEU, with binding effect on the courts of the Member States, it was imperative to study the case law of the Court of Justice in order to construe the prerequisites of this legal concept.  Therefore, the study examines the leading judgments of the Court of Justice on lis pendens (including the paramount decisions Gubish/Palumbo, Tatry/Maciej Rataj, Drouot Assurances), through which the CJEU developed its theory for identifying claims, the so-called Kernpunkttheorie. The first chapter concludes with some critical observations on the Court of Justice definitions of “same parties, same cause of action and same subject matter”. The second chapter focuses on the dynamic aspects of the institution, starting with priority rule, which is compared to common law doctrine of forum non conveniens. It then explores the cases of exception to the priority rule in the application of lis pendens i.e. exclusive jurisdiction by law and exclusive jurisdiction agreements. The analysis of the legal framework continues with regard to the regime governing the lis pendens exception, including the declarations mechanism and means of appeal (as well as the ways for appealing the decision granted in violation of the rule on lis pendens). Finally, the rules on lis pendens and connection with regard to proceedings initiated in States not encompassed in the Europe Union were briefly considered.  Finally, the third chapter explores the relationship between lis pendens and related legal concepts, such as the identification of claims, the res judicata and objective joinder. Particular attention was paid to the issue of the effectiveness of ascertaining the key element in identifying claims for the purposes of lis pendens, the so-called Kernpunkt.  The study of lis pendens rule is complemented by the analysis of the provision on related actions, which, in the European case law is considered to be subsidiary to the lis pendens, thus applicable in cases in which lis pendens cannot be invoked. The concept of related actions, as regulated in the Brussels I-bis Regulation, is therefore also analysed in parallel with lis pendens.  In conclude, this dissertation proposes an alternative definition of the lis pendens rule that differs from the one established by the Court of Justice, the definition here propose is aims to clarify the distinction between lis pendens and related actions, thus drawing clearer boundaries between these two legal concepts.","language":"ita","citation":"LITISPENDENZA E CONNESSIONE NEL REGOLAMENTO BRUXELLES I-BIS / D.r. Ganea ; tutor: S. A. Villata ; coordinatore del corso di dottorato: G. Ludovico. - Università degli Studi di Milano. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2026 Feb 25. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13756.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 24-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/932854"},"title":"IL FORO DI AUGUSTO. ARCHITETTURA E DECORAZIONE ARCHITETTONICA DEI PORTICI E DELLE ESEDRE","internalauthor":"DAL MONTE, LUCA","type":"Tesi di dottorato","year":"2022","abstract":"The PhD project focuses on the architecture and architectural decoration of the porticoes of the Forum of Augustus, through a reconstructive study based on the study of the architectural materials and the walls still in place.","language":"ita","citation":"IL FORO DI AUGUSTO. ARCHITETTURA E DECORAZIONE ARCHITETTONICA DEI PORTICI E DELLE ESEDRE / L. Dal Monte ; tutor: C. Marconi ; correlatore: T. Ismaelli. Dipartimento di Beni Culturali e Ambientali, 2022 Jul 08. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12183.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/932854/2048729/phd_unimi_R12183.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1119273"},"title":"DESIGN AND OPTIMIZATION OF ADVANCED EMULSIONS AS BIOACTIVE COMPOUND CARRIERS FOR LOW-SATURATED FAT FOOD PRODUCTS: TECHNOLOGICAL AND NUTRITIONAL ASPECTS","internalauthor":"LOFFREDI, ELEONORA","type":"Tesi di dottorato","year":"2024","abstract":"Research in food engineering is increasingly using reverse engineering principles to design healthier food products. Growing concerns about the high intake of fat-rich foods and the associated increased risk of chronic diseases like obesity, diabetes, and hypertension are driving the food industry to reformulate full-fat products by reducing total or saturated fat content while maintaining good physicochemical and sensory properties. However, fat provides the food matrix with important features, so its reduction or replacement can generate undesirable outcomes and unacceptability by consumers. One of the most promising strategies to reduce saturated fat content in foods is based on the use of emulsions. Particularly, advanced emulsions can prevent instability phenomena and provide new features, such as the ability to act as carriers for bioactive compounds and the possibility to engineer their interface to control digestive fate.  In this context, the overarching goal of this PhD project was to design advanced emulsions intended as ingredients in low-saturated fat foods, and as potential bioactive compound carriers, thereby creating healthier products.  At first, a complete literature survey about advanced emulsions in terms of composition and process conditions was performed to identify knowledge gaps and define experimental factors and the most suitable methods for emulsion characterization.  Then the effect of emulsifier concentration and corn oil volume phase on single, Pickering, heat-filled gel, and cold-filled gel emulsions were studied by means of Design of Experiments techniques. Soy lecithin (SL), octenyl succinic anhydride starch (OSA), chickpea protein isolate (CPI), and citrus fibers (CF) were used as emulsifiers. Based on the highly significant models calculated for apparent viscosity and droplet size, emulsion formulations were optimized using Response Surface Methodology coupled with the desirability function. All optimized advanced systems outperformed the SL-based single emulsion, particularly in terms of apparent viscosity and stability index.  To evaluate the digestion fate of the optimized emulsions produced with or without the addition of a commercial polyphenol extract, lipolysis was evaluated by applying the harmonized international protocol INFOGEST. There was no interaction between polyphenols and triacylglycerol hydrolysis, whereas the different emulsion structures influenced lipid digestibility. No differences were found in the free fatty acids release at the end of the intestinal phase. Still, significantly lower amounts of mono- and di-acylglycerols were found in the cold-gel emulsion with CF, which also showed the highest amount of unhydrolyzed triacylglycerols at the end of the gastric phase.  The last part of the project focused on reformulating ice cream and cookies to obtain low-saturated fat products. Based on the previous results, CPI cold-gel emulsion was used as a substitute for milk cream in artisanal ice cream, while CPI heat-filled gel emulsion as butter replacer in cookies. The cold-filled gel emulsion produced an ice cream with quality properties comparable to those of the standard product but with improved nutritional features. As for cookies, the heat-filled gel emulsion resulted in higher protein and lower saturated fatty acids content with respect to the standard formulation, but the fracture strength was very high, thus further optimization of the formulation is needed. Studies about reformulated foods’ digestibility are still ongoing.  Future studies should focus on encapsulated polyphenols’ fate during digestion, and on the use of enriched emulsions in food products.","language":"eng","citation":"DESIGN AND OPTIMIZATION OF ADVANCED EMULSIONS AS BIOACTIVE COMPOUND CARRIERS FOR LOW-SATURATED FAT FOOD PRODUCTS: TECHNOLOGICAL AND NUTRITIONAL ASPECTS / E. Loffredi ; tutor: C. Alamprese ; co-tutor: C. del Bo' ;  phd dean : D. Mora. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2024 Dec 20. 37. ciclo","filename":"phd_unimi_R13342_2.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 22-NOV-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1244146"},"title":"STEPHANOS. NOTES ON ARISTOTLE'S RHETORIC. A CRITICAL EDITION AND TRANSLATION","internalauthor":"VALORI, UGO","type":"Tesi di dottorato","year":"2026","abstract":"This dissertation presents the critical edition and first complete English translation of a twelfth-century Byzantine commentary on Aristotle’s 'Rhetoric' attributed by the manuscripts to a certain Stephanos.    Although rhetoric and philosophy occupied a central place in Byzantine education and elite culture, many of the relevant texts remain understudied, unedited, or untranslated, and a comprehensive historical and theoretical framework is still lacking. Stephanos’ Notes stand at the intersection of these disciplines, offering privileged insight into the intellectual practices of the Komnenian period.    The thesis provides a critically grounded text and the first complete English translation of Stephanos’ commentary, based on full collation of all currently identifiable manuscripts and close examination of the manuscript Vat. gr. 1340, demonstrated to be the archetype of the tradition.    The critical edition is preceded by an introductory study that reassesses the intellectual profile of Stephanos. This essay argues that the Notes originate in a scholastic environment and reflect classroom teaching, integrating Aristotelian logic, Hermogenian rhetorical theory, and legal argumentation. It also questions the previous attribution of the commentary to Stephanos Skylitzes, maintaining that internal evidence points toward a different author and a later historical context.","language":"eng","citation":"Stephanos. Notes on Aristotle's Rhetoric. A Critical Edition and Translation / U. Valori ; tutor: S. Martinelli Tempesta, A. Pizzone ; co-tutor: M. Trizio; coordinatore: M. Faraguna, L. Nyholm Kallestrup.. Dipartimento di Studi Letterari, Filologici e Linguistici, 2026. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13850.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 12-NOV-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1197575"},"title":"FACILITATING CLINICAL DECISION-MAKING IN REHABILITATION: INNOVATIVE APPROACHES TO SYNTHESIZE AND TRANSLATE EVIDENCE INTO PRACTICE","internalauthor":"CORDANI, CLAUDIO","type":"Tesi di dottorato","year":"2025","abstract":"Integrating scientific evidence into clinical rehabilitation practice is essential to ensuring effective, data-driven interventions. However, translating this evidence into everyday clinical decision-making presents significant challenges due to the complexity of available information and the need to personalize interventions for individual patients. This project aims to explore innovative approaches to facilitate clinical decision-making in rehabilitation, focusing on synthesizing and applying available evidence to practice.  Building upon the fundamental principle that rehabilitation interventions do not directly target the disease itself but rather address impairments and activity/participation levels, as influenced by the underlying health condition, and acknowledging the lack of direct evidence on rehabilitation for post-COVID-19 condition (PCC), we developed a series of overviews of Cochrane Systematic Reviews (CSRs). These overviews employ a mapping synthesis approach, focusing on the rehabilitative management of key PCC symptoms that have been previously investigated in other health conditions. The mapping syntheses allowed the identification of high-quality evidence relevant to the rehabilitation of fatigue, post-exertional malaise, orthostatic intolerance, dyspnea, arthralgia, dysphagia, dysphonia, olfactory dysfunction, cognitive impairment, anxiety, and depression. The findings have contributed to generating valuable hypotheses for both clinical practice and future research in PCC rehabilitation. Furthermore, these insights have served as the foundation for developing treatment recommendations for PCC symptoms, as published in the World Health Organization Guidelines for clinical practice.    Thereafter, we conducted a systematic review to synthesize the increasing direct evidence on rehabilitation in the context of COVID-19 and PCC, providing practical recommendations for clinicians. This review serves as a valuable resource for informing clinical decisions and promoting the adoption of evidence-based practices.    Finally, we identified a series of clinical conditions of high rehabilitative interest using a Delphi method. Subsequently, after developing a new methodological framework for conducting overviews of CSRs with a mapping synthesis, we applied this methodology to one of these relevant conditions (knee replacement rehabilitation).    In conclusion, evidence mapping and systematic reviews represent an innovative approach to facilitating clinical decision-making in rehabilitation. These tools support practitioners in synthesizing and applying available evidence, promoting personalized, evidence-based interventions to improve patient outcomes.","language":"eng","citation":"FACILITATING CLINICAL DECISION-MAKING IN REHABILITATION: INNOVATIVE APPROACHES TO SYNTHESIZE AND TRANSLATE EVIDENCE INTO PRACTICE / C. Cordani ; tutor: S. Negrini; coordinatore: M. Del Fabbro. - Milano. Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, 2025 Dec 19. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13941.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1197575/3187955/phd_unimi_R13941.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1161515"},"title":"DESIGNING FOUNDATIONAL STRATEGIES FOR DEVELOPING A FAMILY OF FOOD SYSTEMS SUSTAINABILITY ONTOLOGIES","internalauthor":"UBBIALI, GIORGIO ALBERTO","type":"Tesi di dottorato","year":"2025","abstract":"During the last two decades, ontologies – theories for representing knowledge – have shown their potential in cohering heterogeneous perspectives and establishing common semantics across varied stakeholders and domains. Despite that, to date, limited and isolated efforts have been made with regard to sustainability –  a participatory shared language would highly benefit in clarifying and possibly harmonizing the diverse perspectives, metrics, and approaches that currently exist on sustainability.  To deal with those shortcomings, this PhD dissertation provides a toolkit of solid philosophical strategies establishing a suitable foundational basis to support the consistent and interoperable design of ontologies for sustainability. Food systems have served as the core case study of this work, due to being the primary drivers of many of the current global sustainability concerns threatening life on Earth, such as climate change, biodiversity loss, and malnutrition. The proposed toolkit covers three strategies: 1) a review analysis of currently available ontologies regarding sustainability and related theoretical challenges, a roadmap towards a family of interoperable sustainability ontologies, and a Sustainability Core Ontology (SCO), 2) a meta-framework for food systems sustainability, and 3) a methodology for developing food systems sustainability ontologies using the designed meta-framework, and a use-case ontology addressing sustainability in meat systems, named Sustainable Meat Systems Ontology (SuMSO). This PhD dissertation is a collection of three research papers, each dedicated to describing one of these strategies.","language":"eng","citation":"DESIGNING FOUNDATIONAL STRATEGIES FOR DEVELOPING A FAMILY OF FOOD SYSTEMS SUSTAINABILITY ONTOLOGIES / G.a. Ubbiali ; tutor: A. Borghini tutor: M. Lange coordinatore di Dipartimento: F. Guala. Dipartimento di Filosofia Piero Martinetti, 2025 Apr 29. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13545.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1161515/2958509/phd_unimi_R13545.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1156155"},"title":"ELECTROCHEMICAL IODINATION AND DEIODINATION PROCESSES FOR GREEN SYNTHESIS AND WATER REMEDIATION","internalauthor":"SORTI, LETIZIA","type":"Tesi di dottorato","year":"2025","abstract":"This project is devoted to highlight the importance and the great innovation that the application of electrochemistry could bring in the protection of the environment. The aim was to develop cost-effective and eco-friendly methods in both environmental remediation and green chemistry fields, to make electrochemistry considered as a valid alternative to classical methods in the contrast media industry. The first part of the thesis is focused on the study of the electrochemical iodination of N,N’-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (idroamide, IA), an important intermediate for the synthesis of iomeprol (IMP). It has been demonstrated that the use of a carbonaceous anode can successfully transform I-/I2 in iodinating species, leading to a complete iodination of the reagent and almost no by-products. The experimental conditions have been optimized and the potentiostatic electrolysis in a recirculating divided cell (cation exchange membrane) has been successfully scaled for the treatment of 0.8 L of IA 23.5% w/w. A pre-pilot system has been designed and installed and the first tests showed the way forward from here. Parameters related to increasing volumes will be studied, also optimising them for flow chemistry. The success of the scale-up of this study will provide a concrete, as well as green, alternative to the current use of ICl, a highly corrosive iodinating agent that must be handled with great caution. The second part of this work is instead focus on iodinated contrast media (ICM) electrochemical degradation, and, in particular, on reductive processes. Gold was found to be a powerful electrocatalyst in the case of C-I bond breaking and a preliminary study on sputtered 10 nm bilayer films showed promising results about a powerful synergy between gold and silver. The reductive mechanism was also investigated for IMP deiodination, allowing the optimization of the experimental parameters in conditions similar to those of real polluted matrices. Iodine was almost completely recovered as iodides in this case, while in simulated urine and industrial wastewater, where an undivided cell was chosen to promote mineralization, it was accumulated as iodates. Further development will be focused on iodides separation from the polluted matrix, in a iodine circular economy perspective.","language":"eng","citation":"ELECTROCHEMICAL IODINATION AND DEIODINATION PROCESSES FOR GREEN SYNTHESIS AND WATER REMEDIATION / L. Sorti ; tutor: A. Minguzzi ; supervisori: A. Vertova, F. Uggeri ; coordinatore: L. Prati. Università degli Studi di Milano, 2025 Apr 11. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13361_2.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1156155/2730420/phd_unimi_R13361_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1201933"},"title":"SMN DEFICIENCY INDUCES NEUROACTIVE AMINOACIDS DYSMETABOLISM: BRIDGING INSIGHTS FROM PRECLINICAL MODELS TO CLINICAL EVIDENCE IN SMA PATIENTS","internalauthor":"HASSAN, AMBER","type":"Tesi di dottorato","year":"2025","abstract":"ABSTRACT  Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, driven by homozygous loss of the SMN1 gene and reduced SMN protein. Although disease-modifying therapies such as Nusinersen, Risdiplam, and Onasemnogene abeparvovec have markedly improved survival and motor outcomes, they are not curative, and many patients continue to exhibit residual weakness, metabolic instability, and heterogeneous responses. This underscores the need for SMN-independent therapeutic strategies and robust biomarkers to enable personalised disease management.    We investigated how SMN deficiency disrupts amino acid metabolism and neurotransmission across central and peripheral systems, integrating data from SMA mouse models, Drosophila, and patient biofluids. First, we show that excitatory amino acids, including L-glutamate, L-glutamine, D-serine, and D-aspartate, are dysregulated in the CNS and cerebrospinal fluid (CSF) of SMA, compromising glutamatergic neurotransmission—supplementation with D-serine improved motor performance in severe SMA mice, identifying a tractable metabolic target. Second, we discovered a selective deficiency of L-arginine in the spinal cord of SMA mice and in CSF from SMA1 patients, which Nusinersen restored in severe cases. Given L-arginine’s dual role in nitric oxide signalling and nitrogen/energy metabolism, this finding links SMN loss to both synaptic and vascular dysfunction. Third, we identified taurine deficiency in the SMA mice brainstem and CSF of patients, also corrected by Nusinersen in SMA1, nominating an additional candidate for adjunctive therapy.    Extending beyond the CNS, systematic profiling in SmnΔ7 mice revealed widespread depletion of L-arginine and L-alanine across skeletal muscle, liver, kidney, and serum, alongside elevated glutamine/glutamate ratios, a systemic signature conserved in Drosophila SMA models. These metabolic changes were accompanied by stereospecific imbalances in D/L amino acids, as well as DNA damage and innate immune activation, establishing links between SMN loss, metabolic stress, and genome instability.     Collectively, these studies establish amino acid dysregulation spanning central, peripheral, and stereospecific dimensions as a conserved hallmark of SMA. By integrating cross-species evidence, they highlight amino acids as grounded therapeutic candidates for SMN-independent intervention. This work provides a translational framework for developing biomarker-guided combination strategies to improve long-term outcomes in SMA.","language":"eng","citation":"SMN DEFICIENCY INDUCES NEUROACTIVE AMINOACIDS DYSMETABOLISM: BRIDGING INSIGHTS FROM PRECLINICAL MODELS TO CLINICAL EVIDENCE IN SMA PATIENTS / A. Hassan ; supervisor: A. Usiello ; internal supervisor: F. Salvatore ;  internal evaluator: E. M. Valente ; external evaluator: M. Bowerman. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Dec 19. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13515.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1201933/3202179/phd_unimi_R13515.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/888934"},"title":"CLINICAL AND PRECLINICAL STUDIES OF IMPLANTS WITH A MORSE-TAPER IMPLANT-ABUTMENT CONNECTION","internalauthor":"ALBERTI, ALICE","type":"Tesi di dottorato","year":"2021","abstract":"The project  focused on the application of the Morse-taper connection in implant dentistry, which was investigated both through laboratory and through clinical examination.    Mechanical laboratory study  Among the complications that can occur at dental implants, the fracture of any implant component is a relatively infrequent but clinically significant problem. Small diameter implants are at higher risk of such complication. The aim of this laboratory study was to compare the mechanical behavior of a 2.9 mm and a 3.3 mm diameter implant with a conical connection under standard static and dynamic conditions, following the ISO 14801:2017. Finite element analysis was performed to compare the stress distribution on the tested implant systems under a 300 N, 30° inclined force. Static tests were performed with a load cell of 2 kN; force was applied on the experimental samples at 30° with respect to the implant-abutment axis, with an arm of 5.5 mm. Fatigue tests were performed with decreasing loads, at 2 Hz frequency, until three specimens survived without any damage after 2 million cycles. The emergence profile of the abutment resulted the most stressed area in finite element analysis, with a maximum stress of 5829 MPa and 5480 MPa for 2.9 mm and 3.3 mm diameter implant complex respectively. The mean maximum load resulted 360 N for 2.9 mm diameter and 370 N for 3.3 mm diameter implants. The fatigue limit was recorded to be 220 N and 240 N respectively. Despite the more favorable results of 3.3 mm diameter implants, the difference between the tested implants could be considered clinically negligible. This is probably due to the conical design of the connection, which has been reported to present low stress values in the implant neck region, thus increasing the fracture resistance.     Microbiological in vitro test  Tissue inflammation around implants could be due to microbial colonization of the implant-abutment interface (IAI). The aim of the present in vitro study was to evaluate bacterial microleakage at the IAI in Morse-taper implant-abutment connections.   A bacterial suspension containing A. actinomycetemcomitans, F. nucleatum, and P. gingivalis was inoculated into the internal cavity of ten implant-abutment samples with a Morse-taper internal connection. The samples were assembled using a calibrated beater, totally immersed individually into culture tubes, and incubated at 37°C. Turbidity analysis, real-Time PCR, and horizontal electrophoresis were performed at 24, 48 and 72 h. Performed tests were negative for every specimen, except two of them because of contamination during the manipulation of the components.  Morse-taper implants rely on a frictional connection, which results in a very narrow implant-abutment space. This can account for the sealing capability of conical connections against bacterial microleakage. Although in literature no connection type was able to provide a complete bacterial seal at the IAI, Morse-taper connection implants showed less microleakage in comparison with other connection types. The present in vitro evaluation confirmed the sealing capability of Morse-taper connections in static conditions.    Clinical study  The third part of the project is a clinical observational prospective single-arm study on Morse-taper connection implants. The main objective of the study was be to evaluate the survival rate and the clinical and radiographic success of Morse taper connection implants, used for single-tooth and partial rehabilitations, and to assess the incidence of technical and biological complications. The following data were collected:  • implant-related factors: implant type, length, and diameter  • patient-related factors: age, gender, smoking status, systemic diseases, medications, history of periodontal disease, bruxism  • cause of the initial tooth loss: aplasia, unerupted tooth, traumatic injuries, caries, periapical periodontitis, marginal periodontitis  • site-related factors: implant position, bone quantity / quality following the Lekholm and Zarb classification (Lekholm and Zarb 1985)  • prosthesis-related factors: prosthetic restoration extension (single crown, partial fixed denture), prosthetic restoration material (all-ceramic, metal-ceramic, resin).  To evaluate the clinical and radiographic success of the implants used, the following parameters were recorded during follow-up visits, 3, 6, 18, 12 and 24 months after surgery:  • Full-mouth plaque score % (FMPS%)  • Full-mouth bleeding score % (FMBS%)  • probing depth (PD) on the mesial, distal, buccal and palatal/lingual surfaces of the implants. The higher PD and the mean PD, measured as the average of four measured values, was considered for each implant.  • Bleeding scores, assessed on the basis of this scale: 0) no bleeding; 1) bleeding on probing without redness and swallowing; 2) bleeding on probing with redness and swallowing; 3) spontaneous bleeding.  • Plaque scores, assessed on the basis of this scale: 0) no plaque accumulation; 1) plaque accumulation revealed using a probe; 2) moderate accumulation of visible plaque/calculus; 3) high accumulation of visible plaque/calculus.  • distance from the implant crown margin to the coronal border of the peri-implant mucosa (DIM)  • width of keratinized mucosa (KM)  • radiographic distance between the implant shoulder and the first crestal bone-implant contact (DIB), measured on intraoral peri-apical radiographs taken a Rinn alignment system  • radiographic presence of continuous peri-implant radiolucency, measured on intraoral peri-apical radiographs taken a Rinn alignment system   • Prosthesis function  • Technical complications: implant fracture; abutment fracture; screw fracture; veneer fracture or chipping; metal framework fracture; abutment loosening; screw loosening; loss of access hole restoration.  A total of 13 patients were treated with 41 implants. At the time of the last evaluation no implants failed, and all were successful. As for complications, no technical complication occurred. None of the implants showed signs of peri-implantitis, but a diagnosis of peri-implant mucositis was formulated in 3 patients, for a total of 8 implants. Bone resorption was consistent with the phisiological bone remodelling that occurs in the first year after loading. The regression analysis did not reveal any significant effect of any of the parameters on bone resorption, except for the history of periodontitis, which had a small but significant negative effect (p=0.47).","language":"eng","citation":"CLINICAL AND PRECLINICAL STUDIES OF IMPLANTS WITH A MORSE-TAPER IMPLANT-ABUTMENT CONNECTION / A. Alberti ; tutor: L. Francetti ; coordinatore: M. Del Fabbro. Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, 2021 Dec 14. 34. ciclo, Anno Accademico 2021. [10.13130/alberti-alice_phd2021-12-14].","filename":"phd_unimi_R12203.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/888934/1928722/phd_unimi_R12203.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/930979"},"title":"MIXED GRADED MODULES IN HOMOTOPY LIE THEORY","internalauthor":"PAVIA, EMANUELE","type":"Tesi di dottorato","year":"2022","abstract":"The main objective of this thesis is to study mixed graded complexes as a framework where to study derived deformation theory. In particular, I investigated the relationship between mixed graded complexes and derived Lie algebras. The main contributions of this thesis are the following. First, I provided the ∞-category of mixed graded complexes with a complete and non-degenerate t-structure, which exhibits such ∞-category as the left completion of the Beilinson t-structure on the filtered derived ∞-category. Secondly, I constructed a family of Chevalley-Eilenberg ∞-functors computing homology and cohomology of derived Lie algebras, endowing them of a richer structure of mixed graded complexes. Even if it is known that Chevalley-Eilenberg complexes are endowed with such structure, my construction is new and completely model-independent.","language":"eng","citation":"MIXED GRADED MODULES IN HOMOTOPY LIE THEORY / E. Pavia ; tutor: P. Stellari, M. Porta ; coordinatore: V. Mastropietro. Dipartimento di Matematica Federigo Enriques, 2022 Jul 18. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12222.pdf","fileformat":"Adobe PDF","fileversion":"preprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/930979/2042279/phd_unimi_R12222.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1053610"},"title":"OBJECTOS REAPARECIDOS EN EL IMAGINARIOTESTIMONIAL DE LA ÚLTIMA DICTATURA ARGENTINA (1976 - 1983).","internalauthor":"NAGINI, ALICE","type":"Tesi di dottorato","year":"2024","abstract":"The thesis contributes to scholarship on testimonial literature narrating the state violence perpetrated by the last Argentine dictatorship (1976-1983) by investigating the literary representations of the objects that circulated in political prisons and clandestine centers of detention, torture, and extermination. By looking at a corpus of testimonial texts where objects play a significant role at a rhetorical and narrative levels, the dissertation asks how material elements influenced the daily experience of the abductees, thereby affecting collective memory and imagination. The theoretical framework developed in the Introduction draws from the “material turn” in humanities and “object-oriented ontology” to integrate narratological and semiotic approaches with a multidisciplinary perspective on objects. Hence, the textual analysis focuses on classifying and interpreting the objects appearing in these literary testimonies, exploring their narrative and symbolic functions and the ways in which they contribute to shaping the narratives of these traumatic events.  The thesis is structured into three chapters, each identifying a different category of objects. The first two chapters look at the macro-category of “catastrophic objects” which includes instruments of torture used by the perpetrators, such as the picana and blindfolds. The third chapter discusses “objects against incommunication”, i.e., items aimed at restoring communicative and emotional connections under total isolation. The thesis’ conclusions look at how these categories of objects contribute to shaping the archetypal structures of the collective imagination.","language":"spa","citation":"OBJECTOS REAPARECIDOS EN EL IMAGINARIO TESTIMONIAL DE LA ÚLTIMA DICTATURA ARGENTINA (1976 - 1983) / A. Nagini ; tutor: E. Perassi, T. Basile ; coordinatrice: M. V. Calvi. Università degli Studi di Milano, 2024. 35. ciclo","filename":"phd_unimi_R12528.pdf","fileformat":"Adobe PDF","fileaccess":"Closed"}
,{"handle":{"url":"https://hdl.handle.net/2434/1027474"},"title":"FROM EAST TO NORTH-WEST AFRICA: MAGNETOCHRONOLOGY OF THE OLDEST AFRICAN ACHEULEAN SITES","internalauthor":"PERINI, SERENA","type":"Tesi di dottorato","year":"2024","abstract":"In this thesis are presented the chronologies, obtained through magnetostratigraphy, of two key sites of archaeological and paleoanthropological interest, Melka Kunture (Upper Awas Valley, Ethiopia) and Thomas Quarry I (Casablanca, Morocco). These sites of Pleistocene age document the emergence and developments of the Acheulean lithic technology thought to be a major turning point in human evolution, representing over the last two decades a highly debated issue in the study of early technologies.  In East Africa at Melka Kunture, located in the Ethiopian highlands, a time-diagnostic sequence of normal and reverse polarity magnetozones was obtained, representing a magnetochronologic record extending from the Brunhes Chron (<0.773 Ma) to the top of Reunion Subchron (2.116 Ma). The new data were then integrated with 40Ar/39Ar dating from the literature to establish age models of deposition that were used to estimate the mean ages of the main archeological levels contained. In North-West Africa at Thomas Quarry I, located in the outskirts of Casablanca (Morocco), magnetostratigraphy coupled with geochemistry provided a chronostratigraphic framework extending from the Brunhes Chron (<0.773 Ma) to the Matuyama pre-Cobb Mountain (>1.210 Ma) subchron.  Research conducted in the last decade revealed that the Acheulean emergence in East Africa should have occurred around 1.7 Ma. This datum is testified by a few key archeological sites such as Kokiselei 4 (1.76 Ma; West Turkana, Kenya), KGA6-A1 (~1.75 Ma; Konso-Gardula, Ethiopia), FLK West (~1.7-1.65 Ma; Olduvai Gorge, Tanzania). The new magnetostratigraphic results obtained from Melka Kunture archeological area of Ethiopia pushed back the first occurrence of the Acheulean at 1.95 (-0.025; +0.1) Ma, some 200 ka before what previously known, and it also provided evidence of the earliest high-altitude peopling of East Africa at 2.02 (-0.095; +0.096) Ma.  The peculiarity of the Acheulean as a cultural phenomenon lies in the first appearance of Large Cutting Tools (LCTs) representing the most evident novelty relative to the pre-existing Oldowan technology. However, the timing and modes of the technical innovation(s) leading to the Acheulean, their relationship with the pre-existing Oldowan technology and their dispersion across the African continent are still unclear. The age models established for Melka Kunture archeological area allowed also to date other more recent Acheulean sites documenting the continuity of this technology trough time, such as GAR XIIJ at 1.13 (-0.06; +0.05) Ma, GOM II OAM, yielding two fragmentary Homo heidelbergensis fossils (GOM II1-576 and GOM II1-6169), dated to 1.03±0.04 Ma and GOM II “Butchery site” at 0.75 (-0.1; +0.02) Ma. On the other hand, for the two sites GOM Iγ and GOM Iδ only minimum ages were proposed, respectively of ~1.41 and ~1.51 Ma, for lack of chronological constraints in their stratigraphic interval.  Beginning from the new results from Melka Kunture, a chronostratigraphic record was assembled through a critical review of data from the literature of key archaeological and paleoanthropological sites from East Africa in order to infer about the dynamics of origin(s) and dispersal(s) of the Acheulean across the African continent, as well as the potential toolmaker(s) of this innovation. The reconstructed record spans between 2.0 and 1.6 Ma, across the Olduvai normal polarity subchron (1.925-1.770 Ma), which represents a fundamental magnetostratigraphic constraint in this field of research. The new data provided by this thesis suggest that in this time-interval, not one but several Acheulean techno-economic innovations appeared in the East African record emerging in a non-linear evolutionary path. This analysis suggests as novel scenario that there were several early Acheuleans that emerged in East Africa at different times, in different places and with different technical peculiarities derived from a common Oldowan background.  As for Thomas Quarry I (Casablanca, Morocco), the age of ~1.3 Ma obtained for the archeological site ThI-L expanded our knowledge on the Acheulean emergence in Atlantic Morocco. This new age estimate based on magnetostratigraphy coupled to geochemistry makes the Acheulean of ThI-L the earliest of North-West Africa. The dynamics of dispersal and spreading of the Acheulean from its cradle in East Africa to North Africa are not yet clear because of the inherently discontinuous nature of the stratigraphic and archeological records. The wide gap between the Oldowan in Algeria, currently dated ~1.77 Ma, and the early Acheulean of Morocco, dated in this thesis at ~1.3 Ma, does not allow to infer about the origin of the early Acheulean of ThI-L but only further discoveries will clarify the emergence of the North African Acheulean in a whole pan-African perspective.  Furthermore, the new data presented in this thesis allowed to constrain in time the site ThI-GH of Thomas Quarry I, located in a higher stratigraphic unit with respect to ThI-L, yielding Homo fossils associated to faunal remains and Acheulean tools. This site was constrained with magnetostratigraphy to the Brunhes/Matuyama boundary at 0.773±0.004 ka. The human remains from ThI-GH, currently under investigation, will shed light on the critical period of divergence between the Middle Pleistocene archaic lineages of Western Eurasia and Africa, one of which gave rise to the evolutionary line of Homo sapiens.","language":"eng","citation":"FROM EAST TO NORTH-WEST AFRICA: MAGNETOCHRONOLOGY OF THE OLDEST AFRICAN ACHEULEAN SITES / S. Perini ; tutor: G. Muttoni ; co-tutor: R. Gallotti ; coordinatore: M. I. Spalla. - Dipartimento di Scienze della Terra 'Ardito Desio'. Dipartimento di Scienze della Terra Ardito Desio, 2024 Feb 28. 36. ciclo","filename":"phd_unimi_R13077.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1027474/2669097/phd_unimi_R13077.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/956171"},"title":"DISSECTING THE CLINICAL AND BIOLOGICAL RELEVANCE OF DIS3 GENE IN MULTIPLE MYELOMA","internalauthor":"FAVASULI, VANESSA KATIA","type":"Tesi di dottorato","year":"2023","abstract":"Multiple myeloma (MM) is a B cell malignancy characterized by abnormal proliferation of plasma cells (PCs) within the bone marrow. MM is characterized by a wide clinical spectrum ranging from the presumed asymptomatic pre-malignant condition called monoclonal gammopathy of undetermined significance (MGUS), to extra-medullary plasma cell leukemia (PCL). Notably, MM is characterized by a deep genomic instability involving ploidy, structural rearrangements and a high range of mutations involving both putative oncogenes and tumor suppressor genes that may explain its clinical heterogeneity. Half of MM tumors are hyperdiploid, associated with non-random trisomies of odd chromosomes and low prevalence of chromosomal translocations involving the immunoglobulin heavy chain locus (IGH) on chromosome 14q32, whereas the remaining tumors are non hyperdiploid and characterized by the prevalence of IGH translocations affecting several oncogenic loci. Such a large heterogeneous genomic pattern may represent the basis for the abnormal transcriptional expression profile associated with MM.  Despite the remarkable improvements in treatment and patient care, MM remains an incurable disease.   Over the past years, our and other research groups have provided valuable information on coding and non-coding transcripts aberrantly expressed in MM by expression profiling analyses based on microarray or RNAseq approaches. These studies have been of high relevance to better understand the biology of the disease, to identify of novel prognostic and predictive biomarkers and putative therapeutic targets.   DIS3 (chr.13q22.1 localization) is a conserved exoribonuclease and catalytic subunit of the exosome, a protein complex involved in the 3' to 5' degradation and processing of different species of RNA. Recently, aberrant expression of DIS3 has been found to be implicated in a range of different cancers. Notably, DIS3 is recurrently mutated in multiple myeloma (MM) patients. Most of the identified mutations are predominantly missense variants localized in the ribonucleolytic domain (RNB), mainly abolishing the exoribonucleolytic activity and are often accompanied by loss of heterozygosity (LOH) or biallelic inactivation due to 13q14 deletion. Furthermore, it has been reported in the literature that the inactivity or incorrect activity of DIS3 is also associated with the regulation of non-coding transcripts, as well as long non-coding RNA (lncRNA).  Long non-coding RNAs (lncRNAs) are a large class of non-coding RNAs involved in many physiological cellular and genomic processes as well as in carcinogenesis, cancer metastasis and invasion. The knowledge of the role of lncRNAs in MM is progressively expanding. Our group provided recent evidence based on microarray and RNA seq analyses of deregulated patterns of lncRNA expression in MM showing that they may be specifically associated with distinct molecular types of the malignancy.   In a paper published during the first years of the project, it has been shown that MM patients carrying Dis3 gene mutations are associated with a distinct transcriptional signature characterized by many non-coding transcripts, mainly lncRNAs.  Firstly, our interest focused on investigating the deregulation of transcripts (including coding and non-coding portion) associated with DIS3 mutations in MM by analyzing RNA-Seq transcriptional profiles in a proprietary publicly available dataset and CoMMpass study, including approximately 1000 MM patients at diagnosis. We demonstrated that DIS3 mutations clinical relevance strictly depended on del(13q) co-occurrence. We observed that the bi-allelic DIS3 lesions significantly affected PFS (Progression Free Survival) and overall survival (OS). As expected, DIS3 mutations affect MM transcriptome involving cellular processes and signaling pathways associated with RNA metabolism. We found the downregulation of gene sets related to oxidative phosphorylation, RNA or amino acid metabolism, translation, and mitotic spindle checkpoint.   Overall, our comprehensive assessment of the clinical and transcriptional consequences of DIS3 mutations or its deletion in MM strongly indicates that they may play an important role in the mechanisms of transformation and progression of MM.   For these reasons, during the last year of my PhD program I focalized the efforts on the functional investigation of DIS3 putative role as potential therapeutic target in MM. To this aim I took advantage of the experimental silencing strategy based on the use of LNA-gapmeR technology and the gymnotic delivery of the in-house designed DIS3-specific antisense oligonucleotide in multiple myeloma cell lines (HMCLs).  The results obtained show that DIS3 silencing decreases cell growth, increases the percentage of apoptosis, reducing the oncogenic potential of MM cell lines. Indeed, interference with DIS3 expression reveals an important perturbation of the cell cycle distribution accompanied by mitotic defects.   I investigated the possibility of translating these results in combination with an available drug currently in clinical trial, such as ARRY-520, an inhibitor that interferes with the correct organization of microtubules. I found that the effect of DIS3 KD sensitizes MM cell lines in combination with ARRY-520, leading to a mitotic catastrophe.  These results suggest that DIS3 could be an important target for the future therapeutic approach in MM disease.","language":"eng","citation":"DISSECTING THE CLINICAL AND BIOLOGICAL RELEVANCE OF DIS3 GENE IN MULTIPLE MYELOMA / V.k. Favasuli ; tutor: A. Neri ; co-tutor: R. Chiaramonte ; director: N. Landsberger. Dipartimento di Oncologia ed Emato-Oncologia, 2023 Jan 31. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12663.pdf","fileformat":"Adobe PDF","fileversion":"preprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/956171/2147832/phd_unimi_R12663.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1040539"},"title":"SURVIVING UNDER PRESSURE: TRANSLATIONAL REWIRING IN RESPONSE TO MECHANICAL STIMULI","internalauthor":"FRAGALE, GIUSEPPE","type":"Tesi di dottorato","year":"2024","abstract":"An outcome of high mechanical stress in the context of hyperproliferation and increased cellular tension is the reduction in cell volume, that holds the potential to impact cellular density. Both cell size and density homeostasis are integral features of healthy tissues, intricately linked to the regulation of the cell cycle and biosynthesis processes. This connection suggested that achieving density homeostasis could involve a coupling mechanism between the regulation of macromolecular production and osmolytes. Considering the importance of density and protein homeostasis, we decided to explore whether similar mechanisms may play a role in the responses of tumor cells upon mechanical stress.  To shed light on the mechanisms, we have employed several approaches to study the acute alterations in cell size induced by mechanical stress. We used osmotic shocks and compressive stresses, as well as genetic encoded microparticle (GEMs) tracking to infer cytoplasmic density. The combination of these tools with measures of translation rate, polysome profiling, ribogenesis, and protein degradation assays uncovered interesting evidences demonstrating a mechanism that couples the regulation of macromolecular production with rheological adaptation in colorectal cancer cells HCT116. In particular, we have found that the early response to mechanical compression is independent of the mechanistic target of rapamycin complex 1 (mTORC1), while adaptation requires mTORC1 inactivation and subsequent increase of autophagy. Our data provided clues suggesting alternative signaling and biophysical pathways involved in the regulation of protein homeostasis in response to mechanical stress, which provide valuable insights into the pathogenesis of cancer and may represent promising targets for therapeutic intervention.","language":"eng","citation":"SURVIVING UNDER PRESSURE: TRANSLATIONAL REWIRING IN RESPONSE TO MECHANICAL STIMULI / G. Fragale ; tutor: K. Havas ; co-tutor: M. Foiani. Dipartimento di Oncologia ed Emato-Oncologia, 2024 Apr 11. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12683.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1040539/2386490/phd_unimi_R12683.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1205019"},"title":"THE ROLE OF THE CLINICIAN¿S SUBJECTIVE EXPERIENCE IN THE INTERACTION WITH THE PATIENT: A PILOT STUDY ON NEUROBIOLOGICAL CORRELATES","internalauthor":"VIDETTA, GIOVANNI","type":"Tesi di dottorato","year":"2026","abstract":"Background. The Assessment of Clinician’s Subjective Experience (ACSE) is a  questionnaire designed to assess the clinician’s subjective experience during patient interactions. Although previous studies have supported its reliability and clinical validity, its neurobiological underpinnings remain unexplored. Methods. Two clinicians and ten patients were recruited in a three-phase study: (1) a first clinical interview, (2) ACSE administration, and (3) listening to the first clinical interview recording. Electroencephalography (EEG) data were recorded from clinicians during both the first clinical interview and the ACSE administration. EEG data were analyzed using relative power spectral density, node strength, and global efficiency derived from imaginary coherence. Results. Clinicians were psychiatrists, while patients were diagnosed with depressive and anxiety disorders. ACSE scores were highest for Difficulty in Attunement and Engagement dimensions, aligning with prior findings. EEG analyses revealed distinct frequency- and region-specific patterns associated with each ACSE dimension: the dimension of Disconfirmation elicited the most heterogeneous neural responses across all EEG metrics and both clinicians. Connectivity analyses highlighted divergent network profiles: the female clinician showed higher variability in global efficiency, while the male clinician exhibited more stable patterns. Finally, correlational analyses identified specific associations between ACSE dimensions and EEG features. Conclusion. These preliminary findings provide the first neurobiological evidence linking the clinician’s subjective experience with measurable brain activity. They suggest that subjective dimensions in clinical encounters may be partially encoded in distinct EEG patterns, laying the groundwork for future research on the neurobiology of intersubjectivity processes.","language":"eng","citation":"THE ROLE OF THE CLINICIAN'S SUBJECTIVE EXPERIENCE IN THE INTERACTION WITH THE PATIENT: A PILOT STUDY ON NEUROBIOLOGICAL CORRELATES / G. Videtta ; tutor: P. Brambilla ;  co-tutor: A. Picardi ; coordinatore: M. S. Clerici. - Università degli Studi di Milano. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2026 Jan 15. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14017.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1205019/3212445/phd_unimi_R14017.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1025908"},"title":"SYNTHESIS OF PHARMACOLOGICALLY ACTIVE MOLECULES THROUGH BIOCATALYTIC APPROACHES: STUDY OF THEIR STEREOCHEMISTRY AND POLYMORPHISM BY MEANS OF SPECTROSCOPIC AND CRYSTALLOGRAPHIC METHODS.","internalauthor":"CICERI, SAMUELE","type":"Tesi di dottorato","year":"2024","abstract":"Elagolix is the first non-peptide orally active gonadotropin-releasing hormone (GnRH) antagonist, approved for the treatment of sex hormone-dependent diseases, such as endometriosis and uterine fibroids. This PhD project was focused on this drug, studying its conformational features, and improving the synthetic procedures found in the literature. Firstly, theoretical experiments revealed that this drug exists in solution as a mixture of two atropisomers, which belong to class 2 due to an estimated interconversion rotational barrier of 22.3 kcal/mol. This finding could help to face the great challenges in the drug discovery and development of this class of compounds, caused by the conformational instability. In addition, the deepen spectroscopic investigations performed on elagolix and its intermediates allowed for the complete assignment and interpretation of the 1H, 13C, and 15N NMR signals, filling the existing gap in the literature.     Chart 1. The two atropisomeric forms of elagolix sodium salt.  Because the individual atropisomers of a given molecule may differ considerably in their pharmacological properties, we designed and synthesized a new series of elagolix analogues, differently substituted at the 4- or 6-position of the uracil moiety, with the aim of studying the impact of these modifications on atropisomeric properties. Three of the newly obtained compounds have a higher rotational barrier than elagolix, allowing the separation and characterization of their single atropisomers by means of different analytical techniques.   Moreover, since our study on the already disclosed 21-bromoderivative of elagolix resulted in the identification of two thermally stable atropisomers, this compound was selected for the development of a new enzymatic approach for the atropisomers separation.   For the new compounds and their single atropisomers, biological tests are currently underway on HEK-293 cells expressing the human GnRH receptor (hGnRH1R) to verify the good receptor affinity predicted by the molecular dynamics simulations.","language":"eng","citation":"SYNTHESIS OF PHARMACOLOGICALLY ACTIVE MOLECULES THROUGH BIOCATALYTIC APPROACHES: STUDY OF THEIR STEREOCHEMISTRY AND POLYMORPHISM BY MEANS OF SPECTROSCOPIC AND CRYSTALLOGRAPHIC METHODS / S. Ciceri ; tutor: F. Meneghetti, P. Grisenti ; coordinatore: G. Vistoli. - University of Milan. Dipartimento di Scienze Farmaceutiche, 2024 Feb 13. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R12966_01.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1025908/2352216/phd_unimi_R12966_01.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1198762"},"title":"LINKING TRANSCRIPTIONAL AND MORPHOLOGICAL HETEROGENEITY TO THERAPEUTIC VULNERABILITIES IN GLIOBLASTOMA","internalauthor":"IANNUZZI, RAFFAELE MARIA","type":"Tesi di dottorato","year":"2025","abstract":"This thesis is the result of my doctoral studies conducted within the Iorio  Laboratory at Human Technopole and whose overarching goal has been to  design and use data-driven approaches for the integration of molecular and  functional-genetics data from preclinical models with the aim of prioritizing  subtype-specific therapeutics vulnerabilities in Glioblastoma (GBM).  Particularly, in an initial phase of my activities, I have designed and  implemented computational methods for reliability and reproducibility  assessment of “essentiality profiles” from genome-wide recessive pooled  CRISPR-Cas9 screens. Furthermore I have contributed methods and analyses  for benchmarking state-of-the-art computational methods aiming at  preprocessing CRISPR screening data, and correcting technology-specific  biases, such as the tendency of the CRISR-Cas9 system to elicit a  gene-independent detrimental effect on cellular survival when targeting  genomic copy-number amplified regions (CN bias) and spurious effect due to  Cas9-mediated whole chromosome arm truncations (proximity bias).  Subsequently, I have focused on the integration of transcriptomics and  CRISPR-based genome-editing data for prioritizing potential therapeutic  targets that regulate Glioblastoma stem cells (GSCs) morphology and  survival, in collaboration with the Kalebic research group. A key result of this  collaboration has been the identification of adducin-γ (ADD3), a previously  known  morpho-regulator  of human neural progenitor cells, as a  context-specific essential gene in GBM. I further investigated ADD3  expression at the single-cell level in GBM primary tumours, where I found it  to be associated with an oligodendrocyte-progenitorlike (OPC-like) signature,  suggesting a specific role of ADD3 in this transcriptional subtype. Adopting  this specific case as a proof-of-concept, I have then designed an analytical  framework that integrates pharmacogenomics and CRISPR genome-editing  with single cell RNA sequencing (scRNA-seq) data, leveraging the Cancer  13Dependency Map (DEPMAP) resource. This framework aims to prioritize  GBM subtypes’ vulnerabilities upon a broad spectrum of genetics and drugs  perturbation, aiding in the identification of new potential targets and  therapeutic compounds that may be most effective in reducing viability of  specific subtypes.","language":"eng","citation":"LINKING TRANSCRIPTIONAL AND MORPHOLOGICAL HETEROGENEITY TO THERAPEUTIC VULNERABILITIES IN GLIOBLASTOMA / R.m. Iannuzzi ; supervisor: F. Iorio, N. Kalebic, L. Calviello, E. Petsalaki. Dipartimento di Scienze della Salute, 2025 Dec 16. 37. ciclo, Anno Accademico 2025.","filename":"phd_unimi_R13484_2.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1198762/3191918/phd_unimi_R13484_2.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/932346"},"title":"LA DOCUMENTAZIONE INTERDITTIVA ANTIMAFIA:ORDINAMENTO SINGOLARE E CORTOCIRCUITI DELLA LEGALITÀ","internalauthor":"FILIERI, LAVINIA","type":"Tesi di dottorato","year":"2022","abstract":"\"The anti-mafia interdiction documnetation: singular order and short-circuits of legality   The research proposes to address the relationship between administrative tools for combating organized crime and procedural guarantees of their recipients, looking at the potential friction with the supranational system.   Precisely, the reference goes to the \"\"interdiction antimafia documentation\"\", in the form both of communication and information.   Having analyzed its legal nature, the first research question regards the instrument's compatibility pursuant constitutional, Euro-Unitarian and conventional principles, with particular reference to the principle of legality, in its integrated and multi-level status.  Closely related to the former, it is the issue concerning the possibility to extend the judicial interpretation on the \"\"substantially criminal\"\" sanctions or to reach a different solution.   In this way, the essay leverages the link that binds legal instrument of protection with powers of administrative courts.   In order to achieve the expected scientific results, this research follows a path between thematic areas of study placed in logical-argumentative succession.   So, starting from a general framing of the administrative tools in countering organized crime, the thesis ends studying the judicial review limits on technical discretion in anti-mafia interdiction orders.\"","language":"ita","citation":"LA DOCUMENTAZIONE INTERDITTIVA ANTIMAFIA:ORDINAMENTO SINGOLARE E CORTOCIRCUITI DELLA LEGALITÀ / L. Filieri ; tutor: P. Provenzano ; coordinatore: F. Basile. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2022 Jul 11. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12333.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/932346/2046681/phd_unimi_R12333.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/945270"},"title":"VALUTAZIONE NUTRIZIONALE DI DIETE E ADDITIVI NELL'ALIMENTAZIONE DEL CANE","internalauthor":"ROVERE, NICOLETTA","type":"Tesi di dottorato","year":"2022","abstract":"In the last few years, there has been an increased interest in pets’ nutrition and feeding. In term of research both basic and applied nutrition has expanded the knowledge of canine nutrition, it is now known that a well-balanced diet must include not only macronutrients but also an appropriate amount of minerals, vitamins, certain essential amino acids (from proteins), and specific essential fatty acids (from fats). These components are needed to build and maintain tissue and carry out biological reactions, and the necessary amounts vary somewhat with the dog's stage of life (puppy, adult, pregnancy, senior), activities (sport, game, ect.), and physiological state (pregnancy and lactation). Above this in the recent past, there have been an increase in different types of diets present in the market that are characterized by different composition and target market segments (premium, dietetic, ect.). In light of this, in the present thesis three main topics have been addressed:   i) the nutritional characteristics and in vitro digestibility of different dogs’ diets available on the market (premium, super premium, with particular nutritional purposes, wet food and BARF);   ii) the effects of yeast supplementation in pregnant and lactating bitches and their effects in their respective puppies;   iii) the effects of yeast supplementation in adult dogs.  In particular, the thesis investigated the composition the in vitro digestibility of different dogs’ diets, and the effects of two yeasts, Saccharomices cerevisiae and S.cerevisiae var boulardii. In this latter case the studies investigated the effects of yeast on: growth performance (weight, body condition score and feed intake), fecal characteristics (fecal score, dry matter, total apparent digestibility and presence of pathogens), local immune response (IgA), e intestinal microbiota and fecal odor profile (by electronic nose). Thus, it can be suggested that different market names/classifications like premium, super premium, and BARF diets, do not always support big nutritional differences. All diets are in line with dogs ‘main recommendation. When yeast supplementation is consider the effects observed in the present studies seem to be related to an optimization of feed preparation/diet according to the ideal national profile, and for this reason not always so visible in term of recorded figures. A key aspect in defying the response however is also the exposure time that at least in one of the studies, was probably limited. For this reasons large-scale and long-term studies that can generate high-quality nutritional evidence on the relationships between diets and supplements are required.","language":"ita","citation":"VALUTAZIONE NUTRIZIONALE DI DIETE E ADDITIVI NELL'ALIMENTAZIONE DEL CANE / N. Rovere ; tutor: L. Pinotti ; coordinatore: L. Pinotti. Dipartimento di Medicina Veterinaria e Scienze Animali, 2022 Dec 05. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12541.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/945270/2094843/phd_unimi_R12541.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1164355"},"title":"EXTENDED-SPECTRUM Β-LACTAMASE-, AMPC- AND CARBAPENEMASE-PRODUCING BACTERIA IN DOGS AND CATS","internalauthor":"FACCHIN, ALESSIA","type":"Tesi di dottorato","year":"2025","abstract":"Antimicrobial resistance (AMR) is a critical global health challenge, compromising the efficacy of antibiotics and threatening both human and animal health. The rise of multidrug-resistant (MDR) bacteria compromises the efficacy of treatments for infections in humans and animals, leading to prolonged illnesses, increased mortality, and substantial economic burdens. Companion animals are increasingly recognized as reservoirs and potential sources of antimicrobial-resistant pathogens, contributing to the dissemination of resistance genes across ecosystems and posing a zoonotic risk. Understanding the prevalence, genetic mechanisms, and risk factors associated with AMR in dogs and cats is essential for the development of effective control strategies within a One Health approach.  This thesis primarily focused on fecal shedding of extended-spectrum β-lactamase (ESBL)-, AmpC-, and carbapenemase-producing Escherichia coli, considered a key indicator of antimicrobial resistance in bacterial populations. Fecal samples from dogs and cats, including both pets and stray animals were investigated for the presence, genetic determinants, and associated risk factors of these bacteria. An additional investigation focused on dogs with urinary tract infections and analyzed ESBL-, AmpC-, and carbapenemase-producing E. coli as well as Klebsiella pneumoniae, a clinically significant pathogen often linked to resistance to the highest-priority critically important antimicrobials, along with other AMR mechanisms such as biofilm formation in these bacteria isolated from urinary samples.  This thesis is based on four studies. The first study focused on cats, which have been studied less frequently than dogs, and investigated the presence of ESBL/AmpC-producing E. coli in both pet and stray cats. Fecal samples from 97 cats revealed that six (6.2%) carried these resistant bacteria. Genetic analysis detected blaCTX-M in all isolates, along with blaTEM (83.3%), blaSHV (16.7%), and chromosomal AmpC overexpression (1%). All isolates were multi-drug resistant (MDR). Statistical analysis demonstrated significant associations between ESBL/AmpC carriage and unhealthy status or previous antibiotic therapy, underscoring the potential role of cats as reservoirs for resistant bacteria.  The second study focused exclusively on stray cats and included the study of carbapenemase-producing E. coli, due to their importance according to the One Health concept. Among the 94 stray cats analyzed, 18 (19.1%) tested positive for ESBL-/AmpC-/carbapenemase-producing E. coli. Notably, besides ESBL-/AmpC-producing E. coli, this study showed the presence of carbapenemase genes blaNDM and blaOXA-48 in seven (7.4%) samples. Among the isolates analyzed, 17 (94.4%) were identified as MDR. Hospitalization, prior antibiotic treatment, and unhealthy status were identified as significant risk factors. Moreover, ESBL-producing E. coli were detected in healthy stray cats which had not been hospitalized and had likely not been previously treated. Overall results highlight the complex epidemiology of AMR in stray animals suggesting the need for further investigation on the source of infection also focusing on environmental contamination.  Carbapenemase-producing E. coli fecal carriage was further investigated in the third study that focused on dogs, in which carbapenemase-producing bacteria were less frequently studied. The fecal carriage of ESBL-/AmpC-/carbapenemase-producing E. coli was detected in 14/100 (14%) dogs, with 92.9% of isolates exhibiting MDR. Genetic analysis identified blaCTX-M in ESBL-producing isolates, blaCMY-2 in AmpC-producing isolates, and blaOXA-48 in carbapenemase-producing E. coli. Antibiotic treatment was confirmed as a significant risk factor for fecal shedding of these bacteria, emphasizing the need for antimicrobial stewardship in veterinary medicine.  The fourth study investigated AMR bacteria in dogs with bacterial urinary tract infections (UTIs) focusing on the detection of ESBL-/AmpC-/carbapenemase-producing E. coli and K. pneumoniae, including evaluation of biofilm production of isolates, a factor that contributes to bacterial persistence and resistance. Among 133 urine samples analyzed, 53 (39.8%) were culture-positive. E. coli was the predominant pathogen (28; 21.1%) and six (4.5%) samples tested positive for K. pneumoniae. ESBL production, driven by blaCTX-M group 1, was detected in 4/34 (11.8%) E. coli/K. pneumoniae isolates and was significantly associated with K. pneumoniae. Furthermore, 11 (32.4%) isolates exhibited MDR. Biofilm formation was observed in 23 (67.6%) isolates, with moderate biofilm production significantly associated with K. pneumoniae. These findings emphasize the need for in vitro susceptibility testing and careful antibiotic use in treating canine UTIs.  Overall, these studies underline the critical role of companion animals in the spread of antimicrobial-resistant bacteria. The detection of MDR and carbapenemase-producing E. coli is of concern and reinforces the need for enhanced surveillance programs and antimicrobial stewardship within a One Health framework, evaluating the risk of transmission to humans due to the close interaction of pets with their owners. Addressing AMR in companion animals is essential to safeguard both veterinary and public health, reinforcing the need for a collaborative One Health approach.","language":"eng","citation":"EXTENDED-SPECTRUM Β-LACTAMASE-, AMPC- AND CARBAPENEMASE-PRODUCING BACTERIA IN DOGS AND CATS / A. Facchin ; PhD supervisor: S. Lauzi ;  PhD coordinator: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2025 May 26. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13577.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open from 14-NOV-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1023670"},"title":"EXPLORING AND EXPLOITING THE CANNABIS VIROME FOR ADVANCING BIOTECHNOLOGICAL TOOLS IN HEMP RESEARCH","internalauthor":"MIOTTI, NICCOLO'","type":"Tesi di dottorato","year":"2024","abstract":"Cannabis sativa cultivation is experiencing a period of renewed interest due to the new opportunities for its use in different sectors including food, techno- industrial, construction, pharmaceutical and medical, cosmetics, and textiles. Moreover, its properties as a carbon sequestrator and soil improver make it suitable for sustainable agriculture and climate change mitigation strategies. The increase in cannabis cultivation is generating conditions for the spread of new pathogens. While cannabis fungal and bacterial diseases are better known and characterized, viral infections have historically been less investigated. Many viral infection reports on cannabis have recently been released, highlighting the increasing threat and spread of known and unknown viruses. However, the available information on these pathogens is still incomplete and fragmentary, and it is therefore useful to organize it into a single structured document to provide guidance to growers, breeders, and academic researchers. This review aims to present the historical excursus of cannabis virology, from the pioneering descriptions of virus-like symptoms in the 1940s/50s to the most recent high- throughput sequencing reports. Each of these viruses detected in cannabis will be categorized with an increasing degree of threat according to its potential risk to the crop. Lastly, the development of viral vectors for functional genetics studies will be described, revealing how cannabis virology is evolving not only for the characterization of its virome but also for the development of biotechnological tools for the genetic improvement of this crop.","language":"eng","citation":"EXPLORING AND EXPLOITING THE CANNABIS VIROME FOR ADVANCING BIOTECHNOLOGICAL TOOLS IN HEMP RESEARCH / N. Miotti ; tutor: P. Casati; co-tutor: C. Ratti. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2024 Jan 22. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12859.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1023670/2344664/phd_unimi_R12859.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1196935"},"title":"ASSOCIATION OF INCIDENT DIALYSIS MODALITY WITH PATIENT SURVIVAL: A SYSTEMATIC REVIEW AND META-ANALYSIS","internalauthor":"NARDELLI, LUCA","type":"Tesi di dottorato","year":"2025","abstract":"Background: Although the choice of dialysis technique is based on several factors, patient survival is undoubtedly one of the most relevant. In a context where randomization to either peritoneal dialysis (PD) or hemodialysis (HD) proved to be extremely challenging, previous meta-analyses were greatly limited due to the inclusion of historical studies.   Methods: We performed a systematic review by searching multiple databases up to April 22nd, 2022. The primary outcome was the association between dialysis modality (PD vs HD) and mortality assessed via hazard ratios (HR). Subgroup analyses were conducted to explore potential sources of heterogeneity, including sex, age, diabetes, dialysis vintage, geographical location, HD access, and study cohort inclusion period.  Results: Database search yielded 5317 citations, from which, 27 observational studies met the eligibility criteria, including 1 033 362 incident dialysis patients. The pooled mortality HR for PD versus HD was 1.01 (95% CI 0.93–1.10). Heterogeneity was substantial (I2 = 94%) and was largely explained by different baseline features of the included populations. A statistically significant subgroup effect was demonstrated for age (>65 vs.<65 years; p=0.01), geographical location of the studies (Oceania vs. Europe vs. Asia vs. North America; p<0.01), and HD vascular access (central venous catheter vs. arteriovenous fistula; p<0.01, only one study included).  Conclusions: This meta-analysis suggests that overall PD and incentre HD likely carry equivalent survival benefits. However, differences were detected among subgroups based on age, geographic location, HD access type, but not on sex, diabetes status, dialysis vintage and study cohort inclusion period.","language":"eng","citation":"ASSOCIATION OF INCIDENT DIALYSIS MODALITY WITH PATIENT SURVIVAL: A SYSTEMATIC REVIEW AND META-ANALYSIS / L. Nardelli ; tutor: G. Castellano ; doctoral program chair:  M. Del Fabbro. Dipartimento di Scienze Cliniche e di Comunità, 2025 Dec 19. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13904.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1196935/3186441/phd_unimi_R13904.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1204118"},"title":"THE ROLE OF CD4+ T MEMORY SUBSETS IN HIV INFECTION: IMMUNE RESPONSE IN PEOPLE WITH HIV AND LATENCY ESTABLISHMENT","internalauthor":"SCAGLIONI, SUSANNA","type":"Tesi di dottorato","year":"2025","abstract":"T lymphocytes comprise diverse subsets which differ in phenotype, function and maturation level. Among them, T memory stem cells (TSCM) represent the more developmentally immature subpopulation of the memory pool, endowed with longevity, self-renewing capacity and multipotency, other than recall   capabilities. These features make them pivotal for maintaining durable immune memory and controlling persistent infections. In the context of vaccination, the induction of vaccine-specific TSCM is a key determinant of long-term protection. In the context of human immunodeficiency virus (HIV), CD4⁺ TSCM, serve as target of infection as well as reservoir, sustaining long-lived, self-renewing pools of latently infected cells despite antiretroviral therapy (ART). Thus, TSCM are central to both protective immunity and the persistence of HIV reservoir. In people with HIV (PWHIV), vaccine-induced immune responses are generally attenuated as a consequence of residual inflammation and immune dysfunction that might persist under ART treatment. HIV infection profoundly disrupts the homeostasis of T cell subsets, leading to a marked depletion of   developmentally immature T lymphocytes. However, the effects of this chronic immune dysregulation on TSCM remain poorly defined, thus elucidating the functional characteristics of TSCM in PWHIV is of particular importance. By taking advantage of the longitudinal sampling during the COVID-19 vaccination campaign, we examined the humoral and cellular immune response of PWHIV, with a focus on the T memory phenotype and vaccine-induced TSCM. To this purpose, we enrolled 22 PWHIV and a control group of 14 healthy donors (HDs) who received mRNA-1273 vaccine. PWHIV   were stratified according to CD4+ T cell count and CD4/CD8 ratio, two markers of immune reconstitution after ART initiation. The humoral and cellular immune responses to the vaccine were studied using pseudoviruses-based neutralization assay, Activation-Induced Markers (AIM) assay and   intracellular Cytokine Staining (ICS). We observed a decrease in SARS-CoV-2 Spike-reactive CD4+ TSCM in PWHIV with an incomplete immune reconstitution (defined as CD4+ T count below 500 cells/µL   and a CD4/CD8 ratio below 0.4). This functional impairment was accompanied by a stronger commitment to exhaustion. Indeed, we measured a higher expression of immune checkpoint molecules by CD4+ TSCM and T central memory (TCM) and we measured a higher frequency of T progenitors   committed to exhaustion (defined as TSCM and TCM co-expressing PD-1 and TIGIT) in PWHIV with incomplete immune reconstitution. In these participants, TCF-1, a master regulator of T cell stemness, was less expressed across all T memory subsets. It has been recently shown that GSK3β inhibition could   arrest CD8+ T cell differentiation, trigger the formation of stem cell-like memory T cells, and a more functional state of CD8+ T cells. Therefore, we analyzed the effects of GSK3β inhibition on the homeostasis and function of TSCM from the participants of our cohort. GSK3β inhibition restored TCF-1 expression in CD4+ TSCM from PWHIV which led to a partial rescue of their functionality. To investigate the mechanisms determining CD4⁺ T memory cells differentiation and HIV latency establishment, we analyzed the transcriptome landscape of primary human CD4⁺ T cells exposed to γc-cytokines or T cell receptor (TCR) agonists prior to infection with a dual-reporter HIV (HIV-pMorpheus) that allows detection of both productively and latently infected cells. The distribution of HIV latent and productive infection across the CD4+   T memory subsets and their propensity to latency was examined through flow cytometry. TCR stimulation drove proliferation, metabolic activation, and apoptosis, leading to expansion of differentiated subsets and a bias toward productive infection. Conversely, γc-cytokines preserved subset homeostasis and viability while favoring latent infection in the less differentiated memory populations. In conclusion, our findings reveal impaired vaccine-induced CD4+ TSCM responses and enrichment of exhausted T progenitor populations in PWHIV with incomplete immune reconstitution, highlighting the need for tailored vaccination strategies in this vulnerable population. Furthermore, modulation of the GSK3β–TCF-1 axis emerges as a promising avenue to restore T cell stemness and enhance TSCM functionality, although context-specific effects must be carefully considered. Finally, our mechanistic dissection of T cell stimulation pathways highlights the influence of subsets differentiation on the outcome of HIV infection, with less differentiated memory cells exhibiting greater propensity to latency. Collectively, these studies provide novel insights into the interplay between HIV persistence, TSCM biology, and immune modulation strategies.","language":"eng","citation":"THE ROLE OF CD4+ T MEMORY SUBSETS IN HIV INFECTION: IMMUNE RESPONSE IN PEOPLE WITH HIV AND LATENCY ESTABLISHMENT / S. Scaglioni ; supervisor: L. Manganaro ; co-supervisor: R. De Francesco ; coordinator of PhD school: G. D. Norata. - Dipartimento di Scienze Farmacologiche e Biomolecolari, Via Balzaretti 9, 20133 Milano, MI. Dipartimento di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti, 2025 Dec 16. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13965.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1204118/3209323/phd_unimi_R13965.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1100248"},"title":"UNA MISTERIOSA DIALETTICA. MOVIMENTO DELLA VITA E SENSO DELL'AZIONE STORICA, A PARTIRE DA HEIDEGGER E PATOČKA","internalauthor":"MOLLISI, MATTEO ANGELO","type":"Tesi di dottorato","year":"2024","abstract":"In my doctoral thesis, I intended to start from the following observation: Heidegger's philosophy has shaped the dialectical rift in twentieth-century philosophy in a similar way as Hegel did from the previous century. Taking up the famous formulation used by Marx with regard to the Hegelian dialectic, what I have attempted to do is to separate the «rational core» of Heidegger's dialectic, namely the «general forms of movement» of experience described by it, from its «mystical rind», alluding by the latter term to the «grounds» on which Heidegger found these forms. These grounds, in Heidegger's work, are essentially two: first, the formal concept of «existence», in the phase of his meditation that culminates in Being and Time, and then the «history of being», following the so-called «turn». Similarly to how Marx intended to «make the Hegelian dialectic walk on its feet, rather than on its head», finding its forms not on the mystifying and superstructural level of consciousness and Idea but on the concrete and structural level of the socio-economic organisation of a form of life and the conflicts that run through it, I have considered, starting from the first season of French phenomenology, some of the concrete grounds on which the general forms of movement described by Heidegger have been traced, starting from the plane of corporeality. This «deformalisation» of Heidegger's ontology has served, by contrast, to highlight its extraordinary coherence from the point of view of its formal scheme, which contemporary philosophy has often inherited and maintained to the very extent that it has extended and applied it to theories of experience that intended to demystify both the existential and the historical-ontological planes explored by Heidegger. In my analysis of this formal scheme, I intended, first of all, to highlight its roots, which lie above all in the Heideggerian operation of «ontologizing» the categories of proto-Christian anthropology (Part I); then, its articulation, which defines a movement of «self-extraneation» of experience that differs from that described by the Hegel-Marxian dialectic (Part II). In this way, using an interpretation of Jan Patočka's mature philosophy, I was able to reflect on the limits of the «paradigm» that Heidegger's dialectic has imposed on contemporary philosophy (Part III). Dialoguing mostly with the «ontological-political» reading of the «Heideggerian paradigm» recently proposed by Roberto Esposito, I asked: doesn't the very adherence to the laws of movement described by Heidegger, however much it may be applied to different and more concrete planes than those to which he limited them, have in turn, and in themselves, decisive implications? And what are the risks of these implications, particularly at the level of praxis, of the meaning of action in history, of the posture to be adopted in the face of the question: «what is to be done»? To this question I then connected another: does the application of this form not have, perhaps, limits? Is there not a deeper plane of experience, beyond which it ceases to be valid? And, if so, what relationship does this outlook, this dimension that cannot be colonised by Heideggerian forms of movement, have to the inherent risks of this very form? Is it able to denounce them, mitigate them, dispel them? Or does it not rather risk deepening them?","language":"ita","citation":"UNA MISTERIOSA DIALETTICA. MOVIMENTO DELLA VITA E SENSO DELL'AZIONE STORICA, A PARTIRE DA HEIDEGGER E PATOČKA / M.a. Mollisi ; tutor: C. Di Martino; supervisori: T. Campbell, C. Palermo ; coordinatore: N. Guicciardini. Università degli Studi di Milano, 2024 Sep 20. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13083.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1100248/2537212/phd_unimi_R13083.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/965339"},"title":"SELECTIVE GLYCOMIMETIC LIGANDS OF C-TYPE LECTIN RECEPTORS","internalauthor":"POLLASTRI, SARA","type":"Tesi di dottorato","year":"2023","abstract":"C-type lectin receptors (CLRs) are calcium-dependent proteins dedicated to sensing glycan motifs, including those expressed on the surface of invading pathogens. Although this recognition event usually leads to induction of an immune response, many pathogens have evolved mechanisms to exploit lectins to promote infection. A number of viruses of major impact on public health, such as HIV-1, Ebola and SARS-CoV-2, adopt this strategy to subvert host defence responses and enhance the infectious process. Selective inhibitors of lectins have thus high potential as therapeutic agents, but their use is limited by the intrinsic low affinity and selectivity of carbohydrate-based molecules towards CLRs. These limitations can generally be overcome through the use of chemically modified analogues of sugars that emulate carbohydrate activities but presents improved drug-like properties.   In this thesis we disclose a glycomimetic approach to selectively target the C-type lectin DC-SIGN and its homologue L-SIGN, which are involved in the recognition of several viruses (e.g. HIV-1, Ebola, Dengue, SARS-CoV-2). A library of monovalent mannose-based glycomimetic ligands has been synthetized by varying the nature and the position of the functionalization. Ligand affinity towards target lectin receptors has been evaluated through SPR (Surface Plasmon Resonance) competition assays, performed in the group of Prof. Fieschi in Grenoble (IBS). The most promising ligands were then selected for construction of multivalent glycoconjugates, to further increase ligand affinity and selectivity. Multivalent constructs were built on different platforms and the synthetized ligands were evaluated as DC/L-SIGN antagonists via SPR direct interaction assays. The determination of their antiviral activity in cellular studies is currently ongoing in the group of Dr. Delgado (Hospital Universitario 12 de Octubre, Madrid).","language":"eng","citation":"SELECTIVE GLYCOMIMETIC LIGANDS OF C-TYPE LECTIN RECEPTORS / S. Pollastri ; tutor: A. Bernardi ; coordinatore: D. Passarella. Dipartimento di Chimica, 2023 Apr 20. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12753.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/965339/2181479/phd_unimi_R12753.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/853301"},"title":"LE AFFINITÀ ELETTIVE. IL RAPPORTO TRA MAFIA E CAPITALISMO IN LOMBARDIA","internalauthor":"FARINA, PIERPAOLO","type":"Tesi di dottorato","year":"2021","abstract":"The dissertation analyzes the causes of the growing «mafia demand» in Lombardy, a region unanimously considered the «locomotive of Italy», which can boast a long and important civic and entrepreneurial tradition, but which in recent years has been affected by the first convictions for mafia association of some of its entrepreneurs.    Recovering Pierre Bourdieu's concept of «elective affinities», the research work reconstructs the stages of Mafia roots in the socio-economic, political and cultural fabric of the region, particularly in the city of Milan. From a diachronic perspective, it investigates the genesis and evolution of the relationship between the mafia phenomenon and the Lombard economic ruling class, through an in-depth study of significant events within the historical periodization adopted («mafia sowing», in 1950s-1960s - «the great transformation», in 1970s - «hybridization», in 1980s-1990s - «symbiosis», in 2000s).    Starting from the assumptions that «the mafia is not a cancer that has proliferated by chance on healthy tissue» and that «the real strength of the mafia is outside the mafia», the research has identified those «potentially kindred» elements of the Lombard entrepreneurial culture and investigated the historically relevant causes that have allowed the various forms of the mafia phenomenon to become, in the span of 70 years, quasi-normal social actors of the Lombard socio-economic and political scenario.","language":"ita","citation":"LE AFFINITÀ ELETTIVE. IL RAPPORTO TRA MAFIA E CAPITALISMO IN LOMBARDIA / P. Farina ; tutor: F. Dalla Chiesa ; coordinatore: F. Basile ; revisori: I. Sales, G. Muti. Università degli Studi di Milano, 2021 Jul 13. 33. ciclo","filename":"phd_unimi_R11961.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/853301/2466290/phd_unimi_R11961.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/960797"},"title":"MOLECULAR MECHANISMS UNDERLYING CLINICAL BEHAVIOR OF NEUROENDOCRINE TUMORS: STUDY OF NEW POSSIBLE BIOMARKERS PREDICTABLE OF PHARMACOLOGICAL RESISTANCE AND TARGETS","internalauthor":"MANGILI, FEDERICA","type":"Tesi di dottorato","year":"2023","abstract":"Neuroendocrine tumors (NETs) represent a heterogeneous group of malignances arising from the diffuse neuroendocrine system whose incidence is rising over the years. Due to their complexity and unusual features, first-line therapeutical approach is represented by surgical resection, even if it is not completely resolutive in most of cases, due to recurrence and metastasis accompanied by pharmacological resistance. In this scenario, the lack of effective pharmacological approaches is making hard the treatment of these pathologies.   Within the pharmacological context, lot of attention was given to somatostatin and dopamine system, because of prevalent expression of somatostatin receptors (SSTs) and dopamine receptor type 2 (DRD2) in about all NETs that represented, over the years, the main targets for treatment with somatostatin analogs (SSAs) and dopamine agonists (DAs) for these pathologies.  Nevertheless, the molecular mechanisms underline pharmacological resistance and the development of novel biomarkers useful to identify patients that may benefit of specific treatments are steel needed, together with the development of novel in vitro pre-clinical model better resembling human tumor behavior. This thesis aimed to investigate possible biomarkers underlining pharmacological resistance and predictable of SSAs/DAs responsiveness in NETs, more specifically focusing on G-proteins and β-arrestins DRD2-mediated signaling pathways in PitNETs and on somatostatin/cortistatin system in novel PanNENs cell models.  Briefly, β-arrestin 2 has been highlighted as novel potential biomarker of pharmacological responsiveness to DAs, and that combined therapy with DAs avoids everolimus escape feed-back in PitNETs. The role of \uf062-arrestin 2 in regulating both AKT phosphorylation and cell proliferation in tumoral lactotrophs and NF-PitNETs was demonstrated, elucidating a new molecular mechanism that contributes to confer sensitivity or resistance to DAs in PitNETs. In tumoral lactotrophs and NF-PitNETs, the lack of \uf062-arrestin 2 prevents the inhibitory effect of DRD2 on AKT pathway activation with a consequent resistance to the antimitotic action of DAs. In accordance, it was showed that cabergoline improved everolimus efficacy by blocking AKT upstream reactivation in NF-PitNETs and tumoral lactotrophs. In fact, the combined treatment with cabergoline strongly reduced the increase of AKT activity, correlating with its antimitotic effect. The role of \uf062-arrestin 2 has been highlighted in mediating cabergoline inhibition of both p-AKT activity and cells proliferation after everolimus cotreatment: the lack of β-arrestin 2 reverted the antimitotic effect induced by the combined treatment.       Moreover, the cytoskeleton actin binding protein filamin-A (FLNA) emerged as an important player in the regulation of PitNETs drug responsiveness and invasiveness. At this regard our data showed that activation of the cAMP pathway and DRD2 agonist regulated FLNA activity by increasing or decreasing, its phosphorylation, respectively. FLNA phosphorylation has been identified as potential biomarker for tumor responsiveness to DAs, in DRD2 expressing PitNETs, since it participates in mediating DRD2 intracellular signalling, additionally turning out that FLNA phosphorylation prevented DRD2 signaling in PRL- and ACTH-secreting PitNETs.  At last, a potential of novel pharmacological compounds of the SS/CST family exerted antiproliferative effects in new human resembling PanNENs models.  To sum up, this work identified the role of specific molecular mechanism underlying pharmacological resistance in PitNETs, paving the way for possible combined approaches to overcome drug resistance and the pilot study on novel PanNENs cell lines strongly suggests that testing new pharmacological compounds of the SS/CST family can lead to an innovative discovery to expand the therapeutic arsenal to treat PanNENs and set novel approaches with a personalized perspective.","language":"eng","citation":"MOLECULAR MECHANISMS UNDERLYING CLINICAL BEHAVIOR OF NEUROENDOCRINE TUMORS: STUDY OF NEW POSSIBLE BIOMARKERS PREDICTABLE OF PHARMACOLOGICAL RESISTANCE AND TARGETS / F. Mangili ; tutor: G. Mantovani Giovanna, MD, PhD ; coordinatore: C. Sforza Chiarella, MD, PhD. Dipartimento di Scienze Cliniche e di Comunità, 2023 Apr 18. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12490.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/960797/2166455/phd_unimi_R12490.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1221309"},"title":"SUGAR EDITING FOR THE SYNTHESIS OF GLYCOMIMETICS","internalauthor":"CAVAZZOLI, GIANLUCA","type":"Tesi di dottorato","year":"2026","abstract":"This doctoral thesis explores strategies for the synthesis of structurally advanced glycomimetics. The first project focuses on the design of selective antagonists of C-type lectins, specifically targeting L-SIGN over DC-SIGN, two closely related receptors involved in viral recognition and SARS-CoV-2 infection. Inspired by the selective ligand Man84, a library of C2-triazole-modified mannosides bearing guanidine isosteres was synthesized. Structure–activity relationship studies combined with SPR assays identified several potent and selective L-SIGN ligands, including Man96, Man97, and Man102, displaying low micromolar affinity. X-ray crystallography of the L-SIGN/Man96 complex revealed the key interactions determining affinity and selectivity, highlighting the important role of residues E370, F325, and N385 in L-SIGN CRD. The second project develops a nickel-photoredox methodology for the synthesis of α-C-arylglycosides via deoxygenative arylation of unprotected anomeric hydroxyl groups. By replacing expensive iridium photocatalysts with sustainable organic dyes such as 5CzBN, an efficient and economical catalytic system was established. The protocol proved compatible with various monosaccharides and (hetero)aryl bromides, affording α-selective C-arylglycosides under mild conditions. Mechanistic investigations, including fluorescence quenching experiments, supported a radical pathway initiated by reductive quenching of a sugar–NHC adduct. The third project investigates racemic crystallization as a novel strategy for structural studies of glycans. Through automated glycan assembly, both D- and L-enantiomers of a galactosylated xyloglucan hexasaccharide were synthesized. Preliminary results suggest that racemic crystallization may overcome longstanding challenges in glycan structural analysis.   Overall, this work expands the chemical space of glycomimetics, introduces sustainable synthetic methodologies for C-arylglycosides, and pioneers structural approaches for complex oligosaccharides, contributing to the advancement of medicinal and structural glycoscience.","language":"eng","citation":"SUGAR EDITING FOR THE SYNTHESIS OF GLYCOMIMETICS / G. Cavazzoli ; tutor: A. Bernardi ;  coordinator: D. Passarella. - Aula V1, Settore Didattico, via Venezian 15, 20133 Milano (MI). Dipartimento di Chimica, 2026 Mar 03. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13900_1.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 04-SET-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1157220"},"title":"ANTIMICROBIAL PEPTIDES FOR A SUSTAINABLE AGRICULTURE","internalauthor":"MARONE FASSOLO, ELENA","type":"Tesi di dottorato","year":"2025","abstract":"Modern agriculture relies mainly on the use of chemical pesticides to protect crops from pathogens   and pests. However, the extensive use of these compounds has led to the emergence of resistant   strains, environmental pollution, and harm to non-target organisms. To address these issues,   sustainable and eco-friendly alternatives to conventional pesticides are needed. Antimicrobial   peptides (AMPs) offer a promising solution due to their high specificity, efficacy, and rapid   degradation with low permanence in the environment. Some AMPs have already been   commercialized as plant protection products. Genetically encoded peptide libraries (GEPLs) provide   a powerful tool for discovering peptides with specific binding or inhibitory properties. While this   technology has been primarily used in the development of human therapeutics, its potential for   agricultural applications remains unexplored. In my PhD project, a GEPL was employed to identify   cyclic peptides (CPs) able to counteract oomycete/ascomycete-induced diseases. Four target   proteins from Phytophthora infestans, Zymoseptoria tritici and Pseudocercospora fijiensis were   selected and screened against a GELP of cyclic peptides (CYCLIC). Several cyclic peptides (CPs) that   exhibited antimicrobial activity against these pathogens were identified. Notably, Pi_LPMO_71 and   Pi_LPMO_109, which bind to P. infestans LPMOs, showed significant efficacy in controlling late blight.   Similarly, Zt_Ssk1p_42 and Zt_Ssk1p_49, which interact with the Z. tritici Ssk1p effector, also   demonstrated antimicrobial activity. The identified CPs were evaluated in vitro and ex vivo assays.   Pi_LPMO_109 was also tested in greenhouses trials where it has demonstrated a robust protection   rate on tomato and grapevine plants. Combined with a favourable toxicological profile on off-target   organisms, this pipeline demonstrates its potential for the development of novel and sustainable   plant protection products. Pi_LPMO_109 shows potential for future improvements, as the   implementation with adjuvants in the formulation or the production through biomanufacturing.","language":"eng","citation":"ANTIMICROBIAL PEPTIDES FOR A SUSTAINABLE AGRICULTURE / E. Marone Fassolo ; tutor: A. Tagliani ; supervisor: P. Pesaresi ; phd coordinator: S. Ricagno. Dipartimento di Bioscienze, 2025 Apr 15. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13598.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1157220/2743865/phd_unimi_R13598.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1151201"},"title":"NOVEL INSIGHTS ON ALLAN-HERNDON-DUDLEY SYNDROME: TRANSCRIPTIONAL PROFILING AND FUNCTIONAL CHARACTERIZATION OF THREE GENETIC VARIANTS IN SLC16A2 GENE","internalauthor":"ESPOSITO, LETIZIA","type":"Tesi di dottorato","year":"2025","abstract":"Allan-Herndon-Dudley Syndrome (AHDS) is a rare genetic X-linked pediatric disorder, affecting essentially males, with intellectual and motor development impairment. It is caused by mutations in the SLC16A2 gene, which encodes for MCT8, a transporter responsible for thyroid hormone (TH) transport across cell membranes. THs are crucial for the development of several organs, mainly the brain and are involved in many physiological processes. Variants in SLC16A2 impact on the functionality and localization of MCT8 in various ways. The resulting clinical condition is characterized by brain hypothyroidism and thyrotoxicosis in peripheral tissues, leading to a range of symptoms, including cognitive delays, hypotonia, spasticity, and dystonia.   In this study, we provide a deep investigation about the impact of three different pathological variants in SLC16A2 gene, identified in AHDS affected pediatric patients, on the pathogenetically mechanisms of AHDS. Particularly, from skin biopsies, we isolated primary fibroblasts from 3 AHDS patients and 2 healthy controls matched by sex and age to study the pathological readouts of the disease and identify novel related molecular pathways. With this purpose, we applied different techniques, including MTT and Live&Dead assays to characterize the obtained fibroblast cell lines.  Moreover, we performed RT-qPCR, Western Blot, Immunofluorescence experiments, to investigate the functioning and the localization of MCT8 transporter in these cells. RNA-sequencing analysis provided us an overview about differentially expressed genes correlated to distinctive mechanisms of the disease, such as neuronal and glial specification deregulation; a reduced protein synthesis as a result of ribosome structural components’ impairment, a reduced mitochondrial activity and lipid droplets’ accumulation as a result of a disrupted thyroid hormone signaling.   Overall, our study confirms the use of patients’ derived fibroblasts as a reliable model to study in vitro rare conditions, as well as showed us the importance of personalized medicine when patients carry different mutation related to the disease.   Nevertheless, major limitations of the study are also exposed to represent the first starting point for overcoming them and finding a definitive cure for this debilitating condition.","language":"eng","citation":"NOVEL INSIGHTS ON ALLAN-HERNDON-DUDLEY SYNDROME: TRANSCRIPTIONAL PROFILING AND FUNCTIONAL CHARACTERIZATION OF THREE GENETIC VARIANTS IN SLC16A2 GENE / L. Esposito ; tutor: G. V. Zuccotti ;  co-tutor: C. Cereda ;  coordinator: F. Cheli. Dipartimento di Scienze Biomediche e Cliniche, 2025 Mar 26. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13619.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1151201/2705187/phd_unimi_R13619.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1118608"},"title":"DETERMINATION OF CONTAMINANTS IN FISHERY PRODUCTS TO SUPPORT FOOD SAFETY","internalauthor":"MOSCONI, GIACOMO","type":"Tesi di dottorato","year":"2024","abstract":"The contamination of fish and fishery products poses significant challenges to food safety, necessitating a comprehensive understanding of pollutants and their potential risks. This thesis focuses on different contaminants such as Persistent Organic Pollutants (POPs) as defined by the Stockholm Convention [1] and Persistent bioaccumulative toxic substances (PBTs), Potentially Toxic Elements (PTEs), whose study remains crucial for consumer protection; Perfluoroalkyl Substances (PFASs) some of which are POPs and Microplastics (MPs); these two classes have been particularly considered due to their condition of contaminants of emerging interest.   The study employs advanced analytical techniques, such as Liquid Chromatography coupled to High-Resolution Mass Spectrometry (LC-HRMS), Gas Chromatography tandem Mass Spectrometry (GC-MS/MS), Inductively coupled plasma-optical emission spectrometry (ICP-OES) and Fourier-transform infrared spectroscopy (µFT-IR), to investigate the presence and concentrations of PFASs, and other POPs, PTEs, and MPs respectively in various fish species and products.  In addition to the analytical aspect, the thesis explores the potential health implications associated with the consumption of contaminated fishery products, considering both acute and chronic effects. Special attention is given to vulnerable populations, such as pregnant women and children as well as high consumers, who may be more susceptible to the adverse effects of these contaminants, considering the unique characteristics of each contaminant class.  As emerging environmental contaminants, PFASs have drawn increased attention due to their prevalence in aquatic ecosystems and potential health implications. So, the first article focuses on PFASs, tracing their occurrence in seabass (Dicentrarchus labrax), seabream (Sparus aurata), perch (Perca fluviatilis), Mediterranean shad (Alosa agone), and European whitefish (Coregonus lavaretus). Through LC-HRMS analysis, the study reveals the presence of PFBA and PFOS in both lake and sea fish, with PFBS exclusively found in lake fish. The observed concentrations were used to estimate the intake of PFOS, highlighting that the recommended tolerable weekly intake (TWI) by EFSA was not exceeded, even for the 99th percentile consumers. This underscores the significance of assessing the impact of aquatic pollution on food safety. The research contributes to build a database on PFASs in fish, evaluating contamination levels, and aiding in the formulation of reliable risk assessments for the consumer population.  Addressing the presence of POPs in fishery products, the research utilizes GC-MS/MS analysis to assess their concentrations and compliance to regulatory limits. So, in the second article, the investigation turns to POPs in European seabass, gilthead seabream, and Mediterranean shad from Northern Italy lakes. GC-MS/MS analysis demonstrates that none of the analytes exceeded established maximum limits, and substances without specific limits remained below provisional tolerable daily intake (PTDI) levels. This study highlights the importance of monitoring and regulatory measures in maintaining the safety of fishery products and minimizing risks associated with pollutant exposure.  The third article analyses PFAS and PTE in anchovies (Engraulis encrasicolus), a staple of the Italian diet. In the face of a paucity of previous data on these contaminants in anchovies, the study uncovers low levels of PFAS and PTE, stating that the assessed risk is reassuring for consumers, even those with higher consumption habits. This research highlights the need for continued vigilance in monitoring emerging contaminants and their potential impact on food safety.  The inclusion of Microplastics (MPs) in the study acknowledges the emerging concern of plastic pollution in aquatic environments. The research characterizes the presence of MPs in fish different tissues, namely gills, gastrointestinal tract, and fillet, focusing on potential human exposure through fish consumption. So, the final article addresses the pervasive issue of microplastics in seabream and seabass from Mediterranean aquaculture facilities. The study identifies the gastrointestinal tract as a primary site of plastic accumulation, with higher contamination observed in fish from specific geographical areas, such as Turkey. The research sheds light on the potential human exposure through fish consumption, confirming the presence of MPs also in the edible tissues, and prompts reflection on sustainable aquaculture practices to mitigate pollution and safeguard food safety.  Overall, this thesis emphasizes the importance of a multidimensional approach to the study of contaminants in fish and fishery products, and the articles collectively contribute to a nuanced understanding of the complex interplay between pollution in the aquatic environment and its profound implications for food safety, emphasizing the importance of continued research, monitoring, and regulatory efforts to ensure the integrity of fishery products in Italy. The utilization of different matrices, such as fresh fish and canned products, coupled with advanced analytical methods, provides a more comprehensive understanding of the distribution, bioaccumulation, and potential risks associated with PFASs and other POPs, PTEs, and MPs. The outcomes contribute to the enhancement of food safety protocols and regulatory measures in the seafood industry.","language":"eng","citation":"DETERMINATION OF CONTAMINANTS IN FISHERY PRODUCTS TO SUPPORT FOOD SAFETY / G. Mosconi ; tutor: L. Chiesa ; coordinatore: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2024. 36. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R12867.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1118608/2590233/phd_unimi_R12867.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/917208"},"title":"LE GRIDE MILANESI NEL CINQUECENTO. CIRCOLAZIONE, PRODUTTORI E FUNZIONI SOCIALI","internalauthor":"FRANCALANCI, MARCO","type":"Tesi di dottorato","year":"2022","abstract":"This research was conducted with the aim of considering the impact that the introduction  of printing had on the practices of institutional communication. This choice has led us to  identify the sixteenth century as the chronological area of analysis. In fact, the sixteenth  century is a moment of extreme restructuring of communication techniques and of profound  coexistence between the practices of manual copying and those of printing. In order to  propose accurate considerations, we have also limited the geographical area to the city of  Milan, a very important center in the early modern landscape.  In order to reach accurate reflections, we have chosen to approach the problem from four  different perspectives. First of all, we tried to show the channels through which the “gride”  were circulating. These were the officers in charge of the management of this material, and  how such documents were framed within the Milanese administration. This section  introduces the work as it is relevant for both the manuscripts and the typographical  documents.  A further aspect that we have taken into consideration is the logic by which the  administration chose to commission the printing of official writings to certain printers. This  subject is at the center of chapter two, in which we open up to themes belonging to the history  of the book: we have shown the importance that such assignments had in the business of the  printers.  A third section is devoted to the characteristics that the typographical “gride” assumed  over the years. In this sense, the material aspects of the documents have been studied, with  consideration taken in relation to the social functions they had to perform. We have also  highlighted the roles that languages other than the vernacular, especially Latin and Castilian,  played within these writings. From this perspective emerges the complexity of the Milanese  linguistic landscape and the political importance that languages other than the vernacular  could assume in the 16 th century.  Lastly, we gave an account of the plural life of these documents. To begin, we emphasized  the spaces that were maintained by manuscript production even in the mid-sixteenth century.  Then we pointed out the production processes that accompanied the realization of  typographical documents. In this sense emerged the role that the agents of the chancery  maintained in the production of printed material. We also highlighted the autonomy that  pertained to the printers. Moreover we took into account the importance of the participation  of different actors in the production phases, in terms of both tasks and cultural horizons.  Finally, we have considered the value that the normative.","language":"ita","citation":"LE GRIDE MILANESI NEL CINQUECENTO. CIRCOLAZIONE, PRODUTTORI E FUNZIONI SOCIALI / M. Francalanci ; tutor: L. Braida; co-tutor: A. Castillo Gómez; coordinatore: M. Soresina. Dipartimento di Studi Storici, 2022 May 18. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12151.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/917208/2004965/phd_unimi_R12151.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/891480"},"title":"PRENATAL ANTIBIOTIC THERAPY PREDISPOSES TO NEONATAL SEPSIS INDUCED BY E.COLI: A ROLE FOR BREAST MILK IGA?","internalauthor":"PIETRASANTA, CARLO","type":"Tesi di dottorato","year":"2021","abstract":"Antibiotics are administered to 20-30% of pregnant women, to treat maternal  infections or to prevent fetal and neonatal bacterial colonization in selected  cases of high infection risk, such as premature rupture of membranes (PROM).  Despite the administration of antibiotics to neonates, i.e. in the first days of  life, is known to increase the risk for subsequent late-onset sepsis (LOS),  necrotizing enterocolitis (NEC), and possibly of long term adverse outcomes  such as obesity and allergic manifestations, the effect of prenatal antibiotics  on neonatal immune development and function is poorly understood. Here,  using a murine model of prenatally-restricted antibiotic therapy (Abx), we  show that newborn mice born to mothers previously treated with Abx are  more susceptible to LOS caused by Escherichia coli, in correlation with an  increased bacterial translocation to distant organs (mesenteric lymph nodes,  spleen, liver). Increased neonatal mortality after maternal Abx did not  correlate with major modifications in blood or spleen populations of immune  cells (neutrophils, activated monocytes, CD4+ and CD8+ T cells), nor with  changes in gut epithelial structure and integrity, but correlated with a  significantly lower amount of fecal IgA, stomach IgA, IgA-coating of  intestinal bacteria, and IgA production by plasma cells of the maternal  mammary gland. Cross fostering experiments reinforced the evidence that  low breast milk IgA after maternal Abx was a key factor to increase the  mortality rate of pups. Moreover, the adverse effect of prenatal Abx persisted  after the interruption of breastfeeding, in weaned young adults. At 28 days of  life, prenatal Abx caused a reduction in IgA+ plasma cells, both CD11b+ and  CD11b-, in the lamina propria (LP) of the ileum, a reduction in faecal sIgA,  and decreased the amount of colonic T-regs and of Th17-like lymphocytes   (CD4+ RORgt+ antigen-specific T cells). Maternal supplementation with  postbiotics during the last 5 days of pregnancy was not sufficient to revert the  antibiotic-induced phenotype, at least in our experimental setting. Our data  highlight the importance of breast milk IgA for the prevention of neonatal  LOS, and the influence of prenatal Abx. If confirmed on human samples,  these results may lay the foundation for screening strategies of IgA in breast  milk, especially in selected high-risk situations such as prenatal Abx  administration, and/or extremely preterm neonates receiving maternal (or  donor) breast milk.","language":"eng","citation":"PRENATAL ANTIBIOTIC THERAPY PREDISPOSES TO NEONATAL SEPSIS INDUCED BY E.COLI: A ROLE FOR BREAST MILK IGA? / C. Pietrasanta ; tutor: F. Mosca; co-tutor: M. Rescigno ; the chair of the doctoral program: L. Pinotti. Dipartimento di Scienze Cliniche e di Comunità, 2021 Dec 16. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12277.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/891480/1936505/phd_unimi_R12277.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/803981"},"title":"ARCHEOLOGIA DEL VINO: ANFORE E PALMENTI RUPESTRI. IL CASO DELLA CALABRIA","internalauthor":"SURACE, DOMENICO MICHELE","type":"Tesi di dottorato","year":"2021","abstract":"\"That wine has been playing a significant role in the Italian economy and culture since ancient times is a known fact, just as well as it is acknowledged that it represents a matter of great historical and archaeological interest.  In particular, the vine and the wine have performed an important function in Calabria’s economic history since the origins of the cultivation of the Vitis Vinifera by the Oenotrians. The important role of wine continues being evident during the Greek phase, through the advent of a different breeding technique, as well as in the Roman, Magno-Greek and Byzantine phases: the society had been transformed, yet the methods of vine-cultivating and wine-making remained roughly the same over the centuries.  As of today, however, the research on \"\"wine archeology\"\" is characterized by a double limitation: from one side, by the disciplinary sphere (addressing the topic of the ancient wine production from a single point of view, connected either only to the socio-cultural and economic value of the product or to the environment and vegetation), and from the other side, by the contextual sphere (considering only individual geographical areas that only rarely get connected to each other).  The work for the doctoral thesis aims at going beyond a unidirectional consideration of data and intends to pursue a multidisciplinary study that allows to integrate the aspects of the historical-archaeological investigation with those of the agronomic and environmental research.  In consideration of this approach and according to these premises, the study on Calabria examines different fields: after having investigated the ancient rural landscape of the region and the parameters of its exploitation, with specific reference to the vine, the project intends to analyze the ancient structures of wine production (the rock-cut units), the system of the production in the Roman age (through the presentation of an overview and an in-depth analysis of the villae of the territory), then the trade of the wine (by examining the ports and the streets as well as the vinary amphorae of Calabrian origin) in order to determine chronologies and trace the ancient social and cultural networks.\"","language":"ita","citation":"ARCHEOLOGIA DEL VINO: ANFORE E PALMENTI RUPESTRI. IL CASO DELLA CALABRIA / D.m. Surace ; coordinatore UNIMI: D. Bassi; supervisore e tutor UNIMI: O. Failla; tutor UNIMI: G. Olcese; coordinatore UB: F. J. Laviña Gómez; supervisore e tutor UB: M. A. Cau. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2021 Jan 15. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12462.pdf","fileformat":"Adobe PDF","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/803981/1671073/phd_unimi_R12462.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1181295"},"title":"PUBLIC OPINION TOWARDS TECHNOCRACY: ATTITUDES, PREFERENCES AND VOTING BEHAVIOR","internalauthor":"ROSCO, JESSICA","type":"Tesi di dottorato","year":"2025","abstract":"This dissertation investigates public opinion toward technocratic governance and its compatibility with liberal representative democracy. While technocracy and democracy are often portrayed as conceptually opposed—one grounded in expertise, the other in popular sovereignty—empirical developments across Europe reveal more hybrid configurations. From the growing reliance on experts by institutions like the EU to the appointment of technocratic executives in parliamentary systems, contemporary democracies routinely incorporate technocratic practices. Against this backdrop, the dissertation asks: how do citizens make sense of these hybrid arrangements when forming political preferences? Does support for expert-led governance reflect disillusionment with democracy, or a reconfiguration of its normative foundations?    Adopting a demand-side perspective, the dissertation explores whether technocratic attitudes signal a rejection of democratic norms or a reinterpretation of them. It argues that citizens do not necessarily see technocracy and democracy as mutually exclusive. Rather, support for technocratic governance often emerges as a response to perceived failures of party-based politics, particularly during crises.    The first empirical chapter uses the 2021 SOLID survey, covering 16 EU member states, to examine the distribution and structure of technocratic attitudes across Europe. Contrary to earlier claims about the existence of a distinct technocratic public (Bertsou & Caramani, 2020a), the analysis finds no evidence of a cohesive “technocratic” attitudinal profile. Instead, technocratic orientations often overlap with populist attitudes and dissatisfaction with elites. This hybridity—often referred to as “technopopulism”—suggests that support for expert-led governance is less about technocratic values per se and more about disaffection with representative institutions. Significant cross-national variation further underscores the contextual nature of public opinion toward technocracy.    The second chapter narrows the focus to Italy, a country with a unique record of alternating between party-based, populist, and technocratic governments. Using a forced-choice conjoint experiment during the 2022 energy crisis, it investigates voter preferences for technocratic versus political ministers. Results reveal a consistent preference for technocratic profiles, especially among younger, highly educated, and institutionally trusting respondents. This suggests that technocracy enjoys public legitimacy during crises—not as a rejection of democracy, but as a corrective to its perceived limitations. However, support for technocrats is strongest among those who already trust institutions, raising questions about technocracy’s potential to rebuild wider legitimacy.    The third chapter analyzes accountability under technocratic rule by examining Italian voting behavior between 2019 and 2022. Findings suggest that technocratic rule reframes, rather than neutralizes, democratic accountability: voters reward or punish parties based on their support for the technocratic executive. Accountability remains possible but becomes indirect, shaped by party positioning and crisis context.    Overall, the dissertation shows that technocracy and democracy are not inherently incompatible. Their relationship is shaped by institutions, trust, crises, and party dynamics. Combining cross-national and case-specific analysis, it offers new insights into how citizens perceive and respond to technocratic governance in Europe.","language":"eng","citation":"PUBLIC OPINION TOWARDS TECHNOCRACY: ATTITUDES, PREFERENCES AND VOTING BEHAVIOR / J. Rosco ; relatore: C. Vezzoni ;  correlatore: A. Pellegata ; coordinatore: F. Franchino. - Milano. Dipartimento di Scienze Sociali e Politiche, 2025 Oct 30. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13270.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1181295/3131213/phd_unimi_R13270.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/952913"},"title":"INVOLVEMENT OF THE CONTACT PATHWAY IN COVID-19 COAGULOPATHY","internalauthor":"CAPECCHI, MARCO","type":"Tesi di dottorato","year":"2022","abstract":"Background. A novel acquired coagulopathy characterized by a severe procoagulant imbalance is common in COVID-19 patients and is associated with the clinical severity of the disease.  Aims. Our study aims at elucidating the underlying mechanisms of coagulation activation in COVID- 19 patients.  Methods. The study is composed of two phases. In the first and second part, 62 and 112 symptomatic COVID-19 patients, respectively, were consecutively enrolled and stratified into 3 groups based on the intensity of care: low, requiring only high-flow oxygen by nasal cannula (21 and 23 patients); intermediate, requiring continuous positive airway pressure (20 and 47 patients); high, requiring mechanical ventilation (20 and 42 patients). During the first phase of the study blood samples were tested for markers currently used to diagnose disseminated intravascular coagulation (DIC) (PT, aPTT, fibrinogen, D-dimer, platelet count), the pro- (FII, FVIII) and anticoagulant factors (antithrombin, protein C, protein S) and those indicating endothelial perturbation (von Willebrand factor). During the second phase of the study blood samples were tested for markers of activation of the intrinsic pathway (FXI, FXII, FXIa, FXIIa) together with its physiologic inhibitor (C1-inhibitor), of the extrinsic pathway (FVII, FVIIa), global activation of the coagulation cascade (D-dimer, FDP, FM) and fibrinolysis (plasminogen, t-PA, \ud835\udefc2-antiplasmin, PAI-1).  Results. Results of the first phase of the study demonstrated that COVID-19 coagulopathy represents a new entity, not fulfilling the criteria for DIC, characterized by endothelial activation, while the second part of the study showed a prevalent activation of the contact pathway over the extrinsic pathway of the coagulation cascade.  Conclusions. Our study showed an acquired coagulopathy associated with hyperacute inflammation, hypercoagulability, and endothelial perturbation proportional to the clinical severity  3  of the infection, characterized by a prevalent activation of the intrinsic pathway of the coagulation cascade, opening the possibility for targeted therapies.","language":"eng","citation":"INVOLVEMENT OF THE CONTACT PATHWAY IN COVID-19 COAGULOPATHY / M. Capecchi ; tutor: F. Payvandi ; coordinator: C. Sforza. Università degli Studi di Milano, 2022 Jun 07. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12160.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/952913/2133186/phd_unimi_R12160.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1206524"},"title":"THE MANY FACES OF REGENERATION: ENGINEERING MULTIFUNCTIONAL SCAFFOLDS FOR CRANIOMAXILLOFACIAL APPLICATIONS","internalauthor":"DALFINO, SOPHIA","type":"Tesi di dottorato","year":"2026","abstract":"A mandibular bone defect is a part of the lower jaw where bone is missing. People affected by large mandibular defects face consequences that go far beyond esthetics. For example, they often struggle to chew or speak, and this can affect daily life and overall well-being. Mandibular defects can arise from congenital conditions, accidents or, in most cases, from surgical removal of tumors in the mouth. Oral cancers continue to increase worldwide and so does the number of patients who require jaw reconstruction.   To date, the gold-standard treatment has been to replace the missing bone with a piece of the patient’s own fibula, taken from the leg. However, the procedure is extremely complex. It requires long surgeries, advanced microsurgical skills, and two surgical interventions, exposing patients to pain and high-risk potential complications. In addition, the fibula does not naturally match the shape, size, or mechanical properties of the jaw. This mismatch can make it difficult to restore facial appearance or place dental implants correctly.   These limitations have motivated researchers to explore new solutions based on bone tissue engineering, a field that aims to help the body regenerate its own bone. Instead of taking bone tissue from another part of the body, scientists design 3D porous structures (i.e. scaffolds), made from biodegradable materials that temporarily support cells as they grow new bone tissue. The scaffolds can be made of different materials and can be customized to fit the shape of a patient’s defect. The use of additive manufacturing technologies to fabricate these constructs gives great freedom in terms of shape and materials. Despite many promising results, engineered scaffolds still struggle to break into clinical use, mainly due to failure in repairing large defects and ensuring vascularization.   The work described in this thesis focuses on developing new strategies to design scaffolds that can better support both bone formation and the growth of blood vessels, which are essential for the survival of newly formed tissue. We started by an analysis of the state of art (Chapter 2) to understand the main approaches that are currently being investigated and their limitations. We then explored several aspects involved in the design of a scaffold, presenting alternative or complementary solutions.   One strategy focused on the shape of the scaffold pores (Chapter 3). Inspired by natural bone structures, we developed two different pore geometries (star and diamond) and showed their influence on stem cells differentiation into bone-forming cells. We found that diamond pores enhanced expression of osteogenic genes, while the star pores promoted stronger mineral deposition. These results highlighted how geometry can guide different aspects of bone formation.  Another approach focused on the materials used to fabricate the scaffolds (Chapter 3 & 4). We proposed mixing polymers with bioactive materials containing ceramics or bioactive glasses. These materials resemble the chemical composition of natural bone and can release ions that stimulate cells to differentiate into bone-forming cells and encourage blood vessel growth. Our results showed that these composite scaffolds improved osteogenic and angiogenic marker expression in stem cells and the ability of endothelial cells to form vessel-like structures.   To accelerate biological effects even further, we also developed surface coatings to release pro-angiogenic molecules from the scaffold surface (Chapter 5). These molecules not only induced hypoxic response, pushing cells to activate formation of blood vessels, but also enhanced the differentiation of stem cells into bone-forming cells. We demonstrated that this coating triggered activation of both angiogenic and osteogenic pathways, confirming the strong interplay between these two processes.   Finally, we explored the possibility of pre-vascularizing scaffolds before implantation (Chapter 6). We created a hybrid scaffold by combining a hard scaffold with a soft hydrogel and were able to grow micro-capillary-like structures in vitro before implantation. This showed that a pre-vascularized construct could support early blood vessel organization, a critical step for improving implant integration in large bone defects.   Together, these strategies provided new insights into the design of next-generation mandibular implants. Although challenges remain before such scaffolds can fully replace current surgical approaches, the work of this thesis pushes a step closer to less invasive and more effective treatments for patients who need jaw reconstruction.","language":"eng","citation":"THE MANY FACES OF REGENERATION: ENGINEERING MULTIFUNCTIONAL SCAFFOLDS FOR CRANIOMAXILLOFACIAL APPLICATIONS / S. Dalfino ; supervisori: C. Dolci, L. Moroni, G. Tartaglia. Dipartimento di Scienze Biomediche per la Salute, 2026 Jan 29. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13817.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1206524/3218743/phd_unimi_R13817.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1115085"},"title":"ADVANCEMENTS IN PDFS DETERMINATION: INCORPORATION OF QED EFFECTS AND NEW THEORETICAL IMPROVEMENTS IN A MODERN DEEP LEARNING FRAMEWORK","internalauthor":"LAURENTI, NICCOLO'","type":"Tesi di dottorato","year":"2024","abstract":"The focus of this Ph.D. thesis is the improvement in the determination of parton distribution functions (PDFs)  through the inclusion of new theoretical effects in the theoretical predictions that are compared to experimental data.  Such effects are the inclusion of Quantum Electrodynamics (QED) corrections, the inclusion of the so-called missing  higher orders uncertainties (MHOUs)  and the inclusion of approximate next-to-next-to-next-to-leading order contributions (aN$^3$LO).  This work aims to overcome the NNPDF4.0 PDFs determination, that did not include such effects and whose methodology is at   the basis of this analysis.  We first present the methodology used in the NNPDF4.0 PDFs fit.  Then, we explain how the QED effects have been added in the NNPDF4.0 fitting framework, describing the details of the implementation,  the resulting PDFs determination and the impact on physical processes of such PDFs.  Moreover, we explain how the MHOUs and aN$^3$LO effects have been included in NNPDF4.0, presenting the results of the two effects  both separately and combined.  We also show how the QED effects have been combined to MHOUs and aN$^3$LO and we will present the results of the PDFs  determination that includes all the three effects.  In conclusion, we will show an application to Monte Carlo event generator of the implementation of the QED effects  and of the development of a more flexible and efficient theory pipeline for the computation of the theoretical predictions  that has been interfaced to the NNPDF4.0 code and is at the basis of all the work described in this thesis.","language":"eng","citation":"ADVANCEMENTS IN PDFS DETERMINATION: INCORPORATION OF QED EFFECTS AND NEW THEORETICAL IMPROVEMENTS IN A MODERN DEEP LEARNING FRAMEWORK / N. Laurenti ; supervisore: S. Forte ; director of the school: A. Mennella. - Dipartimento di Fisica Aldo Pontremoli. Dipartimento di Fisica Aldo Pontremoli, 2024 Nov 08. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13427.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1115085/2576387/phd_unimi_R13427.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/958857"},"title":"DEVELOPMENT OF NEW PEPTIDE-BASED NANOMATERIALS AS POTENTIAL TOOLS FOR CRYOPRESERVATION OF TISSUES AND ORGANS","internalauthor":"IMPRESARI, ELISA","type":"Tesi di dottorato","year":"2023","abstract":"Transplant practise has improved life duration and quality of many patients. However, the worldwide need is not met yet due to the limited number of donor organs and the inefficient preservation methods, that hinder their long-term preservation. The main obstacle to achieve a successful cryopreservation is represented by the freezing and thawing processes needed to achieve cryogenic temperatures that can cause permanent and irreversible cellular damages. The solution to this issue may be found in nature, as several organisms living in extreme conditions produce specific proteins, termed antifreeze (glyco)proteins (AF(G)Ps), that are able to depress the freezing point of body fluids, control the ice crystal nucleation and inhibit their growth. In particular, the latter AFP property, the ice recrystallization inhibition (IRI), is highly desirable for new synthetic antifreeze materials as ice recrystallization during thawing is associated to cellular damage during cryopreservation. Therefore, one of the main challenges in biomedical research for organ transplantation is finding non-toxic and biocompatible antifreeze compounds that enable subzero storage and cryopreservation without causing tissue damage. As the synthesis of molecules to be used for cryopreservation represents an urgent need, in the last decades researchers have been extensively focused on it. Since the production of AF(G)Ps is expensive and presents several difficulties in its scale-up, and considering their potential cytotoxicity/immunogenicity and their tendency to denature, efforts have been focused on synthesising macromolecular cryoprotectant-polymers or minimising the AFP primary sequence through the synthesis of peptides or lastly, increasing the antifreeze activity through the exploitation of a multimeric approach, taking advantage from self-assembly processes or the simultaneous presentation of several ice binding motifs, that allows to reduce the concentration required for the effect. Although extensive efforts have been devoted to the synthesis of novel peptide or peptide-based cryoprotectants, limited results were achieved probably due to the poor understanding of the AF(G)Ps mechanism of action at molecular level and the lack of comprehensive structure-activity relationships. Considering the relevance and the global impact of that research field, finding new effective antifreeze compounds that can be translated into clinic represents an urgent need.  Being inspired by the multimeric approach, the aim of this PhD project was to develop new peptide-capped materials possessing an antifreeze activity by conjugating the N-terminus of peptides derived from type I AFP HPLC6 to different moieties that are known for their self-assembling ability. The goal of decorating nanoparticles (NPs) with peptides relies on combining the ice binding capability of peptides with the size of a NP, mimicking the globular protein bulkiness. In order to reach the goal, different approaches were exploited, as i) the on-resin peptide functionalization with lauric acid, ii) the in-solution peptide functionalization with the FDA approved polymer poly(lactide-co-glycolide) (PLGA) or iii) to gold nanoparticles (AuNPs), by inserting in peptide sequence a thiol-bearing binding functionality, and lastly, iv) the on-resin peptide functionalization with Aggregation-Induced Emission (AIE) luminophores, organic molecules characterized by uniquely fluorescent properties in the aggregate or solid state.     First of all, the synthesis of the precursor peptides has been optimized and their secondary structure has been characterized by circular dichroism (CD) and Attenuated Total Reflection-Fourier Transform Infrared (ATR-FTIR) spectroscopy. Considering the presence of different conformations and the lack of a preferred helical one, the secondary structure of the minimised sequence of type I AFP HPLC6 was stabilised using a click chemistry reaction, the copper(I)-catalysed azide-alkyne cycloaddition (CuAAC), by the insertion of the i, i+4 side-chain-to-side-chain triazole as conformational constraint. The conformation analyses carried out in solution revealed that the helical structure of both the obtained stapled peptides was successfully stabilised.   Afterwards, the different approaches to obtain different types of nanoparticles exposing multiple copies of the synthesised antifreeze-derived peptides were described.   First, soft NPs were synthesised by N-terminus functionalization of the precursor and stapled peptides with lauric acid. The secondary structure of the synthesised lipopeptides was assessed both in solution and in the solid state by CD and ATR-FTIR, respectively, whereas their tendency to self-assemble was investigated using a solvent displacement technique and characterised by Dynamic Light Scattering (DLS).   Another strategy was the in-solution functionalization of the purified peptides with PLGA. As for the lipopeptides, the four obtained conjugates were characterised based on their secondary structure and their self-assembly abilities.     The antifreeze peptides were also used to functionalize gold nanoparticles (AuNPs) by inserting in their sequence an appropriate binding functionality, able to stabilise the nanocolloidal systems with a set of helical, Ala-rich model peptides. Once synthesised and purified, the secondary structure of the thiol-derived antifreeze peptides was evaluated by CD and ATR-FTIR. Their conjugation to citrate-capped AuNPs via ligand exchange procedure was investigated by UV-Vis, DLS and zeta potential measurement.   Besides, the peptides were conjugated to AIE luminophores. To this aim, two hybrid compounds were synthesised, combining the AIE unique properties and the surfactant features of fatty acids, to be used as N-terminus capping agents in SPPS. These molecules were found to self-assemble into different supramolecular emissive structures depending on the chemical composition and water content. Furthermore, to assess the feasibility of the synthetic strategy, a model peptide was N-terminus functionalised, leading to the obtainment of luminescent fibrillary materials that were not cytotoxic and were able to create supramolecular gels in aqueous environment. Unluckily, the use of the two hybrid compounds for the synthesis of antifreeze peptide materials resulted in the formation of highly insoluble fluorescent compounds, characterized by a low purity degree.   Finally, the IRI activity of the peptides and peptide-capped based conjugates was evaluated. The ability of the different compounds to inhibit the ice crystal growth was assessed by optical microscopy, using the ‘sucrose sandwich’ assay. While the investigated peptides were not IRI active in the evaluated conditions, and the synthesised lipopeptides and PLGA peptide-based conjugates were found insoluble, the thiol-bearing peptides and the peptide-capped AuNPs showed an ice crystal growth rate lower than the sucrose solution or the naked gold nanoparticles.   In particular, the gold nanoparticles conjugated with the stapled thiol-derived peptide outperformed the other systems in decelerating, although partially, the ice recrystallization.","language":"eng","citation":"DEVELOPMENT OF NEW PEPTIDE-BASED NANOMATERIALS AS POTENTIAL TOOLS FOR CRYOPRESERVATION OF TISSUES AND ORGANS / E. Impresari ; tutor: S. Pellegrino ; coordinatore: G. Vistoli. Dipartimento di Scienze Farmaceutiche, 2023 Mar 27. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12640.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/958857/2160758/phd_unimi_R12640.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1197595"},"title":"RNA-MEDIATED PHASE SEPARATION OF 53BP1: CONNECTING CONDENSATE BIOPHYSICS TO DNA DAMAGE RESPONSE","internalauthor":"TERRANEO, FEDERICA","type":"Tesi di dottorato","year":"2025","abstract":"Biomolecular condensates, also known as membraneless organelles, are intracellular compartments which can form via liquid-liquid phase separation (LLPS) where biochemical reactions concentrate within the cell. An example of such condensates are DNA damage response (DDR) foci, proteins and RNA assemblies where DNA damage signaling and repair occur. We previously demonstrated that the DDR involves both proteins and sequence-specific RNAs and that DNA damage-induced long non-coding RNAs (dilncRNAs) and their processed shorter forms DDR RNAs (DDRNAs) facilitate the recruitment of DDR factors around DNA double-strand breaks (DSBs). Recently, we reported that among DDR components, 53BP1 accumulates at DNA damage sites in liquid-like foci, with RNA supporting this process and aiding the DNA repair pathway. However, mechanisms regulating 53BP1 condensation by RNA remain elusive.  Here, we identify 53BP1 molecular determinants driving RNA-mediated LLPS. By combining computational analyses, in vitro microscopy, and binding assays, we demonstrate that the oligomerization domain (OD) and its C-terminal disordered region containing a glycine-arginine-rich (GAR) motif are essential for phase separation. Mutagenesis experiments revealed that arginine residues in the GAR motif are crucial for RNA binding and condensate formation, while lysine substitutions only partially retain these functions. Using Differential Dynamic Microscopy (DDM), FRAP, and coalescence assays, we characterize the microrheological properties of 53BP1-RNA condensates. They exhibit a two-component behavior, with a viscoelastic gel-like core surrounded by a more fluid interfacial layer. A progressive loss of fluidity of the condensates also suggests a time- dependent maturation process, transitioning toward a more solid-like state, confirmed also by FRAP in living cells. Importantly, R>K substitutions in the GAR motif not only impair RNA binding but also induce aberrant LLPS, leading to condensates with reduced internal mobility and arrested fusions, further supporting the central role of arginine residues in the physiological assembly of 53BP1 foci. Notably, we show that the GAR motif of 53BP1 is required for efficient non-homologous end joining (NHEJ) of deprotected telomeres, as measured by the frequency of telomere fusions, highlighting its functional relevance in DNA repair. Finally, we prove that antisense oligonucleotides (ASOs) targeting telomeric transcripts reduce protein-RNA binding affinity, providing a possible mechanistic explanation for ASO-induced dissolution of DDR foci.  Collectively, we propose that the GAR motif of 53BP1 drives RNA interactions that are necessary for protein LLPS, and that RNA, by enriching into condensates, reshapes the composition of 53BP1 foci, creating a highly viscous liquid phase that possibly enables efficient DNA repair.","language":"eng","citation":"RNA-MEDIATED PHASE SEPARATION OF 53BP1: CONNECTING CONDENSATE BIOPHYSICS TO DNA DAMAGE RESPONSE / F. Terraneo ; tutor: F. d'Adda di Fagagna; internal advisor: V. Costanzo; external advisor: D. Durocher; PhD coordinator: D. Pasini. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Nov 12. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13502.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 21-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1018369"},"title":"BEYOND CHEMICAL SIGNALING: MECHANICAL FORCES AS DRIVERS OF MITOTIC AND METABOLIC CONTROL","internalauthor":"PORCELLA, GIANCARLO","type":"Tesi di dottorato","year":"2023","abstract":"Mechanotransduction, the process through which cells sense and respond to mechanical stimuli, plays a crucial role in cell homeostasis, survival and proliferation. Different types of human tissues present various mechanical properties, determinant for cell fate and health. Metabolic regulation and mitosis are among the most essential processes carried out by the cell. Although both have been extensively characterized biochemically and genetically, less is known about their mechanics and the central role played by mechanotransduction in their modulation. To elucidate these mechanisms, we deployed novel tools to exert mechanical stress on cells while monitoring their response. First, we investigated the effects of compression on cell division while targeting the DNA damage response kinase ATR. ATR mediates nuclear mechanotransduction and chromosome segregation, and its inhibition resulted in defective cell division and mitotic errors in presence of compression. Tumors are mechanically challenging microenvironments, and ATR inhibition may represent a strategy to increase tumor vulnerability. Secondly, to study the crosstalk between metabolism and mechanotransduction, we combined carbon starvation to mechanical stimulation in normal and cancer cells. Malignancy is accompanied by metabolic rearrangements, hindering the efficacy of therapies. We showed that modulation of mechanical forces and nutrient availability leads to differential responses in different cell types. Metabolic interventions could thus leverage the mechanics of a tumor as key components of therapy. Here, we developed ways to isolate the effects of mechanical stress on metabolism and cell division, confirming the importance of an integrated perspective on cell biology that includes mechanotransduction as a fundamental component.","language":"eng","citation":"BEYOND CHEMICAL SIGNALING: MECHANICAL FORCES AS DRIVERS OF MITOTIC AND METABOLIC CONTROL / G. Porcella ; supervisor: M. Foiani ; internal advisor: G. Scita ; external advisor: G. V. Shivashankar. Dipartimento di Oncologia ed Emato-Oncologia, 2023 Dec 12. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12705.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1018369/2327713/phd_unimi_R12705.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1197995"},"title":"POCKET-DETECTION METHOD WITH REAL-TIME INVASION ASSESSMENT AND ENDOSCOPIC RESECTION (PRIME) ALGORITHM FOR RECTAL LESIONS: A PROSPECTIVE COHORT STUDY","internalauthor":"SORGE, ANDREA","type":"Tesi di dottorato","year":"2025","abstract":"Background and Aims     The muscle-retracting sign (MRS) has shown moderate-to-high diagnostic accuracy in predicting deep submucosal invasion in rectal cancer. This study evaluated the technical outcomes of a diagnostic and therapeutic algorithm combining MRS evaluation and endoscopic resection for rectal lesions.      Patients and Methods      Prospective data from consecutive rectal lesions at risk of submucosal invasion at a tertiary centre between August 2023 and August 2025 were analyzed. An algorithm incorporating deep-margin optical diagnosis using the pocket-detection method (PDM) followed by endoscopic resection was applied.      Results      Among the 47 rectal lesions included, PDM was successful in all cases, with MRS detection in 34.0% (16/47) of the lesions. The technical success rate of endoscopic resection was 97.9% (46/47), with endoscopic submucosal dissection performed in 30 lesions (63.8%), endoscopic intermuscular dissection in 10 (21.3%), knife-assisted full-thickness resection in 5 (10.6%), and device-assisted full-thickness resection in 1 (2.1%) patient. En bloc, R0 resection, and R0 vertical margin rates were 100% (46/46), 93.5% (43/46) and 97.8% (45/46), respectively. Adverse events occurred in 10.6% (5/47) of patients (AGREE grade I, II and IIIa). 44.7% (21/47) of the included lesions were adenocarcinomas, and MRS accuracy for deep submucosal invasion was 85.1%.     Outcomes in MRS-positive and MRS-negative lesions did not differ significantly, including technical success (93.7% vs 100%), en bloc resection (100% vs 100%), and R0 resection (93.5% vs 93.3%; all p > 0.05). Rectal preservation rate was 91.5% (43/47).          Conclusion      The PRIME algorithm demonstrated that deep margin optical diagnosis can reliably guide rectal endoscopic resection, yielding excellent radical resection rates and safety in both MRS-positive and MRS-negative lesions.","language":"eng","citation":"POCKET-DETECTION METHOD WITH REAL-TIME INVASION ASSESSMENT AND ENDOSCOPIC RESECTION (PRIME) ALGORITHM FOR RECTAL LESIONS: A PROSPECTIVE COHORT STUDY / A. Sorge ; tutor: D. J Tate ; correlatori: G. E. Tontini, M. Vecchi ; coordinatore: M. Del Fabbro. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2025. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13869.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 24-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/936093"},"title":"LONG-DISTANCE TURGOR CHANGES INDUCE SYSTEMIC ACTIVATION OF PLANT GLUTAMATE RECEPTOR-LIKE CHANNELS","internalauthor":"GRENZI, MATTEO","type":"Tesi di dottorato","year":"2022","abstract":"Throughout their life plants, being sessile organisms, are continuously exposed to environmental challenges that need to be properly perceived and that require appropriate local and systemic responses. Calcium ion (Ca2+) is a key second messenger in all living beings that couples the perception of extracellular stimuli to characteristics intracellular responses. The specificity of the Ca2+-based signalling is achieved through the generation of specific spatial and temporal transient elevations in the cytosolic Ca2+ concentration [Ca2+]cyt, which are referred to as “Ca2+ signatures”. The interplay of Ca2+ signatures with a toolkit of cognate Ca2+-binding proteins that decode these increases allow the plant to implement a series of tailored physiological responses (e.g., gene expression, metabolism, developmental reprogramming) to withstand the stress. In plants, transient increases in the [Ca2+]cyt have been documented to be involved in several physiological processes including root or pollen tube growth and fertilization, abiotic stress responses, plant-microbe interaction. Ca2+ transients with unique magnitude, frequency, shape, and duration are generated by the orchestrated action of Ca2+ influx and efflux systems that include Ca2+ channels, pumps, and exchangers located at different cellular membranes. Given the importance and universality of Ca2+-based signalling, the identification of actors of the molecular machinery that govern the generation of Ca2+ signals is of primary importance. In this context, the study of Ca2+ dynamics in vivo represents a powerful tool.   In the frame of my PhD, I explored the marvellous world of Ca2+ imaging using some of the instruments made available from a vast universe of genetically encoded fluorescent Ca2+ biosensors. I learned and refined techniques to produce high-end images of in vivo Ca2+ dynamics both at the entire organism and single-cell level. The expertise that I acquired allowed me to contribute to different projects, all unified by the common denominator that is the master regulatory role of Ca2+ in many signalling processes. I therefore contributed to the study of: (i) the [Ca2+]cyt responses of root tip cells in response to different amino acids, helping to define the molecular determinants involved in the process (Alfieri et al., 2020); (ii) the characterization of [Ca2+]cyt transients induced by the administration of natural auxins and auxin analogues, and the deciphering of the role of molecular actors involved in the genesis of the auxin-induced [Ca2+]cyt response (Wang, Himschoot, Grenzi et al., 2022); (iii) the development of a novel genetically encoded Ca2+ biosensors to unravel the role of the endoplasmic reticulum in the shaping of the Ca2+ signature in developmental processes, as well as in response to various stimuli (Resentini, Grenzi et al., 2021); (iv) the modulatory effects of chemicals on the spontaneous [Ca2+]cyt oscillations of guard cells that govern the opening and closing of stomata. I also contributed to the preparation of reviews linked to the field of Ca2+ signalling. All the published manuscripts, as well as works in preparation, are attached at the end of this dissertation, to which I kindly redirect the readers. Here, I am presenting the main work of my PhD project which focused on the understanding of how local damages can trigger inducible defence mechanisms in systemic organs and tissues.  Systemic responses are mediated by long-distance signalling that requires the activity of Glutamate Receptor-Like channels (GLRs). GLRs are homologs of animal Ionotropic Glutamate Receptors (iGluRs) which are ligand-gated cation channels in the central nervous system. Even though iGluRs are gated through the binding with the L-Glutamate, the mechanism throughout GLRs are activated in planta is poorly understood. As an example, we still do not know if the GLRs binding of amino acids is necessary for their activity.   In this PhD thesis, we took the advantage of the recently obtained crystal structure of the Arabidopsis thaliana AtGLR3.3 Ligand Binding Domain (LBD) to identify residues involved in the amino acid-binding. We, therefore, introduced single point mutations in the genome sequence of the AtGLR3.3 gene to prevent or abolish its amino acid-binding, and with the obtained constructs we complemented the glr3.3 KO. By combining high-end imaging, genetics, and bioelectronics we prove that leaf injury, such as wound and burn, and root-applied hypo-osmotic stress induce the systemic apoplastic increase of L-Glutamate that activates GLR channels through their LBD.  In addition, our work supports the evidence that long-distance signalling is governed by a systemic change in the turgor state and that GLRs are downstream of it.","language":"eng","citation":"LONG-DISTANCE TURGOR CHANGES INDUCE SYSTEMIC ACTIVATION OF PLANT GLUTAMATE RECEPTOR-LIKE CHANNELS / M. Grenzi ; tutor: A. Costa ; supervisore: A. Costa ; coordinatore: A. Costa. Dipartimento di Bioscienze, 2022 Jul 21. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12264.pdf","fileformat":"Adobe PDF","fileversion":"preprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/936093/2059845/phd_unimi_R12264.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1201975"},"title":"¿CHIOS MASTIC GUM FROM PISTACIA LENTISCUS AS A MODULATOR OF INFLAMMATION AND INTESTINAL BARRIER FUNCTION: AN IN VITRO AND CLINICAL INVESTIGATION.¿","internalauthor":"XYNOMILAKIS, ORNELLA","type":"Tesi di dottorato","year":"2026","abstract":"Inflammatory Bowel Disease (IBD) is an immune-mediated disorder characterized by dysregulated inflammation and impaired intestinal barrier function. Although effective, current therapies present limitations, highlighting the need for complementary approaches. Chios Mastic Gum (CMG), a resin from Pistacia lentiscus, has shown anti-inflammatory and barrier-protective properties in preclinical models. During this PhD project, an integrated clinical and mechanistic study was conducted to evaluate CMG (trade name Selpic) in patients with IBD.  A randomized, double-blind, placebo-controlled trial involved 31 adults diagnosed with ulcerative colitis or Crohn's disease who were in clinical remission yet exhibited subclinical inflammation. Standardized questionnaires and faecal biomarkers (calprotectin, zonulin), were utilized to assess clinical outcomes. Concurrently, in vitro experiments compared Selpic with its isolated Supermastic® triterpene fraction in Caco-2 cells and lipopolysaccharide-stimulated THP-1 macrophages. Clinically, no significant differences were observed in the questionnaires and calprotectin levels, although a downward trend was noted for the latter (p=0.062). Faecal zonulin levels showed a significant decrease over time (p=0.017), with within-group analysis indicating a significant reduction in the Selpic group (p=0.036). No intergroup treatment effect was identified (p=0.107). In vitro, Selpic was found to suppress pro-inflammatory cytokine levels, diminish reactive oxygen species, encourage anti-inflammatory macrophage polarization, and enhance the expression of ZO-1 tight junction protein. Still, it modulated the endocannabinoid system by reducing N-acylethanolamines SEA and PEA. Analysis of gut microbiota indicated no alterations in α-diversity, but a temporal shift in β-diversity was observed within the Selpic group.  In conclusion, faecal zonulin levels decreased over time, with a significant reduction in the Selpic group, though no intergroup treatment effect was confirmed. These results, combined with in vitro immunomodulatory and barrier-restorative effects, support Selpic potential as an adjuvant nutraceutical in IBD management. Larger multicentre trials are warranted to validate its clinical utility.","language":"eng","citation":"Chios Mastic Gum from Pistacia lentiscus as a Modulator of Inflammation and Intestinal Barrier Function: An In Vitro and Clinical Investigation / O. Xynomilakis ; tutor: P. Ciuffreda ; cotutor: R. Ottria ; coordinator: F. Cheli. Dipartimento di Scienze Biomediche e Cliniche, 2025 Jan 26. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14010.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 04-DIC-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1166644"},"title":"URBAN EXILES. MIGRATION GOVERNANCE, ASYLUM, DISPLACEMENT AND SEGREGATION IN ATHENS.","internalauthor":"SOSSICH, ERASMO","type":"Tesi di dottorato","year":"2025","abstract":"The research examines the appearance of new figures of segregation and displacement following the turn in European migration governance. As new governmental instruments of containment, dispersal and concentration combine, new geographies of mobility and immobility (Tazzioli & Garelli, 2018) gradually reshape the spaces of the ‘urban diaspora’ described by Arbaci (2018) and new figures of global and urban displacement intertwine, reshaping cities, mobilities, and subjectivities (Roast et al., 2022). The thesis proceeds by reconstructing Athens' urban development, focusing on the urbanization process and the role played by internal and international migrations, going on to trace the gradual emergence of its social geography and segregation patterns. The research then focuses on the transformation of ‘border regimes’, reception policies, and displacement strategies after the so-called “refugee crisis”, and their direct and indirect spatial productivity on the wider process of urban change, suggesting an ongoing transformation of previously established residential patterns. Thus, it is suggested that the ongoing process of ‘campization’ of reception systems (Kourachanis, 2018b; Kreichauf, 2018) and the emergence of a segmented integration regime, mirroring the stratification of the Greek ‘mobility regime’, has altered previous patterns of segregation, combining extra-urban confinement and the institutional segregation of a growing population within the camp system with the radicalization of both “vertical” and “horizontal” segregation in specific districts and specific segments of the housing market, the underground short-term rental market. Moreover, the housing careers of these ‘migrantized’ subjects (Tazzioli & De Genova, 2023) appear to be marked by continuous and repeated evictions, removals, and relocations, i.e. a continuous cycle of endless displacement (Sossich, 2024). The thesis finally moves onto the case of Eleonas camp, the last refugee camp in Athens, evicted in 2022 in order to pursue a major regeneration project, despite the strong opposition of its residents. Reconstructing the dynamic of this conflict and addressing the role of the ethnographer within a “field” shaped by structural violence, the reflection moves on the connection between the “right to the city” and the exclusion from “citizenship” implied in the process of extra-urban confinement and the ongoing transformation of asylum in a new form of urban exile. Finally, the Eleonas case highlights how the analysis of dispersal and displacement technologies and trajectories can help shed light on new forms of segregation, but also on the ways in which urban and migration governance combine to promote new forms of accumulation through displacement.","language":"eng","citation":"URBAN EXILES. MIGRATION GOVERNANCE, ASYLUM, DISPLACEMENT AND SEGREGATION IN ATHENS / E. Sossich ; tutor e supervisors: G. Semi, Professore Ordinario Dipartimento Interateneo di Scienze, Progetto e Politiche del Territorio (DIST) - Università degli Studi di Torino (UniTo) ;  M. Ambrosini; Professore Ordinario Dipartimento di Scienze Sociali e Politiche - Università Statale di Milano (UniMi) coordinatore del dottorato: P. Rebughini. - Università degli Studi di Milano. Università degli Studi di Milano, 2025 May 14. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R13022.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 26-NOV-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1234396"},"title":"BIOMEDICAL, IMMUNOLOGICALS AND EPIDEMIOLOGICAL STUDIES ON LEISHMANIA","internalauthor":"CATTANEO, GIULIA MARIA","type":"Tesi di dottorato","year":"2026","abstract":"Abstract of the thesis  Leishmania tarentolae is a non-pathogenic protozoan parasite generally associated with reptiles, which has recently emerged as a versatile model in biothecnological and biomedical research. It is characterized by rapid growth rate, low maintenance cost, and can be handled under Biosafety Level 1 (BSL-1) conditions, making it a safe and accessible laboratory system. Despite being non-pathogenic, L. tarentolae retains molecular and biological features common to pathogenic Leishmania species, representing a relevant model for host–parasite interaction studies.  L. tarentolae is increasingly used as a eukaryotic expression platform for the production of heterologous protein. Unlike Escherichia coli, it performs mammalian-like post-translational modifications, including glycosylation, while avoiding the hyper-mannosylation introduced by yeast systems, which may compromise protein folding and functionality for biomedical use. Compared with mammalian cell cultures, L. tarentolae o[ers lower operational costs, high scalability, and reduced biosafety constraints. These combined features reinforce its attractiveness as a cell factory for biotechnological and therapeutic applications.  This PhD research investigates the technological, immunological and diagnostic potential of L. tarentolae through four major lines of investigation:  • Development of a chemically defined medium for L. tarentolae growth, enabling its  conformity with biomedical research guidelines;  • Application of L. tarentolae as a mucosal delivery system for recombinant antigens,  demonstrated with the experimental SARS-CoV-2 vaccine LeCoVax-2;  • Exploitation of L. tarentolae as a mucosal vaccine vector, to explore its potential to elicit a  specific immune response.  • Evaluation of host–parasite interactions, focusing on primary canine macrophages cell line.  In addition, considering the current limited knowledge on the distribution of Leishmania tarentolae, this thesis also investigates the epidemiology and diagnostic detection of this parasite in northern Italy. Particular attention is given to the possible involvement of sand fly Sergentomyia minuta, which is traditionally considered the vector of L. tarentolae and has previously tested positive for L. infantum DNA. Furthermore, L. tarentolae DNA detection in human and canine blood raises questions about the potential expansion of its host range.  6  Considering this, the thesis also examined the presence of Sauroleishmania in additional hosts, including fire salamanders and geckos, while focusing on the role of synanthropic reptiles. This investigation is particularly relevant considering that the close association of these hosts with human environments and domestic animals may facilitate the circulation of Leishmania parasites.  Basing on this evidences, the research conducted in this thesis focuses also on:  • The development of a highly sensitive method for simultaneous detection of the non- pathogenic L. tarentolae and the pathogenic L. infantum in sand flies and reptile blood samples.  • A screening of L. tarentolae and L. infantum in synanthropic reptiles and in sand fly vectors in the northern Italy.  • Investigation of the host range of Sauroleishmania species in non-traditional hosts, including fire salamanders and African geckos.  The results obtained in these studies are presented in eight publications included in the thesis:  Article 1: A novel chemically defined medium for the biotechnological and biomedical exploitation of the cell factory Leishmania tarentolae.  [published in: Scientific Repors].  This study describes the development of a medium without animal supplementation for the cultivation of L. tarentolae cultures, enabling its applications in the biomedical field. The chemically-defined medium was also tested and validated on recombinant L. tarentolae clones, higliting its potential for the production of recombinant proteins and its exploitation as cell factory.  Article 2: EQicacy of mucosal vaccination using a protozoan parasite as a vehicle for antigen delivery: IgG and neutralizing response after rectal administration of LeCoVax-2, a candidate vaccine against COVID-19.  [published in: Pharmacological Research]    This study investigates the potential of recombinant L. tarentolae clones as vehicle for mucosal vaccine delivery, exploiting an engineered L. tarentolae clone expressing a SARS-CoV-2 antigen. This article aims to explore the possibility of inducing systemic and mucosal immune reponses, including IgG and neutralizing anitbodies, through a rectal administration. This innovative strategy contributes to revealing the potential versatility of L. tarentolae platform.  Article 3: Rectal Administration of Leishmania Cells Elicits a Specific, Th1-Associated IgG2a Response in Mice: New Perspectives for Mucosal Vaccination against leishmaniasis, after the Repurposing of a Study on an Anti-Viral Vaccine Candidate.  [published in: Tropical Meidcin and Infectious Disease]  This study investigates L. tarentolae as a mucosal vaccine vector against leishmaniasis via rectal administration in a murine model, demonstrating its ability to induce a robust Th1- oriented immune response, which is associated with protective immunity against Leishmania. These findings open new avenues for alternative vaccination routes.  Article 4: Intracellular persistence of Leishmania tarentolae in primary canine macrophage cells.  [published in: Acta Tropica]  This study focused on the interaction between primary canine macrophages and L. tarentolae, exploring its intracellular behaviour, evaluating the possible cytopathic e[ects and the host immune response. The results indicate that L. tarentolae is non-pathogenicity and can persist intracellularly without inducing cytopathic e[ects, higliting its potential as a versatile platform for biomedical applications.  Article 5: Development of a novel ddPCR assay for the simultaneous detection of the protozoan parasites Leishmania infantum and Leishmania tarentolae. [published in: Parasites&Vectors]  This study describes the development of a digital droplet PCR (ddPCR) assay for the simoultaneous detection of the non-pathogenic L. tarentolae and the pathogenic L. infantum. This research aims to develope an highly sensitive and specific assay that can provide and higher accuracy in Leishmania diagnostics avoiding cross-reaction results.    Article 6: Sand Fly Fauna and Prevalence of Leishmania spp. in a Newly Investigated Area of Northern Italy: Emerging Epidemiological Scenarios? [published in: Transboundaries and Emerging Diseases]  This study investigates the circulation and distribution of L. tarentolae and L. infantum in Northern, focusing of sand flies and reptile blood samples. A ddPCR developed during the PhD period was employed to obtain a higly sensitive detection. This research evaluate also the potential role of synanthropic reptiles as reservoirs, and assess emerging epidemiological scenarios for Leishmania transmission.  Articole 7: Beyond reptiles: the fire salamander as a potential host for Leishmania (Sauroleishmania) tarentolae [published in International Journal of Parasitology: Parasites and Wildlife]  This study investigates the potential role of fire salamanders as hosts for Leishmania (Sauroleishmania) tarentolae, expanding the understanding of the parasite’s host range. The research evaluates the presence of the parasite in non-traditional hosts, considering the ecological implications for parasite circulation and transmission dynamics.  Article 8: Unveiling Sauroleishmania in southern Africa: An investigation and supplementary description of Leishmania (Sauroleishmania) zuckermani from the gecko host Chondrodactylus bibronii [published in International Journal for Parasitology: Parasites and Wildlife]  This study presents a work carried out during a three-months research period abroad at the University of Free State (Bloemfontein, South Africa), exploring the distribution and host associations of Sauroleishmania in African geckos. The research provides insights into the ecology and host specificity of Sauroleishmania species, highlighting potential new reptile hosts and contributing to the understanding of parasite circulation in non-European regions.  In conclusion, the results presented in this thesis provide a comprehensive overview of L. tarentolae as both an emerging biotechnological tool and a parasite of epidemiological relevance. The study highlights the potential of L. tarentolae as a safe and scalable platform for recombinant protein production and mucosal vaccine delivery, while also exploring its immunomodulatory properties and host–parasite interactions in mammalian cells.  9    Furthermore, this thesis addressed the development of sensitive molecular tools for the simultaneous detection of L. tarentolae and L. infantum. Investigations on sand flies and synanthropic reptiles further contribute to understanding parasite circulation and potential transmission pathways in Northern Italy. Finally, studies on non-traditional hosts, including fire salamanders and African geckos, expand our knowledge of Sauroleishmania host range and distribution.  Collectively, these studies underscore the dual significance of L. tarentolae as both a biotechnological resource and a topic of epidemiological interest.","language":"eng","citation":"BIOMEDICAL, IMMUNOLOGICALS AND EPIDEMIOLOGICAL STUDIES ON LEISHMANIA / G.m. Cattaneo ; tutor: C. Bandi ;  co-tutor: S. Epis ;  coordinatore del corso di dottorato:  M. P. M. Guarino. Dipartimento di Bioscienze, 2026 Apr 22. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13795.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1234396/3302147/phd_unimi_R13795.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1128195"},"title":"THERAPEUTIC POTENTIAL OF TARGETING THE FLNA-REGULATED WEE1 KINASE PATHWAY IN ADRENOCORTICAL CARCINOMAS.","internalauthor":"ESPOSITO, EMANUELA","type":"Tesi di dottorato","year":"2025","abstract":"Adrenocortical carcinomas (ACC) are highly aggressive tumors with very limited treatment options. Alterations in cell cycle-related genes have been identified as key ACC drivers, and they are largely present in the most aggressive tumor subtypes.  Compared to benign adenomas (ACA), the cytoskeletal protein filamin A (FLNA) is poorly expressed in ACC. Of note, its presence, even at low levels, is associated to a less aggressive tumor behaviour, potentially due to its role in negatively regulating the insulin-like growth factor 1 receptor (IGF1R) signalling. Upregulation of Wee1 nuclear kinase, a key regulator of G2/M cell cycle checkpoint, was shown in mouse neural progenitor cells lacking FLNA, and it has been reported in several cancers. The first part of this PhD thesis is focused 1) on the analysis of Wee1 expression in ACC and its regulation by FLNA, 2) on the effects of the specific Wee1 inhibitor AZD1775, 3) and lastly on the impact of FLNA on its efficacy in three different ACC cell lines (H295R, MUC-1, and TVBF-7) and in patient-derived primary cultured ACC cells. Analysis of FLNA and Wee1 proteins revealed elevated Wee1 and reduced FLNA in ACC compared to normal adrenal gland (NAG). FLNA knockdown increased Wee1 protein in H295R, MUC-1, and in primary ACC cells. Higher p-CDK1 and cyclin B1 were shown in FLNA-silenced MUC-1, while decreased Wee1, p-CDK1 and cyclin B1 resulted after FLNA overexpression. Notably, Wee1 depletion was reverted by lactacystin treatment, and FLNA transfection increased Wee1 phosphorylation at Ser123 residue, suggesting FLNA role in targeting Wee1 for proteasomal degradation. AZD1775 dose-dependently reduced proliferation and viability in ACC cell lines and primary cultures, and it triggered MUC-1 cells death. Similar effects were induced by Wee1 silencing. FLNA depletion augmented AZD1775 efficacy in reducing proliferation and potentiating apoptosis in MUC-1 and primary cells. In conclusion, we demonstrated that FLNA regulates Wee1 expression by promoting its degradation, suggesting that low FLNA typical of ACC leads to increased Wee1 with consequent cancer cells growth. Therefore, it proposes Wee1 inhibition as a new potential therapeutic approach for ACC, particularly for those lacking FLNA.   Polo-like kinase 1 (PLK1) and cyclin-dependent kinases (CDKs) 1/2/4 are among the most overexpressed cell cycle-related genes in ACC human samples. Previously, the efficacy of the polo-box domain (PBD)-targeting PLK1 inhibitor Poloxin has been demonstrated in ACC cell lines (H295R, MUC-1, CU-ACC2). The second part of this PhD thesis is centred on testing 1) the efficacy of Poloxin and of the kinase domain (KD)-targeting PLK1 inhibitor Plogosertib, and 2) the efficacy of the multi-CDKs inhibitors Dinaciclib, SNS-032, and AT7519, as well as that of the CDK1-cyclin B1 inhibitor Cucurbitacin E, on cell proliferation, viability, and apoptosis; lastly, 3) the combinatorial effect of Plogosertib and Dinaciclib on ACC cells proliferation. Experiments were carried out in four human ACC cell lines, including H295R, MUC-1, TVBF-7 and the recently acquired JIL-2266. PLK1 inhibitor Poloxin reduced cell proliferation and viability at very high doses, reaching a maximum effect at 100 µM, and increased apoptosis at 10 µM. At much lower doses, Plogosertib induced a dose-dependent reduction of cell proliferation and viability, and an increase of caspase 3/7 activity. The multi-CDKs inhibitor Dinaciclib reduced cell proliferation at low nanomolar concentrations, having a very strong effect in the MUC-1 and JIL-2266 cell lines. It also increased apoptosis, particularly of TVBF-7 cells. Cucurbitacin E reduced proliferation in all ACC cells, but its effects were less pronounced than that induced by Dinaciclib. Synergistic inhibition of cell proliferation by combined treatment with the PLK1 inhibitor Plogosertib and multi-CDKs inhibitor Dinaciclib was observed in H295R and TVBF-7 cells. In conclusion, we identified Plogosertib and Dinaciclib as the most effective PLK1 and multi-CDKs inhibitors on all cell lines, respectively, therefore representing interesting novel treatment options for ACC. Moreover, the combination of these drugs showed a significant synergistic effect, suggesting a potential benefit of using both of them to increase therapeutic efficacy and to reduce potential side effects.","language":"eng","citation":"Therapeutic potential of targeting the FLNA-regulated Wee1 kinase pathway in adrenocortical carcinomas / E. Esposito ; tutor: E. M. Peverelli ; director: N. Landsberger. - LITA Segrate, aula C. Dipartimento di Scienze Cliniche e di Comunità, 2025 Jan 15. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13306.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1128195/2617750/phd_unimi_R13306.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1023372"},"title":"IDENTIFICATION OF GENES RELATED TO BIOTIC STRESS RESISTANCE IN GRAPEVINE","internalauthor":"RICCIARDI, VALENTINA","type":"Tesi di dottorato","year":"2024","abstract":"Downy mildew (Plasmopara viticola) and powdery mildew (Erysiphe necator) are some of the biggest threats affecting grapevine production. Part of the solution to the problem could be the development of breeding programs for resistant varieties.  In this context, the aim of this PhD project has been the identification of new resistance and susceptibility genes for future exploitation in the development of grapevine resistant varieties.  To do that, the project has been divided in different work packages. The first one was about the genome assembly and study of Mgaloblishvili, the first identified downy mildew resistant Vitis vinifera variety. In the genome, three resistance loci, Rpv29, Rpv30 and Rpv31, were successfully identified and analyzed for gene content and expression during P. viticola infection.   The second work package was about the validation assay of VviLBDIf7, a candidate gene of susceptibility to downy mildew. Similarly, the third work package was dedicated to the screening for new candidate genes of susceptibility to downy mildew, starting from a previously published RNA-sequencing experiment and focusing on nitrogen metabolism. Both in the second and third work package a transient RNA interference (RNAi) approach based on the exogenous application of dsRNA was applied, and VviLBDIf7 was proved to be a promising candidate S gene.  Finally, the fourth work package was about a Genome Wide Association Study (GWAS) for the identification of new resistance loci to downy mildew and powdery mildew. The study was conducted on a population of V. vinifera varieties originated in the Caucasus and neighboring regions, one of the two domestication centers of grapevine. Four new loci where identified and analyzed for gene content. Interesting new candidate genes of resistance were hypothesized.  All together, these results will contribute to the increase of knowledge on plant-pathogen interaction and, hopefully, to viticulture sustainable disease management.","language":"eng","citation":"IDENTIFICATION OF GENES RELATED TO BIOTIC STRESS RESISTANCE IN GRAPEVINE / V. Ricciardi ; tutor: G. De Lorenzis ; coordinatore: P. A. Bianco. - Università degli Studi di Milano. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2024 Jan 22. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12871.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1023372/2343204/phd_unimi_R12871.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1156035"},"title":"MODIFYING PHYLLOTAXIS IN BRASSICA SEED CROP SPECIES FOR YIELD IMPROVEMENT","internalauthor":"FERRARIO, CARLOTTA CLAUDIA","type":"Tesi di dottorato","year":"2025","abstract":"In a world that is continuously growing and developing, it is crucial to enhance agricultural  yields to ensure an adequate food supply for the population while minimizing environmental  impact. Plant yield is influenced by a range of factors, among which inflorescence  architecture and its geometrical organization, known as phyllotaxis. Despite centuries of  studies, the mechanism behind phyllotactic patterning is still partially unknown, especially  in non-model plant species. Furthermore, the direct impact of phyllotaxis on overall yield  is not well understood.  In this thesis, we started to tackle these knowledge gaps. First, we reported support to the  hypothesis of a direct link between phyllotaxis and yield by describing several Arabidopsis  REM mutants with a permutated phyllotaxis and an increased number of siliques on the main  stem.  Consequently to this result, we aimed to investigate the conservation of such a mechanism  in the economically important crop Brassica napus.  We identified the candidate homologous genes in rapeseed and confirmed their expression  in reproductive tissues. Moreover, we demonstrated that they can influence phyllotaxis in  Arabidopsis, suggesting a retained role between these two species. Protein interaction tests  further suggested that some interaction between REMs themselves and the auxin pathway  can be conserved.  To finally prove the mechanism in rapeseed, we aimed to generate the homolog REM mutants  in the species by CRISPR-Cas9 gene editing. After an in silico and experimental selection of  the gRNAs, we focused on the Agrobacterium mediated transformation of rapeseed.  According to our results, both the transformation protocol as well as the editing need to be  optimized if we want to apply up to date molecular techniques in Brassica napus.  Indeed, we detected inefficiency and high technical requirements in the transformation  protocol and a low functionality of the editing machinery in transformants, the latter being  reported in literature too.  Optimizing such techniques can exponentially speed up basic and applied research in  rapeseed and open new possibilities in crop design. Indeed, multiple mutants are very often  required to get phenotypes in high redundant genomes such as the one of Brassica napus  and producing them by random mutagenesis is highly time consuming.  Overall, this application-driven study unveils novel genes associated with phyllotaxis and  yield in the Brassicaceae family, contributing to our understanding of plant architecture and  offering insights into sustainable strategies for improving crop productivity.","language":"eng","citation":"MODIFYING PHYLLOTAXIS IN BRASSICA SEED CROP SPECIES FOR YIELD IMPROVEMENT / C.c. Ferrario ; scientific supervisor: M. M. Kater ; tutor: V. Gregis, F. Caselli ;  PhD school coordinator: R. Mantovani. - dipartimento di bioscienze - Università degli studi di Milano. Dipartimento di Bioscienze, 2025 Mar 31. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13439.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1156035/2725817/phd_unimi_R13439.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1229395"},"title":"DEVELOPMENT AND APPLICATION OF COMPUTATIONAL APPROACHES FOR SINGLE CELL RNA SEQUENCING DATA ANALYSIS","internalauthor":"TRAVERSA, DANIELE","type":"Tesi di dottorato","year":"2026","abstract":"During my PhD, I focused on the development and application of bioinformatics methods for  the analysis of data produced by single-cell technologies, with a particular focus on single-cell  RNA sequencing (scRNA-seq). A critical challenge in this field is the automatic annotation of  cell identity, where no standardized strategy currently exists due to inherent limitations such as  data sparsity, low transcript detection, and dependence on heterogeneous reference datasets.  To address this gap, I developed SCARLET, a novel probabilistic framework that defines cel-  lular identity as the transcriptional program that most likely explains a cell’s gene expression  profile. SCARLET integrates bootstrap-based gene selection with a mutual-information ap-  proach to derive transcriptional programs and quantify their similarity, and employs likelihood-  based modeling to assign cells to one or multiple plausible identities. Unlike existing methods,  SCARLET explicitly accounts for the limitations of scRNA-seq. Benchmarking confirmed its  competitive or superior performance relative to state-of-the-art tools. Applied to large-scale  datasets encompassing more than 5 million cells, SCARLET reduced redundant labels while  preserving annotation concordance, demonstrating both scalability and robustness.  Beyond methodological advances, I applied single-cell approaches to two biological contexts.  In rice shoot apical meristems, snRNA-seq analysis revealed transcription factor families dy-  namically regulating floral transition, while underscoring current obstacles in plant single-cell  research, including incomplete transcriptome coverage and limited reference resources. In  breast cancer, scCROP-seq analysis uncovered mechanisms of tumor heterogeneity and evolv-  ability under estrogen deprivation, identifying both perturbation-specific and shared transcrip-  tional programs that illuminate adaptive survival strategies.  Overall, this work advances computational strategies for cell identity annotation, delivers new  biological insights, and highlights the need for improved data quality, multi-omics integration,  and broader application of single-cell methods across diverse organisms.","language":"eng","citation":"DEVELOPMENT AND APPLICATION OF COMPUTATIONAL APPROACHES FOR SINGLE CELL RNA SEQUENCING DATA ANALYSIS / D. Traversa ; supervisore: M. Chiara; scientific committee progress report: I. Barozzi ; scientific committee progress report: M. Cereda, S. Ricagno ; scientific committee progress report: M. Delledonne ; external evaluator: I. Barozzi ; external evaluator: D. A. Silvestris. Dipartimento di Bioscienze, 2026 Mar 27. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13894.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1229395/3286412/phd_unimi_R13894.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1211155"},"title":"INTEGRATING URBAN FOREST COOLING, THERMAL MONITORING, AND ECOLOGICALDYNAMICS FOR CLIMATE-RESILIENT CITIES","internalauthor":"SAINI, MICHEL","type":"Tesi di dottorato","year":"2026","abstract":"Urban forests are increasingly recognized as vital assets in mitigating urban heat stress, one of  the most pressing climate-related hazards across Europe. Yet important uncertainties still  constrain their effective design and management. A first challenge lies in the limited knowledge  of how far cooling benefits extend beyond forest edges, and how this spatial reach depends on  canopy density and structural features. To address this, a network of 169 air temperature  sensors was deployed across nine urban forests in the Milan Metropolitan Area. Results  showed that cooling extended up to 180 meters from forest cores, with reductions of up to –3.5  °C in mean temperature and –5.5 °C in maximum temperature during the hottest months, and  that higher canopy density consistently amplified both the intensity and extent of this effect.  A second limitation arises from the way urban cooling is typically measured. Most studies rely  on satellite-derived Land Surface Temperature (LST), despite persistent doubts about its  suitability as a proxy for the air temperature actually experienced by citizens. By comparing  ground-based measurements against Landsat data, systematic biases were revealed: LST  underestimated air temperature under cooler conditions, but shifted to substantial  overestimation during extreme heat, with the bias intensifying alongside rising LST values.  These errors were strongly mediated by vegetation cover and local microstructure,  underscoring the need for caution in using LST to infer human thermal exposure.  A third challenge concerns the establishment of urban forests themselves, since the long-term  delivery of cooling depends on planting strategies adopted in the earliest phases. By testing  different planting densities in mixed-species plantations, the study found that intermediate  densities (≈2000 trees per hectare) optimized root biomass while balancing competition,  creating conditions for healthier, more resilient stands.  8  Together, these studies address three interlinked gaps - spatial reach, measurement accuracy,  and establishment strategy - while providing concrete evidence to overcome them. They  demonstrate that the heat mitigation potential of urban forests depends not only on canopy  structure, but also on how their performance is measured and how plantations are initially  designed. Integrating precise, ground-level monitoring with ecologically informed planting  practices emerges as a necessary pathway for delivering durable and equitable cooling  benefits in increasingly heat-stressed urban environments.","language":"***","citation":"Integrating urban forest cooling, thermal monitoring, and ecological dynamics for climate-resilient cities / M. Saini ; tutor: I. Vagge ; co-tutors: G. Vacchiano (UniMi), G. Ovando (UNC), R. Tognetti (UniBz) ; coordinatore: M. Guarino. - Milano. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2026 Jan 22. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14020.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 23-GEN-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/916008"},"title":"GENETIC DYSLIPIDAEMIAS IN THE ITALIAN AND RUSSIAN POPULATIONS:FROM THE CLINIC TO THE BENCH","internalauthor":"ALIEVA, ASIIAT","type":"Tesi di dottorato","year":"2022","abstract":"Genetic dyslipidemias are a heterogeneous group of disorders, and familial hypercholesterolemia (FH) is the most common one, that are characterized by abnormal levels of circulating lipoproteins and leading to premature cardiovascular diseases (CVD).  Despite the need for an accurate and timely diagnosis due to high cardiovascular risk of those patients  - there is still no well-managed system for a diagnosis and treatment of patients with severe dyslipidemias,  - there are still some gaps between clinical and genetic diagnosis scores that need to be improved to increase their reliability at the population level.  To overcome the above mentioned challenges, national registries on lipid disorders have been created as a tool to improve a screening programs and to make a progress towards formulating a joint consensus on methods to improve accuracy of its diagnosis and cardiovascular risk stratification.  The Italian and Russian Genetic Network (a background for the current PhD project) has been initiated with the primary focus on familial hypercholesterolemia as a genetically determined lipid disorder with the highest prevalence worldwide.  The key goal of the current PhD thesis was to provide a phenotype – genotype characterization of the two populations aiming to use these data for searching of new approaches for improvement of an accuracy of FH diagnostics and cardiovascular risk stratification to promote in a future personalized approach in a disease management. The additional advantage of the current Network is an availability of a two-population validation of potential new markers for FH detection to will allow for an improvement of current algorithms.   Thus, we studied two cohorts from north cities of Italy and Russia (Milan and Saint Petersburg), a phenotype – genotype characterization for both cohorts was performed as well as concreate gaps between clinical and genetic diagnosis were described. The ultrasound measurement of Achilles tendon thickness was considered as a potential marker to fill in the gap between clinical and genetic FH diagnosis that brings an additional value to identification of FH subjects with higher LDL-C burden that may affect the level of the aggressiveness for the therapeutic strategies. Furthermore, proteomic data analysis demonstrated that a set of immune-inflammatory proteins associated with increased CVD risk, significantly characterize the clinically determined FH phenotype. Crossing the clinical phenotype with genetic analysis allowed to identify genetically positive FH individuals that, in addition to a higher LDL-C burden, were also characterized by a peculiar set of immune-inflammatory proteins as compared to genetically negative ones. By pairing genetically positive and negative FH patients for LDL-C levels, a number of significantly different proteins was indicated, that let to suggest that the prognostic value of these proteins should be longitudinally addressed.  In conclusion, the Italian and Russian Genetic Network contributed to reinforcing of knowledge about FH in both countries within the access to performing and interpretation of genetic results and analysis of approaches for an increase FH detection and risk stratification accuracy to driving improvement in standards of care for FH patients globally.","language":"eng","citation":"GENETIC DYSLIPIDAEMIAS IN THE ITALIAN AND RUSSIAN POPULATIONS:FROM THE CLINIC TO THE BENCH / A. Alieva ; tutor: A. L. CATAPANO ; PhD programme coordinator: G. D. Norata. Dipartimento di Scienze Farmacologiche e Biomolecolari, 2022 Apr 04. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12307.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/916008/2001785/phd_unimi_R12307.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1118252"},"title":"INTEGRATIVE MODELLING FOR THE CHARACTERISATION OF THE STRUCTURE AND DYNAMICS OF BIOMOLECULES","internalauthor":"BALLABIO, FEDERICO","type":"Tesi di dottorato","year":"2024","abstract":"This work explores the benefits of integrating computational structural biology techniques with experimental data to overcome the inherent limitations of each approach. Integrative modelling provides a more comprehensive understanding of the structure, dynamics, and function of complex biomolecular systems. Experimental data can guide computational methods, improving accuracy, reducing limits and approximations, and validating results, while computational techniques inspire new experimental designs and provide explanations for observed phenomena. In this work, I have reported on some personal contributions that exemplify the application of computational techniques in the context of integrative modelling, with a particular focus on three main manuscripts. The first paper describes the development of a small-angle scattering model for the in silico reconstruction of scattering intensities from atomic coordinates during molecular dynamics (MD) simulations. This model can be coupled with restraining strategies, such as metainference, to generate conformational ensembles at atomistic resolution in agreement with the experimental data using MD simulations. This approach was used to determine the closed state conformations of the human gelsolin, a plasma protein. The second manuscript investigates the inactivation mechanism of the human olfactory receptor OR51E2. MD simulations revealed that calcium ions play a key role in stabilising the inactive state of the protein. This study integrates different computational techniques to propose a novel molecular mechanism of receptor inactivation and provides a rationale for future experimental validation. The third manuscript explores the molecular basis of a pale green phenotype in the barley population TM2490, linked to a mutation in magnesium chelatase subunit I, an enzyme involved in the chlorophyll synthesis pathway. AI-based structural modelling and molecular docking studies elucidate how this mutation might affect ATP binding, providing insights for future crop breeding strategies aimed at improving photosynthetic efficiency.","language":"eng","citation":"INTEGRATIVE MODELLING FOR THE CHARACTERISATION OF THE STRUCTURE AND DYNAMICS OF BIOMOLECULES / F. Ballabio ; tutor: C. Camilloni ; coordinatore S. Ricagno. Dipartimento di Bioscienze, 2024 Nov 29. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13343.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1118252/2588134/phd_unimi_R13343.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/927157"},"title":"ON THE NF-Y REGULOME IN DIFFERENT CELLS","internalauthor":"RONZIO, MIRKO","type":"Tesi di dottorato","year":"2022","abstract":"NF-Y is a trimeric sequence-specific transcription factor (TF) that binds the conserved CCAAT-box DNA element. Upon their dimerization, the histone-like subunits NF-YB and NF-YC interact with the DNA-binding subunit, NF-YA. The CCAAT-box is enriched in promoters of genes deregulated in cancer. As a pioneer TF, NF-Y plays a relevant role in organizing chromatin nearby transcription start sites as well as recruiting other factors and cofactors. The growing ENCODE repository stores ChIP-seq data of hundreds of transcription factors and cofactors in various cell lines. The integration of TFs ChIP-seq datasets is a useful resource for building genome-wide regulatory networks around DNA binding proteins. By integrating the available data about TFs in the ENCODE compendium, we outlined groups of NF-Y TFs modules involved in the regulation of gene expression in human genome, according to different criteria and implementing a computational pipeline developed by us. NF-Y is involved in the control of different basic cellular activities, such as cell cycle progression and cellular metabolism in normal and transformed cells. NF-YA exists in two different isoforms, NF-YAs (short) and NF-YAl (long), differing in 28 amino acids, coded by exon 3 and being part of the trans-activation domain. The short NF-YA is involved in stemness maintenance of mouse embryonic stem cells. In mouse muscle satellite cells, we found that NF-YA expression is fundamental to preserve the pool of muscle stem cells and its loss triggers DNA damage. On the other side, in epithelial tumors, there is evidence that NF-Y may play a role due to its regulatory function in cell cycle. Inspecting TCGA bulk RNA-seq data and deconvoluting it from scRNA-seq in various epithelial cancer datasets, we discovered that NF-YA is up-regulated in all investigated tumors, whereas histone-like subunits are more variable. Specifically, NF-YAs is primarily overexpressed in CCAAT-driven cell cycle related molecular subtypes, whereas NF-YAl isoform tends to correlate with mesenchymal and metastasis-prone identity.","language":"eng","citation":"ON THE NF-Y REGULOME IN DIFFERENT CELLS / M. Ronzio ; tutor: D. Dolfini. Dipartimento di Bioscienze, 2022 May 16. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12384.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/927157/2030798/phd_unimi_R12384.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1119203"},"title":"3D SENSING APPROACHES FOR PRECISION AGRICULTURE: APPLICATIONS TO PLANT FEATURES CHARACTERIZATION AND TO WEED CONTROL IN MAIZE","internalauthor":"TORRENTE, MARCO DAVIDE MICHEL","type":"Tesi di dottorato","year":"2024","abstract":"This PhD thesis investigates the application of 3D data acquired by Time-of-Flight (ToF) sensors and stereo cameras for agronomic measurements. The main objectives are the characterization of plant geometric properties, biomass estimation with non-destructive methods and discrimination between crops and weeds for use in precision agriculture applications.  Following an introductory section, the first part of the work, which corresponds to Chapters 3 and 4, involves the volumetric characterization of lettuce plants to estimate biomass using non-destructive measurements. This was performed both in preliminary laboratory trials and in a field application. In the field application the depth sensor was integrated with a robotic platform to ensure the possibility to collect data at the individual plant level, with all data that can be stored in a data lake. In both cases, the assumed volumetric reconstruction algorithms achieved very satisfactory results, obtaining accurate dry biomass weight (DM) estimates from the developed models for both laboratory scale (with a root mean square error (RMSE) of 0.12 g and a mean absolute percentage error (MAPE) of 12%.) and greenhouse conditions (with a RMSE of 1.07 g and MAPE 16%). The different ability to estimate the DM obtained in the two contexts, although minimal, depends mainly on the different spatial resolutions obtainable with the acquisition setups designed for the two experiments and on the conditions under which the measurements were carried out. Considering the technological characteristics of the ToF sensors, under field conditions they are disturbed by solar radiation, which contributes to decreasing the level of accuracy of the measurement obtained.  The second part of the thesis, which corresponds to Chapters 5, 6, 7 and 8, deals with the comparison of two sensing techniques, two-dimensional based on color (RGB) and three-dimensional that consider distance in addition to color (RGBD) to optimize the process of target identification for use in precision weed control spraying that aims to reduce chemical inputs using advanced techniques. Regarding 2D imagery, a comparative analysis was conducted on images captured using drones (UAV – Remote sensing) and those obtained in proximity to vegetation (proximal sensing). The objective was to assess the capacity of these approaches to estimate soil cover, a critical driver that can indirectly indicate the degree of weed infestation. Proximal images demonstrated superior accuracy in estimating this phenomenon, achieving a coefficient of determination (R²) of 0.93, compared to UAV-acquired images, which yielded an R² of 0.8 in validation tests based on 90 ground control points established within the field. When comparing the two monitoring techniques at a field scale, UAV imagery was found to provide an estimate of soil cover that, in 75% of the sampled area, was lower than that derived from proximal images under experimental conditions.  In this context, which highlights the superior representativeness of information obtainable through proximal monitoring, the contribution of 3D sensing techniques to estimating weed presence was subsequently evaluated in comparison to proximal 2D images. To this end, several algorithms specifically designed to utilize both sensing techniques were developed.  Using 2D images, two algorithms were developed. The first is a simpler approach that enables uniform treatment decisions across areas of 0.75 m² (Management Zones - MZ) based on assessing vegetation soil cover. The second, an innovative algorithm known as Local Cover Fraction (LCF), is more complex, employing a hybrid technique to simultaneously detect weeds between rows and subsequently characterize the spatial distribution of remaining soil cover along each crop row. This allows identification of areas where biomass distribution deviates from the clean-field conditions recorded at the experiment's start.  In parallel, a classification algorithm based on 3D sensing was developed, with two distinct implementation strategies proposed. The first, Treat All Weeds (TAW), aims to target all areas identified as weeds and the second, Treat Weed in Majority (TWM), activates actuators only when they can cover a greater surface area classified as weeds than of crops.  To evaluate the results and quantify the contribution of these methods compared to traditional uniformly distributed (UD) techniques, precision spraying treatments based on the MZ, LCF, and 3D-based algorithms were simulated, and the outcomes were compared.  Simulations yielded promising results, forecasting a reduction in both the quantity of herbicide applied and the environmental impact for most developed algorithms. Herbicide reductions were observed as follows: 10% for the MZ method, 45% for the LCF method, and for the 3D sensing approach, a 22% reduction for the TAW strategy and 28% for TWM. However, the TAW strategy was the only approach to achieve a statistically significant reduction in both herbicide quantity and environmental impacts without a notable decrease in treatment effectiveness, which remained statistically comparable to the uniformly distributed (UD3D) treatment simulation.  The results obtained with both imaging techniques surpassed expectations. Compared to the 2D imaging-based method for estimating weed control treatments, the 3D survey produced even more favorable results, owing to its enhanced capability for target classification, which proved more robust than the 2D method. This advanced classification capability enabled the design of crop-targeted treatments through simulations of localized biostimulant distribution, achieving full crop surface coverage with a sensitivity of 0.99. This approach reduced product waste from ground distribution by 85% and minimized the undesired effect of weed biostimulation by 75%.  Finally, in Chapter 9, a low-cost simulator prototype is proposed for the hardware and software management of highly precise, localized treatments based on proximal imaging. This simulator is designed to perform real-time monitoring and execute the required treatment actions.  In general, considering the results obtained in both fields of application investigated in this thesis work, the use of 3D sensors demonstrated significant outcomes across all evaluated contexts, both in initial laboratory tests and in field application trials.","language":"eng","citation":"3D SENSING APPROACHES FOR PRECISION AGRICULTURE: APPLICATIONS TO PLANT FEATURES CHARACTERIZATION AND TO WEED CONTROL IN MAIZE / M.d.m. Torrente ; tutor: R. Oberti ; co-tutor: A. Calcante ; coordinatore: R. Pilu. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2024 Dec 16. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13214_1.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1119203/2592766/phd_unimi_R13214_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1020888"},"title":"STEERING THE QUANTUM: FROM REMOTE STATE PREPARATION TO QUANTUM TRANSPORT","internalauthor":"FRIGERIO, MASSIMO","type":"Tesi di dottorato","year":"2023","abstract":"Quantum information science is a vast and rapidly developing field of research in physics, which accompanies and partially guides the parallel development of quantum technologies, with the common goal of harnessing quantum phenomena to achieve tasks that are classically unfeasible or to greatly improve current technological strategies. It can be broadly identified through a general feature: a contribution to quantum information science usually entails a fine control of quantum degrees of freedom, be it direct or not, which is uncommon in all other branches of physics exploiting quantum mechanics: experimental violations of Bell’s inequalities, quantum teleportation and transport, quantum computation and essentially all topics in quantum information require a true control of quantum states and they often unveil the unperceived details of the quantum nature underlying everyday experience. Because of this intersectional character, it finds application in a wide spectrum of modern physical research, encompassing cosmology, black holes physics, solid state physics, quantum computation, foundational questions on the quantum theory itself and it even propels and inspires the development of better classical algorithms. Of paramount importance in quantum information science is the ability to prepare desirable quantum states and to steer their evolution in a predictable, tuneable and useful way. This thesis would aspire to contribute to an infinitesimal development towards these goals. After an introductory overview of the basic tools, in Part I we discuss continuous-variable quantum information with a focus on Gaussian steering and quantum metrology, the first relating to the remote preparation of quantum states and properties, P-nonclassicality in particular, and the second as the most important tool to characterize quantum systems.   In Part II, the different approach of attaining target quantum states on discrete structures through continuous-time quantum walks is undertaken and several recent results on chiral quantum walks are presented cohesively, together with a physical intuition for these systems.","language":"eng","citation":"STEERING THE QUANTUM: FROM REMOTE STATE PREPARATION TO QUANTUM TRANSPORT / M. Frigerio ; tutor: M. G. A. Paris ; supervisor: M. G. A. Paris ; coordinatore: M. G. A. Paris, R. Vecchi. Dipartimento di Fisica Aldo Pontremoli, 2023 Dec 21. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12798.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1020888/2335393/phd_unimi_R12798.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1119273"},"title":"DESIGN AND OPTIMIZATION OF ADVANCED EMULSIONS AS BIOACTIVE COMPOUND CARRIERS FOR LOW-SATURATED FAT FOOD PRODUCTS: TECHNOLOGICAL AND NUTRITIONAL ASPECTS","internalauthor":"LOFFREDI, ELEONORA","type":"Tesi di dottorato","year":"2024","abstract":"Research in food engineering is increasingly using reverse engineering principles to design healthier food products. Growing concerns about the high intake of fat-rich foods and the associated increased risk of chronic diseases like obesity, diabetes, and hypertension are driving the food industry to reformulate full-fat products by reducing total or saturated fat content while maintaining good physicochemical and sensory properties. However, fat provides the food matrix with important features, so its reduction or replacement can generate undesirable outcomes and unacceptability by consumers. One of the most promising strategies to reduce saturated fat content in foods is based on the use of emulsions. Particularly, advanced emulsions can prevent instability phenomena and provide new features, such as the ability to act as carriers for bioactive compounds and the possibility to engineer their interface to control digestive fate.  In this context, the overarching goal of this PhD project was to design advanced emulsions intended as ingredients in low-saturated fat foods, and as potential bioactive compound carriers, thereby creating healthier products.  At first, a complete literature survey about advanced emulsions in terms of composition and process conditions was performed to identify knowledge gaps and define experimental factors and the most suitable methods for emulsion characterization.  Then the effect of emulsifier concentration and corn oil volume phase on single, Pickering, heat-filled gel, and cold-filled gel emulsions were studied by means of Design of Experiments techniques. Soy lecithin (SL), octenyl succinic anhydride starch (OSA), chickpea protein isolate (CPI), and citrus fibers (CF) were used as emulsifiers. Based on the highly significant models calculated for apparent viscosity and droplet size, emulsion formulations were optimized using Response Surface Methodology coupled with the desirability function. All optimized advanced systems outperformed the SL-based single emulsion, particularly in terms of apparent viscosity and stability index.  To evaluate the digestion fate of the optimized emulsions produced with or without the addition of a commercial polyphenol extract, lipolysis was evaluated by applying the harmonized international protocol INFOGEST. There was no interaction between polyphenols and triacylglycerol hydrolysis, whereas the different emulsion structures influenced lipid digestibility. No differences were found in the free fatty acids release at the end of the intestinal phase. Still, significantly lower amounts of mono- and di-acylglycerols were found in the cold-gel emulsion with CF, which also showed the highest amount of unhydrolyzed triacylglycerols at the end of the gastric phase.  The last part of the project focused on reformulating ice cream and cookies to obtain low-saturated fat products. Based on the previous results, CPI cold-gel emulsion was used as a substitute for milk cream in artisanal ice cream, while CPI heat-filled gel emulsion as butter replacer in cookies. The cold-filled gel emulsion produced an ice cream with quality properties comparable to those of the standard product but with improved nutritional features. As for cookies, the heat-filled gel emulsion resulted in higher protein and lower saturated fatty acids content with respect to the standard formulation, but the fracture strength was very high, thus further optimization of the formulation is needed. Studies about reformulated foods’ digestibility are still ongoing.  Future studies should focus on encapsulated polyphenols’ fate during digestion, and on the use of enriched emulsions in food products.","language":"eng","citation":"DESIGN AND OPTIMIZATION OF ADVANCED EMULSIONS AS BIOACTIVE COMPOUND CARRIERS FOR LOW-SATURATED FAT FOOD PRODUCTS: TECHNOLOGICAL AND NUTRITIONAL ASPECTS / E. Loffredi ; tutor: C. Alamprese ; co-tutor: C. del Bo' ;  phd dean : D. Mora. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2024 Dec 20. 37. ciclo","filename":"phd_unimi_R13342_1.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 22-NOV-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1119918"},"title":"SHEDDING LIGHT ON HIGGS BOSON SELF-INTERACTIONS IN THE BBƔƔ CHANNEL. PHOTON AND B-JET CALIBRATIONS, AND SEARCHES FOR HIGGS BOSON PAIRS WITH THE ATLAS EXPERIMENT.","internalauthor":"MAZZEO, ELENA","type":"Tesi di dottorato","year":"2024","abstract":"The work presented in this thesis is based on proton-proton collision data of the  Large Hadron Collider (LHC), recorded by the ATLAS detector between 2015 and  2018 (Run 2), amounting to a total integrated luminosity of 140 fb−1. This work focuses on two analyses, one in the Standard Model (SM) context, and one related to probing new physics scenarios, whose common theme is the study of the Higgs boson self-interactions through the search for Higgs boson pair production in the final state with two photons and two bottom quarks (bbγγ).  The first analysis is a search for SM Higgs boson pairs (HH) in the bbγγ final state.  No excess of events with respect to the SM background is observed. An observed  upper limit of μHH < 4.0 is set at 95% confidence level (CL) on the di-Higgs signal  strength, corresponding to the di-Higgs production cross-section normalised to its SM prediction. The corresponding expected upper limit under the assumption of no HH production (SM HH production) is 5.0 (6.4). The observed 95% confidence intervals for the coupling modifiers are −1.6 < κλ < 6.9 and −0.5 < κ2V < 2.7, while the corresponding expected results are −2.8 < κλ < 7.8 and −1.1 < κ2V < 3.3, yielding the most stringent expected constraints on κλ achieved by a single analysis to date. This analysis is combined with all the other HH searches in various final states, thus providing the most complete picture on HH production with the Run 2 dataset. The combined observed (expected) upper limit on the signal strength is μHH < 2.9 (2.4) at 95% CL. The observed 95% confidence intervals for the coupling modifiers are −1.2 < κλ < 7.2 and 0.6 < κ2V < 1.5, with corresponding expected intervals −1.6 < κλ < 7.2 and 0.4 < κ2V < 1.6.  The second analysis is a search for a new heavy scalar resonance X, decaying into  a Higgs boson and another scalar particle S (X → SH), in the final state where the  Higgs boson decays into two photons and the S particle decays into two bottom  quarks. This is the first search for asymmetric Higgs boson pair production in the  bbγγ channel using ATLAS data. It searches for a X → SH → bbγγ signal within  a wide range of masses for the two resonances X and S (denoted mX and mS), covering 170 ≤ mX ≤ 1000 GeV and 15 ≤ mS ≤ 500 GeV. No significant excess above the expected background is found and 95% CL upper limits are set on the cross section times branching ratio, ranging from 39 fb to 0.09 fb. The largest deviation from the background-only expectation occurs for (mX , mS ) = (575, 200) GeV with a local (global) significance of 3.5 (2.0) standard deviations.","language":"eng","citation":"SHEDDING LIGHT ON HIGGS BOSON SELF-INTERACTIONS IN THE BBƔƔ CHANNEL. PHOTON AND B-JET CALIBRATIONS, AND SEARCHES FOR HIGGS BOSON PAIRS WITH THE ATLAS EXPERIMENT / E. Mazzeo ; committee: P. Ferrari, M. Donegà, F. Cerutti ; referees: P. Ferrari, M. Donegà ; supervisors: L. Carminati, R. Turra, S. Manzoni ; coordinator: A. Mennella;. Dipartimento di Fisica Aldo Pontremoli, 2024 Dec 19. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13417.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1119918/2607047/phd_unimi_R13417.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1144603"},"title":"GEOCHEMISTRY OF LARGE EXPLOSIVE ERUPTIONS FROM THE MAIN ETHIOPIAN RIFT","internalauthor":"LANGONE, FEDERICA","type":"Tesi di dottorato","year":"2025","abstract":"The Main Ethiopian Rift (MER) is located in a geodynamic setting controlled by continental spreading, which has occurred since Eocene-Oligocene. In this area, the active tectonics has repeatedly favoured magma ascent along the rift axis resulting in intense volcanic activity characterized by a wide compositional range (from basalts to per-alkaline rhyolites with scarce intermediate products). During the Quaternary, numerous high-magnitude explosive eruptions fed by SiO2-rich magmas, blanketed extensive areas both within and beyond the Rift Valley, making their deposits important stratigraphic markers at a regional scale. These eruptions represent the culmination of various processes leading to the accumulation of large volumes of evolved magmas at upper crustal levels. Over the last decades numerous studies have been dedicated to the petrological and geochemical investigation of these ignimbrites, but several questions remain unanswered: 1) are the most evolved rhyolitic compositions a product of fractional crystallization processes from the associated transitional basalts or do they derive from melting of crustal lithologies due to thermal perturbations during basaltic underplating? 2) why are the intermediate compositions minor in the geological record? 3) What are the conditions that allow the development of peralkalinity in the SiO2-rich magmas?  This thesis mainly focuses on the study of two large, low crystallinity, and compositionally heterogenous ignimbrites erupted from the MER: the Golja (~1.16 Ma) and Kencherra (~1.26 Ma) ignimbrites. The study of these units is particularly intriguing due to the presence of basaltic (plagioclase-hosted melt inclusions), rhyolitic and, above all, intermediate compositions coexisting within the same pyroclastic sequence. The study of these ignimbrites will shed light on the genetic relationship (if any) between the different magma compositions and on the pre-eruptive history of the magma bodies that fed these two large eruptions.  In addition to the Goljia and Kencherra ignimbrites, in this thesis I expanded the geochemical analyses to distal deposits of other SiO2-rich and far travelled explosive eruptions sourced from the MER. The goal is to use these data to complement the stratigraphic reconstructions of volcano-sedimentary sections from the archeological area of Melka Kunture, situated to the west of the rift valley, where important archeological findings were identified in close association with tephra layers. The geochemical fingerprinting of these tuffs will support  stratigraphic correlations between different sections and providing further constraints to its chronological interpretation.","language":"eng","citation":"GEOCHEMISTRY OF LARGE EXPLOSIVE ERUPTIONS FROM THE MAIN ETHIOPIAN RIFT / F. Langone ; advisor: F. Forni : co-advisor: F. Farina ; coordinatore: M. I. Spalla, G. Muttoni. - Aula C03 - Via Mangiagalli, 25. Dipartimento di Scienze della Terra Ardito Desio, 2025 Feb 28. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13334.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1144603/2670687/phd_unimi_R13334.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1048754"},"title":"NOVEL SYNTHETIC PROCESSES FOR THE INDUSTRIAL PREPARATION OF ACTIVE PHARMACEUTICAL INGREDIENTS","internalauthor":"ROSITANO, VINCENZO","type":"Tesi di dottorato","year":"2024","abstract":"The project deals with the development of new synthetic processes for the industrial preparation of two emerging active pharmaceutical ingredients (API). Specifically, the process for the preparation of a new paclitaxel prodrug, namely octadecanedioc acid-paclitaxel, was defined. This paclitaxel derivate has shown better results in vivo trials, against a wide range of tumors, in terms of toxicity and efficacy, compared to other conventional formulations of PTX like Abraxane and Cremophor-EL. In order to have an easily scalable process and a final product with high purity a novel synthetic strategy was developed. The second part of the project focused on the development of a process for the industrial preparation of voclosporin, a semi-synthetic analogue of cyclosporin A. This new derivate has been approved for the immunosuppressant medication treatment of Lupus nephritis. A four synthetic steps process was developed to afford the product with the required purity and isomeric composition.","language":"eng","citation":"NOVEL SYNTHETIC PROCESSES FOR THE INDUSTRIAL PREPARATION OF ACTIVE PHARMACEUTICAL INGREDIENTS / V. Rositano ; tutor: A. Bernardi ; co-tutor: L. Senaldi ; coordinatore: D. Passarella. Dipartimento di Chimica, 2024 May 24. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13184.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1048754/2407707/phd_unimi_R13184.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1156375"},"title":"COLLAGEN AND ANTIOXIDANTS FROM SEA URCHINS: WASTE VALORIZATION CHALLENGES TOWARDS REGENERATIVE MEDICINE","internalauthor":"MARTINELLI, GIORDANA","type":"Tesi di dottorato","year":"2025","abstract":"Sea urchins (mainly Paracentrotus lividus) are well known worldwide as a delicacy that is processed in the food industry or consumed directly in restaurants. The gonads are the only edible part of these marine animals, while the rest (more than 90-95% of their total mass) is discarded as waste. From the point of view of the circular economy, there is now a great interest in food waste, pointing to the valorization of biomasses to obtain products with added value. In fact, it's already been shown that sea urchin waste contains highly valuable collagen derived from by-product tissues such as the peristomal membrane, which can be used as an innovative biomaterial for tissue engineering. The remaining part of the waste (test and spines) can be an additional source of biologically interesting compounds. Indeed, it contains potent natural antioxidants named polyhydroxynaphthoquinones (PHNQs). The research aims to address the dual challenge of waste reduction and valorization through the development of innovative bioactive biomaterials ranging from basic formulations to advanced technologies, with potential applications in tissue regeneration and wound healing.  Given the wide biodiversity of edible sea urchins that are marketed annually, the first aim was to investigate the potential of different species that make up the global waste stream as sources of antioxidants and collagen, in order to increase the potential of the “sea urchin circular supply chain” by exploiting waste other than P. lividus. Therefore, a comparative study on the extraction of PHNQs and collagen was carried out between P.lividus and another Mediterranean species: Sphaerechinus granularis. PHNQs extraction yields were compared, pigments were quantified and identified, and antioxidant activities were assessed and correlated to specific PHNQ presence and abundances. Similarly, collagen extraction yields were evaluated, and the resulting collagen-based biomaterials were compared in terms of their ultrastructure, degradation kinetics, and resistance to compression. Results showed a partially similar PHNQs profile in both species, with significantly higher yield in P. lividus, while S. granularis exhibited better antioxidant activity. P. lividus samples showed higher collagen extraction yield, but S. granularis scaffolds showed higher stability.  Subsequently, the study was focused on the development and characterization of collagen-based scaffolds added with PHNQs (Coll-PHNQ), successfully incorporated into biomaterials, enhancing scaffold stability and integrity and providing additional antioxidant functionalities. Water uptake, mechanical properties and degradation kinetics of the composite scaffolds were evaluated and compared with standard scaffolds (Coll). Results indicated that Coll-PHNQ scaffolds exhibited superior chemical stability and slower degradation rates, attributed to strong interactions between collagen and PHNQs, also verified through in silico investigations. Furthermore, it was confirmed that the antioxidant activity of PHNQs was retained in the composite scaffolds, providing additional therapeutic benefits. As a successive step, aiming at developing structurally stable hydrogels and improving the structural properties of the produced scaffolds, methacrylation of collagen was carried out. Methacrylated collagen hydrogels (CollMA- UV) demonstrated improved enzymatic resistance, thickness retention and lower swelling compared to the standard scaffolds (Coll), enhancing biomaterial structural performance. In addition, CollMA-UV exhibited a fibril network with interconnected pores and the characteristic collagen banding pattern, comparable to standard Coll. Further technologic advancements in this work involved the development of inks for 3D printing, combining sea urchins collagen with polysaccharides (such as alginate or ulvan) to achieve biomaterials printability. The printed hydrogels (Coll-P) allowed the production of shape- customizable scaffolds with interconnected pores. Coll-BioP hydrogels were characterized for their ultrastructure, degradation kinetics and structural stability and compared to the following sea urchins collagen-based scaffolds: standard scaffolds (Coll), stabilized scaffolds (Coll-UV), composite scaffolds (Coll-PHNQ), methacrylated scaffolds (CollMA-UV) and commercial bovine membrane (Integra®). The Coll-P hydrogel’s ultrastructure highlights a unique alignment of collagen fibrils, interconnected porosity and demonstrated area and thickness expansion when hydrated. Coll-P’s hydration properties closely resemble those of CollMA-UV, suggesting that it achieves stability without chemical modification. Finally, under enzymatic conditions, Coll-P hydrogel exhibited a degradation rate that balances structural integrity, comparable to established commercial materials like Integra®.  In conclusion, by leveraging a circular economy approach, this study successfully demonstrated the feasibility of valorizing sea urchin waste from different species through PHNQs and collagen extraction, offering diverse applications in the biomedical field, according to specific technical requirements. In addition, the work introduced sustainable and innovative strategies for developing biomaterials suitable for tissue engineering and regenerative medicine. Future research should focus on extending the antioxidant activity to CollMA-UV and Coll-P, which has been demonstrated by adding PHNQs for Coll- PHNQ development, and in vivo evaluations to validate the efficacy and scalability of these biomaterials, ensuring their translation into real-world biomedical applications.","language":"eng","citation":"COLLAGEN AND ANTIOXIDANTS FROM SEA URCHINS: WASTE VALORIZATION CHALLENGES TOWARDS REGENERATIVE MEDICINE / G. Martinelli ; tutor: M. Sugni ;  co-tutor: S. Marzorati ;  coordinatore del corso: M. P. M. Guarino. Dipartimento di Scienze e Politiche Ambientali, 2025 Apr 10. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13587.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1156375/2734087/phd_unimi_R13587.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/966576"},"title":"OPTIMIZATION OF PHOTOGRAMMETRIC 3D ASSETS","internalauthor":"MAGGIORDOMO, ANDREA","type":"Tesi di dottorato","year":"2023","abstract":"The photogrammetric 3D reconstruction pipeline has emerged in recent years as the prominent technology for a variety of use cases, from heritage documentation to the authoring of high-quality photo-realistic assets for interactive graphics applications. However, the reconstruction process is prone to introduce modeling artifacts, and models generated with such tools often require careful post-processing before being ready for use in downstream applications. In this thesis, we face the problem of optimizing 3D models from this particular data source under several quality metrics.    We begin by providing an analysis of their distinguishing features, focusing on the defects stemming from the automatic reconstruction process, and then we propose robust methods to optimize high-resolution 3D models under several objectives, addressing some of the identified recurring defects.    First, we introduce a method to reduce the fragmentation of photo-reconstructed texture atlases, producing a more compact UV-map encoding with significantly fewer seams while minimizing the resampling artifacts introduced when synthesizing the new texture images.     Next, we design a method to address texturing defects. Our technique combines recent advancements in image inpainting achieved by modern CNN-based models with the definition of a local texture-space inpainting domain that is semantically coherent, overcoming limitations of alternative texture inpainting strategies that operate in screen-space or global texture-space.    Finally, we propose a method to efficiently represent densely tessellated 3D data by adopting a recently introduced efficient representation of displacement-mapped surfaces that benefits from GPU hardware support and does not require explicit parametrization of the 3D surface. Our approach generates a compact representation of high-resolution textured models, augmented with a texture map that is optimized and tailored to the displaced surface.","language":"eng","citation":"OPTIMIZATION OF PHOTOGRAMMETRIC 3D ASSETS / A. Maggiordomo ; tutor: M. Tarini, P. Cignoni ; coordinator: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2023 Apr 27. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12625.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/966576/2186001/phd_unimi_R12625.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1137676"},"title":"POPULATION DYNAMICS AND GEOCHEMISTRY OF BENTHIC AND PLANKTONIC FORAMINIFERA TO INTERPRET THE PALEOCEANOGRAPHIC CHANGES ACROSS THE CENOMANIAN-TURONIAN OCEANIC ANOXIC EVENT 2 AT LOW AND HIGH LATITUDES","internalauthor":"AMAGLIO, GIULIA","type":"Tesi di dottorato","year":"2025","abstract":"This PhD research project has investigated benthic and planktonic foraminiferal dynamics   across one of the greatest environmental perturbations that occurred throughout the Earth’s   history, namely the Cenomanian-Turonian Oceanic Anoxic Event 2 (OAE 2). It is globally   marked by a positive δ13C excursion due to the deposition and burial of large amounts of   organic matter in the ocean. The exact causes of OAE 2 are still studied but it is understood   that it might be due to a combination of different factors including the emplacement of the   Large Igneous Provinces (LIPs), fluctuations of the sea-level, changes in ocean circulation.    For this study, four stratigraphic sections have been selected to document how global   changes impacted at low and high latitudes. The stratigraphic sections are Clot Chevalier in   the Vocontian Basin (SE France) and Eastbourne in the Anglo-Paris Basin (SE England) at   low latitudes and IODP Sites U1513 and U1516 in the Mentelle Basin (SW Australia) at high   latitudes.    Taxonomy, quantitative and statistical analysis have been performed on foraminifera to   reconstruct paleoenvironmental and paleoceanographic changes across the OAE 2. In   addition, boron isotopes analysis on foraminiferal tests of DSDP Site 463 and of IODP Sites   U1513 and U1516 have been conducted to obtain information about ocean acidification   across the OAE 2.    Samples at low and high latitudes show a continuous foraminiferal record across the OAE 2   displaying high adaptability to extreme environmental conditions, except for a distinct low   carbonate interval at Sites U1513 and U1516 characterized by the absence of calcareous   taxa.    Foraminiferal abundance patterns exhibit notable variances between low and high latitudes   with relatively low species diversity and dominance of opportunistic taxa at Sites U1513 and   U1516 and with moderate abundances and high species diversity at Clot Chevalier and   Eastbourne.   This study has delineated six intervals across the Cenomanian-Turonian boundary interval,   each marked by unique foraminiferal assemblages reflecting distinct environmental   conditions. -   Below the OAE 2: high latitudes show low diversity with dominance of opportunistic taxa   in the water column that identify a weak stratification and warm waters. At the seafloor   benthic foraminifera exhibit taxa tolerant of high organic fluxes, indicating high marine   productivity preceding the OAE 2. At low latitudes, a stratified water column indicating   meso-oligotrophic regimes and low organic fluxes at the seafloor have been observed.   A decrease in ΔpH in surface waters supports enhanced volcanic activity prior to OAE   2, but without significant impacts on foraminiferal tests.    Lower part of OAE 2: at high latitudes, biostratigraphic and geochemical data still   indicate high marine productivity, warm water conditions and an increase in terrigenous   input. In contrast, low latitude planktonic foraminiferal assemblages show the initial   thermal disruptions of the stratified water column. At Clot Chevalier the seafloor   becomes depleted in benthic foraminifera adapted to low organic fluxes, whereas at   Eastbourne a sea-level lowstand is observed.    Plenus Cold Event (PCE): at high latitudes, the positive shift in Zr/Rb ratio, the exclusive   occurrence of Stensioeina truncata, then increase of epi-infaunal taxa and the decrease   in radiolarians indicate improved environmental conditions that might coincide with the   PCE. By contrast, low latitudes display clear evidence of the PCE with the occurrence of   Boreal planktonic foraminifera and of benthic foraminifera associated to more   oxygenated and deeper waters. In addition, a repopulation event is observed at Clot   Chevalier.   Middle part of OAE 2: the thermal maximum at high latitudes exhibits a remarkable lack   of calcareous foraminifera and the dominance of radiolarians indicating extremely high   marine productivity. An intensification of the hydrological cycle with increase in rainfall,   weathering intensity, and riverine discharge may have disrupted normal oceanic   circulation, expanding the Oxygen Minimum Zone (OMZ). At low latitudes, the extinction   of Boreal taxa and the dominance of warm water taxa indicate the emplacement of   more eutrophic conditions, and a decrease in oxygen levels is observed at the seafloor.    Upper part of OAE 2: at low latitudes, unstable eutrophic conditions still occur, but with   the diversification of planktonic foraminifera and the decrease in radiolarians at the top   of this interval. A change in the benthic foraminiferal assemblage occurs probably due   to a slight deepening of the seafloor. ΔpH values in surface waters slightly decrease   compared to ΔpH before the OAE 2, but showing a gradual increasing trend upward   that supports the hypothesis of the emplacement of more stable conditions.   Comparisons with Eastbourne and Clot Chevalier reveal contrasting environments:   Eastbourne shows eutrophic conditions, high productivity and sea-level highstand, while   Clot Chevalier shows a stable mesotrophic regime.    Above OAE 2: high latitudes show generally a turnover toward more eutrophic   conditions with a decrease in ΔpH in surface waters. Low latitudes are characterized by   a turnover towards more mesotrophic conditions and the establishment of a stratified   water column as also testified by the higher ΔpH values in surface waters, but showing   fluctuations toward more eutrophic regimes.","language":"eng","citation":"POPULATION DYNAMICS AND GEOCHEMISTRY OF BENTHIC AND PLANKTONIC FORAMINIFERA TO INTERPRET THE PALEOCEANOGRAPHIC CHANGES ACROSS THE CENOMANIAN-TURONIAN OCEANIC ANOXIC EVENT 2 AT LOW AND HIGH LATITUDES / G. Amaglio ; tutor: M.R. Petrizzo ;   PhD coordinator: M.I. Spalla, G. Muttoni. Dipartimento di Scienze della Terra Ardito Desio, 2025 Feb 07. 37. ciclo","filename":"phd_unimi_R13376.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1137676/2642129/phd_unimi_R13376.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/888609"},"title":"MOLECULAR DYNAMICS AND CHEMINFORMATICS METHODS TO EXPLORE THE CHEMICAL REALITY","internalauthor":"GANDINI, ENRICO","type":"Tesi di dottorato","year":"2022","abstract":"Part I: Antifreeze Peptides    Organisms living in icy environments produce antifreeze proteins to control ice growth and recrystallization. It has been proposed that these molecules pin the surface of ice crystals, thus inducing the formation of a curved surface that arrests crystal growth. Such proteins are very appealing for many potential applications in food industry, material science and cryoconservation of organs and tissues. Unfortunately, their structural complexity has seriously hampered their practical use, while efficient and accessible synthetic analogues are highly desirable. In the present work, we used molecular dynamics based techniques to model the interaction of three short antifreeze synthetic peptides with an ice surface. The employed protocols succeeded in reproducing the ice pinning action of antifreeze peptides and the consequent ice growth arrest, as well as in distinguishing between antifreeze and control peptides, for which no such effect was observed. Principal components analysis of peptides trajectories in different simulation settings permitted to highlight the main structural features associated to antifreeze activity. Modeling results are highly correlated with experimentally measured properties, and insights on ice-peptide interactions and on conformational patterns favoring antifreeze activity will prompt the design of new and improved antifreeze peptides.      Part II: Molecular Similarity    Molecular similarity is an important notion in chemistry, with applications in fields such as chemical databases and drug design. Molecular similarity is also important in chemical legislation, in particular in the evaluation process for orphan drugs (i.e., drugs for rare diseases). A new molecule needs to be dissimilar from any other existing drug for a given disease to be assigned the financially advantageous status of orphan drug. Currently, there are many ways to define whether two molecules are similar or dissimilar. Thus far, the European Medicines Agency has used majority voting on discretional judgments of similarity when assessing new drugs for rare diseases. Similarity in an inherently subjective concept, which depends on individual factors such as gender, age, state of mind, and previous experiences. Automated procedures that quantitatively and objectively evaluate molecular similarity are needed. Existing automated procedures are quite effective, but only take into account 2D molecular properties. We improved upon existing similarity-prediction procedures by including calculated 3D properties in the computational models. We created a new data-set of molecular similarity assessments, that includes complex and borderline similarity scenarios. We used the new data-set to test the existing procedures, and to build new and improved computational models.","language":"eng","citation":"MOLECULAR DYNAMICS AND CHEMINFORMATICS METHODS TO EXPLORE THE CHEMICAL REALITY / E. Gandini ; tutor: S. Pieraccini ; cotutor: D. Passarella ; coordinatore: D. M. Roberto. Dipartimento di Chimica, 2022 Jan 25. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12199.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/888609/1927930/phd_unimi_R12199.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1043591"},"title":"POLISH ROMANTICISM VERSUS REALISM: THE EVOLUTION OF EUROSCEPTICISM IN POLAND","internalauthor":"SZELEWA, BARBARA","type":"Tesi di dottorato","year":"2024","abstract":"The thesis try to answer the question, why Poland, where society has rates of support of the European Union reaching eighty percent just three years after accession, has democratic representatives that repeatedly expressed concerns and disagreement with the decision-making process within the European Union, as well as its organisation and administration to the point, when these politicians became a symbol of a 'blocking' force in the European politics.","language":"eng","citation":"POLISH ROMANTICISM VERSUS REALISM: THE EVOLUTION OF EUROSCEPTICISM IN POLAND / B. Szelewa ; supervisor: N. Pasini ; coordinator of PhD: F. Zucchini. Università degli Studi di Milano, 2024. 21. ciclo","filename":"phd_unimi_R06337.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1043591/2394596/phd_unimi_R06337.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/954141"},"title":"INVESTIGATING THE ORIGINS OF UHECRS USING THE PIERRE AUGER OBSERVATORY AND PALEO-DETECTORS","internalauthor":"GALELLI, CLAUDIO","type":"Tesi di dottorato","year":"2023","abstract":"A very fascinating region for investigating the origins of cosmic rays is the toe of the ultra-high energy cosmic ray (UHECR) spectrum, above ≈ 50 EeV. The potential for small magnetic deflections at these energies is coupled with the presence of flux suppression, which may be a sign of the sources’ maximum acceleration potential or may have an explanation for the interactions of cosmic rays with background photons, effectively restricting the region of interest in the search for UHECR sources to a relatively small bubble around us. In this thesis, I present the latest dataset of cosmic rays at the highest energies collected by the Pierre Auger Observatory, the largest experiment dedicated to UHECR science ever built, and the anisotropy searches carried out using it. I have carried out blind, model-independent searches for overdensities, astrophysical structural correlation analysis, and cross-correlation investigations with catalogs of candidate sources. For UHECRs with energy greater than 38 EeV, the results show evidence of a deviation from isotropy at an angular scale of ≈ 25◦ at the 4σ level. Additionally in this thesis for the first time, I present the possibility of using ancient minerals as paleo-detectors to study the history of the flux of cosmic rays in the past by detecting the tracks left in the mineral structure by the interactions between  ions and energetic secondary cosmic rays present in the extensive airshowers.","language":"eng","citation":"INVESTIGATING THE ORIGINS OF UHECRS USING THE PIERRE AUGER OBSERVATORY AND PALEO-DETECTORS / C. Galelli ; supervisor: L. Miramonti ; cosupervisor: L. Caccianiga ; coordinatore: M. Paris. Università degli Studi di Milano, 2023 Feb 08. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12669.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/954141/2138761/phd_unimi_R12669.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/852343"},"title":"LA VIOLENZA IN OCCASIONE DELLE MANIFESTAZIONI SPORTIVE. IL DASPO E GLI ALTRI STRUMENTI DI PREVENZIONE E REPRESSIONE","internalauthor":"SIBILIO, DAVIDE","type":"Tesi di dottorato","year":"2021","abstract":"The present thesis, dedicated to prevention and repression measures of violence at sporting events, aims to outline a generally complete picture of the system that the Italian legal system has prepared over the years to counter the peculiar phenomenon of fan violence during sporting events (football matches, in particular). The thesis, after a brief clarification of the scope of the research, made through the distinction of the concept of fan violence (or football hooliganism) from sporting violence, is initially concerned with providing a historical reconstruction of the phenomenon, and then moving on to an examination of it in a socio-criminological key, taking into consideration both the scientific elaboration produced abroad (especially in the United Kingdom, but also in other European countries), and the studies carried out in Italy, which have highlighted some characteristics of the typical phenomenon of our country. The paper, in its first part, before dealing with the purely criminal (and procedural criminal) aspects of the matter, attempts to offer, from an interdisciplinary perspective, a key to understanding the phenomenon, useful for subsequently identifying the proportionality and reasonableness of the answer that the Italian legal system offers.  Subsequently, the thesis takes into consideration the supranational sources – especially at European level – that have been issued in order to give common and harmonious answers to a phenomenon not limited by the borders of the individual nations. The 1985 Heysel massacre represents the tragic event that for the first time brought to the attention of both the European Community and the Council of Europe the serious dangers that football hooliganism can generate, especially in connection with major events; from that moment on, there has therefore been the gradual introduction of a supranational regulatory body aimed at standardizing the laws and practices of the European countries most affected by the phenomenon. The reference to these sources is useful, in the economics of the report, to verify whether the measures adopted by Italy are actually adequate to the standards developed by the European Union and the Council of Europe.  The thesis then proceeds to describe, in an analytical way, the turbulent regulatory evolution that has characterized the national legislation to fight violence at sporting events, highlighting both the powerful development of personal prevention in this sector, and the introduction of a series of “differentiated” indictments and procedural provisions, aimed at completing the repressive response to the phenomenon; in describing the regulatory evolution, the critical issues that were proposed from time to time were highlighted: in particular, the various doctrinal positions developed over time were analyzed and the attempts made by jurisprudence (including constitutional) to offer an interpretation of anti-violence legislation that is as coherent and respectful of the rights of the individual as possible.  The last chapter, more focused on prevention measures - both atypical (such as DASPO) and typical - aimed at people with sporting dangers, finally aims to bring out the specific problems that have arisen with regard to the preventive system of violence in stadiums, analyzing in particular the characteristics and criticalities of the “dangerous fan” category, without neglecting some due hints to the broader problems relating to the danger to public safety and, even more generally, to the legitimacy and compatibility with the constitutional system of the prevention measures present in the Italian legal system. In the conclusion of the thesis, there are some reflections on the framing of the preventive-repressive system to combat fan violence within the controversial paradigm of the criminal law of the enemy, as well as some observations on exporting within urban context (through the so-called urban DASPO) of the model effectively tested in relation to fans; Finally, some proposals for improvement of the current legislation are made, firstly, to make the existing measures more respectful of the rights of the individuals that are addressed to them and, secondly, to introduce an intervention on several levels, which does not neglect the cultural and social aspects of the phenomenon, and that it is no longer unbalanced on police repression and prevention, with the hope that the future legislator does not intervene, once again, under the pressure of the emergency.","language":"ita","citation":"LA VIOLENZA IN OCCASIONE DELLE MANIFESTAZIONI SPORTIVE. IL DASPO E GLI ALTRI STRUMENTI DI PREVENZIONE E REPRESSIONE / D. Sibilio ; tutor: F. Basile ; coordinatore: C. Luzzati. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2021 Jun 24. 33. ciclo, Anno Accademico 2020. [10.13130/sibilio-davide_phd2021-06-24].","filename":"phd_unimi_R11930.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/852343/1826600/phd_unimi_R11930.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/982069"},"title":"LA FUNZIONE CONOSCITIVA DEL PARLAMENTO. NORME, PRASSI, PROCEDIMENTI","internalauthor":"LUCIANO, FRANCESCO","type":"Tesi di dottorato","year":"2023","abstract":"The aim of this research is to investigate whether the acquisition of knowledge, information and data can constitute an autonomous parliamentary function, not necessarily linked to other functions. In recent years, Parliaments have increased and developed particularly broad and penetrating fact-finding powers, hence the hypothesis that legislatures have a new and cross-cutting function.   The greater complexity of the issues with which Parliaments are invested has given centrality to fact-finding tools, as the only ones available to all Members of Parliament, both from the majority and the opposition. The use of these tools often constitutes a moment of conciliation between the technical expertise and political decision. And today, in the age of information and big data, this becomes even more relevant, after the health and economic crisis experienced on a global scale.   The purpose of the research is not merely to reach a comprehensive definition. On the contrary, after having formally defined “knowledge” as a parliamentary function, the aim is to examine the concrete practice of this function, examining the provisions of the parliamentary rules of procedures and praxis (codified or not). The review of the tools used in parliamentary activity is useful to understand if the proposed definition finds correspondence in the parliamentary rules and procedures, and how it systematically crosscuts other parliamentary functions, in particular the legislative and oversight ones, in accordance with the principle of multifunctionality of parliamentary procedures.  The acquisition of “knowledge” requires the existence of a requesting actor (the Parliament), and of another actor who provides, in whole or in part, the requested information (the Government). In systems such as the Italian one, it is evidently an interlocutory moment proper to the confidence relationship between the Parliament and the Executive. For this reason, fact-finding parliamentary powers will be examined also with regard to the Government, in order to state if and how the exercise of the aforementioned function invests the prerogatives and functions of the Executive, also on an organizational basis.  The concrete performance of the fact-finding activities in financial and budgetary procedures will then be examined. After all, the system of “checks and balances”, typical of parliamentary forms of government, takes shape in the assuming of financial decisions. When taking financial decisions, Parliament is required to respect certain constraints, and this implies the acquisition of data and information, so as to comply with these constraints. Thus, the preliminary activity carried out by the parliamentary committees is both legislative and financial, since the financial effects of legislative and non-legislative acts are examined.  Methodologically, the research is conducted along two lines: the first is the theoretical one, aimed at formalizing “knowledge” as a parliamentary function; the second is the practical one, aimed at verifying the existence of this function on an empirical level. The first research segment engages with the traditional classifications of parliamentary functions, whereas the second research segment starts with parliamentary rules of procedures. The field of investigation is constituted by the Italian Parliament and the Italian legal system in general, considering both the Chamber of Deputies and the Senate of the Republic. The research also attempts to offer an updated view of the fact-finding tools, excluding from the analysis the scrutiny tools (questions, interpellations) and the parliamentary inquiries.","language":"ita","citation":"LA FUNZIONE CONOSCITIVA DEL PARLAMENTO. NORME, PRASSI, PROCEDIMENTI / F. Luciano ; tutor: F. Biondi ; coordinatore del corso: F. Biondi. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2023 Jul 05. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12525.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/982069/2238637/phd_unimi_R12525.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1122016"},"title":"L¿ABRUZZO AQUILANO DOPO IL TERREMOTO DEL 2009:TERRITORIO, PATRIMONI, POLITICHE, SVILUPPO","internalauthor":"BAIOCCHETTI, GIOVANNI","type":"Tesi di dottorato","year":"2024","abstract":"The research aims to investigate the capacity of L'Aquila's territorial system to develop resilience after the 2009 earthquake, transforming the event into an opportunity to enhance local heritages and undertake new development paths. In the aftermath of the shock, policy documents were elaborated to identify the potential assets for the recovery of a territory that was already affected by declining economic growth, ageing population and depopulation, like most Italian marginal areas. Thus, over the past few years, a series of projects were implemented to foster L'Aquila's vocation as a knowledge, smart, innovative, creative, open and inclusive city. Since reconstruction is still ongoing and further funds for territorial development will be allocated in the coming years, it is considered useful to understand how the territorial fabric has reacted so far. To this end, a quantitative analysis of descriptive statistics on indicators measuring territorial development is proposed, flanked by a qualitative analysis of interviews with local syntagmatic actors to understand their perceptions on the strengths and weaknesses in the territory’s capacity to develop resilience.","language":"ita","citation":"L¿ABRUZZO AQUILANO DOPO IL TERREMOTO DEL 2009:TERRITORIO, PATRIMONI, POLITICHE, SVILUPPO / G. Baiocchetti ; tutor: D. Gavinelli; coordinatore: F. Slavazzi. Dipartimento di Lingue, Letterature, Culture e Mediazioni, 2024 Dec 17. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13363.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1122016/2600311/phd_unimi_R13363.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/821395"},"title":"DIETARY PATTERNS:NUTRITION, HEALTH, AND THE ENVIRONMENT","internalauthor":"TOMAINO, LAURA","type":"Tesi di dottorato","year":"2021","abstract":"Growing evidence stresses the critical role of nutrition and dietary patterns in maintaining human health and preventing several chronic non-communicable diseases and certain types of cancer. In particular during the last decades the Mediterranean Diet acquired more and more importance. Defined a nutritional model shared by the population surrounding the Mediterranean basin around the fifties by Ancel Keys, is nowadays composed by olive oil, cereals, seasonal fruit and vegetables, legumes and nuts, moderate-to-high fish intake, seafood, fermented dairy products, poultry and eggs, together with a limited consumption of red and processed meats and sweets, and a moderate alcohol intake - when culturally allowed. Firstly, the adherence to the MD of a sample of pregnant women from Gran Canaria (Spain) and its possible implications in their newborn anthropometrics, is described. In second instance, 44 subgroup analyses within the scope of the PREDIMED study are presented. It consists of a large, parallel group, multicentre, randomized, controlled, single-blind, nutritional-intervention trial, conducted in Spain in 2003-2011 on 7447 participants, originally designed to assess the effects of the MD on the primary prevention of cardiovascular disease.  Of note, beyond the largely demonstrated beneficial effects of the MD on human health, it is important to observe how food consumption, production and distribution patterns represent one of the main causes of ecological pressure on the environment. If so, global population’s dietary patterns link worldwide human health with the environmental sustainability and, considering population’s growing projections, this becomes an issue of major importance. In this perspective, we propose a new graphical representation of the MD pyramid, revisited according to the environmental aspects of food chain and represented with a third dimension. The overall value of the MD on the environmental, social, cultural, economic and nutritional/health dimensions, makes it a model that is considered as intangible heritage of humanity, but with added environmental value. The virtues of the MD and particularly its value for environmental preservation and protection need to be efficiently communicated and applied in an integrated manner at multiple levels. In this way diet will have a potential to nourish human beings and preserve our environment.","language":"eng","citation":"DIETARY PATTERNS:NUTRITION, HEALTH, AND THE ENVIRONMENT / L. Tomaino ; tutor: C. La Vecchia ; supervisor:Serra Majem, Lluis ; coordinator: C. La Vecchia. Dipartimento di Scienze Cliniche e di Comunità, 2021 Mar 10. 34. ciclo, Anno Accademico 2020. [10.13130/tomaino-laura_phd2021-03-10].","filename":"phd_unimi_R12435.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/821395/1725172/phd_unimi_R12435.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1219260"},"title":"INTEGRATING SEDIMENTOLOGY, STRATIGRAPHY, GEOCHEMISTRY AND 3D GEOLOGICAL MODELLING: CONTRIBUTION TO GEOLOGICAL MAPPING FOR LAND KNOWLEDGE (CARG SHEET 081 ¿ROVERETO¿)","internalauthor":"COCCIA, NICCOLO","type":"Tesi di dottorato","year":"2026","abstract":"Geological maps are thematic representations illustrating the distribution of geological features exposed at the Earth’s surface. They are essential tools for land use planning, natural hazard mitigation, groundwater management, mineral resource exploration and environmental protection. In Italy, a country characterized by considerable geological fragility, the need for detailed geological knowledge and mapping has long been recognised. Shortly after its national unification, geological mapping was entrusted to the Italian Geological Survey, nowadays part of ISPRA (Istituto Superiore per la Protezione e la Ricerca Ambientale-Institute for Environmental Protection and Research). The whole national territory is currently covered by a 1:100000 scale geological map (surveyed since the XIX century and completed in the ‘70s of the last century) but the necessity for a larger-scale map led ISPRA to launch the Geological CARtography project (CARG). The CARG project aims to produce a geological map of Italy at a 1:50000 scale, made up of 634 map sheets, in collaboration with territorial authorities, research centres and universities. The project represents an essential and strategic long-term investment in scientific knowledge, with direct socio-economic benefits that ultimately support sustainable land management and decision-making.  In this framework, the compilation of the CARG sheet 081 “Rovereto” provided an opportunity to promote collaboration between the Provincia Autonoma di Trento (Autonomous Province of Trento), representing the territorial administration, and the University of Milan, along with other universities and research centres, providing scientific support.  Based on this collaboration, the present PhD thesis focuses on the Rhaetian(?)-Tithonian carbonate succession of the Trento Platform, one of the Jurassic structural highs of the Western Tethys Ocean, cropping out in the Folgaria plateau and in the Pasubio Massif areas (Trentino-Alto Adige region, N Italy). The Trento Platform carbonate succession, characterized by abrupt vertical facies changes, is now exposed in the Southern Alps, a fold-and-thrust belt that developed between the Late Cretaceous and the latest Eocene in response to the Alpine orogenesis.  One of the most striking aspects of the studied sedimentary succession is the sharp vertical transition from shallow-water carbonates to red, condensed pelagic deposits rich in ammonites across a flat erosional unconformity, which marks the drowning of the Trento Platform. Despite extensively studied, the causes driving the drowning of the Trento carbonate platform are still poorly understood. Results from this study suggests that this sector of the platform underwent subaerial exposure possibly during the middle Aalenian, as testified by the local and limited occurrence of pendant cements and dissolution vugs filled with crystal silt immediately below the unconformity. This exposure, attributed to tectonic uplift, halted carbonate sediment production and led to the formation of a platform-scale erosional surface. Subsequent extensional tectonics caused platform subsidence at depths still above the effective wave base, which evolved into a submerged current swept paleostructural high. The relative sea-level rise and the consequent marine transgression resulted in the development of a transgressive wave-ravinement surface, which enhanced the planarity of the unconformity and removed much of the meteoric diagenetic evidence. The following Bajocian sea-level rise, possibly amplified by tectonic subsidence, favoured the abrupt transition of the wave-cut carbonate platform to bathyal settings outside the carbonate productivity window, resulting in the deposition of the red, condensed pelagic sediments directly above the unconformity. The role of extensional tectonics is manifested with the occurrence of neptunian dykes filled with red pelagic sediment.  The red, condensed pelagic deposits rich in ammonites of the Trento Platform (Rosso Ammonitico Veronese) are characterized by Fe-Mn concretions occurring as nodules, crust and dendrites which, according to the literature, mark short- to long-term hiatal intervals characterized by non-deposition and erosion. In the last decades, Fe-Mn concretions have received increasing attention, both for their economic potential due to high concentrations of critical raw materials, and for their scientific significance in understanding genetic processes. However, considering that these concretions typically form at depths of hundreds to thousands of metres on the ocean floor and are difficult to sample directly, the study of comparable “fossil” deposits exposed on land is particularly valuable, providing insights into the paleoceanographic conditions prevailing at the time of their formation. Geochemical analyses revealed a hydrogenetic origin for Fe-Mn nodules, a hydrogenetic origin overprinted by diagenetic fluids for the Fe-Mn crust and a diagenetic origin for the dendrites. Carbonates hosting Fe-Mn concretions were precipitated in oxygenated conditions. Furthermore, the occurrence of Frutexites shrubs associated with Fe-Mn crust and nodules suggests a possible biotic contribution in the oxidation of Fe and Mn.   Moreover, the stratigraphic and sedimentological study of the Rhaetian(?)-Tithonian sedimentary succession of the Trento Platform allowed the identification of 47 distinct depositional facies, forming the basis for the characterization of key features of each geological unit at both the meso- and microscale. The understanding of facies and unit features then facilitated the elaboration of a detailed geological map of the Pasubio Massif and the subsequent realization of a 3D model from surface geological data, adopting an iterative method using an explicit approach with the Move software. Particular attention was given in validating the 3D model, using both field-based and control geological constraints to critically assess the interpolation results performed by the software and to produce a more reliable geological model. Based on field data and stratigraphic constraints, the resulting geological map and 3D model of the study area depict a monoclinal gently dipping towards the north, characterized by geological units showing constant thicknesses. This last observation contrasts with previous interpretations, which envisaged abrupt thickness changes of the Lower Jurassic geological units as related to syn-depositional tectonics.   By integrating sedimentology, stratigraphy, geochemistry and 3D geomodelling, this study provides novel insights for a better knowledge of the land and may represent a basis for the future compilation of the explanatory notes accompanying the ongoing sheet 081 “Rovereto” of the official geological map of Italy at 1:50000.","language":"eng","citation":"\"INTEGRATING SEDIMENTOLOGY, STRATIGRAPHY, GEOCHEMISTRY AND 3D GEOMODELLING: CONTRIBUTION TO GEOLOGICAL MAPPING FOR LAND KNOWLEDGE (CARG SHEET 081 \"\"ROVERETO\"\") / N. Coccia ; tutor: F. Berra ; co-tutor: M. Marini ; coordinatori: E. Damiani, F. Ragusa. Dipartimento di Scienze della Terra Ardito Desio, 2026 Feb 27. 38. ciclo, Anno Accademico 2024/2025.\"","filename":"phd_unimi_R14044.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 26-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1047250"},"title":"NORMAL FORM METHODS FOR SOME NON  LINEAR HAMILTONIAN PDES IN HIGHER DIMENSION","internalauthor":"MONZANI, FRANCESCO","type":"Tesi di dottorato","year":"2024","abstract":"The thesis deals with perturbation theory for non-linear Hamiltonian partial differential equations on high dimensional compact manifolds. In particular, we prove almost global existence for some PDEs of general interest and we provide a suitable algebraic and geometric framework. Proofs are based on normal form methods.","language":"eng","citation":"NORMAL FORM METHODS FOR SOME NON  LINEAR HAMILTONIAN PDES IN HIGHER DIMENSION / F. Monzani ; tutor: D. Bambusi ; coordinatore: D. Bambusi. Dipartimento di Fisica Aldo Pontremoli, 2024 Apr 23. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R12804.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1047250/2403716/phd_unimi_R12804.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1147536"},"title":"DEVELOPMENT OF BIODEGRADABLE BACTERIAL BIOSENSORS FOR THE IDENTIFICATION OF HUMAN HEALTH MARKERS BY PROTEOMIC EXPRESSION.","internalauthor":"MALI RAI, POOJA","type":"Tesi di dottorato","year":"2025","abstract":"ABSTRACT  Purpose  This study investigates, through proteomic expression, the biosensing capability of Lactobacillus rhamnosus GG in the oral environment. The primary objective is to evaluate LGG as a bacterial biosensor for biomarkers indicative of oral and systemic health conditions.  Materials and Methods  LGG was cultured and then exposed to phosphate buffer, sucrose solution, lactic acid, and filtered saliva from several subjects. Proteomic profiling was done by high-resolution mass spectrometry, and data analysis was done, focusing on the expression of bacterial proteins under different conditions. Statistical comparisons outlined proteomic changes, with a focus on upregulated and downregulated proteins relevant to stress response, metabolism, and adaptation.  Results  Based on different exposures of LGG to a variety of microenvironments, there existed distinct proteomic profiling. Under nutrient-rich conditions, massive downregulation was realized in the case of proteins linked with stress; each salivary composition also induced its characteristic unique proteomic signature. Identifications of key proteins associated with metabolic regulation, response against oxidative stress, and bacterial adaptation were possible using heatmaps and volcano plots. Robust clustering and patterns of variance signified that LGG can recognize altered conditions of its ambiance and even provide bio signals thereof.  Conclusion  This study highlights the potential of LGG as a non-invasive biosensor of oral and systemic health biomarkers. Early detection of dysbiosis and changes in the environmental niche show that LGG is able to serve as a backbone in developing novel diagnostic tools. Real-time health monitoring will now be facilitated toward the development of personalized medicine and preventive healthcare.","language":"eng","citation":"DEVELOPMENT OF BIODEGRADABLE BACTERIAL BIOSENSORS FOR THE IDENTIFICATION OF HUMAN HEALTH MARKERS BY PROTEOMIC EXPRESSION / P. Mali Rai ; PhD coordinator: M. Del Fabbro ;  tutor : G. M. Tartaglia ;  co-tutor: F. Goker. - AULA MAGNA DEVOTO PAVILION, POLICLINICO - MILAN. Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, 2025 Feb 28. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13624.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1147536/2678515/phd_unimi_R13624.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1209695"},"title":"NOVEL MOLECULAR CANDIDATES WITH PROPHYLACTIC AND THERAPEUTIC POTENTIAL AGAINST HIV AND MEASLES INFECTIONS","internalauthor":"LATERZA, GIULIA","type":"Tesi di dottorato","year":"2026","abstract":"Immunizations prime the body to defend itself against viruses, significantly reducing the risk of infection and, more importantly, the risk of severe disease and death. This is the underlying idea of this thesis, and it addresses two major objectives: (1) to evaluate novel anti-idiotype antibody-derived fragments as potential Human Immunodeficiency Virus type 1 (HIV-1) immunogens, and  (2) to develop therapeutic antibodies against measles virus (MeV) central nervous system (CNS) complications; all in pre-clinical settings. As of 2024, more than 40 million people worldwide were living with HIV-1, including over 1.4 million children aged 0 to 14. Even though long-lasting antiretroviral therapy (ART) allows the decrease of the viral load to an undetectable value, there is currently no available treatment that completely eradicates HIV-1.  Therefore, the necessity of an effective vaccine emphasizes the medical need to continue researching novel molecules, and a prophylactic approach appears  promising. Over the years, different pieces of evidence have suggested that immunoglobulins generated against the idiotype region of an anti-HIV-1 antibody could have a paratope structurally similar to the primary antibody. This similarity could allow them to bind to the original target. Moreover, engineered antibody fragments also offer new biopharmaceutical opportunities because of their smaller size. For this reason, antigen-binding fragment (Fab), single-chain variable fragment (scFv), and minibody (Mb) derived from an anti-idiotype HIV-1 antibody (P1) were administered in vivo in both rabbits and non-human primates (NHPs) following two distinct vaccination protocols. The objective was to determine whether several anti-idiotype antibody-derived fragments could elicit a specific immune response against the outer envelope glycoprotein gp120, which is HIV-1’s main antibody target. Only the Mb VHVL format appeared to be highly effective in generating strong and long-lasting anti-gp120 antibodies in rabbits. This discovery is promising and raises the possibility of investigating this antibody-derived  fragment as an HIV-1 immunogen in further detail. Rather, NHPs did not exhibit a distinct HIV-1 anti-gp120 humoral response with none of the P1-derived fragments tested. Modifications in vaccine immunization, including combining multiple P1 antibody fragments while boosting with the trimeric SOSIP constructs, and either changing or employing adjuvant combinations, should be explored to evaluate an enhancement in immunogenicity and so in  the overall antibodies elicited. The second part of this thesis focuses on MeV, another major global health threat. As of August 2025, 32 measles outbreaks were officially reported in the United States (U.S.), with 92% of cases occurring in unvaccinated individuals. The rise of vaccine hesitancy contributes to a decrease in MeV vaccination, resulting in 10.3 million infected people worldwide in 2023. MeV is highly contagious and, since herd immunity has not been reached, poses a severe threat to all vulnerable populations who cannot receive the live-attenuated measles vaccine. Furthermore, when MeV infection happens in children less than 12 months old, the CNS experiences complications, including the lethal subacute sclerosing panencephalitis (SSPE), which occurs in the same children at a rate of 1:609, years after the disease has been cleared. In this thesis, an ‘antibody cocktail’ consisting of three anti-MeV humanized antibodies (77.1, Y10F, and H55) was initially tested in vitro to evaluate its potential for both prophylactic and therapeutic applications. Briefly, 77.1 binds to the pre-fusion conformation of the F MeV protein, stabilizing it in an intermediate state. Y10F recognizes the apex region of the F protein, locking the F in the pre-fusion conformation, while H55 binds the H protein, preventing the F protein from activating and interacting with the receptor. Therefore, combining all three antibodies resulted in a significant increase in inhibitory capacity, indicating a synergistic activity. Following, since MeV CNS complications are currently untreatable, a three amino acid modification (M252Y/S254T/T256E [YTE]) in the constant fraction (Fc) of 77.1 (77.1YTE) was tested in vivo to determine whether this modification would increase the antibody CNS localization in comparison to its unaltered version (77.1). As a result, 77.1YTE efficiently localizes in the CNS, remaining detectable still after 168 hours post-injection. Furthermore, 77.1YTE retains the ability to bind the natural conformation of the MeV F protein, suggesting that 77.1YTE could be efficient against CNS-adapted MeV viruses, representing a first significant advancement as a potential therapeutic approach.","language":"eng","citation":"NOVEL MOLECULAR CANDIDATES WITH PROPHYLACTIC AND THERAPEUTIC POTENTIAL AGAINST HIV AND MEASLES INFECTIONS / G. Laterza ; tutor: A. Soggiu; co-tutor: R. A. Diotti; supervisors: J. Carrillo, M. Porotto ; coordinator: F. Parazzini. Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, 2026 Jan 15. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14085.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 16-LUG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/820647"},"title":"CHARACTERIZATION OF NANOSTRUCTURED METALLIC FILMS WITH NON-LINEAR ELECTRICAL PROPERTIES FOR THE FABRICATION OF NEUROMORPHIC DEVICES AND UNCONVENTIONAL DATA PROCESSING","internalauthor":"MIRIGLIANO, MATTEO","type":"Tesi di dottorato","year":"2021","abstract":"Unconventional computing paradigms are subject of increasing interest for the design and the development of computing systems that aim to overcome the limitations of standard digital technologies related to low power efficiency and intrinsic integration limits in the fabrication processes. Networks of nano-objects fabricated exploiting the self-assembling of their building blocks at the nanoscale, are promising physical substrate for the fabrication of neuromorphic devices thanks to their non-linear electrical properties and dynamic behavior in response to external applied voltage. Recently, cluster-assembled metallic films showed resistive switching properties under the application of an external electrical films and the possibility to fabricate multi-electrode device capable to implement information processing systems [9, 10]. Here I studied the non local and correlated electrical behaviour of multi-electrode cluster-assembeld gold films and I proposed a device that exploits the coduction porperties of these systems to implement efficient and autonomous data processing.","language":"eng","citation":"CHARACTERIZATION OF NANOSTRUCTURED METALLIC FILMS WITH NON-LINEAR ELECTRICAL PROPERTIES FOR THE FABRICATION OF NEUROMORPHIC DEVICES AND UNCONVENTIONAL DATA PROCESSING / M. Mirigliano ; tutor: P. Milani ; phd coordinator: M. Paris. Dipartimento di Fisica Aldo Pontremoli, 2021 Feb 23. 33. ciclo, Anno Accademico 2020. [10.13130/mirigliano-matteo_phd2021-02-23].","filename":"phd_unimi_R11890.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/820647/1722584/phd_unimi_R11890.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1205217"},"title":"TARGETING Α-SYNUCLEIN AGGREGATION AND INFLAMMATION IN PARKINSON¿S DISEASE: THE ROLE OF POLY-Γ-GLUTAMIC ACID","internalauthor":"NOVELLO, CLAUDIA","type":"Tesi di dottorato","year":"2026","abstract":"Parkinson’s disease (PD) is a complex multifactorial neurodegenerative disorder affecting more than 10 million people worldwide. As a synucleinopathy, PD is characterized by the pathological accumulation of misfolded and aggregated α-synuclein in both the central and peripheral nervous system. In this context, many efforts have been made to counteract α-synuclein aggregation, propagation, and associated inflammatory responses, which are key features of the disease. However, despite the tremendous effort and research investment, no disease-modifying therapies are currently available, and symptomatic approaches remain the standard cure for the treatment of PD.  In this work we aimed to evaluate the therapeutic potential of commercially available poly-γ-glutamic acid (γ-PGA) polymers, a natural, non-toxic and non-immunogenic biopolymer, in different in vitro models of PD, focusing on its properties as anti-inflammatory agent and modulator of aggregation. Indeed γ-PGA has gained significant interest in biomedicine due to its antioxidant, anti-inflammatory, and neuroprotective effects, providing evidence for its beneficial value in neurodegenerative disorders.  To investigate these biological properties, we selected complementary in vitro models that recapitulate different aspects of PD pathogenesis. Primary murine astrocytes were employed for their central role in α-synuclein clearance and neuroinflammation, given their involvement in the interplay between protein aggregation and immune responses in the central nervous system. Macrophages were selected to assess peripheral immune cell activation, which is strongly implicated in PD pathogenesis. Finally, neuronal in vitro model and cell free system assay were employed to assess the specific effect of γ-PGA in interfering with α-synuclein aggregation.  Using primary murine astrocytes exposed to α-synuclein preformed fibrils (PFFs) we demonstrated that γ-PGA restored cell viability, reduced astrocyte inflammation, and decreased α-synuclein pathology burden. These effects were associated with the reduced internalization of aggregates and the direct interference with α-synuclein aggregation, as confirmed by cell-free system assays. In addition, we examined the impact of α-synuclein aggregates on macrophage immune response, focusing on their polarization. Using an in vitro model of macrophages, we observed that PFFs induced a mixed M1/M2 phenotype without affecting cytotoxicity and ROS production, and that γ-PGA administration attenuated this polarization, suggesting a modulatory role in α-synuclein-induced immune response. Finally, in a neuronal in vitro model, γ-PGA polymers significantly reduced the burden of early-stage α-synuclein aggregates supporting its direct anti-aggregation capacity.  4  Overall, this work provides in vitro proof-of-concept evidence that γ-PGA can modulate α-synuclein aggregation and aggregate-induced inflammatory response, highlighting its potential as a safe and effective therapeutic strategy for PD. Interestingly, given its additional role as a prebiotic able to modulate the gut microbiome, and the emerging evidence that dysbiosis is linked to PD, future research that explores γ-PGA effects on the gut-brain axis and focuses on inflammation and microbiota modulation in the gut, as well as α-synuclein propagation and neuronal function in PD pathogenesis, holds promise.","language":"eng","citation":"TARGETING Α-SYNUCLEIN AGGREGATION AND INFLAMMATION IN PARKINSON' S DISEASE: THE ROLE OF POLY-Γ-GLUTAMIC ACID / C. Novello ; tutor: G. Cappelletti ; phd coordinator: S. Ricagno. - Dipartimento di Bioscienze. Dipartimento di Bioscienze, 2026 Jan 15. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13953.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1205217/3213534/phd_unimi_R13953.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1154659"},"title":"INSIGHTS INTO THE SELECTION AND FUNCTION OF COPY-NUMBER ALTERATIONS DURING CANCER EVOLUTION","internalauthor":"ALFIERI, FABIO","type":"Tesi di dottorato","year":"2025","abstract":"Cancer evolution is a complex process mostly driven by genomic instability, including large- and small-scale alterations, such as copy-number alterations (CNAs) or single-nucleotide mutations, respectively. Those alterations play a critical role in tumor development, genetic diversity, and resistance to therapies. This thesis explores the selection and functional role of CNAs, aiming to uncover insights into how these alterations shape cancer evolution. By integrating computational analyses, machine learning approaches, and experimental techniques, we provide insights into the forces that drive CNA patterns, their impact on tumor progression and we examine how CNAs interact with other evolutionary pressures and cellular functions. These approaches reveal how selection and structural constraints influence CNA landscapes, uncovering adaptive mechanisms that enable cancer cells to tolerate genomic instability while maintaining essential functions. The connections between these investigations highlight the interplay of genomic architecture, selective forces, and functional outcomes. By combining data-driven insights with experimental evidence, we identify fundamental principles underlying CNA evolution and its context-dependent dynamics across cancer types.      This integrative approach underscores the importance of using diverse methodologies to dissect the complexity of cancer genomes. Ultimately, the findings presented in this thesis advance our understanding of CNA-driven tumor evolution and may help in the identification of new potential vulnerabilities that could inform novel therapeutic strategies.","language":"eng","citation":"INSIGHTS INTO THE SELECTION AND FUNCTION OF COPY-NUMBER ALTERATIONS DURING CANCER EVOLUTION / F. Alfieri ; tutor: M. Schaefer ; internal advisor: F. Nicassio ; external advisor: T. Davoli ; phd coordinator: D. Pasini. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Apr 03. 36. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13165.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1154659/2715501/phd_unimi_R13165.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1114248"},"title":"YEAR ONE HUNDRED REFOUNDATION: A DIDACTIC PROPOSAL FOR A CULTURAL UNDERSTANDING OF QUANTUM MECHANICS","internalauthor":"LOVISETTI, LUISA","type":"Tesi di dottorato","year":"2024","abstract":"In the late nineteenth century, classical physics seemed unassailable, firmly grounded in Newton’s mechanics for macroscopic bodies and Maxwell’s electromagnetic theory for radiation. This confidence was bolstered by the technological successes that marked a significant phase of the Industrial Revolution.  However, beneath this facade, classical physics faced emerging difficulties, struggling to accommodate certain experimental facts within its theoretical framework. These contradictions hinted at the need for new approaches, ultimately leading to the development of quantum mechanics in the mid-1920s. Early attempts to explain microscopic phenomena evolved into a comprehensive theory through contributions from numerous physicists. Quantum mechanics addressed empirical anomalies that classical physics could not, marking a significant scientific breakthrough.  The development of quantum mechanics represented and still represents today a remarkable scientific journey, important not only historically but also culturally and educationally. It revolutionized our understanding of reality, making it a fundamental aspect of modern physics. However, despite its significance, quantum mechanics remains largely absent from people’s cultural background, often perceived as mysterious and incomprehensible.   Integrating quantum mechanics into people’s general knowledge is thus crucial, starting with students’ education. This research project, developed within the physics education group at the University of Milan, aims to prioritize quantum mechanics in physics education. It analyzes current teaching methods, identifies their shortcomings, and proposes an effective educational reconstruction of the theory, including its historical development. The goal is to design a didactic approach for teaching quantum mechanics in high schools and non-physics degree programs, configured as both a significant and formative educational experience as well as a cultural framework.","language":"eng","citation":"YEAR ONE HUNDRED REFOUNDATION: A DIDACTIC PROPOSAL FOR A CULTURAL UNDERSTANDING OF QUANTUM MECHANICS / L. Lovisetti ; supervisor: M. Giliberti ; co-supervisor: M. Paris ; director of the school: A. Mennella. Dipartimento di Fisica Aldo Pontremoli, 2024 Oct 28. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13279.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1114248/2573312/phd_unimi_R13279.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1118829"},"title":"THE SPINTERFACE PROBLEM: AB-INITIO STUDIES OF FE-PHTHLOCYANINE ON TRANTITION-METAL OXIDES.","internalauthor":"MARINO, MARCO","type":"Tesi di dottorato","year":"2024","abstract":"At the interface between a transition-metal oxide and a metal-organic molecule, electrons form interesting hybrid electronic states that characterize what is commonly called an organic spinterface. The central idea of our study is the possibility of exciting a spin coherent wave inside the substrate through a light-induced excitation of the molecule - in other words, actively perturbing the spinterface to modify its magnetic state. In this framework, the spinterface is studied for its electronic, magnetic and optical properties through ab-initio approaches.     Specifically, we selected the transition-metal oxides: NiO(001), CoO(001) and Cr2O3(0001) as substrates. These materials are antiferromagnetic at high and/or room temperature and are characterized by low spin-orbit interaction, making them promising candidates for spin-excitation transport. For the metal-organic molecule, we chose Fe-phthalocyanine, a versatile species valued for its adaptability across various applications.    In addition to the insights specific to each molecule/substrate combination revealed by our ab-initio simulations, three main findings emerged regarding the goal of activating the spinterface by light. First, significant hybridization between the molecule and the substrate is advantageous for maximizing the transfer of the light-induced molecular excitation onto the magnetic couplings between substrate spins. Second, to impact the substrate's magnetic couplings, this hybridization needs to be spin-unbalanced. In this regard an adsorption configuration breaking the spin symmetry of the substrate is sufficient, so that the adsorption of a magnetic molecule is not required. Third, effective control over spinterface tunability requires a distinct retention of molecular and substrate character: hybridization should not be so strong that they become indistinguishable.  In terms of light excitation spectra, this translates into high-intensity transitions between states with identifiable molecular and substrate characteristic.","language":"eng","citation":"THE SPINTERFACE PROBLEM : AB-INITIO STUDIES OF FE-PHTHALOCYANINE ON TRANSITION-METAL OXIDES / M. Marino ; supervisor: G. Fratesi ; co-supervisor: S.  Achilli ; coordinator: A. Mennella ; external referee: M. Cococcioni ; external referee: P. Puschnig. , 2024 Dec 22. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13386_2.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1118829/2590464/phd_unimi_R13386_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1229776"},"title":"CONTROLLED AND AUTOMATIC PROCESSES IN MORAL DECISION-MAKING","internalauthor":"RAIA, RENATO","type":"Tesi di dottorato","year":"2026","abstract":"A popular dual-process theory of moral decision-making, that put forward by Joshua Greene,   proposes that deontological judgments are produced by affective intuitions while consequentialist   judgements usually are the product of cognitive deliberation. Greene and colleagues (2001, 2004)   have backed up this claim with empirical evidence coming from fMRI studies, cognitive load studies,   and pathology. Greene (2008, 2014, 2017) has used this evidence to propose two normative   derivations, the direct and indirect route, about deontological moral judgments. The arguments aim   to show that, given their origin in affective and intuitive processes, deontological judgments led us   astray in many modern moral problems, and in many philosophical problems like the famous trolley   problem or Peter Singer’s (1972) problem on the moral effect of spatial distance. In this thesis I   attempt to flesh out a criticism against some aspects of Greene’s dual-process model and to propose a   new theory, by disentangling some theoretical classifications (intuition-deliberation, emotioncognition, deontology-consequentialism) that, in Greene’s theory, are mapped one upon the other. I   argue that the emotion-cognition distinction is not a useful theoretical tool; and I follow the theories   of the education of moral intuitions proposed by Jillian Craigie (2011), Hanno Sauer (2012a),   Richmond Campbell and Viktor Kumar (2012) in positing a diachronic effect of deliberation over   intuitions. I propose that the education of intuitions in the moral sphere is best characterized as a   process of skill acquisition rather than habitualization, as this better accounts for its automatic yet   rational nature (Christensen, Sutton and McIlwain, 2016; Stichter, 2018). Following an intuition by   Peter Railton (2014), I provide a defense of deontological judgments from the normative claims of   Greene’s theory, and I offer a more balanced view of the role of intuition within moral decisionmaking, providing a reinterpretation of the role it plays in Haidt’s Twin Problem, in the trolley   dilemma, and in Singer’s Puzzle. My reinterpretation is centered on the capacity of intuition to react   to the general story proposed by these problems rather than on specific factors. Thus, I argue that   intuition is much more nuanced and indeed necessary in morality. My own positive theory is centered   around the notion that moral judgments might proceed from self-centered thoughts and feelings or   from other-centered ones. I propose that broadly agreed upon judgments are those which find a balance   between these two extremes, while deliberation is needed to reach more extreme and less common   judgments. Finally, following a model by Kahane and colleagues (2018), I advance the hypothesis   that consequentialist judgments might be perceived as more uncommon than deontological ones.","language":"eng","citation":"CONTROLLED AND AUTOMATIC PROCESSES IN MORAL DECISION-MAKING / R. Raia ; tutor: J. Michael (Unimi), S. Butterfill (Warwick University, UK)  coordinatore: A. Sereni. Dipartimento di Filosofia Piero Martinetti, 2026 Mar 06. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14007.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1229776/3289152/phd_unimi_R14007.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1064588"},"title":"CLASSIFICATION OF PATIENTS WITH PAROTID CANCER USING DYNAMIC CONTRAST AND DIFFUSION EXAMINATIONS WITH RADIOMICS AND MACHINE LEARNING TECHNIQUES","internalauthor":"TORTORA, SILVIA","type":"Tesi di dottorato","year":"2024","abstract":"Objectives: The aim of this study is to evaluate the role of MRI-based radiomics analysis and machine learning using both DWI with multiples B values and dynamic contrast-enhanced T1-weighted sequences to differentiate pleomorphic adenoma (A), Warthin’s tumor (W) and malignant (M) tumors.   Materials and Methods: This retrospective study involving 41 patients (19 male, 22 female, age 18–88, median 59.4) with parotid gland lesions (10 W, 15 A and 18 M) who underwent a neck MRI examination at San Paolo Hospital of Milan between April 2020 and July 2023 and histopathologically-confirmed. In total, 13 radiomics features were extracted from DWI with 11 B values and dynamic contrast-enhanced T1-weighted sequence. The intensity of association between features and type of tumor class (A, W and M) has been evaluated using three different features importance algorithms: Receiver operating characteristic (ROC) analysis, ReliefF, and Recursive Feature Elimination (RFE) that allowed the identification of the association between each considered radiomics predictor and the patient class (A, M, W), thus enabling the selection of an ensemble of optimal features to train the machine learning classification algorithm. Two different classification algorithms have been adopted to model the dataset under study, namely the Support Vector Machine (SVM) and the artificial Neural Networks (NN).  Results: The SVM model provides a slightly higher overall accuracy (80%) compared to the NN one (78%). However, both models still provide a non-negligible number of false negatives, especially for class A and M, which exhibit lower sensitivity scores (below 80%), thus leaving room for further improvements to make the model more robust by increasing the dataset size and balance (as measured through the Shannon Entropy) to enhance the sensitivity score and therefore decrease the false negative rate. Analogous considerations can be done for the positive predictive value for patients in class W, which is slightly below 70% in the NN model compared to a higher value (75%) in the SVM model, thereby indicating that the SVM model could be potentially a more reliable model compared to NN one.  Conclusions: Radiomics and machine learning allow a good diagnostic performance in differentiating pleomorphic adenoma, Warthin’s tumor and malignant tumor.","language":"eng","citation":"CLASSIFICATION OF PATIENTS WITH PAROTID CANCER USING DYNAMIC CONTRAST AND DIFFUSION EXAMINATIONS WITH RADIOMICS AND MACHINE LEARNING TECHNIQUES / S. Tortora ; tutor: G. Carrafiello ; coordinatore: M. Del Fabbro, M. Sansone. Università degli Studi di Milano, 2024 Jul 01. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13068.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1064588/2445994/phd_unimi_R13068.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1118824"},"title":"OPTIMIZATION OF THE PRODUCTION OF TERBIUM RADIONUCLIDES FOR THERANOSTIC APPLICATIONS","internalauthor":"COLUCCI, MICHELE","type":"Tesi di dottorato","year":"2024","abstract":"The field of nuclear medicine has significantly advanced since the discovery of artificial radioactivity in 1934. Among the developments, theranostics has emerged as a promising approach combining diagnostics and therapy using radiopharmaceuticals labeled with chemically identical radionuclide pairs. In particular, the terbium isotopes 149Tb, 152Tb, 155Tb, and 161Tb have shown great potential due to their unique decay properties, enabling precise imaging and effective treatment modalities.  This thesis focuses on the optimization of terbium radioisotopes production using charged-particle-induced nuclear reactions. Due to the scarcity of experimental data and discrepancies in the literature, cross-sections for five nuclear reactions involving terbium, gadolinium, europium, and dysprosium targets were measured using cyclotron facilities at GIP ARRONAX (France) and LASA (Italy). The study addresses several challenges in radionuclide production, including yield maximization, radionuclidic purity, and specific activity, which are crucial for theranostic applications.  The results demonstrate optimal production routes for 155Tb through the indirect 159Tb(p,x)155Dy reaction, achieving a high yield of 1.2 GBq/µA and radionuclidic purity above 99.9 %. Similarly, potential production methods for 152Tb and 155Tb via natural and enriched europium targets were evaluated. However, the direct production of 149Tb remains challenging due to low yields and complex separation processes.  In addition, a radiochemical separation protocol using extraction chromatography was developed for purifying terbium from gadolinium and dysprosium contaminants. The findings highlight key production pathways and offer valuable insights for future clinical applications of terbium radionuclides in theranostics, potentially overcoming existing production limitations and expanding their use in personalized cancer treatment.","language":"eng","citation":"OPTIMIZATION OF THE PRODUCTION OF TERBIUM RADIONUCLIDES FOR THERANOSTIC APPLICATIONS / M. Colucci ; supervisor: F. Groppi ; co-supervisor: S. Manenti ; coordinatore: A. Mennella. - Laboratori Accelarori e Superconduttività Applicata, LASA, Via Fratelli Cervi 102, Segrate (MI). Dipartimento di Fisica Aldo Pontremoli, 2024 Dec 04. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13220_2.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1118824/2590454/phd_unimi_R13220_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1177455"},"title":"SUPPORTING COMPANIES IN THEIR DIGITAL TRANSITION TO SMART MANUFACTURING SYSTEMS","internalauthor":"DE MARTINO, GIUSEPPE","type":"Tesi di dottorato","year":"2025","abstract":"Industry 4.0 (I4.0), which is considered to be the fourth industrial revolution, is now a well-established concept. However, it presents significant challenges for several manufacturing sectors. Luxury fashion is a key example, showing two blocking factors. First, the need to keep not only design, but also production data in-house, to protect industrial secrets, prevents the export of production or design data to external cloud services. Second, the need to keep using specially tailored legacy machines, which are not I4.0 compliant by design, leads to the lack of automated data pipelines capable of seamlessly connecting industrial machines to Business Intelligence (BI) applications.    In fact, existing integration solutions often require invasive interventions on production lines, potentially disrupting operational continuity or exposing sensitive processes and intellectual property. This drawback acts as a barrier to adoption, especially in sectors where preserving traditional workflows and data confidentiality is critical.    Despite these challenges, several factors facilitate this transition. For instance many companies operate with legacy machinery, which is already capable of generating and transferring industrial production data. Furthermore, most companies have on-premises servers, often pre-configured for data warehouse implementation. An additional incentive comes from government funding, which provides financial support to businesses embarking on the digital transformation journey.    This thesis proposes a non-invasive architectural solution to support the digital transition of companies in high-quality production sectors towards smart manufacturing systems. It integrates an innovative data pipeline based on machine learning, capable of automatically recognizing sensors from unknown machinery. The proposed solution is intended to be non-invasive, as no change in the core production machines, and no IT intervention is required for the core business development of textile companies, in order to preserve intellectual property and avoid interfering with the normal workflow of textile operators. The main goal is to design and develop a novel data pipeline architecture to support the digital transition of textile companies seamlessly and adaptively.    The research addresses the following research questions:    RQ1: Which hardware / software technologies and tools are necessary to implement a software architecture for the transition to I4.0?    RQ2: How can such an architecture be designed to be non-invasive, minimum human industrial configuration, seamless integration of new machines?    RQ3: How to design a data pipeline which enables self configuration (i.e. how to design effective Machine Learning (ML) pipelines)?    RQ4: How can such an architecture serve to build intelligent manufacturing systems with adherence to a set of I4.0 rules, standards, regulations, and guidelines that govern the textile sector?    The proposed conceptual architecture is constructed and validated incrementally with real installations and data from Italian luxury fashion manufacturing companies. The architecture is divided into three layers: Physical, comprising legacy industrial machinery equipped with sensors, actuators, and PLCs; Edge Node, the core component that includes a message broker and an intelligent data filter for data processing and transformation; and Cloud On-Premises, which leverages the existing IT infrastructure in companies for production monitoring and management via Manufacturing Execution System (MES) or Decisional Support System (DSS). A key component is the Smart Interface (SI), an SBC (Single-Board Computer) device that extracts data from PLCs and publishes it to a message broker. The Intelligent Data Filter, based on ML techniques, is responsible for filtering, categorizing, and recognizing new machinery connected to the company network. From a pure methodological point of view, the ML-based semantic recognizer is based on a novel ML pipeline for solving a peculiar time series classification problem involving mutual exclusion. We also explore the algorithmic optimization of specific logistics systems, such as the sorting of hanging garments, which are triggered by our architecture, demonstrating how such an approach can further enhance overall company efficiency in their digital transition toward I4.0.    Some modules of our architecture have already been provided to over 50 clients in the high-quality textile sector in Italy, managing the data flow of more than 580 IoT devices, corresponding to tailored industrial machinery. Thanks to this infrastructure, these companies have obtained competitive advantages, as well as the necessary certifications to access tax incentives related to the digital transition.","language":"eng","citation":"SUPPORTING COMPANIES IN THEIR DIGITAL TRANSITION TO SMART MANUFACTURING SYSTEMS / G. De Martino ; advisor: A. Ceselli ; co-advisor: P. Scandurra ; coordinator: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2025 Sep 22. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13446.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1177455/3117848/phd_unimi_R13446.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1022348"},"title":"PLANT BIOACTIVE COMPOUNDS FOR SUSTAINABLE NUTRITION AND PREVENTION OF METABOLIC DISEASES","internalauthor":"HEINZL, GIUDITTA CARLOTTA","type":"Tesi di dottorato","year":"2024","abstract":"Chronic metabolic diseases, including diabetes, obesity, and cardiovascular disorders, represent a significant global health challenge. Their prevalence continues to rise, necessitating  innovative approaches to prevention and treatment. This work focus on bioactive compounds derived from legumes and pseudocereals that have emerged as promising therapeutic agents  for the treatment of metabolic-related chronic diseases. These compounds include polyphenols and peptides, both renowned for their distinctive bioactivity. Central to this thesis is the  rigorous evaluation of the bioactive compounds' efficacy in preventing and ameliorating metabolic-related chronic diseases, such as type 2 diabetes, cardiovascular diseases, and obesity. In vitro and ex vivo studies provides insights into the peptides' therapeutic potential.  These studies elucidate the compounds' mechanisms of action and their ability to modulate crucial pathways including their role in modulating glucose metabolism, mitigating oxidative stress, and exerting anti-inflammatory effects. Subsequently, the investigation delves into the characterization of protein’s glycosylation. Advanced analytical techniques, including chromatography and light scattering analysis, are harnessed to elucidate the structural and biochemical attributes of glycoproteins that influence not only their bioactivity but also can contribute to their allergenic potential. In fact, crucial in the study of bioactive peptides, potentially usable for the treatment of chronic disorders, is their potential allergenicity. Cross reactivity  with known allergens such as soybean or peanut is indeed a potential issue in the development of these products. In this work, we therefore also focused on studying the interaction of proteins and peptides with dendritic cells and their ability to develop allergic  reactions with IgE and IgG antibodies. Furthermore, sustainability considerations play a pivotal role throughout this research. The significance of vegetable proteins lies not only in their role as an alternative protein source but also in their potential to address pressing global challenges as their cultivation typically requires fewer resources, such as land, water, and energy, compared to conventional livestock farming. By shedding light on the bioactive  compounds of legumes and pseudocereals and their potential in the context of metabolicrelated chronic disease treatment, this research contributes to the evolving landscape of nutritional sciences. Ultimately, this work aspires to facilitate the development of innovative dietary interventions that hold promise in enhancing public health and fostering a sustainable future.","language":"eng","citation":"PLANT BIOACTIVE COMPOUNDS FOR SUSTAINABLE NUTRITION AND PREVENTION OF METABOLIC DISEASES / G.c. Heinzl ; tutor: A. Scarafoni ; coordinatore: L. Pinotti. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2024 Feb 08. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12836.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1022348/2340393/phd_unimi_R12836.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1149575"},"title":"FOOD SECURITY: INNOVATIVE PLANT REPRODUCTIVE STRATEGY IN A CHANGING ENVIRONMENTAL CONDITION","internalauthor":"BANFI, CAMILLA","type":"Tesi di dottorato","year":"2025","abstract":"With the climate changing and the population increasing, the global food security issue is currently one of our main concerns. In this framework, the development of advanced plant breeding strategies is essential to ensure population feeding. Apomixis is an asexual reproductive mechanism in which the seeds are produced clonally. In apomictic plants, the female meiosis is altered or bypassed thus generating unreduced spores and consequently gametes that develop in embryos without fertilization. The advantage of this reproduction type is the fixation of highly resistant and productive varieties through generations, without segregation of the traits. However, the introduction of apomixis in crop plants is challenging, because its regulation is still largely unknown.  During my PhD, I have characterized this process at the cytological and molecular level, highlighting the main differences with sexual reproduction especially during the first meiotic division. Furthermore, I have used different approaches to unveil the genes potentially involved in apomixis regulation in the natural apomictic species Taraxacum officinale – the common dandelion. I have contributed to characterize the molecular function of VACUOLAR PROTEIN SORTING 13 (VPS13), one putative regulator required for the formation of unreduced and clonal female gametes in dandelion, and ovule development in the model sexual species Arabidopsis thaliana, assessing its downstream pathways.  Due to the lack of Taraxacum vps13 loss of function mutants, to understand the mechanism of action of VPS13 I have characterized in detail the Arabidopsis vps13 mutant. By studying ovule development, I have demonstrated that this gene is necessary for the correct specification of the female germline and the progression of megasporogenesis. In particular, I have established VPS13's role in the small RNA pathway and its interaction with meiotic proteins. All in all, my work has contributed to the understanding of the molecular regulation of sexual and apomictic reproduction, and it will contribute to the application of asexual reproduction to agriculture.","language":"eng","citation":"FOOD SECURITY: INNOVATIVE PLANT REPRODUCTIVE STRATEGY IN A CHANGING ENVIRONMENTAL CONDITION / C. Banfi ; scientific tutor: L. Colombo ;  course coordinator: S. Ricagno. Dipartimento di Bioscienze, 2025 Feb 27. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13633_4.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1149575/2692921/phd_unimi_R13633_4.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1245977"},"title":"THE INTERGENERATIONAL IMPACT OF ENVIRONMENTAL EXPOSURES: MOLECULAR INSIGHTS FROM MODELLING PLURIPOTENCY TRANSITIONS THROUGH THE HUMAN GERMLINE","internalauthor":"STUCCHI, SARAH","type":"Tesi di dottorato","year":"2026","abstract":"How environmental exposures shape inheritance across generations is a fundamental question in biology, with far-reaching implications for human health. Despite evidence of such inheritance in animal models, its mechanisms and relevance in humans remain elusive due to key challenges: (i) the inaccessibility of developing germ cells from exposed individuals; (ii) the predominance in the field of methodological approaches based on the investigation of single molecular layers; (iii) the impossibility of studying multiple human generations in laboratory settings; (iv) the scarcity of multi-generational human data precisely linking environmental exposures and health outcomes.  Considering the central role of endocrine signalling during development, in this PhD thesis, I tackle these challenges by focusing on the paradigmatic case of the intergenerational impact of endocrine disrupting chemicals (EDCs), widespread compounds that interfere with hormonal signalling causing several adverse health effects. To overcome these challenges, I first implemented in the lab publicly available protocols to differentiate human induced pluripotent stem cells into primordial germ cells-like cells (hPGCLCs) and pro-spermatogonia/oogonia. Following their comprehensively characterization at the transcriptomic, DNA methylation, and protein-marker levels and benchmarking against human fetal reference datasets, we confirmed their ability of recapitulating key aspects of human germ cell development. Since these cells also express key hormone receptors, we considered them suitable for studying the molecular and cellular responses to EDC exposure. We also investigated the role of lipid droplet (LD) accumulation and metabolism in these cells, as a relevant cellular component that interplays with transcriptomic and epigenomic layers. We noted that, interfering with LD accumulation in different time windows, impacts differentially on hPGCLC specification and differentiation. This provided a comprehensive view of germ cell state under physiological and perturbed conditions, becoming a starting point to move from approaches based on the investigation of a single-layer and a predominantly (epi)genetic-centric view toward a cell-centric view of inheritance.  However, making any claim about inheritance, requires showing whether and how these changes in germ cells, the enduring link across generations, are transmitted to the next generation(s). To address this, we developed and characterized an innovative in vitro model capable of capturing transcriptomic and epigenetic dynamics across generations, thus making epigenetic inheritance experimentally tractable in humans. We then used this model to investigate the intergenerational impact of EDCs on human neurodevelopment. To this aim, we also leveraged epidemiological data from a multi-generational human cohort, the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy study (SELMA), exposing our in vitro model to agonists of key hormonal pathways and to epidemiologically relevant EDCs, to evaluate their impact on the germline transcriptome and to identify EDC-induced molecular changes in the germline that are maintained upon conversion back to a pluripotent state, as potential mechanistic underpinnings of intergenerational effects of EDC exposure in humans. We found that these compounds seem to have relatively subtle effects on hPGCLCs, possibly reflecting an intrinsic resilience of these cells to perturbations, being the founder cells of the germ cell lineage. Ongoing work is addressing potential genotype-specific responses, by testing the effect of these compounds on multiple hiPSC lines, using a mosaic approach. We are also evaluating their impact at later developmental windows, leveraging in vitro differentiated prospermatogonia and oogonia.  Overall, by integrating in vitro modelling, multi-layer molecular phenotyping and epidemiological data, this work aims to establish a framework for studying the intergenerational impact of chemical exposure on human health, to shed light on the extent to which environmentally induced and inherited changes influence human development and disease risk, ultimately providing scientific evidence to guide the reduction of adverse effects on present and future generations caused by widespread EDC environmental exposures.","language":"eng","citation":"THE INTERGENERATIONAL IMPACT OF ENVIRONMENTAL EXPOSURES: MOLECULAR INSIGHTS FROM MODELLING PLURIPOTENCY TRANSITIONS THROUGH THE HUMAN GERMLINE / S. Stucchi ; tutor: G. Testa ;  added supervisor: N. Caporale ; internal advisors: O. Harschnitz, J. Davila-Velderrain ;  phd program coordinator: D. Pasini. Dipartimento di Oncologia ed Emato-Oncologia, 2026. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13501.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 18-NOV-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1118829"},"title":"THE SPINTERFACE PROBLEM: AB-INITIO STUDIES OF FE-PHTHLOCYANINE ON TRANTITION-METAL OXIDES.","internalauthor":"MARINO, MARCO","type":"Tesi di dottorato","year":"2024","abstract":"At the interface between a transition-metal oxide and a metal-organic molecule, electrons form interesting hybrid electronic states that characterize what is commonly called an organic spinterface. The central idea of our study is the possibility of exciting a spin coherent wave inside the substrate through a light-induced excitation of the molecule - in other words, actively perturbing the spinterface to modify its magnetic state. In this framework, the spinterface is studied for its electronic, magnetic and optical properties through ab-initio approaches.     Specifically, we selected the transition-metal oxides: NiO(001), CoO(001) and Cr2O3(0001) as substrates. These materials are antiferromagnetic at high and/or room temperature and are characterized by low spin-orbit interaction, making them promising candidates for spin-excitation transport. For the metal-organic molecule, we chose Fe-phthalocyanine, a versatile species valued for its adaptability across various applications.    In addition to the insights specific to each molecule/substrate combination revealed by our ab-initio simulations, three main findings emerged regarding the goal of activating the spinterface by light. First, significant hybridization between the molecule and the substrate is advantageous for maximizing the transfer of the light-induced molecular excitation onto the magnetic couplings between substrate spins. Second, to impact the substrate's magnetic couplings, this hybridization needs to be spin-unbalanced. In this regard an adsorption configuration breaking the spin symmetry of the substrate is sufficient, so that the adsorption of a magnetic molecule is not required. Third, effective control over spinterface tunability requires a distinct retention of molecular and substrate character: hybridization should not be so strong that they become indistinguishable.  In terms of light excitation spectra, this translates into high-intensity transitions between states with identifiable molecular and substrate characteristic.","language":"eng","citation":"THE SPINTERFACE PROBLEM : AB-INITIO STUDIES OF FE-PHTHALOCYANINE ON TRANSITION-METAL OXIDES / M. Marino ; supervisor: G. Fratesi ; co-supervisor: S.  Achilli ; coordinator: A. Mennella ; external referee: M. Cococcioni ; external referee: P. Puschnig. , 2024 Dec 22. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13386_1.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1118829/2590463/phd_unimi_R13386_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/804105"},"title":"THE REGENERATION OF EDENTULOUS ATROPHIC RIDGES: PROS, CONS, AND EFFECTIVENESS OF THREE DIFFERENT SURGICAL OPTIONS","internalauthor":"TOMMASATO, GRAZIA","type":"Tesi di dottorato","year":"2021","abstract":"INTRODUCTION  During the three-year doctoral period, the candidate developed 3 research projects which, although different, are all related to one of the most controversial topics of advanced implant dentistry which include procedures to make it possible the use of dental implants also in case of severely atrophic edentulous ridges.    During the last decade, a variety of surgical procedures have been proposed, each of them with specific indications, contraindications, advantages and disadvantages. Despite the publication of numerous systematic reviews and meta-analyses focused on this fascinating topic, much controversy is still present between clinicians and researches.  The aims of the PhD candidate have been to focus on three main areas related to the correction of severely atrophic edentulous ridges in order to: 1) update the present knowledge on this particular field thank to a systematic analysis of the available literature; and 2) develop three different research projects specifically dedicated to regeneration/reconstruction procedures.      More in detail, one line of research was focused on the evaluation of medium to long-term results of dental implants placed in severely atrophic jaws reconstructed with autogenous calvarial bone blocks covered with bovine bone mineral and collagen membranes. Seventy-two patients and 330 implants were involved in this retrospective study with a mean follow-up after implant loading of 8 years, ranging from 3 to 19 years.     The second project, similar in structure to the previous one, was designed to evaluate retrospectively the medium and long-term results (with a mean follow-up of 10 years) of implants placed in atrophic edentulous ridges grafted with autogenous mandibular blocks covered with bovine bone mineral and collagen membranes. Seventy-five patients, 82 sites, and 182 implants were involved in this study.    The third line of research allowed the candidate to design a prospective study which involved edentulous and atrophic patients treated with guided bone regeneration using CAD-CAM customized titanium meshes. The effectiveness of digitally customized titanium meshes in association with autologous bone particles and bovine bone mineral for the regeneration of atrophic edentulous sites, and the survival rate of implants placed in the reconstructed areas were evaluated. A histomorphometric analysis of mandibular regenerated bone were also performed.  Forty-one patients, 53 sites, and 106 implants were involved in this study and the follow-up of implants before and after loading ranged from 2 to 23 months (mean: 11 months), and from 1  to 15 months (mean: 6 months), respectively.   This latter research is of particular interest, as the literature supporting this particular technique is scarce, and available data are difficult to be compared, because they have been collected in a non- systematic way and mainly retrospectively.    In all these studies, a dedicated questionnaire, adapted from the OHIP-14 survey, was performed to evaluate patients’ satisfaction (patient reported outcome measurements – PROMs) as regards the treatment received.     It was therefore possible to elaborate a discussion of the results on two different levels: the first associated to the specific regenerative / reconstructive technique; the second allowed a comparison among the different treatment solutions.    AIMS  The aim of the first and second project, two retrospective longitudinal cohort studies, is to present the medium to long-term outcome of bone reconstructions with calvarium or mandibular grafts , respectively by evaluating: a) complication rate of the reconstructive procedure; b) bone resorption before implant placement; c) peri-implant bone resorption; d) implant-related complications; e) implant survival rate; and, f) patient’s satisfaction inquired with a dedicated questionnaire.    The aims of the third project, a prospective, single-arm clinical study, are to evaluate: a) the effectiveness of digitally customized titanium meshes in association with autologous bone particles and BBM and covered with collagen membranes for the regeneration of atrophic edentulous sites; b) the survival rate of implants placed in the regenerated areas and, c) PROMs inquired with a dedicated questionnaire.      MATERIALS & METHODS  Project 1 – calvarium  From 1998 to 2014, 72 patients presenting with severe bone defects were reconstructed with autogenous calvarial bone blocks covered with bovine bone mineral granules and collagen membranes. Four to 9 months later, 330 implants were placed and loaded 3 to 9 months later. The follow-up ranged from 3 to 19 years (mean: 8.1 years).   Project 2 – ramus  from 1997 to 2015, 75 patients presenting with bone defects of the jaws were grafted with autogenous mandibular bone blocks. One-hundred-eighty-two implants were placed 4 to 12 months later and loaded 3 to 10 months later: the mean follow-up was 10 years (range: 3-16 years).  Project 3 – GBR with Ti-mesh  41 patients, presenting with 53 atrophic sites were enrolled between 2018 and 2019. GBR was obtained with titanium meshes filled with autogenous bone chips and bovine bone mineral (BBM). After a mean of 7 months (range: 5-12 months), meshes were removed and 106 implants placed. After a mean of 3.5 months (range: 2-5 months), implants were uncovered and prosthetic restorations started.    RESULTS  Project 1 – calvarium  No patients developed severe complications, such as complete loss or resorption of the grafts. A dehiscence occurred in 6 patients, which developed a mild graft resorption. The mean peri-implant bone resorption before implant placement was 0.13 mm (SD ± 0.71). All patients received the planned number of implants. Three patients were lost during the follow-up. The survival rate of implants at the end of the observation period was 98.5%. The mean peri-implant bone resorption ranged from 0.00 mm to 4.87 mm (mean: 1.11 mm). Finally, 90% of the patients were very satisfied as regards the treatment received.  Project 2 – ramus  Post-operative recovery was uneventful in the majority of patients. An early dehiscence occurred in three patients, but with no significant bone loss, while 3 experienced temporary paresthesia. The mean vertical and horizontal bone resorption before implant placement was 0.18 mm (standard deviation (SD)=0.43) and 0.15 mm (SD=0.42), respectively.   The mean peri-implant bone loss ± standard deviation was 1.06±1.19 (range 0.00 to 5.05) at patient level, and 1.11±1.26 (range 0.00 to 5.20) at implant level.  Two  implants  in 2 patients lost integration and were removed; 10  implants in 7 patients developed peri-implantitis, but healed after surgical treatment.   The cumulative implant survival and success rates were 98.11% and 85.16%, respectively. PROMs were very positive: 95.5% of patients would have undergone the procedure again.    Project 3 – GBR with Ti-mesh  out of 53 sites, 11 underwent mesh exposure: 8 of them were followed by uneventful integration of the graft, while 3 by partial bone loss. The mean vertical and horizontal bone gain after reconstruction was 4.78±1.88mm (range 1.00 to 8.90mm), and 6.35±2.10mm (range 2.14 to 11.48 mm), respectively. At the time of implant placement, mean changes of initial bone gain were -0.39±0.64mm (range -3.1 to +0.80mm), and -0.49±0.83mm (range –3.7 to +0.4mm), in the vertical and horizontal dimensions, respectively. Reduction of bone volume was significantly higher (P<0.001 for both dimensions) in the exposed sites.   At histologic analysis, mesh appeared well osseointegrated, except that in sites where membrane exposure occurred. In all sites, newly formed tissue resulted highly mineralized, well-organized and formed by 35.88% of new lamellar bone, 16.42% of woven bone, 10.88% of osteoid matrix, 14.10% of grafted remnants and 22.72% of medullary spaces. Blood vessels were the 4 % of the tissue.The mean follow-up of implants after loading was 10.6±6.5months (range: 2 to 26months). The survival rate of implants was 100%. PROMs were very positive: 92.5% of patients would have undergone the procedure again.      DISCUSSION  These three projects have offered, on one side, a relevant opportunity to evaluate the short, medium, and long-term outcomes of both reconstructions with autogenous bone blocks and guided bone regeneration with an innovative, customized, titanium mesh.   On the other side, “intrinsic” methodologic limits have appeared during the development of this PhD thesis, such as:    o heterogeneity of patient samples and type of defects;  o retrospective and prospective type of study;  o duration of the observation period;  o presence/absence of evaluation of bone gain and with different methods;  o different methods used to evaluate bone resorption before implant placement.      Despite these limits, results from these three researches offered relevant information as regards the behaviour of the transplanted /regenerated bone as well as the behaviour of peri-implant bone over time.   Although the three projects significantly differ among them as regards details in the reconstructive procedures, it must be underlined that many aspects are in common.   Therefore, to reduce redundancies it has been decided to write a “unified” discussion which will make it possible a direct comparison of pros, cons, indications and contra-indications of each of them.        More in detail, each of the following issues will be discussed reporting and comparing obtained from each study:  1. bone gain;  2. complication rate of the reconstructive procedure;   3. bone resorption before implant placement;  4. peri-implant bone resorption;  5. survival rate of implants and implant-related complications;  6. patient’s satisfaction inquired with a dedicated questionnaire.      CONCLUSION  Despite the descriptive nature of the first two retrospective longitudinal cohort studies and the variability of the selected patients (including different patients anamnesis, defects locations, defect morphologies, and prosthetic rehabilitations), medium- to long-term results seem to confirm the efficacy of reconstruction of atrophic ridges using autogenous bone blocks taken from both the calvarium and the mandibular ramus covered by a protective layer of bovine bone mineral and stabilized by a collagen membrane. The use of autogenous calvarial grafts may be prefer in case of severely deficient edentulous ridges, when the ramus can offer an insufficient quantity of bone. The low postoperative morbidity, the stability over time of the augmented bone, the high survival rate of implants placed in a prosthetically driven way, leading to very satisfactory prosthetic restorations, confirmed the long-term reliability of these procedures.    Preliminary results of the third prospective study, on the other hand, despite the limited number of patients, implants, short follow-up, and the non-negligible incidence of Ti-mesh exposures, seem to demonstrate that CAD-CAM customized Ti-meshes may represent a reliable GBR option for the correction severely atrophic edentulous ridges in terms of vertical bone gain, limited peri-implant bone resorption and survival rate of implants. It is however worth noting that if on one hand it is possible to simplify the reconstructive procedure thanks to the customization of Ti-meshes, on the other hand surgeons have to face the non-negligible incidence of Ti-mesh exposures and the higher complexity of their removal at the time of implant placement. Therefore, studies involving a higher sample of patients and with longer follow-ups are necessary.     PROMs seem to validate the use of all the regenerative and reconstructive procedures, with high value of patient’ satisfaction.","language":"eng","citation":"THE REGENERATION OF EDENTULOUS ATROPHIC RIDGES: PROS, CONS, AND EFFECTIVENESS OF THREE DIFFERENT SURGICAL OPTIONS / G. Tommasato ; SUPERVISORI DELLA TESI: L. TROMBELLI, U. CONSOLO ; COORDINATORE: M. DEL FABBRO ; TUTOR: M. F. CHIAPASCO. Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, 2021 Mar 01. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12047.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/804105/1671508/phd_unimi_R12047.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/943307"},"title":"SEARCH FOR ELECTROWEAK PRODUCTION OF SUPERSYMMETRIC PARTICLES IN COMPRESSED MASS SPECTRA WITH THE ATLAS DETECTOR AT THE LHC","internalauthor":"BALLABENE, ERIC","type":"Tesi di dottorato","year":"2022","abstract":"In this thesis, two analyses searching for the production of supersymmetric particles through the electroweak interaction are presented: the chargino  search, targeting the pair production of charginos decaying into W bosons and neutralinos, and the displaced track search, looking for mildly displaced charged tracks arising from the decays of higgsinos into pions. These searches target compressed phase spaces, where the mass difference between the next-to-lightest and lightest supersymmetric particle is relatively small. The searches use proton-proton collision data collected at a centre-of-mass energy of 13 TeV with the ATLAS detector at the LHC.    In the chargino search, the targeted difference in mass between charginos and neutralinos is close to the mass of the W boson. In such phase space, the chargino pair production is kinematically similar to the WW background, which makes the chargino signal experimentally challenging to be discriminated from the WW background. A final state with two leptons from the leptonic decays of the W bosons, missing transverse momentum and no hadronic activity is considered, while advanced machine learning techniques are adopted to separate the supersymmetric signal from the backgrounds.  Chargino masses up to about 140 GeV are excluded at 95% confidence level in the case of a mass splitting between chargino and neutralino down to about 100 GeV. The results supersede the previous ATLAS results in particularly interesting regions where the chargino pair production could have hidden behind the looking-alike WW background.      In the displaced track search, the difference in mass between the produced supersymmetric particles and the lightest neutralinos goes down to 0.3 GeV.  The experimental signature is one jet, missing transverse momentum, and a low momentum charged track with an origin displaced from the collision point, the last element being the first time it is used in a search of this kind at a hadron collider. The results show that the analysis has the sensitivity to exclude different signal hypotheses for higgsino masses up to 175 GeV if no excess is observed in data. For lower masses, the larger signal cross-section allows to achieve higher significance values for different mass splitting scenarios. All these signal hypotheses have not been probed by any existing analysis of LHC data.","language":"eng","citation":"SEARCH FOR ELECTROWEAK PRODUCTION OF SUPERSYMMETRIC PARTICLES IN COMPRESSED MASS SPECTRA WITH THE ATLAS DETECTOR AT THE LHC / E. Ballabene ; supervisor: T. Lari ; coordinator: M. Paris. Università degli Studi di Milano, 2022 Nov 17. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12752.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/943307/2087869/phd_unimi_R12752.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1045024"},"title":"SUSTAINABILITY AND INNOVATION OF CATALYTIC PROCESSES FOR THE SYNTHESIS AND TRANSFORMATION OF HETEROCYCLIC SYSTEMS OF BIOLOGICAL INTEREST","internalauthor":"MOLTENI, LETIZIA","type":"Tesi di dottorato","year":"2024","abstract":"Functionalized heterocycles represent one of the most widespread structural motifs found in both molecules of natural origin and in synthetic compounds exhibiting diverse activities across biological, pharmacological, agrochemical fields, and as materials endowed with different properties.   For these reasons, the demand for new, cleaner, and sustainable processes for the syntheses of heterocyclic compounds is continually increasing, as the known heterocyclic-forming reactions are often expensive, wasteful, and produce by-products. Among the modern synthetic methods, transition-metal catalysed reactions have emerged as a powerful and efficient tool for constructing a variety of heterocycle rings, resulting in shorter reaction times and higher yields when compared to other well-known methods reported in literature.   On these bases, the project proposed herein studies and develops synthetic strategies for heterocycles, based on different transition-metals i.e. copper, platinum, ruthenium, alongside organocatalysis and metal-free reactions. The involved reactions aim to be innovative, leading to sustainable, green, and cost-efficient preparation of this important class of compounds.","language":"eng","citation":"SUSTAINABILITY AND INNOVATION OF CATALYTIC PROCESSES FOR THE SYNTHESIS AND TRANSFORMATION OF HETEROCYCLIC SYSTEMS OF BIOLOGICAL INTEREST / L. Molteni ; tutor: E.M. Beccalli ; coordinatore: G. Vistoli. Dipartimento di Scienze Farmaceutiche, 2024. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R13005.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1045024/2398006/phd_unimi_R13005.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1028876"},"title":"MISSISSIPPIAN MUD MOUNDS OF DERBYSHIRE (ENGLAND, UK): FACIES ARCHITECTURE AND BIOTIC EVOLUTION","internalauthor":"CARNITI, ALESSANDRO PAOLO","type":"Tesi di dottorato","year":"2024","abstract":"Mud mounds are carbonate buildups, part of the reef spectrum, consisting dominantly of carbonate mud, with no or minor skeletal framework. The carbonate mud commonly shows texture (clotted peloidal, homogeneous with primary cavities), indicative of an origin through in-situ precipitation by biologically-induced and biologically-influenced processes mediated by a microbial-metazoan marine benthic community (automicrite). Mud mounds are the dominant reef type in the Mississippian but have no extant analogue, which hampers the understanding of their growth style, depositional environment, and palaeoecology. The factors influencing mud mound growth and the role of the metazoan dwellers still remain a matter of debate. In particular, the distribution and role of brachiopods in Mississippian mud mounds are scarcely constrained, despite brachiopods are among the most common marine benthic invertebrates in the Mississippian.  The brachiopod-rich mud mounds occurring in the uppermost Monsal Dale Limestone For-mation, upper Visean (Brigantian), Mississippian, of the Derbyshire Carbonate Platform succession (UK), were selected as object of this thesis to address some of the open ques-tions on Mississippian mud mounds. Comparative investigation of mud mound lithofacies architecture, texture, and composition and brachiopod fauna in various depositional set-tings on the platform (north-eastern outer platform, intraplatform ramp, southern outer plat-form) allows investigating the factors influencing the growth of the mud mounds and bra-chiopod fauna colonization. Derbyshire mud mounds are decametre-scale lens-shaped buildups frequently coalesced into mud mound complexes, with a massive automicrite-rich core passing laterally outwards into skeletal packstone inclined flank beds transitional to off-mud mound, originally nearly horizontally bedded, skeletal packstone. Commonly bed-ded units occur below (basal unit) and on top (cap unit) of the mud mounds.  Chapter 1 presents the introduction to this thesis. Chapter 2 is a literature review of the mud mound concept, the Mississippian record of mud mounds, and the associated brachiopod fauna.  Chapter 3 contains a systematic study of a brachiopod fauna collected mainly from one of the Monsal Dale Limestone Fm mud mound complexes cropping out at Ricklow Quarry, developed in the intraplatform ramp. The brachiopod fauna consists of taxa of seven orders: Productida, Orthotetida, Orthida, Rhynchonellida, Spiriferida, Spiriferinida, Terabratulida. Substrate variety in the mud mound complex (soft allomicrite, stiff to hardened in-situ pre-cipitated automicrite, skeletal grains) sustained the brachiopod diversity. Seminfaunal productides were adapted to soft allomicrite substrates while pedicle-attached to ambitopic brachiopods (mainly orthides, rhynchonellides, spiriferides, terebratulides) were adapted to live on a wide range of substrates, often showing adaptations to increase the surface/vol-ume ratio to prevent sinking in soft muddy substrates. Food resources seem to have played the major control on brachiopod fauna composition and distribution: spinose, concavo–convex productides are dominant in the mud mound complex basal unit and core, both in terms of the number of specimens, species, and biovolume; their success was favoured by scattered food resources which they better exploited through their simple feeding appa-ratus, providing a comparative advantage over spiriferides.  Chapter 4 provides a study on the lithofacies character and architecture and brachiopod distribution of the mud mound complex at Ricklow Quarry. The mud mound complex grew below fair-weather wave base in middle ramp environment following a relative sea level rise and accommodation creation, overlying inner ramp strata . The mud mound complex core is 10 m thick, 250 m wide, and dominated by clotted peloidal automicrite boundstone with early-marine fibrous calcite cement. The basal bedded unit and inclined flank beds consist of dense automicrite (leiolite, closely-packed clotted peloidal micrite) mixed with skeletal packstone, with no fibrous calcite cement. The mud mound complex is capped by the regional subaerial exposure marking the top of the Monsal Dale Limestone Fm, and overlain in onlap against the exposure surface by wackestone to packstone beds of the Eyam Limestone Fm. Major skeletal components in the mound basal unit and core are fenestellid bryozoans, brachiopods, and siliceous sponge remains (calcified spicules, few sponge bodies), whereas crinoids are common in the flank and off-mud mound complex beds. Contrary to previous interpretations, brachiopods are not confined to storm-scoured 'pockets' in the core, but are abundant and widespread in all mud mound complex lithofa-cies. Thus, the upper Visean mud mounds of Derbyshire are identified as a newly-defined fenestellid bryozoan–brachiopod–siliceous sponge mud mound sub-category, a sub-type of the fenestellid bryozoan–crinoid–brachiopod Type 3 buildups of Bridges et al. (1995).  Chapter 5 expands the investigation on lithofacies architecture and brachiopod fauna to other mud mounds in the uppermost Monsal Dale Limestone Fm developed in the north-eastern outer platform (Linen Dale, Bradwell Dale), intraplatform middle-outer ramp (Bradford Dale), and southern outer platform (National Stone Centre). All mud mounds developed below fair-weather wave base following a relative sea-level rise, overlying units deposited in shallower protected to open marine settings above fair-weather wave base. The core lithofacies variability was influenced by the depositional setting (hydrodynamic energy, water depth); clotted peloidal automicrite boundstone dominated in the in-traplatform ramp and in the lower part of mud mounds on the southern outer platform, while fenestellid bryozoan boundstone/skeletal grainstone with early-marine fibrous calcite cement dominated in the north-eastern and southern outer platform. Flank beds always consist of automicrite boundstone passing downslope to skeletal packstone. The cap unit, absent at Ricklow Quarry, consists of mixed automicrite boundstone and skeletal wack-estone, packstone to grainstone/floatstone to rudstone, and was deposited in all settings from below to above the fair-weather wave base. Deposition of the cap unit reflects pro-gressive accommodation filling during mud mound growth and relative sea-level fall lead-ing to the capping regional subaerial exposure at the top of the Monsal Dale Limestone Fm. The brachiopod fauna is widespread and abundant in all the mud mounds but in the lower mud mound core of Bradford Dale, possibly for limited larval transport in the deeper (outer) part of the intraplatform ramp. Diverse substrates sustained seven orders of brachiopods, with dominant seminifaunal productides, suggesting a mesotrophic environment. The main control on brachiopod distribution and diversity was exerted by the food resources and competition with crinoids, able to access a higher tiering level. Higher relative abundance of seminfaunal productides in outer platform than in intraplatform ramp mud mounds is possibly due to less abundant food resources than in the restricted intraplatform ramp set-ting.  In synthesis, the comparative analysis of mud mounds in the uppermost Monsal Dale Lime-stone Fm of Derbyshire in a wide spectrum of depositional environments allows to point out that:  -Derbyshire upper Visean mud mounds are dominated by precipitated automicrite associ-ated with siliceous sponges, previously underestimated, whereas the contribution of detrital micrite, allomicrite, is minor.  -Brachiopods are abundant and diverse in all mud mounds in Derbyshire and indicative of mound growth in mesotrophic conditions. Brachiopod shells contributed to the growth and stability of the mud mounds. Brachiopod distribution was mainly controlled by the availa-bility and distribution of food resources and competition with crinoids, though substrate variety played a role in promoting brachiopod diversity.  -Derbyshire upper Visean mud mounds grew following a relative sea-level rise on the Der-byshire Carbonate Platform, with decreased sedimentation rate. Accommodation creation was probably linked to tectonic activity. Mud mound growth was halted by forced regres-sion driven by a, possibly eustatic, sea-level fall leading to regional subaerial exposure. During the following transgressive phase only limited mud mound occurrences are just few, in intraplatform inner ramp environment.  -Derbyshire mud mounds are part of a spectrum of upper Visean (Brigantian) automicrite-dominated mud mounds differing from older upper Visean (Asbian) reefs (e.g., Cracoean reef of Yorkshire) and mud mounds in the absence of calcareous algae, corals, less skeletal diversity, and possibly deeper depositional setting.","language":"eng","citation":"MISSISSIPPIAN MUD MOUNDS OF DERBYSHIRE (ENGLAND, UK): FACIES ARCHITECTURE AND BIOTIC EVOLUTION / A.p. Carniti ; tutor: L. Angiolini ; co-tutor: G. Della Porta, Michael Stephenson ; coordinatore: M. I. Spalla. - Milano. Dipartimento di Scienze della Terra Ardito Desio, 2024 Feb 28. 36. ciclo [10.13130/carniti-alessandro-paolo_phd2024-02-28].","filename":"phd_unimi_R12901_02.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1028876/2359941/phd_unimi_R12901_02.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1161315"},"title":"NEURAL PRECURSOR CELLS AS A POTENTIAL THERAPEUTIC APPROACH FOR RETT SYNDROME: IDENTIFICATION OF THE INVOLVED MOLECULAR MECHANISMS","internalauthor":"BALBONTIN ARENAS, MARIA","type":"Tesi di dottorato","year":"2025","abstract":"Rett syndrome (RTT) is a rare, progressive, and profoundly debilitating neurodevelopmental disorder (NDD) and represents the leading cause of severe intellectual disability in females, with an estimated incidence of 1 in 10,000 live births. More than 95% of RTT cases result from sporadic mutations in the MECP2 gene, which is located on the X chromosome (Xq28) and encodes the methyl-CpG binding protein 2 (MeCP2), a nuclear protein that functions as an epigenetic regulator. Affected girls initially exhibit apparently normal development until 6 - 18 months of age, when they enter a severe regression phase characterized by the loss of previously acquired cognitive and motor skills. RTT is an extremely crippling disorder with significant phenotypic variability, influenced by the specific genetic variants causing the disease and by the degree of X chromosome inactivation (XCI). Common symptoms include communication impairments, stereotypical hand movements, respiratory abnormalities, and seizures. At the cellular level, RTT is associated with defects in neuronal morphology, activity, and synaptic transmission.  Since the landmark discovery of RTT’s potential reversibility in 2007, significant progress has been made in elucidating the functional role of MECP2 and the consequences of its deficiency. Despite major advances over the past decades, the precise mechanisms underlying RTT pathophysiology remain poorly defined, and a definitive cure remains elusive. Indeed, currently, affected individuals receive symptomatic treatments. However, a significant milestone was reached in 2023 when the U.S. Food and Drug Administration (FDA) approved Trofinetide (DayBue) as the first treatment specifically designed for RTT.  Despite this breakthrough, there remains an urgent need for additional therapeutic approaches to improve the severely compromised quality of life of affected individuals.   This study was conducted within the broader context of identifying innovative therapeutic strategies for RTT and focused on investigating the potential of neural precursor cell (NPC) transplantation as a promising therapeutic approach for RTT. NPCs are multipotent stem cells that persist in the adult brain. Their therapeutic potential has been extensively explored in both preclinical and clinical studies of neurodegenerative diseases, where they have been shown to be safe and to exert beneficial effects primarily through “bystander” mechanisms. In the context of NDDs, we previously demonstrated that NPC transplantation in Mecp2 knockout (KO) mice rescued the characteristic cognitive and motor deficits in treated animals.  When analyzing the transcriptomic profile of NPC-treated mice, we revealed an activation of the IFNγ pathway, that we further validated by observing symptoms improvements after direct IFNγ administrations. These preliminary results suggested a pivotal role for this cytokine in the therapeutic effects of NPCs. Building upon these findings, this study further explored the mechanisms underlying NPC-mediated benefits and leveraged NPCs as a platform to identify new molecular targets for RTT treatment.  Using an in vitro transwell co-culture system, we demonstrated that NPC-secreted factors (NPC-SF) specifically rescued synaptic defects in Mecp2 KO neurons without affecting wild-type neurons. Furthermore, we characterized the temporal dynamics of NPC-neuron interactions. Notably, we found that NPCs respond specifically to the RTT pathological environment by releasing factors that promote synaptic repair in Mecp2 KO neurons.  Remarkably, we demonstrated that Mecp2 KO NPCs exhibited therapeutic efficacy comparable to the one of wild-type NPCs, paving the way for patient-derived isogenic transplantation strategies. Furthermore, we investigated the role of IFNγ in our in vitro system and confirmed its involvement in NPC-mediated beneficial effects, particularly in the presynaptic compartment.  To further elucidate the molecular basis of NPC-mediated effects, we performed transcriptomic analyses of Mecp2 KO neurons treated with NPCs, as well as of NPCs exposed to RTT neuronal media. RNA sequencing confirmed that NPC-SF promotes neuronal maturation, as evidenced by enrichment in synaptic and plasticity-related pathways, while also modulating IL-17 production in Mecp2 null treated neurons. Transcriptional profiling of NPCs highlighted genotype-specific adaptations and further implicated IFNγ in these processes. These findings suggest a multifaceted mechanism underlying NPC-mediated repair and underscore the dynamic interplay between NPCs and the RTT microenvironment.  In conclusion, this study highlighted the therapeutic potential of NPCs in RTT and established the relevance of IFNγ in NPC-mediated beneficial effects in in vitro systems. Additionally, it demonstrated the capacity of NPCs to adapt to pathological environments and identifies novel pathways, such as IL-17 modulation, as promising targets for future research.","language":"eng","citation":"NEURAL PRECURSOR CELLS AS A POTENTIAL THERAPEUTIC APPROACH FOR RETT SYNDROME: IDENTIFICATION OF THE INVOLVED MOLECULAR MECHANISMS / M. Balbontin Arenas ; tutor: N. Lansdberger ;  co-tutor: A. Frasca ;  director: N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2025 Apr 29. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13576.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1161315/2948163/phd_unimi_R13576.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1191735"},"title":"A DATA-DRIVEN PRIORITIZATION ALGORITHM FOR MEDICATION REVIEW IN OLDER ADULTS: FROM REAL-WORLD EVIDENCE TO CLINICAL PRACTICE","internalauthor":"ROSSI, ANDREA","type":"Tesi di dottorato","year":"2025","abstract":"Inappropriate prescribing in older adults represents a growing challenge for healthcare systems worldwide, given the rising multimorbidity and polypharmacy in aging populations. Inappropriate pharmacological regimens not only increase the risk of adverse drug reactions and hospitalizations but also contribute to excessive healthcare costs and a decline in patient quality of life.   Given their unique clinical complexity and physiological vulnerability, older adults are particularly exposed to the risks associated with inappropriate medication use, making them a critical target for preventive strategies aimed at optimizing pharmacotherapy and reducing avoidable harm. Among these measures, periodic implementation of medication review is recommended. However, healthcare professionals- particularly general practitioners -are central to the management of chronic therapies, face increasing time constraints often hinder the systematic implementation of medication reviews. In this context, there is a pressing need for flexible, data-driven tools that can support clinicians in identifying patients most likely to benefit from medication review interventions, thereby optimizing the allocation of time and resources.   This thesis presents the development of a prioritization algorithm aimed at prioritizing older patients expected to gain the greatest benefit from medication review interventions, based on comprehensive real-world data. Conducted over a three-year doctoral research project, the work addresses a pressing public health concern- polypharmacy and inappropriate drug use among the elderly- and proposes a pragmatic, data-driven solution to enhance prescribing safety and optimize clinical resources in primary care.  After in depth literature review, six prescribing inappropriateness indicators (PIIs) were identified:   • Potentially inappropriate medications (PIMs);  • Potential drug–drug interactions (pDDIs);  • Fall-risk-increasing drugs (FRIDs);  • Therapeutic duplications (TDs);  • High anticholinergic cognitive burden (ACB);  • High sedative load (SL).  The identification of these indicators was based on established international criteria, adapted to the Italian drug market and validated through robust operational definitions.  The work was conducted using health care administrative databases from four Local Health Units in Lombardy (Italy), covering over 640,000 individuals aged 65 years or older between 2015 and 2018. Exposure to each PII was determined by operational definitions accounting for drug dispensation dates, ATC classification, Defined Daily Doses and co-prescribing windows. Individuals with first exposure between January 2015 and September 2018 were followed for 90 days to evaluate the risk of all-cause hospitalization, using a risk-set matching strategy with one control per exposed individual, matched on age and sex. Multivariable logistic regression models, adjusted for high-dimensional propensity scores, were used to estimate the odds ratios (ORs) of all-cause hospitalization associated with each PII.  All six PIIs were significantly associated with increased hospitalization risk. The highest risks were observed for FRIDs (OR 1.62, 95% CI: 1.51–1.73), PIMs (OR 1.55, 95% CI: 1.48–1.62), and TDs (OR 1.52, 95% CI: 1.46–1.58). SL score (OR 1.43, 95% CI: 1.31–1.56) and ACB score (OR 1.52, 95% CI: 1.43–1.61)   Established the baseline OR for each PII, we developed decision tree models for each indicator to identify high-risk patient profiles- i.e., combinations of demographic and clinical characteristics associated with significantly elevated hospitalization risk beyond that conferred by exposure alone. Each scenario was validated using conditional logistic regression in comparison with the overall risk of the indicators alone. Across multiple bootstrap samples, 59 distinct high-risk scenarios were identified: 14 for SL, 14 for TDs, 11 for FRIDs, 10 for pDDIs, 7 for PIMs, and 4 for ACB. These scenarios characterize subgroups of patients who should be rapidly prioritized for clinical attention, as they are at particularly high risk of hospitalization.  To estimate the real-world impact of using the algorithm, we applied the scenarios to a cohort of 501,785 older adults in the first half of 2018. A total of 55.3% (n=270,487) of individuals had at least one PII. Among these, 11.2% matched at least one high-risk scenario, representing 20.2% of those with inappropriate exposure. SL score and PIMs exhibited lower prioritization efficiency (4.5% and 3.5% respectively). Conversely, pDDIs and TDs flagged over one-third of exposed individuals as high-risk. By considering prioritizing all individuals with at least three indicators, as well as those with one or two indicators who fell into the highest-risk scenarios, a total of 49–52 patients per physician would be selected.  This work presents a novel and pragmatic framework to support prioritization in medication review processes. By leveraging routinely collected administrative data, the proposed algorithm enables targeted identification of older adults at heightened risk for adverse drug events. The model’s integration of individual-level risk profiles and cumulative burden metrics offers a powerful and scalable tool for supporting deprescribing strategies in real-world clinical practice, particularly within constrained primary care settings. This work lays the foundation for future prospective validation studies and the potential integration of the algorithm into digital clinical decision support systems.","language":"eng","citation":"A DATA-DRIVEN PRIORITIZATION ALGORITHM FOR MEDICATION REVIEW IN OLDER ADULTS: FROM REAL-WORLD EVIDENCE TO CLINICAL PRACTICE / A. Rossi ; supervisor: M. Casula ;  co-supervisor: P. Magni ; coordinator: G. D. Norata. - Milano. Dipartimento di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti, 2025 Dec 15. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14114.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1191735/3169750/phd_unimi_R14114.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1045014"},"title":"EARLY LIFE STRESS EXPOSURE AND HYPOTHALAMIC PITUITARY ADRENAL AXIS: FROM MECHANISMS TO PERIPHERAL BIOMARKERS OF VULNERABILITY","internalauthor":"MAZZELLI, MONICA","type":"Tesi di dottorato","year":"2024","abstract":"It is well known that environmental factors, and in particular stressful life events exposures, are strongly associated with an enhanced risk for the development of stress-related psychiatric disorders with differences in the severity, age of onset, according to the temporal window and duration of the exposure. Stress, especially when experienced early in life, induces profound and long-lasting effects on the brain function and organization. This is mainly because during the early life period the brain is still under development and, therefore extremely sensitive to stressors that can affect the integrity of neuronal circuits especially in those brain regions involved in the regulation of emotions and in stress response.   One of the biological systems investigated in the context of early life stress is represented by the hypothalamic-pituitary-adrenal (HPA) axis, with the glucocorticoids as the main players exerting negative effects on brain development and also on other biological systems such as inflammation.  Therefore, based on this evidence, the overall aim of this project is to better elucidate the role of the HPA axis in mediating the effect of early life stress exposure on altered behaviours.  To reach this aim, based on our published papers where we demonstrated a key role of the gene Serum-and Glucocorticoid-inducible Kinase 1 (SGK1) as biomarker of stress vulnerability, here I have used a cross-tissues and a cross-species approach where I have combined data from an animal model of stress early in life (the prenatal stress, PNS, paradigm) with data from a preclinical in-vitro model and, finally, with data from a clinical cohort. Interestingly, I found alterations in the mRNA expression levels of Sgk1 in all the species and tissues; moreover, in the PNS animal model I evaluated longitudinal trajectories of Sgk1 during neurodevelopment, allowing the identification of adolescence as the temporal window associated the most with PNS exposure, in the hippocampus of both male and female animals.    Moreover, to go more in depth into the role of the HPA axis in mediating the effect of PNS, I evaluated possible alterations on a panel of HPA axis-related genes in male and female rats both at adolescence (PND44) and adulthood (PND84) in three different brain regions: the dorsal (DH) and ventral (VH) hippocampus, and the paraventricular nucleus of the hypothalamus (PVN). Moreover, at adolescence I tested the reactivity of the HPA axis after an acute challenge both in control and PNS exposed animals and I have found that there is a more pronounced effect on Sgk1 and Nr3c1 expression in those animals previously exposed to PNS, suggesting that such early in life exposure may prime the brain affecting its ability to cope with adverse challenging events, contributing to the onset of a latent pathological condition.   In a dedicated experiment I also tested the association between alterations in HPA axis functionality with behavioural alterations due to PNS. Therefore, animals at adulthood were tested for different behavioural domains, including sociability and based on the outcome I was able to divide them into vulnerable or resilient.   I then tested whether alterations in mediators within HPA axis including the stress responsive genes and the corticosterone in adrenal glands were able to map those vulnerable or resilient animals and I have also performed RNAseq analyses in the paraventricular nucleus of the hypothalamus of male adult rats. I reported an opposite pattern of corticosterone levels in male versus female animals, with the most pronounced effect in vulnerable animals, both in males and females.  RNAseq identified alterations in the glutamatergic and GABAergic transmission in association with PNS exposure and the modulation of specific pathways related to inflammation and immune system only in vulnerable animals.  In conclusion, PNS exposure induces an overall dysregulation of the HPA axis functionality and the onset of a vulnerable phenotype above to be related with a different pattern in the modulation of genes involved in HPA axis regulation, is also associated with biological processes related to inflammation.","language":"eng","citation":"EARLY LIFE STRESS EXPOSURE AND HYPOTHALAMIC PITUITARY ADRENAL AXIS: FROM MECHANISMS TO PERIPHERAL BIOMARKERS OF VULNERABILITY / M. Mazzelli ; tutor: M. A. Riva; co-tutor: A. Cattaneo ; coordinatore: G. D. Norata. Dipartimento di Scienze Farmacologiche e Biomolecolari, 2024 Apr 18. 36. ciclo","filename":"phd_unimi_R13047.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1045014/2397983/phd_unimi_R13047.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1200936"},"title":"DECIPHERING THE ORAL MICROBIOTA IN FOOD ALLERGY: INSIGHTS INTO THE CANDIDATE PHYLA RADIATION AND NOVEL METHODOLOGICAL APPROACHES","internalauthor":"STERZI, LODOVICO","type":"Tesi di dottorato","year":"2026","abstract":"Food allergies are abnormal immune reactions to otherwise harmless food antigens, influenced by multiple factors, including the oral microbiota. During my PhD, I contributed to studies investigating the oral microbiota in food-allergic children, with a particular focus on the Candidate Phyla Radiation (CPR), an elusive bacterial group increasingly implicated in health and disease. We assessed available protocols for quantifying CPR in human salivary samples and performed in silico analyses to identify alternative genetic markers, highlighting RecA as a strong candidate. Building on this, we explored its potential for bacterial community profiling, developing a machine learning algorithm that accurately infers taxonomy from RecA sequences across bacterial diversity. This algorithm was implemented in a software  that provides ultra-fast, accurate taxonomic profiling from raw shotgun metagenomic reads. In parallel, we analyzed the oral microbiota of allergic children using absolute rather than relative quantification, revealing patterns of microbial susceptibility and resilience to immune pressure. We also studied children who achieved antigen tolerance, observing microbial shifts that partially restored a healthy-like composition. Finally, I contributed to a study clarifying diagnostic markers for food-protein–induced allergic proctocolitis.","language":"eng","citation":"DECIPHERING THE ORAL MICROBIOTA IN FOOD ALLERGY: INSIGHTS INTO THE CANDIDATE PHYLA RADIATION AND NOVEL METHODOLOGICAL APPROACHES / L. Sterzi ; tutor: E. D'Auria; co-tutor: F. Comandatore; coordinatore: F. Cheli. Dipartimento di Scienze Biomediche e Cliniche, 2026 Jan 26. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13882.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 02-GIU-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1210635"},"title":"VERSO UNA SANITÀ VALUE-BASED: IL RUOLO DELLA DIGITALIZZAZIONE E DELLA TELEMEDICINA","internalauthor":"INFANTE, GABRIELE","type":"Tesi di dottorato","year":"2026","abstract":"This thesis explores how digital health, and telemedicine in particular, can contribute to the realization of value-based healthcare, by integrating the Value-Based Health Care (VBHC) perspective with a co-creation of value framework adapted to the digital context. The general objective is to analyse and operationalize this model, understanding how antecedents, managerial activities and outcomes combine to generate personal, technical, allocative and social value for patients, professionals, organizations and communities.    At the theoretical level, the work develops a co-creation framework for digital health that distinguishes three main blocks: antecedents (factors related to user, professional, provider and service), managerial activities (planning, accountability, management of patients and professionals), and outcomes (for patients, professionals, providers and communities), all located within a technology-enabled ecosystem. This framework is linked to the four value dimensions of VBHC through a matrix that crosses the framework blocks with personal, technical, allocative and social value, used as an interpretive grid for the empirical cases.    Methodologically, the thesis adopts a multi-method and multi-stakeholder design, combining quantitative surveys, development of measurement tools, design of digital solutions and configurational analysis. Five main case studies and several additional projects cover different actors and settings: a national survey on patients and professionals (case study A) and a multicentre survey on medical students and residents (case study B) analyse the digital antecedents of telemedicine adoption; a telehomecare experiment in paediatrics (case study C) examines digital co-creation between patient, caregiver and clinical team; a real-time business intelligence platform for a diagnostic services network (case study D) and an indicator system for the surgical pathway in a public healthcare organization (case study E) show how data can enable management by outcomes and costs. The additional projects address telehealth and artificial intelligence, the development of digitally supported care pathways with remote monitoring, and the design of methods to exploit new data sources.    The results show, first, that digital antecedents (in particular digital health literacy, familiarity with digital services and attitudes towards technology) explain more than socio-demographic variables the propensity of users and future professionals to use and co-produce telemedicine. Second, they show that digital co-creation generates personal and social value when it is supported by coherent managerial activities: clear roles, targeted training for patients, caregivers and professionals, structured communication channels, explicit rules of engagement and responsibilities. Third, the provider-side cases demonstrate that interoperable platforms, clinical–managerial dashboards and sets of standardized indicators make it possible to measure, in an integrated way, clinical outcomes, patient-reported outcomes, processes and costs along the care cycle, thereby enabling reallocations from low- to high-value care and making the VBHC agenda operational.  The thesis finally proposes a governance view in which telemedicine functions as a device to compose tensions between personal and allocative value, taking social value as the key reference criterion. Data interoperability, the presence of an enabling socio-technical infrastructure and sustained investment in the capabilities of patients and professionals emerge as necessary conditions for digitalization to translate into stable co-creation of value, rather than into a mere addition of technology. Overall, the thesis provides a theoretical contribution (integration of VBHC and digital co-creation in a multi-stakeholder perspective), a methodological contribution (operationalization of the framework through a framework × value matrix and measurement systems), and a practical contribution (implications for governance, organization, and the design of platforms and telemedicine pathways oriented to value).","language":"ita","citation":"VERSO UNA SANITÀ VALUE-BASED: IL RUOLO DELLA DIGITALIZZAZIONE E DELLA TELEMEDICINA / G. Infante ; tutor: M. Marsilio ; co-tutor: M. Frontini ; coordinatore: F.Parazzini. - Fondazione IRCCS Ca’ Granda - Ospedale Maggiore Policlinico. Dipartimento di Scienze Biomediche e Cliniche, 2025 Jan 15. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14106.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open from 26-GEN-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1157078"},"title":"INFLAMMATORY AND T-CELL HOMEOSTASIS PARAMETERS IN DUAL AND TRIPLE COMBINATION ANTIRETROVIRAL THERAPY (CART) FOR HIV INFECTION","internalauthor":"BONO, VALERIA","type":"Tesi di dottorato","year":"2025","abstract":"Primary HIV infection (PHI) plays a pivotal role in establishing the viral reservoir, leading to persistent immune activation and inflammation despite combination antiretroviral therapy (cART). While cART has transformed HIV into a manageable chronic condition, it remains unable to eradicate the virus or fully restore immune homeostasis. This study explores two critical aspects of HIV management: (i) the impact of early cART initiation during PHI on inflammation, immune activation, and microbial translocation, and (ii) the effects of innovative therapeutic strategies, including dual cART regimens and long-acting injectable treatments, on immune regulation and T-cell homeostasis.    The research is structured around three key objectives: (1) investigating the HIV reservoir, circulating Th1/Th2 cytokines, gut integrity, and microbial translocation in individuals with PHI and chronic HIV infection (CHI) before and after cART initiation; (2) assessing immune parameters, gut barrier dysfunction, and mitochondrial stress in PLWH switching from triple to dual INSTI-based cART; and (3) evaluating T-cell homeostasis and activation in virally suppressed individuals transitioning to the long-acting injectable regimen cabotegravir plus rilpivirine (CAB+RPV).    By providing deeper insights into how different treatment strategies affect immune activation and inflammation, this study aims to refine therapeutic approaches and mitigate long-term complications in people living with HIV.","language":"eng","citation":"INFLAMMATORY AND T-CELL HOMEOSTASIS PARAMETERS IN DUAL AND TRIPLE COMBINATION ANTIRETROVIRAL THERAPY (CART) FOR HIV INFECTION / V. Bono ; tutor: C. Tincati : revisori: M. Lichtner, G. Madeddu; coordinatore: M. Clerici, C. Sforza. Dipartimento di Scienze della Salute, 2025 Mar 24. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13584.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1157078/2743227/phd_unimi_R13584.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/908966"},"title":"RECONSTRUCTING COMMUNITY DYNAMICS AND FUNCTIONS IN DEGLACIATED AREAS THROUGH AN AD HOC ENVIRONMENTAL DNA METABARCODING TECHNIQUE","internalauthor":"GUERRIERI, ALESSIA","type":"Tesi di dottorato","year":"2022","abstract":"Deglaciated areas are increasing worldwide due to the global glacier shrinkage and are undergoing rapid colonization by multiple lifeforms, thus representing experimental systems to study community dynamics and ecosystem functioning. Our understanding of biotic colonization after glacier retreat has greatly advanced in recent years thanks to the integration of methodological innovations and ecological theories. The development of standardized, robust and previously tested molecular tools can shed light on fundamental gaps in ecological research. Here, I show how classical approaches can be combined with environmental DNA (eDNA) metabarcoding and functional trait analysis to document the formation of multitrophic communities, improving our understanding of the biotic processes that occur following the retreat of glaciers. This work contributed to both a methodological advancement of the eDNA metabarcoding technique and a conceptual advancement in the understanding of the dynamics of communities in deglaciated areas. In the first half of my thesis, I show how some important methodological approaches can be optimized to improve the strength and reliability of datasets built using eDNA metabarcoding. Specifically, I compare several approaches to soil preservation, and show that both low temperature and desiccation can enable long-term soil conservation before eDNA extraction. Subsequently, I compare thresholds for the bioinformatics clustering of metabarcoding data, and evaluate how optimal thresholds can be defined on the basis of study aims and markers. In the second half of the thesis, I analyse how environmental factors influence the colonization of glacier forelands by several taxonomic groups (bacteria, fungi, microeukaryotes and animals). By using a multi-taxa approach, I investigate how soil depth and time since glacier retreat influence the colonization of ice-free areas, and show that different groups colonize the forelands in a similar way, with communities homogenizing through different depths with time. Finally, I evaluate how time since glacier retreat, soil features and climate interact in determining the velocity of colonization of nematodes, and show how they shape community structure and functionality through succession. Understanding how metabarcoding data can be properly used to assess the colonization of glacier forelands and how different factors influence this process is particularly important in the context of ongoing climate change and for the extrapolation of current observations to the future. Besides helping to understand the biological consequence of the retreat of glaciers, the advancements provided here may allow the development of scenarios on how mountain environments can change over the next century.","language":"eng","citation":"RECONSTRUCTING COMMUNITY DYNAMICS AND FUNCTIONS IN DEGLACIATED AREAS THROUGH AN AD HOC ENVIRONMENTAL DNA METABARCODING TECHNIQUE / A. Guerrieri ; tutor: G. F. Ficetola. Dipartimento di Scienze e Politiche Ambientali, 2022 Feb 22. 34. ciclo, Anno Accademico 2021. [10.13130/guerrieri-alessia_phd2022-02-22].","filename":"phd_unimi_R12246.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/908966/1983433/phd_unimi_R12246.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1128038"},"title":"FUNCTIONAL STUDY OF THE NONCODING REGULOME OF THE NUCLEAR FACTOR Y IN HUMAN CANCER","internalauthor":"PAGANI, GIULIA","type":"Tesi di dottorato","year":"2025","abstract":"Backgroud. Noncoding RNAs (ncRNAs) are key regulators of several biological processes, and their altered expression and function are associated with tumorigenesis. In this work, we focused on antisense RNAs (asRNAs), which play a critical role in gene expression regulation. Generally thought to modulate their sense genes in cis through sequence complementarity or through the act of transcription, asRNAs can also regulate different molecular targets in trans, in the nucleus or in the cytoplasm. We also explored the role of the alternative polyadenylation (APA) of mRNAs in sustaining tumor aggressive features. Indeed, shortening of the 3’ untranslated region (3’UTR) leads to oncogene activation by microRNA binding site elimination with consequent relief from their repression in cancer cells. We focused on the nuclear transcription factor Y (NF-Y), a master regulator of proliferation in normal and tumor cells. Since its physiological role and involvement in cancer are well-documented, we aimed to study the ncRNA-mediated regulation of NF-Y activity in the development and progression of human cancers.    Aims. We aimed to explore the noncoding regulome of the NF-Y transcription factor in human cancer. Specifically, we studied the asRNA NFYC Antisense 1 (NFYC-AS1) and investigated APA of NFYA, which encodes for the regulatory subunit of NF-Y.    Results. On the one hand, we molecularly characterized NFYC-AS1 by assessing its expression, transcript structure, and biological function. Moreover, we dissected its mechanism of action by employing different loss-of-function strategies, including Gapmer antisense oligonucleotides (ASOs) and CRISPR/Cas9-mediated deletion of the transcription start site. We reported NFYC-AS1 as a cell cycle-regulating asRNA with a dual mode of action in cis and in trans, exploiting both its transcription- and RNA-dependent functions. On the other hand, we functionally characterized NFYA APA by annotating the 3’UTR isoforms and studying their biological effects on transcript stability, cellular localization, translation efficiency, and microRNA-mediated regulation. Additionally, we manipulated NFYA APA by using both CRISPR/Cas9-mediated deletion of the most used polyadenylation signal (PAS) and ASOs masking the different PASs of NFYA 3’UTR. We demonstrated that APA appeared to be a relevant post-transcriptional mechanism that controls NF-YA activity in cancer.    Conclusions. We functionally characterized two distinct noncoding RNA-mediated mechanisms important for the regulation of NF-Y expression and activity. Notably, the emerging application of ASOs in the clinics opens the possibility to target pathogenic asRNAs or mask PASs of deregulated genes in cancer to therapeutically manipulate their protumorigenic activity.","language":"eng","citation":"FUNCTIONAL STUDY OF THE NONCODING REGULOME OF THE NUCLEAR FACTOR Y IN HUMAN CANCER / G. Pagani ; supervisor: P. Gandellini. - Università degli studi di Milano, Milano, Italia. Dipartimento di Bioscienze, 2025 Jan 09. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13459_4.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1128038/2617396/phd_unimi_R13459_4.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1164495"},"title":"LUMINESCENT 2D COORDINATION NETWORKS (CNS): STRUCTURAL AND EXFOLIATION STUDIES","internalauthor":"BLASI, DELIA","type":"Tesi di dottorato","year":"2025","abstract":"After the discovery of graphene in 2004, the scientific community has increasingly focused on the investigation of two-dimensional (2D) materials, with the objective of integrating them into new technologies and devices while minimizing their environmental impact. Within the field of materials science, coordination polymers (CPs), crystalline, porous materials composed of metal ions or clusters bridged by organic ligands, have garnered significant attention. This is largely due to their structural versatility, tunable properties, and a wide range of applications, including gas adsorption and separation, sensing, drug delivery, and more.  Among the most intriguing characteristics of CPs is their luminescence, which arises from various electronic transitions such as intraligand, metal-centered, guest-centered, metal-to-ligand charge transfer (MLCT), and ligand-to-metal charge transfer (LMCT). The designability of CPs enables the synthesis of novel 2D luminescent coordination polymers (LCPs) with superior photophysical properties compared to their conventional counterparts.  In recent years, the design and synthesis of new 2D materials have emerged as a distinct subfield of the solid-state chemistry, aiming to develop and isolate layered networks with unique functionalities suitable for next-generation technologies.  This research project focused on the synthesis and comprehensive characterization of novel 2D luminescent coordination polymers (LCPs), achieved by employing newly developed emissive organic linkers in combination with closed-shell transition metals such as Ag(I), Cd(II), Zn(II), and Cu(I). A significant part of the work was also devoted to the exfoliation of both the newly synthesized LCPs and selected known compounds with specific properties, in order to obtain metal-organic nanosheets (MONs). The structural, photophysical, and functional properties of these nanostructured materials were extensively studied, with particular attention on their potential applications in chemical sensing, exploiting their remarkable luminescent behavior.","language":"eng","citation":"LUMINESCENT 2D COORDINATION NETWORKS (CNS): STRUCTURAL AND EXFOLIATION STUDIES / D. Blasi ; tutor: L. Carlucci; co-tutor: P. Mercandelli; coordinatore di dottorato: L. Prati. - Via Golgi 19, aula G16. Dipartimento di Chimica, 2025 May 15. 36. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13012.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1164495/3069421/phd_unimi_R13012.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1194003"},"title":"STRUCTURAL INSIGHTS INTO RNA POLYMERASE III PRE-INITIATION COMPLEX AND THE PIONEER ROLE OF OCT1","internalauthor":"SHAH, SYED ZAWAR","type":"Tesi di dottorato","year":"2025","abstract":"Despite the central role of small non-coding RNAs in RNA metabolism and gene  regulation, the mechanisms by which RNA polymerase III (Pol III) is selectively  recruited to snRNA promoters remain poorly understood. This is particularly notable because Pol II- and Pol III-transcribed snRNA promoters share highly similar architectures and rely on the same core transcription factor, SNAPc. How a single complex enables mutually exclusive recruitment of two distinct RNA polymerases remains an unresolved question. To address this, we determined high-resolution cryo-electron microscopy (cryo-EM) structures of the human Pol III pre-initiation complex (PIC) assembled on the U6 snRNA promoter. Captured in melting and open DNA states (3.2–4.2 Å resolution), these structures reveal distinct SNAPc conformations when engaging Pol III versus Pol II. Through integrative modeling and crosslinking mass spectrometry, we structurally localized the SNAPC2 and SNAPC5 subunits near promoter DNA. These subunits had previously been proposed to act as an autoinhibitory module, and our work provides a structural framework supporting this regulatory role. Together, these findings uncover the structural basis of polymerase specificity and reveal critical differences between human and yeast Pol III PICs, suggesting evolved regulatory mechanisms in higher eukaryotes. In parallel, we investigated OCT1 (POU2F1), a transcription factor known to bind distal sequence elements (DSEs) upstream of Class III Pol III promoters. Although widely expressed and implicated in gene regulation, OCT1’s potential role as a pioneer transcription factor has not been structurally defined. Motivated by its consistent presence at Class III promoters, we used cryo-EM to determine the structure of OCT1’s DNA-binding domain bound to nucleosomes. The data reveal three distinct binding modes: one sequence-specific interaction at the DSE and two non-specific contacts at superhelical locations that engage and remodel histone H4 tails. These interactions reposition histone tails and displace linker histone H1, resulting in chromatin destabilization and increased DNA accessibility. Altogether, this thesis provides structural and mechanistic insights into transcription initiation by Pol III at snRNA promoters and uncovers OCT1 as a chromatin-interacting factor with pioneer-like activity. These findings advance our understanding of polymerase recruitment and chromatin regulation in non-coding RNA gene expression.","language":"eng","citation":"Structural Insights into RNA Polymerase III Pre-Initiation Complex and the Pioneer Role of OCT1 / S.z. Shah ; tutor:  A. Vannini ;  examiners: F. Werner, M. Mapelli. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Jul 29. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13509.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 07-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1181576"},"title":"CO AND CO2 HYDROGENATION BY FISCHER TROPSCH SYNTHESIS PROMOTED WITH IRON BASED HETEROGENEOUS CATALYSIS: DATA COLLECTION AND PROCESS DESIGN","internalauthor":"GRAINCA, ARIAN","type":"Tesi di dottorato","year":"2025","abstract":"The reduction of CO₂ emissions into the atmosphere has become a global priority, given the crucial role of this greenhouse gas in climate change. A promising approach to mitigate CO₂ is its conversion into fuels and chemicals through processes such as Fischer–Tropsch (FT) synthesis. Traditionally, FT relies on syngas (CO/H₂) over transition-metal catalysts, but the direct hydrogenation of CO₂ has been less explored, particularly with Fe-based heterogeneous catalysts. Iron is an abundant and inexpensive metal, already known for its high activity in conventional FT from CO. This research aims to develop novel Fe-based catalysts effective in both CO and CO₂ derived FT, while also addressing the interconnected challenges of environmental sustainability, operational safety, and predictive process modelling. The ultimate goal is to provide a holistic solution for upgrading CO₂ into hydrocarbons, bridging existing gaps in the development of materials (e.g., Fe-based metallosilicates and hydrotalcites) that have been scarcely investigated to date. To this end, innovative iron-based catalysts were synthesized, tested under CO and CO₂ FT conditions, and evaluated through Life Cycle Assessment (LCA), HAZOP/LOPA safety analysis, and artificial intelligence tools (artificial neural networks) for performance optimization. This integrated approach provides a comprehensive perspective on CO/CO₂ conversion, representing an important step toward the practical implementation of Carbon Capture and Utilization (CCU) technologies.  Two main classes of Fe-based heterogeneous catalysts were investigated: (1) mixed oxides derived from hydrotalcites (e.g. Mg-Fe-Cu), synthesized via ultrasound-assisted co-precipitation (US) and, in some cases, subjected to ball milling (BM), and (2) iron catalysts supported on mesoporous metallosilicates, synthesized by non-hydrolytic sol-gel routes. All catalysts were promoted with potassium and copper, both known to enhance activity and selectivity toward heavier FT hydrocarbons. Potassium acts as an electronic promoter, suppressing methane formation and favouring carbon-chain growth, while the Mg-Fe based mixed oxide matrix provides basicity, enhancing the Water Gas Shift (WGS) reaction and thereby benefiting CO₂ conversion.  Catalytic testing in a fixed-bed reactor yielded highly promising results. With syngas (CO/H₂), the Fe-based catalysts reached high CO conversion levels (up to ~95–98% at 300 °C) and notable selectivity toward liquid hydrocarbons (C₅⁺ fraction, ~40–50 wt%), while maintaining low methane production (<5%). For instance, a hydrotalcite-derived Mg-Fe-Cu/K catalyst (denoted Fe30) achieved ~96% CO conversion at 300 °C, with ~40% selectivity to the heavy fraction and ~5% to methane. These performances are comparable or superior to those reported for reference systems: Fe30 matched the activity of Fe/K/Cu catalysts supported on conventional oxides (alumina), reaching >80% conversion at lower temperatures, and outperformed analogous catalysts on mesoporous silicates in terms of stability and selectivity toward heavy products. This confirms that the hydrotalcite-derived nanostructure provides excellent dispersion of active sites and a favourable chemical environment which promote FT reactivity while minimizing undesired byproducts. In direct CO₂ hydrogenation, the iron catalysts displayed significant activity, although the reaction pathway is strongly coupled with the reverse WGS reaction (CO₂ → CO), resulting in notable co-production of CO. Accordingly, CO₂ feeds yielded higher selectivity to CO and CH₄ compared with syngas operation. However, introducing cobalt into the catalyst formulation substantially improved liquid hydrocarbon yields: Mg-Fe-Co-Cu/K catalyst (denoted Co45, containing ~42% Co and ~30% Fe) produced a larger C₇⁺ fraction and fewer gaseous byproducts than pure Fe catalysts, particularly at higher temperatures. Thus, Co45 proved more efficient in directly hydrogenating CO₂ into long-chain hydrocarbons, with lower CO selectivity and reduced methane formation. This behaviour is attributed to cobalt’s intrinsic higher activity in FT from CO₂, which remains effective even at 350 °C, whereas iron tends to favour secondary methanation and Boudouard (carbon deposition) reactions under the same conditions. Overall, catalyst composition optimization (Fe ratio, Co incorporation, K promotion) was crucial: the Fe-Co catalyst provided the best balance, maximizing heavy hydrocarbon production while minimizing undesired gaseous emissions, and highlighted the trade-off between catalytic performance and the environmental cost of materials (given cobalt’s higher extraction impact relative to iron). The experimental dataset generated thus constitutes a valuable benchmark for both sustainability evaluation and predictive modeling (see chapter 5).  Given the strongly exothermic and high-pressure nature of FT synthesis, safety considerations for the laboratory-scale pilot unit were systematically addressed using industrially derived methodologies. A Hazard and Operability (HAZOP) study was conducted on the FT unit, followed by a Layer of Protection Analysis (LOPA), with the aim of identifying potential hazard scenarios and verifying the adequacy of existing safeguards. This represents an innovative application of such frameworks in an academic setting, motivated by the frequent manual interventions and transient operations typical of laboratory plants. The HAZOP identified several critical deviations from normal operation, such as risks of H₂/CO gas leaks, line blockages, or overheating, particularly in the FT reactor and feeding system, which emerged as the most vulnerable nodes. In some cases, existing protections were found to be insufficient to mitigate the consequences of potential incidents. The subsequent LOPA quantified the level of additional protection required, identifying and prioritizing further independent protection layers. Key recommendations included: increasing automation (to reduce reliance on manual operations), implementing safety interlocks and automatic control loops (e.g., shutdown valves upon leak detection, pressure/temperature control loops), and adding redundancy to critical components. Passive measures were also emphasized, such as improved ventilation (exhaust hoods, fume extraction) and enhanced operator training for correct handling during operation and emergencies. The adoption of these strategies will minimize accident risks and unplanned downtimes, bringing the laboratory-scale setup closer to industrial safety standards. In conclusion, the combined HAZOP–LOPA approach in an academic environment proved effective in raising safety standards and in creating a replicable framework for managing operational risks in complex experimental projects like FT synthesis.  To evaluate the overall sustainability of the process and developed materials, a Life Cycle Assessment (LCA) was carried out. The LCA covered both the production phase of catalysts (from raw material extraction through Fe-based catalyst synthesis) and the operational phase of CO₂ FT conversion into hydrocarbons. Three representative catalysts were compared: Fe30, Fe40, and Co45 (all Cu/K-promoted, with varying Fe/Co ratios) the same tested experimentally, assessing their environmental footprint under optimal operating conditions (350 °C) for the production of 1 kg of C₂⁺ hydrocarbons. The analysis was conducted with SimaPro software (CML-IA method, using IPCC GWP100 and CED indicators), evaluating impact categories such as Global Warming Potential (GWP), Cumulative Energy Demand (CED), and toxicity/ecotoxicity metrics. Results clearly indicated that catalytic efficiency strongly dictates environmental performance: the less efficient Fe40 catalyst generated the highest impacts across nearly all categories. For instance, Fe40 exhibited the largest carbon footprint (~2.39 kg CO₂-eq per kg of product), compared with ~1.31 kg for Fe30 and ~0.98 kg for Co45. In other words, for the same quantity of synthetic fuel, Fe40 contributed roughly double the greenhouse gas emissions of the cobalt-containing catalyst. Similarly, Fe40 showed higher impacts in other categories, e.g., ~67% greater abiotic depletion relative to Co45 and ~41% greater than Fe30. This disparity is due to Fe40’s lower catalytic efficiency, which demands higher energy inputs and produces more byproducts per unit of fuel synthesized. Conversely, Co45, despite incorporating cobalt, a critical and environmentally costly metal, compensated through its high activity in operation, leading to lower per-product impacts. In summary, the LCA highlighted a performance vs. environmental impact trade-off: improving catalytic activity (e.g., through Co promotion) can significantly reduce lifecycle impacts per product, even when catalyst production has higher initial burdens. These findings underscore the importance of integrating environmental assessment early in catalyst and process design. The Fe/Co combination emerged as the most promising pathway, suggesting directions for future development of FT catalysts that are both efficient and sustainable.  In parallel with experiments, machine learning (ML) techniques were applied to model and predict FT process performance. Specifically, an Artificial Neural Network (ANN) was trained on the experimental dataset to correlate input variables (operating parameters such as temperature, pressure, GHSV, H₂/CO₂ ratio, and catalyst composition) with performance outputs (CO₂ conversion, CH₄ selectivity, C₂–C₄ fraction, C₅⁺ fraction, CO selectivity). The ANN architecture was optimized to minimize prediction error and capture nonlinear relationships, thus providing an alternative predictive tool to conventional kinetic models that require detailed mechanistic knowledge. ANN results showed good accuracy in predicting certain key aspects (e.g., CO₂ conversion and C₂-C₄ selectivity), consistent with trends reported in the literature. Sensitivity analysis confirmed the positive influence of higher Fe content and K promotion in increasing liquid hydrocarbon yields and conversion efficiency. However, limitations emerged: the ANN struggled to accurately predict heavy hydrocarbon (C₅⁺) formation and CO selectivity, likely due to the limited size and diversity of experimental data. This suggests that future models should incorporate larger datasets and potentially more advanced architectures (e.g., hybrid AI or deep learning). To complement the ANN, a Random Forest (RF) model was also applied on the same dataset. RF proved particularly robust with limited data, mitigating overfitting risks through ensemble averaging. While RF predictions were comparable in accuracy to ANN, it offered a distinct advantage in interpretability: feature-importance analysis identified which operating conditions and catalyst properties most strongly affected outcomes, aligning well with chemical intuition (e.g., temperature and catalyst composition as dominant factors). Thus, ML models demonstrated their potential as decision-support tools, enabling rapid virtual screening of catalyst/process combinations and accelerating the optimization cycle.    In conclusion, this thesis develops a comprehensive framework for the sustainable conversion of CO₂ into fuels, combining innovation in catalyst design, process optimization, and integrated assessments of safety and environmental impacts. Results demonstrate that Fe-based catalysts, suitably promoted, can achieve high CO₂ FT performance, while Co incorporation further enhances liquid fuel yields and reduces per-product impacts. In parallel, rigorous HAZOP/LOPA studies ensure that such processes can be conducted safely even at laboratory scale, and LCA provides quantitative guidance to steer technological choices toward genuinely sustainable solutions. Finally, the application of AI-based predictive tools offers new perspectives for accelerating catalyst and process development, uncovering hidden correlations, and directing future experimental efforts more effectively. The synergy of these disciplines: industrial chemistry, safety engineering, environmental analysis, and data science, constitutes a holistic and highly innovative approach. This integrated vision facilitates the transition of CO₂-to-fuel FT technology from laboratory to industry, contributing to circular economy goals and decarbonization. Ultimately, the work lays the foundation for CO₂-to-fuels systems that are more efficient, safe, and sustainable, outlining strategies with tangible impact in the context of the ongoing energy and ecological transition.","language":"eng","citation":"CO AND CO2 HYDROGENATION BY FISCHER TROPSCH SYNTHESIS PROMOTED WITH IRON BASED HETEROGENEOUS CATALYSIS: DATA COLLECTION AND PROCESS DESIGN / A. Grainca ; tutor: C. Pirola ; co-tutor C. L. Bianchi ; coordinator L. Prati. Università degli Studi di Milano, 2025 Sep 26. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13529.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1181576/3132576/phd_unimi_R13529.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1065428"},"title":"IL PUBBLICO MINISTERO NELL'ORDINAMENTO DELL'UNIONE EUROPEA: VERSO L'AFFERMAZIONE DI UN MODELLO INDIPENDENTE E IMPARZIALE?","internalauthor":"CIPRANDI, AGNESE ANGELA","type":"Tesi di dottorato","year":"2024","abstract":"Public prosecutors have always been considered among the main expressions of the “national identity” of member states, thus remaining deeply linked to the specificities of individual systems. They are, in fact,  the subjects called upon to operate (not only, but above all) in the area of criminal justice, an area of substantive law – criminal law, substantive and procedural – which, more than the others, has encountered obstacles towards a form of integration between states, due to its particular “hypersensitivity”. However, despite the traditional “jealousy” that states seem to wish to retain in defining their prerogatives and status, now more than ever, the idea that prosecuting authorities represent figures devoid of interest in the European Union legal system cannot be shared. This dissertation, therefore, aims to examine the figure of the prosecutor in the broader supranational context, from the perspective of the guarantees of independence and impartiality that assist the exercise  of its functions. Specifically, the objective of the investigation is twofold: first, to verify, at present, the possibility of identifying a “European” model of an independent and impartial public prosecutor through a comparison between the Court’s caselaw and the existing norms on the matter; second, to verify whether, in the systems of the member states, there is the prospect of an institutional reform of the public prosecutor in the light of the European guidelines previously identified.  To this end, the first chapter is concerned with highlighting the link between the independence of the judiciary and a fundamental value of the European Union, the rule of law, with a specific focus on the relationship between the latter and the role of prosecutors. The second chapter analyzes in detail the guarantees of the prosecutor as they emerge from the framework of the case law of the Court of Justice.  Consequently, having identified a possible model of prosecutor in the Court’s opinions, the third chapter deals with examining the safeguards placed to guarantee the independence and impartiality of the new European Public Prosecutor’s Office; requirements expressly imposed in its founding regulation. The fourth chapter is devoted to identifying the fundamental principles that should guide the status of the prosecutor and his institutional role at the international level, through both the analysis of the principal institutional documents on the subject and the caselaw of the European Court of Human Rights. Lastly, in the light of the conclusions of the previous chapters, possible institutional reforms that member states might have to initiate in order to ensure effective independence and impartiality of the prosecuting judiciary – as a result of both the opinions of the Court and the above-mentioned newly established European Public Prosecutor’s Office – are envisaged.","language":"ita","citation":"IL PUBBLICO MINISTERO NELL'ORDINAMENTO DELL'UNIONE EUROPEA: VERSO L'AFFERMAZIONE DI UN MODELLO INDIPENDENTE E IMPARZIALE? / A.a. Ciprandi ; tutor: C. Amalfitano ; coordinatore: F. Biondi. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2024 Jul 09. 36. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R12941.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1065428/2447892/phd_unimi_R12941.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1022953"},"title":"BALANCING DOMAIN DECOMPOSITION BY CONSTRAINTS PRECONDITIONERS FOR VIRTUAL ELEMENT DISCRETIZATIONS OF SADDLE-POINT PROBLEMS","internalauthor":"BEVILACQUA, TOMMASO","type":"Tesi di dottorato","year":"2024","abstract":"The Virtual Element Method (VEM) is a novel family of numerical methods for approximating partial differential equations on  general polygonal or polyhedral computational grids.  This thesis aims to propose a Balancing Domain Decomposition by Constraints (BDDC) algorithms to compute the solution of the saddle-point linear systems arising from the VEM discretization of the two and  three dimensional incompressible Stokes and Oseen equations. These methods are an evolution of Balancing Neumann Neumann preconditioners where, to obtain scalability in the number of subdomains, a coarse space has to ensure global transport of information. In the Stokes model, these methods act as preconditioners making the linear system symmetric and positive definite, this allows to use the conjugate gradient method to accelerate the convergence. For the Oseen model, due to the lack of symmetry the system is still positive definite, but the solution is performed with the  generalized minimal residual method (GMRES).  In the symmetric framework, we prove the scalability and quasi-optimality of the algorithm and confirm the theoretical findings with several numerical test with parallel computations, including a time analysis for the three dimensional case. We also provide a proof for a Stokes optimal VEM interpolant in the three dimensional framework, needed to complete the analysis of the preconditioner.   We extend the BDDC algorithm applied to the non-symmetric saddle point problem that arises from the VEM discretization of the Oseen problem, providing some numerical simulations including scalability and optimality tests in both two and three dimensions. Exploiting the advantages of the VEM methods all our experiments have been performed on different type of meshes with different type of partition techniques.  We propose different adaptive technologies to enrich the coarse space both in two and three dimensions, which require the solution of eigenvalue problems on the interface of the subdomains. These techniques are able to control the conditioning of the system and keep it limited below a certain threshold decided a priori. We also provide an heuristic approach that, for some specific cases, efficiently enrich the coarse space overcoming these extra computations. Numerical results with adaptively generated coarse spaces and the new heuristic approach, confirm the method's robustness in the presence of large jumps in the viscosity and with high-order VEM discretizations.","language":"eng","citation":"BALANCING DOMAIN DECOMPOSITION BY CONSTRAINTS PRECONDITIONERS FOR VIRTUAL ELEMENT DISCRETIZATIONS OF SADDLE-POINT PROBLEMS / T. Bevilacqua ; tutor: S. Scacchi, coordinatore: D. Bambusi. Dipartimento di Matematica Federigo Enriques, 2023. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12799.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1022953/2342096/phd_unimi_R12799.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1018170"},"title":"A MULTIORGANELLE PLATFORM REGULATES EGFR ENDOCYTOSIS AND SIGNALLING","internalauthor":"SALVI MESA, DEBORAH","type":"Tesi di dottorato","year":"2023","abstract":"Endocytosis plays a crucial role in regulating the signalling of the epidermal growth factor receptor (EGFR). The internalization of the EGFR can occur through different mechanisms. Clathrin-mediated endocytosis (CME) operates at all concentrations of EGF and in all cell contexts, directing the majority of receptors towards recycling. In contrast, non-clathrin endocytosis (NCE) is activated only at high (but physiological) EGF concentrations, alongside CME, and leads to the degradation of EGFR. Thus, the NCE pathway can serve as an intrinsic cellular system to suppress EGFR levels and signalling, which could be particularly relevant in situations where the receptor or its ligands are excessively upregulated, such as in cancer.  Through a proteomics investigation of EGFR-loaded NCE vesicles coupled with RNA interference screening, several functional regulators of NCE have been discovered, including the endoplasmic reticulum (ER)-shaping factor reticulon-3 (RTN3) and various mitochondrial proteins. RTN3 plays a critical role in EGFR internalization via NCE by promoting the formation of contact sites between the ER and the plasma membrane (PM). These contact sites are essential for the formation and elongation of NCE intermediates known as tubular invaginations (TIs). Calcium, released from the ER at these sites through the inositol trisphosphate receptor (IP3R), is required, along with the dynamin, for the fission of TIs and the completion of EGFR-NCE.  Preliminary data from our laboratory suggested the possible involvement of mitochondria in EGFR-NCE: a significant enrichment in mitochondrial proteins was observed in isolated NCE vesicles. Electron microscopy (EM) analysis of PM-ER contact sites also revealed the presence of mitochondria adjacent to these structures. Hence, the main objectives of this thesis were to investigate the precise role of mitochondria in EGFR-NCE and to gain an understanding of the potential crosstalk between EGFR signalling and the specific subset of mitochondria at NCE contact sites. Specifically, we aimed to determine whether EGFR signalling can directly influence mitochondrial metabolism and, if so, what the impacts of this would be on broader cellular responses.  Importantly, using EM, we established that EGFR activation enhances the physical association between internalizing EGFR-NCE structures, ER stacks, and mitochondria, forming a tripartite interorganelle platform. At the molecular level, using intracellular calcium sensors targeted to the PM or mitochondria, we discovered that calcium signalling at these sites occurs through oscillatory waves that are sensed by mitochondria, leading to an increase in mitochondrial energetics. Furthermore, the activation of EGFR-NCE results in a localized burst of ATP, as measured by an ATP-dependent enzyme (Luciferase) targeted to the PM. This accumulation of ATP in the subplasmalemmal region depends on EGFR-NCE activation. The interplay between active EGFR, calcium signalling, and mitochondrial metabolism has a dual impact on cell physiology. It is crucial for the recruitment of the actin machinery, which acts in concert with dynamin in the fission of NCE TIs. Additionally, it regulates the remodelling of cortical actin, thereby promoting cell migration, as evidenced in wound healing assays performed on human immortalized keratinocytes (HaCaT cells).  In conclusion, the tripartite structure involving the PM, ER, and mitochondria not only plays a role in the endocytosis of EGFR but also serves as a signalling platform that mediates cellular responses to high-dose EGF stimulation. This work reveals an additional layer of complexity in the regulation of EGFR signalling, involving a new player (NCE multiorganelle platform) that connects EGFR endocytosis to cellular metabolism and, ultimately, to the wider cellular response, e.g., cell motility. It is worth noting that while NCE acts as a negative regulator of EGFR signalling by promoting receptor degradation in the presence of excess ligand, it also serves as a positive regulator of EGF-related cellular responses in specific cell contexts, such as the migration of normal keratinocytes. Thus, considering the crucial role of NCE in the regulation of EGFR signalling and the fact that EGFR signalling is frequently altered in pathological conditions, this research could improve our understanding of how EGF-induced biological responses are regulated in the physiological contexts. Additionally, it may shed light on novel mechanisms responsible for the dysregulation of EGFR signalling in diseases like cancer, offering valuable insights for the development of innovative therapeutic strategies that combine EGFR- and mitochondria-targeting therapies.","language":"eng","citation":"A MULTIORGANELLE PLATFORM REGULATES EGFR ENDOCYTOSIS AND SIGNALLING / D. Salvi Mesa ; tutor: P. P. Di Fiore ; internal advisor: S. Santaguida ; added tutor: S. L. G. Sigismund ; PhD coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2023 Dec 12. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12709.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1018170/2326841/phd_unimi_R12709.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1045408"},"title":"ROLE OF CIRCULAR PVT1 IN ISCHEMIC HEART FAILURE","internalauthor":"BIBI, ALESSIA","type":"Tesi di dottorato","year":"2024","abstract":"Circular RNAs (circRNAs) are involved in the pathogenesis of several cardiovascular diseases (CVDs), including heart failure (HF). circRNAs can bind microRNAs (miRNAs), acting as competing endogenous RNAs (ceRNA), thus regulating the expression levels of miRNA target mRNAs. However, these interactions and their respective functions in ischemic HF (IHF) remain largely unknown. This study aimed to identify circRNA-based ceRNA networks in non-end-stage IHF.   Transcriptome analysis of left ventricles of IHF patients identified significant differentially expressed circRNAs, miRNAs and mRNAs. Potential miRNAs interacting with validated circRNAs as well as mRNA targets of sponged miRNAs were determined using bioinformatics tools. Predicted miRNAs and mRNAs were filtered for their dysregulation in IHF, resulting in 662 circRNA-miRNA-mRNA interactions. KEGG terms of the identified interacting mRNAs indicated CVD-related signaling pathways.   circPVT1 emerged as one of the main hubs of circRNA-miRNA-mRNA network in IHF. RNA-Seq analysis following circPVT1 knockdown in immortalized human cardiomyocytes identified differentially expressed genes mainly involved in fibrosis and in cellular senescence. Interestingly, circPVT1 expression significantly increased in cardiac fibroblasts after TGF-β1 treatment. circPVT1 silencing attenuated the levels of pro-fibrotic markers induced by TGF-β1, highlighting a pro-fibrotic role of circPVT1. RNA pull-down assays confirmed the interaction between circPVT1 and three fibrosis-related miRNAs, miR-30a-5p, miR-125b-5p and miR-369-5p. The levels of these miRNAs were not altered upon circPVT1 knockdown. However, the expression of their mRNA targets was deregulated upon circPVT1 silencing, suggesting that circPVT1 modulate miRNA cellular bioavailability. Inhibition of either miR-30a-5p or miR-125b-5p, but not miR-369-5p, significantly reversed the reduced expression of TGF-β1-induced pro-fibrotic markers following circPVT1 silencing, indicating that both miR-30a-5p and miR-125b-5p act as downstream effectors of circPVT1 in cardiac fibroblast activation. Our findings suggest that circPVT1 has a pro-fibrotic function and regulate cardiac fibroblast activation via miR-30a-5p and miR-125b-5p sponging.","language":"eng","citation":"ROLE OF CIRCULAR PVT1 IN ISCHEMIC HEART FAILURE / A. Bibi ; tutor: A. Barbuti ; co-tutor: F. Martelli ; phd school coordinator: R. Mantovani. Dipartimento di Bioscienze, 2024 May 07. 36. ciclo","filename":"phd_unimi_R13115.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1045408/2398736/phd_unimi_R13115.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1205016"},"title":"LEARNING UNDER STRUCTURE AND UNCERTAINTY: ALGORITHMS FOR BANDIT AND ONLINE DECISION MAKING","internalauthor":"RUMI, ALBERTO","type":"Tesi di dottorato","year":"2025","abstract":"This thesis investigates the design and analysis of algorithms for online decision-making under uncertainty, with a particular focus on the multi-armed bandit and online learning frameworks. At the core of these settings lies a simple yet powerful interaction protocol: at each round the learner receives a question (information available prior to a decision), provides an answer (an action or prediction), and observes a feedback signal that may be partial, noisy, or structured. This iterative loop captures a wide range of sequential decision problems and serves as the unifying perspective for the contributions of this thesis. We address this challenge across four distinct, fundamental problems in online learning.    First, we address settings in which the learner receives no additional information prior to making a decision (i.e., the question is implicit), and must adapt to a nonstationary environment under bandit feedback. We introduce a parameter-free algorithm achieving optimal dynamic regret guarantees without prior knowledge of the environment's variability. This result resolves a long-standing open problem in the field.    Next, we enrich the answer phase by allowing the learner to abstain. We propose an efficient algorithm, that leverages this option to obtain cumulative reward guarantees that can outperform standard methods, while matching their worst-case performance. This framework is then extended to the adversarial contextual bandit problem with abstention.    We investigate problems with combinatorial answers, where the learner selects a subset of actions and the reward feedback is defined by a sum-max function, a rich subclass of monotone submodular functions. We design an algorithm for this bandit problem, and prove it achieves significant improvement in regret with respect to standard algorithms for monotone submodular functions.     Finally, we consider the Stochastic Shortest Path problem, where the additional structure is dictated by an underlying Markov Decision Process. We analyze the impact of sparse cost feedback, demonstrating that standard methods fail to exploit it. We design a novel family of regularizers that achieves an optimal, sparsity-adaptive regret bound. This result, complemented by a matching lower bound, provides a complete characterization of the benefits of sparsity in this setting.    The contributions in this thesis demonstrate that by designing principled algorithms that recognize and exploit structure within the question, answer, feedback loop, we can achieve strong, adaptive guarantees for learning under uncertainty.","language":"eng","citation":"LEARNING UNDER STRUCTURE AND UNCERTAINTY: ALGORITHMS FOR BANDIT AND ONLINE DECISION MAKING / A. Rumi ; tutor: N. Cesa-Bianchi ; cosupervisor: F. Vitale ; coordinator: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2025. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13858.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1205016/3212341/phd_unimi_R13858.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1217659"},"title":"PERFECT FLUIDS AND SIGMA MODELS: A MATHEMATICAL INVESTIGATION BETWEEN GENERAL RELATIVITY AND COTTON GRAVITY","internalauthor":"MASTROPIETRO, FILIPPO","type":"Tesi di dottorato","year":"2026","abstract":"In this thesis, we deal with two physics-inspired structures on Riemannian manifolds, depending  on a smooth map φ between Riemannian manifolds and several other functions and constants; they  are called Cotton φ-Perfect Fluids (C-φ-PF) and φ-static perfect fluids space-times (φ-SPFST).  The latter are special solutions of the Einstein field equations on a static space-time with matter  sources modelled by a perfect fluid and a map φ, while the former are the natural generalization of  φ-SPFSTs in the framework of a gravitational theory of recent introduction, called Cotton Gravity.  We highlight the role of the Introduction in clarifying the physical background of this work and  the expected contributions that such structures might give to Riemannian Geometry. In Chapter  1 we fix the notations and conventions and review some of the basics of Riemannian Geometry  and General Relativity.  We begin Chapter 2 by introducing the theory of Cotton Gravity and showing how it preserves the  solutions of General Relativity. We then derive the equations of C-φ-PF and show their variational  origin; the class of variations that we need to consider is such that the connection, instead of the  metric, is the fundamental entity. To obtain the main result of this chapter, a rigidity result for  a C-φ-PF under some curvature conditions which are inspired by the theory of Ricci solitons, one  needs to face a novel and specific property of Cotton Gravity, that of depending on third order  derivatives of the metric tensor. In doing so, we will unveil the special relevance that Codazzi  tensors hold in this theory, as well as the important relations between the equations of C-φ-PF  and the first integrability condition of a φ-SPFST. Inspired by some works in conformal geometry,  we then conclude this chapter by studying the obstruction to a C-φ-PF to be a φ-SPFST and  relating it to some special algebraic properties of the Weyl tensor.  In Chapter 3 we deal with φ-SPFSTs. We derive other rigidity results under new curvature condi  tions, for both manifolds with and without boundary. The proof in the two cases are surprisingly  different, but both rely on some special integral identities that make our assumptions effective. We  then prove an Obata-type theorem that characterizes the standard spheres as the only compact  manifolds supporting a closed, conformal vector field and a structure of generalized Harmonic  Einstein manifold; we apply it to deduce a rigidity result for a closed φ-SPFST for which a suitable  modification of the Schouten tensor is Codazzi and has some elementary symmetric function in its  eigenvalues which is positive and constant.","language":"eng","citation":"PERFECT FLUIDS AND SIGMA MODELS: A MATHEMATICAL INVESTIGATION BETWEEN GENERAL RELATIVITY AND COTTON GRAVITY / F. Mastropietro ; tutor: M. Rigoli; co-tutor: P. Mastrolia; coordinatore: G. Ciraolo. Dipartimento di Matematica Federigo Enriques, 2026 Feb 25. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13989.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1217659/3256676/phd_unimi_R13989.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1216621"},"title":"LA TUTELA DELL¿ACQUIRENTE DI OPERE D¿ARTE: UNO STUDIO DI DIRITTO COMPARATO","internalauthor":"GATTILLO, FEDERICA","type":"Tesi di dottorato","year":"2026","abstract":"This dissertation aims to examine, from a comparative perspective, the evolution in the application of classical legal paradigms—traditionally grounded in rigor and clarity—to the “art system,” a notoriously opaque sphere shaped by heterogeneous practices. The exponential growth of the art market has been accompanied by a corresponding surge in legal issues underlying the transfer of ownership, inherently linked to the need to verify and guarantee the authenticity of artworks. In the near-total absence of dedicated regulatory frameworks—a feature common to many contemporary legal systems—the principal source of disputes and complexity, in both civil law and common law jurisdictions, arises from the lack of clarity regarding the application, to movable cultural goods, of traditional remedies such as contract rescission and annulment for mistake. The analysis focuses on key jurisdictions of the Western Legal Tradition—Italy, France, the United Kingdom, and the United States—selected for their historical, normative, and operational relevance in the international art market. The study seeks to provide a faithful representation and reasoned systematization of existing practices, mapping and assessing the resilience of traditional contractual paradigms in this peculiar context. In civil law countries, an acquirer of a misattributed artwork—where the purchase was primarily motivated by reliance on the correspondence between a specific work and its supposed author—may invoke classical remedies. Italy and France, for example, share the possibility of seeking contract rescission for the absence or defect of essential qualities of the work or, alternatively, under the doctrines of aliud pro alio/non-conformité, as well as annulment for vitiated consent. In France, particularly in light of recent reforms, rescission appears rarely employed, being a subsidiary remedy to the principal action of annulment for mistake. In Italy, annulment has a recognized, though limited, application, contingent on the absence of express representations or warranties regarding authenticity. By contrast, common law jurisdictions generally frame sales contracts under the strict principle of caveat emptor. Buyers of artworks may, however, protect their position through claims for breach of contract, mistake, or misrepresentation. Within this remedial framework, the dissertation aims to identify points of convergence, cross-cutting trends, and jurisprudential or doctrinal developments that may inform the creation of new interpretative approaches or categories, offering guidance for the rationalization of practices and the functional reformulation of specific legal instruments, while also addressing the general lack of awareness of the underlying complexities of the art market.","language":"ita","citation":"LA TUTELA DELL'ACQUIRENTE DI OPERE D'ARTE: UNO STUDIO DI DIRITTO COMPARATO / F. Gattillo ; tutor: A.  Candian, ordinaria di Diritto Privato Comparato (unimi) co-tutor:  A. Donati, associata di Diritto Privato Comparato (unimib). - Università Statale di Milano. Dipartimento di Diritto Privato e Storia del Diritto, 2026 Feb 09. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13947.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 19-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1196538"},"title":"DECODING THE GENETIC LANDSCAPE OF CONGENITAL HYPOGONADOTROPIC HYPOGONADISM: FROM PATIENT ALLELIC VARIANTS TO FUNCTIONAL INSIGHTS IN ZEBRAFISH","internalauthor":"GENTILE, ILARIA","type":"Tesi di dottorato","year":"2026","abstract":"Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by incomplete or absent puberty and infertility, due to deficient secretion or action of gonadotropin-releasing hormone (GnRH). Although more than 60 causative genes have been described, the genetic heterogeneity of CHH remains only partially understood and many patients still lack a molecular diagnosis. Among the novel candidates, WFS1 and TBX3 have recently emerged as potential candidate genes for isolated CHH. The central research question of this thesis is whether heterozygous variants in WFS1 and TBX3, identified in CHH patients, can disrupt GnRH neuronal development, migration, or regulatory pathways, contributing to the disease pathogenesis.  In our cohort of CHH patients, genetic analysis revealed heterozygous WFS1 variants identified by whole-exome sequencing (WES) and TBX3 variants identified by next-generation sequencing (NGS) panel. To evaluate the functional impact of these variants, we performed site-directed mutagenesis followed by in vitro characterization in cellular models. Specifically, WFS1 wild-type and mutant constructs were evaluated in COS7 cells, while TBX3 constructs were tested in HEK293 cells. Functional assays included Western blotting, immunofluorescence, quantitative real-time PCR, and luminometric assays to investigate protein localization, expression stability, turnover and transcriptional activity.  To validate these findings in vivo, we used the Tg(GnRH3:EGFP) zebrafish line and generated knockdown (KD) model via morpholino of wfs1b and tbx3a/b. This strategy allows direct visualization of GnRH3 neurons development, proliferation and migration steps.  Knockdown of wfs1b in Tg (GnRH3:EGFP) zebrafish embryos disrupted GnRH3 neuronal architecture and downregulated isl1a, a key transcription factor involved in axon guidance. Our findings establish a mechanistic link between WFS1-mediated ER homeostasis, isl1a expression, and GnRH neuron development.   In parallel, tbx3 knockdown revealed defective GnRH3 neurons and kisspeptin neuronal development, associated with a marked downregulation of the Wnt signaling pathway. These results suggest that TBX3 variants may affect both migration and differentiation of GnRH neurons.   In conclusion, this thesis provides novel functional evidence that heterozygous variants in WFS1 and TBX3 converge on the disruption of GnRH and kisspeptin neuronal networks, through distinct but complementary mechanisms: WFS1 via ISL1-related pathways and axon guidance, and TBX3 through Wnt signaling and kisspeptin regulation. These findings enlarge the genetic and mechanistic landscape of CHH, propose zebrafish as a versatile model for functional validation of candidate genes and open new perspectives for targeted therapeutic approaches aiming to restore GnRH neuron function.","language":"eng","citation":"DECODING THE GENETIC LANDSCAPE OF CONGENITAL HYPOGONADOTROPIC HYPOGONADISM: FROM PATIENT ALLELIC VARIANTS TO FUNCTIONAL INSIGHTS IN ZEBRAFISH / I. Gentile ; tutor: L. Persani ;  supervisor: V. Vezzoli ;  director: N. Landsberger. - LITA Segrate. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2026 Jan. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13755.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 18-NOV-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1209415"},"title":"DISSECTING THE ROLE OF THE TETRASPANIN MS4A4A IN MODULATING MACROPHAGE PLASTICITY AND FUNCTION","internalauthor":"TROILO, ALESSIA","type":"Tesi di dottorato","year":"2026","abstract":"MS4A4A belongs to the membrane-spanning 4A (MS4A) family, whose proteins show preferential expression in distinct cell types and structural similarities to tetraspanins, including the ability to interact with and modulate the activity of various immunoreceptors, such as pattern recognition receptors (PRRs) and Ig receptors. MS4A4A is selectively expressed by macrophages, and its expression is upregulated upon treatment with Interleukin-4 (IL-4) and glucocorticoids (Dexamethasone, Dex). However, the molecular mechanisms by which MS4A4A exerts its biological function in macrophages remains largely  uncharacterised.   MS4A4A has been increasingly studied in relation to several diseases with inflammatory components. Specifically, it has been implicated in Alzheimer’s disease, potentially affecting microglial activation. In the context of cancer, we have previously reported that MS4A4A is required for the macrophage-dependent activation of NK cell anti-metastatic functions. Recently, we have shown that MS4A4A+ macrophages are detected in the synovial tissue of rheumatoid arthritis (RA) patients.  Although less extensively studied, MS4A4A expression was associated with inflammatory diseases such as sepsis, atherosclerosis, and inflammatory bowel disease. Macrophages are key players in the pathogenesis of these diseases due to their ability to shift between pro-inflammatory and anti-inflammatory phenotypes, allowing them to drive tissue damage or promote repair.   In this context, the present study aimed to characterize the biological function of MS4A4A in macrophages and its involvement in macrophage activation and function.  Firstly, the structure of MS4A4A was investigated and characterised via artificial intelligence analysis and molecular dynamics simulation, to clarify its role in cellular signaling and potentially linking its structure to specific biological outcomes. Then, having observed only minimal differences in the transcriptional profiles between WT and KO macrophages, further investigation focused on the role of MS4A4A in macrophage activation. This led to the identification of two potential partners: the γ-chain of Fc gamma receptors (FcγRs) and Toll-like receptor 2 (TLR2), suggesting a possible involvement of MS4A4A in their inflammatory signaling. In the context of RA, where macrophages show altered FcγRIII expression, MS4A4A expression was found to be upregulated and positively correlated with disease pathogenesis, as well as with FcγRIII and the FcγR γ-chain expression in RA patients. Notably, both MS4A4A and FcγRIII are induced by Dex. MS4A4A was shown to limit the anti-inflammatory effects of Dex during FcγR-mediated inflammation by affecting the release of TNF-α and CXCL2. This modulatory role of MS4A4A appears to be independent on direct influence on FcγR signaling, and the precise mechanism remains to be defined.  To dissect the role of MS4A4A in macrophage activation mediated by TLR-2, we found that MS4A4A regulates the surface expression of TLR2 and affects the release of the anti-inflammatory cytokine IL-10. This impairment in IL-10 release is not limited to TLR2 stimulation but is also observed with other TLR agonists. Notably, during LPS stimulation, the reduced IL-10 release persists over time, starting as early as 2 hours post-stimulation. Further analysis showed that LPS induces MS4A4A expression and led to the identification of an IL-10 storage pool in resting macrophages. The defect in IL-10 release may result from a role of MS4A4A in regulating IL-10 de novo synthesis and/or the mobilization of this intracellular IL-10 pool. This study provides a valuable contribution to the field, expanding the current knowledge of MS4A4A’s role in macrophage activation and its impact on inflammatory response.","language":"eng","citation":"DISSECTING THE ROLE OF THE TETRASPANIN MS4A4A IN MODULATING MACROPHAGE PLASTICITY AND FUNCTION / A. Troilo ; tutor: M. Locati ; supervisor: E. M. Borroni ; coordinatore: N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2026 Jan 27. 38. ciclo","filename":"phd_unimi_R13814.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1209415/3228505/phd_unimi_R13814.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1146916"},"title":"APPLICATION OF ESCHERICHIA COLI AND 293T MODEL SYSTEMS TO STUDY THE HUMANPOLYRIBONUCLEOTIDE PHOSPHORYLASE","internalauthor":"PIZZOCCHERI, ROBERTO","type":"Tesi di dottorato","year":"2025","abstract":"RNA metabolism refers to all processes of the life of a ribonucleic acid, including  processing and degradation, which are governed by enzymes, among which is  polynucleotide phosphorylase (PNPase). This remarkable enzyme is found across  many prokaryotic and eukaryotic organisms, and it can work either as a 3’–5’  exoribonuclease for RNA degradation or as a polymerase for RNA synthesis. In  humans, PNPase (hPNPase) resides within the mitochondria, although evidence of  its presence in other cellular compartments is reported. Severe conditions can arise  from genetic variants in the hPNPase-encoding gene, termed PNPT1. In this work,  the generation of model systems in Escherichia coli and in 293T human cells was  exploited to test the effect of pathological mutations associated with different  diseases. The integration of data derived from both models has helped to assess  that pathological mutations cause defects in protein stability and expression to  varying extents. In E. coli, activation of the SOS response was observed upon  expression of hPNPase from the chromosome, which is instead abolished when  pathogenic variants are present. This unique phenotype allowed the generation of  a biosensor strain expressing GFP coupled to the activity of hPNPase in E. coli that  can be used for screening campaigns of chemicals restoring the activity of the  mutated variants. In 293T cells, two variants have been introduced by genome  editing, allowing, on one hand, the validation of the results obtained in E. coli, and  on the other, the implementation of a valuable pathogenic cell model in human cells  that could help elucidating cellular defects due to PNPT1 mutations.","language":"eng","citation":"APPLICATION OF ESCHERICHIA COLI AND 293T MODEL SYSTEMS TO STUDY THE HUMANPOLYRIBONUCLEOTIDE PHOSPHORYLASE / R. Pizzoccheri ; supervisore: F. Briani ; coordinator: S. Ricagno. Dipartimento di Bioscienze, 2025 Feb 20. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13353.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1146916/2677172/phd_unimi_R13353.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/886303"},"title":"LINEAR SYSTEMS ON IRREDUCIBLE HOLOMORPHIC SYMPLECTIC MANIFOLDS","internalauthor":"NOVARIO, SIMONE","type":"Tesi di dottorato","year":"2021","abstract":"In this thesis we study some complete linear systems associated to divisors of Hilbert schemes of 2 points on complex projective K3 surfaces with Picard group of rank 1, together with the rational maps induced. We call these varieties Hilbert squares of generic K3 surfaces, and they are examples of irreducible holomorphic symplectic (IHS) manifold.  In the first part of the thesis, using lattice theory, Nakajima operators and the model of Lehn–Sorger, we give a basis for the subvector space of the singular cohomology ring with rational coefficients generated by rational Hodge classes of type (2, 2) on the Hilbert square of any projective K3 surface. We then exploit a theorem by Qin and Wang together with a result by Ellingsrud, Göttsche and Lehn to obtain a basis of the lattice of integral Hodge classes of type (2, 2) on the Hilbert square of any projective K3 surface.  In the second part of the thesis we study the following problem: if X is the Hilbert square of a generic K3 surface admitting an ample divisor D with q(D)=2, where q is the Beauville–Bogomolov–Fujiki form, describe geometrically the rational map induced by the complete linear system |D|. The main result of the thesis shows that such an X, except on the case of the Hilbert square of a generic quartic surface of P^3, is a double EPW sextic, i.e., the double cover of an EPW sextic, a normal hypersurface of P^5, ramified over its singular locus. Moreover, the rational map induced by |D| is a morphism and coincides exactly with this double covering. The main tools to obtain this result are the description of integral Hodge classes of type (2, 2) of the first part of the thesis and the existence of an anti-symplectic involution on such varieties due to a theorem by Boissière, Cattaneo, Nieper-Wißkirchen and Sarti.","language":"eng","citation":"LINEAR SYSTEMS ON IRREDUCIBLE HOLOMORPHIC SYMPLECTIC MANIFOLDS / S. Novario ; tutor: L. Van Geemen, S. Boissière ; coordinatore: V. Mastropietro. Dipartimento di Matematica Federigo Enriques, 2021 Dec 17. 34. ciclo, Anno Accademico 2021. [10.13130/novario-simone_phd2021-12-17].","filename":"phd_unimi_R12353.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/886303/1921621/phd_unimi_R12353.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1051250"},"title":"DEVELOPMENT OF PHYSIOLOGICAL CULTURE SYSTEMS TO ACCESS UNTAPPED OVARIAN RESERVES FOR IMPROVING REPRODUCTIVE EFFICIENCY","internalauthor":"DEY, PRITHA","type":"Tesi di dottorato","year":"2024","abstract":"Female fertility preservation via complete in vitro folliculogenesis is still chimerical.  Recreating folliculogenesis to grow a dormant primordial follicle to the preovulatory  stage in vitro remains the most coveted goal of fertility preservation programs. The  ability to grow undifferentiated oocytes in vitro from primordial follicles would increase  the supply of fully grown oocytes destined for downstream applications in clinical  settings and the livestock industry. To date, the production of live offspring through the  in vitro culture of primordial follicles has only been achieved in mice. While this  demonstrates the potential value of primordial follicles as a source of fully grown  oocytes, it remains a proof of principle. In large mammals, such as humans and  bovine, in vitro follicle culture systems to produce mature oocytes from primordial  follicles are still experimental due to follicle mortality after isolation from the  surrounding tissue. While understanding the cause of follicle death is necessary to  inhibit the induction of programmed cell death, it is also essential to elucidate the  mechanisms responsible for steering primordial follicles toward the following stages of  development, i.e., primary and secondary follicles. Mechanistically resolving both  sides of the story – primordial follicle death and development - would then provide  insight into crucial factors responsible for deciding the fate of the follicles and fueling  their further development in culture. Compilation of the information from transcriptome  studies would then inform the appropriate optimizations of culture systems and  improve the growth of isolated primordial follicles to the subsequent primary and  secondary stages entirely in vitro. To probe our objectives, we first laid the groundwork  by developing a mechanical isolation protocol and serum-free base in vitro system to  culture isolated bovine primordial follicles. We then quantitatively and qualitatively  assessed the isolation efficiency of primordial, primary, and secondary follicle  populations from a defined volume of the ovarian cortex, thereby providing a  conservative strategy to improve assisted reproductive technologies dedicated to  female fertility preservation. Following this, interdisciplinary methods were adopted to  elucidate the web of interacting genes governing primordial follicle fate in vitro and in  vivo. The conducted transcriptome and network analyses indicate that ferroptosis and  autophagy are the elected programmed cell death mechanisms active in isolated  primordial follicles cultured in vitro.  Furthermore, we delineate the essential genes and pathways orchestrating the  consecutive developmental transitions (primordial-to-primary and primary-tosecondary  follicles) in vivo through RNA sequencing of isolated primordial, primary,  and secondary follicles. To extend our findings, we investigated the conservation of  functionally enriched pathways across different species. In conclusion, the studies  conducted during this doctoral program, provide a high-yield protocol that accesses  untapped ovarian reserves, thereby increasing the source of gametes for fertility  preservation. We further define a base system for the in vitro culture of isolated bovine  primordial follicles and shortlist candidate molecular targets that can be modulated to  optimize physiological culture systems, thereby informing the overarching aim of this  research thesis.","language":"eng","citation":"DEVELOPMENT OF PHYSIOLOGICAL CULTURE SYSTEMS TO ACCESS UNTAPPED OVARIAN RESERVES FOR IMPROVING REPRODUCTIVE EFFICIENCY / P. Dey ; tutor: A. M. Luciano  co-tutor: F. Franciosi coordinator: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2024 May 29. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12815.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1051250/2413397/phd_unimi_R12815.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/933291"},"title":"ELITES AND SOCIAL MEDIA. EXPLORATORY STUDY ON ELITES' BEHAVIOUR ON SOCIAL MEDIA AND TECHNOCRATIC, TECHNO-POPULIST AND POPULIST ATTITUDES","internalauthor":"BORDIGNON, MARGHERITA","type":"Tesi di dottorato","year":"2022","abstract":"In light of the vast literature on populism, populist leaders and especially their communication,   the general research aim underlying the present work is to explore elite actors, their behaviour   on social media and their connection with populism, elitism and technocracy. Such research   goals are addressed in this work in three autonomous sections, introduced by an overview of   the literature on the concepts that are common to all chapters and concluded by a recapitulation   chapter.  The first chapter explores and updates the research on elite actors in Italy. Taking our cues   from Carlo Carboni’s efforts in mapping and analysing elite members, we identify, by means   of positional approach, 5246 people at the top of the main elite sectors commonly identified in   political science: politics, public administration, armed forces, private businesses, mass media,   academia and education and voluntary association. To these main sectors, we add those actors   who are part of the religious and cultural elite (i.e. museums’ director) as established by the   literature. Thus, compared to Carboni’s works, we identify the 2.000 core members of the   elites, we underestimate the “second circle” of 6.000 of important, but not all-powerful, actors   in the Italian society. We also collect socio-demographic information about these actors,   including date and place of birth, gender, level of education, type of education, subject of   specialization, position held and institution the actor works for. These allow us to test some   confirmatory hypothesis that vastly confirm Carboni’s analysis. While elite actors become   increasingly diverse in all sectors, with more women participating to the upper echelons of   society, the political elite appears to be most heterogeneous also in terms of education and   provenance. Conversely, we do find a greater representation of economic (20%) and hard   sciences’ degree (around 15%), which goes in contradiction with some of Carboni’s arguments. In particular, linking several of the flaws of the élite class to their education: specialized in   subject  useful  to  maintain  consensus  (i.e.  literature  and  law)  but  lacking  the  technical   competence and knowledge to mobilize it towards innovation.   The second chapter explores elite actors’ behaviour on social media. In particular, we choose   to analyse Twitter for a number of reasons; first, by demographics, it appears to be the one   most adopted by elite actors. Second, and more substantially, Twitter is one of the ‘most open’   social media platforms in terms of data collection. We compile an extensive database of elite   actors on social media, with more than 1500 actors; by means of REST API (application   programming interface), we collect ids, number of followers, network of following of each   member. We test several hypotheses on both the propensity of activation, adoption and early   adoption. Among the other findings, members of the political elite are more likely to both adopt   and being active. Interestingly, however, members of the mass media elite seem to have   embraced social media before. Second, we observe some variations in terms of the field of   specialization; in particular, and as posited by the literature, those specialized in STEM subjects   are less likely to adopt social media. On the other hand, we analyze the networks of following.   By means of exponential random graph model (Ergm), we find significant levels of homophily   within each elite. On the other hand, we test several hypotheses on the likelihood of being a   central actor within the general and restricted networks.   The third chapter explores elites’ attitudes in terms of populism, technocracy and techno-   populism. Research has vastly detailed the existence of such dispositions within public opinion   and traced several profiles of political leaders that have exploited such attitudes. However,   there is still little research concerning if and how other actors in public life express and exploit   such views. The scope of the last chapter is thus to explore whether technocratic, populist and   technocratic-populist attitudes are present in elites’ members communication strategy and   whether such attitudes are rewarded in terms of engagement. We hypothesise that both some socio-demographic characteristics (education, which type of elite they belong to) and external   factors to influence the propensity to adopt such attitudes. On the other hand, we expect the   adoption  of  such  attitudes  to  be  rewarding  in  terms  of  both  engagement  and  positive   engagement. In order to test our hypotheses, we collect 6.000 tweets from 1.575 members of   different elites. We manually code them, relying on the well-established methodology of   quantitative content analysis. Among the other results, we find few differences in how members   of different elites rely on populist or technocratic rhetoric, and how positively they characterise   either populism, technocracy or techno-populism. Likewise, the moment of crisis does not   increase the appreciation for such attitudes. On the other hand, we find that the moment of   crisis generates more engagement (retweets) but does not increase significantly more positive   (likes) engagement. Finally, with some differences among different types of elites, adopting   technocratic attitudes has a positive effect in terms of engagement, but a negative one in terms   of positive engagement.","language":"eng","citation":"ELITES AND SOCIAL MEDIA. EXPLORATORY STUDY ON ELITES' BEHAVIOUR ON SOCIAL MEDIA AND TECHNOCRATIC, TECHNO-POPULIST AND POPULIST ATTITUDES / M. Bordignon ; tutor: G. Legnante ; direttore: M. Jessoula ; coordinatore: L. Papavero. Università degli Studi di Milano, 2022 Jul 25. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12178.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/933291/2050117/phd_unimi_R12178.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/938787"},"title":"NEW NCN-PLATINUM(II) COMPLEXES WITH LUMINESCENT PROPERTIES","internalauthor":"FAGNANI, FRANCESCO","type":"Tesi di dottorato","year":"2022","abstract":"During the doctoral period, my research has been focused on the synthesis and characterization of novel NCN-based platinum(II) complexes, obtaining more than twenty completely new compounds.   These complexes have a terdentate chelating ligand with the general scaffold of a 1,3-di(2-pyridyl)benzene and were designed following different strategies:    i) Complexes PtCl1-PtCl7 have unsubstituted pyridines and different groups in position 5 of the benzene ring, i.e. a mesityl, a triphenylamine, a pyrenyl, a phenyl-carbazole, a carbazole, a 2-thienyl and a methyl.     The synthesis of the NCN ligands started from some dibromo intermediates, obtained in different ways: from a Suzuki-Miyaura coupling of 1,3,5-tribromobenzene with the suitable aryl-boronic acid in the case of L1-L4; from 1,3-dibromo-5-fluorobenzene reacting with carbazole for L5; from a Stille coupling of tribromobenzene and 2-SnBu3-thiophene for L6.    Once obtained the dibromo intermediates, the Stille coupling of them (and of 1,3-dibromotoluene for L7) with 2-SnBu3-pyridine provided the terdentate ligands. Finally, the complexation step with K2PtCl4 in glacial AcOH leads to complexes PtCl1-PtCl7.      ii) The second group of new complexes is composed of fifteen derivatives of the NCN-PtCl compounds PtCl1-PtCl2 and PtCl6-PtCl7, by replacement of the chloride ligand with six anionic species.  These ancillary ligands are two aromatic thiolates, a simple azide, a phthalimide, a thioacetate and an isothiocyanate.  The substitution reactions were carried out in acetone or MeOH, at room temperature and under Argon atmosphere, using a large excess of the new ligand.      iii) Finally, PtCl8-PtCl13 still have the same -Cl ancillary ligand and substituents on the benzene ring (mesityl, 4-NPh2-phenyl, 2-thienyl, methyl) of some previously reported compounds, but new groups (i.e. 4-hexyl-2-thienyl, 4-NPh2-phenyl) have been added to the pyridines, to test the effect of an expanded aromatic system.         These complexes are a development of some compounds of the first group, not having substituents on the pyridines. The synthesis started from the two different 4-aryl-2-chloropyridines (having a hexyl-thienyl or a triphenylamino moiety in para position), whose substituents were introduced by Suzuki-Miyaura coupling. Then, they reacted in a further Suzuki-Miyaura coupling with boronic diesters obtained from the already discussed dibromo intermediates. Finally, the typical complexation reaction was carried out in the presence of K2PtCl4.       For all complexes reported before, the UV-Vis absorption spectra in CH2Cl2 were registered at different concentrations, in order to calculate the molar extinction coefficients (ε). Moreover, most of the complexes were studied from the luminescence point of view, using dearated dichloromethane solutions; in that way, the excitation and emission spectra, together with the absolute Quantum Yields and the Lifetimes, were obtained. The Freeze-Pump-Thaw procedure, used to remove oxygen from the solution, was necessary since the long-living triplet states of the complexes are very efficiently quenched by the fundamental triplet state of O2.     Concerning the Quantum Yields, very high values were achieved in the case of complexes Pt1 (90%), Pt3 (87%), Pt8 (83%), Pt9 (89%) and Pt10 (79%), so the substitution of the -Cl is very often useful to improve the photophysical properties.  Moreover, a remarkable increase of the QY is brought about also by the expansion of the aromatic system via new moieties on the pyridines. In fact, the values pass from 62% (PtCl1) to 96% (PtCl8) and 89% (PtCl12), and from 54% (PtCl6) to 100% (PtCl10).      Complex Pt1, being very interesting because of its luminescence properties, was used for the preparation of three OLEDs having different amounts (8%, 25% and 100%) of NCN-Pt complex in the emissive layer. Since this family of complexes undergoes aggregation when the concentration reaches high values, and consequently a red-shifted emission is observed, the three devices emitted light with different color on the basis of the aggregation level. In this way the emission could be tuned, passing from green (8% Pt1) to yellow (25%) to red (100%).      Up to now, all complexes have been studied from the UV-Vis absorption point of view, calculating the molar extinction coefficient for all of them; moreover, complexes Pt1-Pt3, Pt5, Pt7-Pt10, Pt12-Pt14, PtCl8, PtCl10, PtCl12 and PtCl13 have been fully characterized for their photophysical properties, measuring the excitation and emission spectra, the absolute Quantum Yields and the lifetimes in dichloromethane solutions.   For what concerns the luminescence, some key points have been confirmed:  i) Considering the emission of the monomeric species having unsubstituted pyridines, the emission measured from diluted solutions only depends on the substituent on the benzene ring, not being particularly influenced (besides a negligible shift of few nanometers) by the change of the -Cl ligand.  ii) Regarding the absolute Quantum Yields, the change of the chloride is generally helpful to improve the QY values, in many cases causing an important increase up to 90%; this influence is not observed for the lifetimes, which remain in the ranges typical of the parent Pt-Cl compounds.  iii) The most relevant effects are surely visible for those complexes presenting an expanded aromatic system on the pyridines, since for all of them a very important growth in the QY has been achieved (in the case of PtCl10 reaching unity), together with a noticeable red-shift of the emission.  iv) For all complexes, an emission band at lower energies (with maxima in the range 650-750 nm) appears when the concentration is increased; this is due to formation of aggregates and can be seen also from pure layers of compounds in solid-state analysis; nevertheless, the concurrent formation of excimers, participating in the luminescent properties, cannot be excluded.    In the case of Pt1, the luminescence has been assessed also for the powders, both at Room and Low Temperature; furthermore, the X-ray crystal structure of the compound has been obtained. Compound Pt5, bearing a thioacetate on the Pt center, has been studied non only as powders but also as blend in PMMA matrix at two different concentrations.  Together with Pt9, the aforementioned Pt1 complex has been employed to produce some OLED devices, showing different emission colors on the basis of the amount of compound in the Emitting Layer. These tests can open the way for further strategies of color tuning, designing the device with the proper concentration of complex in order to modulate the emission.  The next thing to do will be surely the study of the remaining complexes, to achieve a complete and clear overview of the photophysical properties of these series of compounds. Moreover, will also be important the testing of the already characterized compounds, both by preparing other OLED devices based on these complexes (to explore the different colors which can be achieved through them) and by applying the synthesized compounds in the biological field, as sensitizers in the bio-imaging of cells and tissues and as active dyes for photodynamic therapies.    To conclude, another important step for the near future can be the synthesis of new members of the NCN-Pt(II) family, in particular following various strategies: i) the substitution of the ancillary -Cl in complexes such as PtCl8, PtCl10, PtCl12 and PtCl13, to observe the variation in the luminescence arising by the replacement with thiolates or azides, which is in general positive for what concerns the QY values; ii) the use of new thiolates or, in general, of new anionic species to replace the chloride ligand; iii) the introduction of new moieties on the pyridines, to confirm the mentioned helpful changes in the properties of such complexes, and to better understand the effect exerted by electron-donor or withdrawing groups, in particular on the emission color.","language":"eng","citation":"NEW NCN-PLATINUM(II) COMPLEXES WITH LUMINESCENT PROPERTIES / F. Fagnani ; tutor:  C. Dragonetti ; co-tutor: A. Colombo ; coordinatore: D. Passarella. Dipartimento di Chimica, 2022 Oct 05. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12748.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/938787/2070602/phd_unimi_R12748.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1224156"},"title":"DISENTANGLING TECTONIC- AND CLIMATE-DRIVEN PROCESSES IN THE EVOLUTION OF QUATERNARY RIVERSCAPES. A FRESH APPROACH INTEGRATING FIELD SURVEY, REMOTE SENSING AND GEOMORPHOMETRY INTO ARTIFICIAL INTELLIGENCE/MACHINE LEARNING","internalauthor":"PEZZOTTA, ANDREA","type":"Tesi di dottorato","year":"2026","abstract":"Rivers are geomorphic agents that profoundly influence the Earth's surface by responding to tectonic and climatic forces, while simultaneously shaping the landscape and triggering various geomorphological processes. These interactions transform topography across multiple scales, from watershed boundaries to alluvial plains, resulting in erosional patterns and complex landforms that reflect the interplay of factors such as tectonics, litho-structural frameworks, and climate variability. A comprehensive understanding of these factors is essential for reconstructing past geological processes and forecasting future landscape evolution.  This thesis presents the results of a three-year investigation into the riverscapes of the central Al-Hajar Mountains (northern Sultanate of Oman), a region characterised by a unique geodynamic setting and arid climate. The Al-Hajar Mountains serve as an ideal natural laboratory for examining the interactions between climate and tectonic activity. Located along the northeastern margin of the Arabian Plate, this orogenic belt is globally renowned for hosting the Semail Ophiolite, one of the most complete and well-preserved obducted ophiolite sequences. Its emplacement during the Late Cretaceous involved the obduction of oceanic lithosphere and deep-sea sediments onto the autochthonous units, comprising pre-Permian sedimentary and volcanic sequences overlain by Permian to Late Cretaceous carbonate platforms. The doming processes, accompanied by regional forebulging, likely coincided with extensional to transtensional regime during obduction and subsequent collapse phases. Quaternary tectonic activity is limited yet evident in the region, primarily through regional uplift, low seismicity, over-incised wadis, marine terraces, and notches.  The research project aims to elucidate the mechanisms driving landscape evolution in such complex geological context, focusing on the roles of tectonic uplift, litho-structural controls, and climatic fluctuations during the Quaternary and pre-Quaternary periods. A multidisciplinary approach - integrating field surveys, remote sensing, geomorphometry, and Deep Learning - has been employed to identify and characterise active and fossil geomorphological processes across various scales. This methodology highlights the close links between surface processes, tectonics, and climatic changes, emphasising that landscape evolution is ongoing. The multidisciplinary approach has been applied to various parts of the Al-Hajar region, utilizing different combinations of methods. Beginning with geomorphological mapping that integrates remote sensing techniques and field surveys, this approach highlights the close relationship between surface processes in both mountainous and plain areas and underlying tectonic, litho-structural, and climatic factors, spanning Quaternary and pre-Quaternary periods. The integration of deep learning and geomorphometric techniques provides quantitative tools to quantify the influence of controlling factors and assess how shifts in riverine regimes impact landscape dynamics. Specifically, geomorphometry enables the detection of disequilibrium in landscape regions, revealing that the current landscape remains in a state of evolution, indicative of ongoing geodynamic processes. Concurrently, Deep Learning enhances the detection and classification of fluvial landforms in high-resolution satellite imagery, shedding light on past hydrological conditions and illustrating the combined effects of climate and tectonics on alluvial fan development at mountain foothills. Therefore, the thesis is organised into 3 case studies, each applying one aspect of the multidisciplinary methodology  to reconstruct landscape evolution of the central region of the Jebel Akhdar dome and its margins.  Chapter 2 features a detailed geomorphological map of Jebel Akhdar dome (JAK), a prominent carbonate dome formed during the obduction of the Semail Ophiolite. This chapter identifies key landforms shaped by complex interactions between tectonics, surface processes, and climate. The region's landscape reflects a long evolutionary history beginning with Late Cretaceous tectonic uplift and doming, followed by Miocene-Quaternary erosion, karstification, and fluvial and gravitational processes.  Tectonic activity has driven the development of structural features such as folds, faults, and monoclinal flanks, while karst processes have created extensive underground networks and surface landforms. Fluvial and gravitative processes have further produced incised valleys, alluvial fans, and pediments, with ongoing Quaternary tectonic activity influencing landscape dynamics.   Chapter 3 combines morphometric analysis and field surveys to examine the central Al-Hajar Mountains, with a focus on JAK. Field evidence underscores the roles of fluvial networks, structural discontinuities, and karst systems in shaping the current topography. Morphometric data reveal significant spatial variability among tectonic units, reflecting differential erosional patterns. Correlations between morphometric indices and fault density point to spatial variations in the structural control over surface processes. The morphometric patterns observed in the northern and eastern flanks of JAK, as well as in the adjacent Semail Ophiolite and western Hawasina nappes, indicate ongoing erosion likely driven by regional crustal uplift associated with slab stagnation. In contrast, the southern flank of JAK shows comparatively lower erosion rates and well-preserved morphostructures. This asymmetry reflects the long-term geomorphic imprint of doming, where uplift and tilting continue to affect the southern sector, maintaining it in a relatively less eroded state.   Chapter 4 develops Deep Learning algorithms for the automated detection of fluvial features to generate a high-resolution geomorphological map of the Barzamani alluvial fan, located at the southern margin of the Al-Hajar Mountains. The region’s extensive alluvial fans, forming coalescing bajada and characterised by minimal vegetation cover due to the semi-arid to arid climate, allow the observation of intricate paleo-drainage systems spanning from the Miocene to Pleistocene. Manual  mapping is labor-intensive and prone to subjectivity, motivating the adoption of Machine Learning techniques. A U-Net-based Deep Learning pipeline was implemented on multispectral SPOT 6 high-resolution satellite imagery to produce probabilistic maps of palaeochannel systems - differentiating between paleochannels and the underlying substrate - enabling improved detection of the past hydrological regimes, thus the understanding of landscape evolution driven by climatic and tectonic influences.  By integrating geomorphological mapping, geomorphometry, and Deep Learning, this thesis offers a comprehensive understanding of the complex interactions between tectonics, litho-structural setting, and climate, allowing for the quantification of the role of both regional tectonic processes and local structural settings in shaping the landscapes of the northern Sultanate of Oman. The findings contribute to broader insights into tectonic processes, landscape resilience, and future evolution in low to moderate tectonically active, arid environments.","language":"eng","citation":"DISENTANGLING TECTONIC- AND CLIMATE-DRIVEN PROCESSES IN THE EVOLUTION OF QUATERNARY RIVERSCAPES. A FRESH APPROACH INTEGRATING FIELD SURVEY, REMOTE SENSING AND GEOMORPHOMETRY INTO ARTIFICIAL INTELLIGENCE/MACHINE LEARNING / A. Pezzotta ; tutor: A. Zerboni ; co-tutor: M. Zucali ; coordinatore: G. Muttoni. Dipartimento di Scienze della Terra Ardito Desio, 2026. 38. ciclo","filename":"phd_unimi_R13738.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 10-SET-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1205655"},"title":"DESIGN, DEVELOPMENT AND VALIDATION OF NOVEL ELECTRICAL CONTACTING SYSTEMS, MECHANICAL ENCAPSULATION SOLUTIONS AND HIGH-RESOLUTION INTEGRATED CHARGE-SENSITIVE PREAMPLIFIERS FOR ADVANCED HIGH-PURITY GERMANIUM DETECTORS","internalauthor":"SECCI, GIACOMO","type":"Tesi di dottorato","year":"2026","abstract":"Segmented High-Purity Germanium detectors are widely used in modern gamma spectroscopy experiments due to their outstanding energy resolution and precise position sensitivity. However, detailed technical and manufacturing specifications for these detectors are typically proprietary, as they are provided by commercial manufacturers. To overcome this limitation, the Italian Institute for Nuclear Physics launched the N3G Project, a strategic initiative aimed at designing a new generation of segmented HPGe detectors while simultaneously building the in-house expertise required to develop, operate and maintain them independently.  Within this framework, this PhD research provides several original contributions. First, an innovative and flexible interconnection system was developed to electrically interface the detector electrodes with the front-end electronics. In parallel, a vacuum tight capsule was designed and fabricated to house the HPGe crystal. Leak testing of the capsule demonstrated excellent vacuum retention, with a pressure increase of only 2 × 10−5 mbar over five days.  In addition, novel integrated charge sensitive preamplifiers were conceived, simulated and  experimentally validated. Based on a new architecture, these circuits exhibited excellent linearity and low noise performance. Specifically, an integral non-linearity below 0.3 ‰was achieved across a 15 MeV dynamic range, and an energy resolution of 0.75 keV FWHM was measured for 1 MeV equivalent energy events and a detector capacitance of 15 pF.   The results of this work validate the feasibility of developing high-performance HPGe detection systems equipped with fully custom-designed electronics, marking a significant step toward technological advancement in the field of gamma spectroscopy. Beyond their immediate application, the solutions developed also offer valuable design principles applicable to a wide range of detector technologies.","language":"eng","citation":"DESIGN, DEVELOPMENT AND VALIDATION OF NOVEL ELECTRICAL CONTACTING SYSTEMS, MECHANICAL ENCAPSULATION SOLUTIONS AND HIGH-RESOLUTION INTEGRATED CHARGE-SENSITIVE PREAMPLIFIERS FOR ADVANCED HIGH-PURITY GERMANIUM DETECTORS / G. Secci ; supervisore: A. Pullia ;  co-supervisore: S. Capra ;  coordinatore: A. Mennella. Dipartimento di Fisica Aldo Pontremoli, 2026 Jan 26. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13699_1.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1205655/3216007/phd_unimi_R13699_1.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1175236"},"title":"THE GENDERED IMPACT OF THE PANDEMIC: EMPLOYMENT, INCOME AND UNPAID DOMESTIC WORK DURING COVID - 19 PANDEMIC IN EUROPE.","internalauthor":"BASHEVSKA, MARIJA","type":"Tesi di dottorato","year":"2025","abstract":"The COVID-19 pandemic brought sudden and profound disruptions to daily life across the globe, reshaping how people work, care, and live. Compared to recent global crisis where the initial impact on employment was more severe for men, the COVID-19 pandemic crisis had a significant initial impact on sectors with higher share of women. The abrupt pandemic driven changes have raised the alarms on the potential detrimental impact this crisis might have on three crucial areas of already persistent gender inequalities on global level—unpaid domestic and care work, employment and earnings. Previous research on the gendered impact of the pandemic has focused mostly on the initial period of the pandemic and offers limited comparative perspective with respect to the contextual, individual, and household level characteristics. Building on the current literature, this thesis aims to explore how the COVID-19 pandemic has affected gender inequalities in employment, income, and unpaid domestic work and childcare across different European contexts, and which are the main underlying mechanisms on individual, meso and macro level that shape the gendered outcomes in times of global pandemic crisis. The first study examines how the division of unpaid domestic work and childcare in couples evolved during the initial shock of the pandemic and the early recovery period in two distinct European welfare and gender regimes, conservative (Germany) and liberal (the UK). Additionally, it explores the role of couples’ employment status in shaping the distribution of unpaid labour during the extended impact of the pandemic.  The results show shift towards more equal division of unpaid housework and childcare in the lockdown and post-lockdown period within couples in the UK. In Germany, shift towards more equal division is only evident for childcare, while division of housework remains without notable shifts compared to the pre-pandemic period. Despite the certain shifts towards less inequality, however, the unequal division of housework and childcare remained significant, particularly for Germany, indicating that the unpaid labour in households (particularly housework) during the pandemic crisis was still mostly considered woman’s responsibility, although the context and the individual and couples’ characteristics, played an important role. The second study investigates the gendered employment outcomes during the pandemic across European countries. It examines the underlying factors on micro-level (i.e. education, employment sector and type of contract, and presence of children in household) and macro-level (i.e. the strictness of the lock-down measures, and countries’ gender inequality levels) which shape the differences in the negative employment outcomes during the pandemic for women and men across Europe. Moreover, it explores the interaction between the micro-level characteristics and macro-level context, indicating how individual-level characteristics are of different importance in different country contexts in times of exogenous shock and crisis. The findings reveal that on individual level, better education, employment sector and unlimited job contract, served as protective factors against the negative employment outcomes during the pandemic, offering consistent protection for both women and men. On the contextual level, the strictness of the pandemic containment measures was particularly relevant for men’s employment outcomes, while the country’s gender inequality levels affected both women and men. The interaction between the individual and contextual characteristics indicates that countries with higher level of gender equality provide more favourable and protective context against negative employment outcomes for women in times of external global economic shocks as the COVID-19 pandemic. Lastly, the third study shifts the focus on the relative income changes during in the first year of the COVID-19 pandemic, exploring how women’s relative income in couples changed during the crisis in a comparative country context, and how different characteristics of couples in terms of educational attainment, parental status and age contribute to varying income outcomes in couples. The results of this study suggest that there was no decrease in women’s relative earnings within couples in the first year of the pandemic in all four analysed countries. In fact, there was evident increase in women’s relative share in Italy and Czechia, while no significant differences observed in Ireland and Sweden. Governments’ support measures likely played an important role in mitigating the effects on income losses—particularly during the initial year of the pandemic. In conclusion, this thesis contributes to the understanding of the intersecting forces on individual, household and contextual level that shaped the gendered outcomes in unpaid labour, employment and earnings in times of pandemic crisis. It shows that the effects of the pandemic on gender equality are not clear-cut, and more nuanced approach can inform more effective policy responses, recovery strategies and socially just welfare arrangements that aim to reduce—rather than reinforce—gender inequalities and long-term consequences for societies.","language":"eng","citation":"THE GENDERED IMPACT OF THE PANDEMIC: EMPLOYMENT, INCOME AND UNPAID DOMESTIC WORK DURING COVID - 19 PANDEMIC IN EUROPE / M. Bashevska ; tutor: G. M. Dotti Sani ; coordinator: P. A. Rebughini. - Department of Social and Political Sciences, University of Milan.. Università degli Studi di Milano, 2025 Jul 02. 36. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R12972.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 17-GEN-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1151235"},"title":"NUTRITIONAL AND FUNCTIONAL CHARACTERISATION OF ALTERNATIVE FEED AND FOOD INGREDIENTS: EMPHASIS ON HEMP-BASED PRODUCTS, CO-PRODUCTS, MICROALGAE AND CULTURED MEAT","internalauthor":"LANZONI, DAVIDE","type":"Tesi di dottorato","year":"2025","abstract":"The growth of the world population has led to an increase in demand for food, particularly meat and dairy products, further intensifying livestock production, resulting in an enhanced use of grain for animal feed and competition with crops for direct human consumption. In parallel, over time, the livestock sector has exerted considerable pressure on resources, with large areas of arable land dedicated to food cultures and grazing, as well as high water use. This highlights the urgent need for action with multidisciplinary approaches. For this reason, the aims of this thesis were to evaluate the nutritional and functional potential of alternative plant-based products, including hemp, cardoon, and camelina, by analysing their antioxidant properties, bioactive peptide profiles, and their impact on the quality of animal-derived products. It also aimed to optimize the culture medium of microalgae, in particular for Euglena gracilis to enhance its functional profile while investigating the risks of nanoplastics and microplastics contamination during cultivation under heterotrophic conditions. Additionally, the research sought to address key challenges in cultured meat production by developing alternatives to fetal bovine serum, scalable biofabrication methods, and the integration of waste-derived components to support cell proliferation and differentiation. These objectives collectively aimed to advance sustainable, ethical, and innovative practices in the agri-food sector.  Hemp based-products and their co-products have demonstrated high nutritional and functional profiles, as observed following in vitro digestion and solvent extraction methods. In support of this, an in vivo trial, conducted on laying hens, showed how the inclusion of a hemp co-product of up to 9% (leaves, non-standard hemp seeds, hulls and stems) improved performance while increasing the functional and nutritional profile of the eggs. However, it is important to emphasise that their applicability in the livestock sector requires a multidisciplinary approach, evaluating not only the positive effects on animal health but also taking into account limiting factors such as availability, high cost and variability.  Among the various possible alternatives, microbial proteins, in particular microalgae, are strong candidates. In particular, as demonstrated in this thesis, the modulation of the culture medium of E. gracilis, cultivated under heterotrophic conditions, led to improvements in the nutritional and functional profile. This result represents a milestone in the formulation of a product that can be specifically designed for the needs of farm animals. However, the widespread use of plastic bioreactors for microalgae cultivation poses potential health challenges for the user. Indeed, plastics can release micro- and nanoplastics into the culture medium, which can accumulate in the biomass and enter the food chain, potentially impacting animal and human health.  Finally, a possible alternative of recent interest is the production of cellular foods. In this field, cultured meat is certainly the most discussed. Although scientific research has tried to find answers to the main questions concerning the production process and its sustainability, many open issues still remain. Among these, alternatives to foetal bovine serum that can guarantee the growth, proliferation and differentiation of muscle cells through an ethical and sustainable process deserve further and necessary investigation. As demonstrated in this thesis, possible alternatives involve co-products of food (e.g. whey proteins), which can support the viability, proliferation and differentiation of C2C12 murine muscle cells.  Although further studies are needed, all these alternatives represent fundamental steps towards the creation of resilient and environmentally friendly food systems. Despite promising results, further research is needed to standardise these approaches and address unresolved issues, ensuring their feasibility in the food, feed and livestock sectors. The exploration of these alternative proteins is in line with global efforts to create sustainable food systems and mitigate the environmental challenges posed by traditional agricultural practices.","language":"eng","citation":"NUTRITIONAL AND FUNCTIONAL CHARACTERISATION OF ALTERNATIVE FEED AND FOOD INGREDIENTS: EMPHASIS ON HEMP-BASED PRODUCTS, CO-PRODUCTS, MICROALGAE AND CULTURED MEAT / D. Lanzoni ; supervisor: C. Giromini ; co-supervisor: E. Pěchoučková ; coordinator: F. Cheli. - Lodi. Università degli Studi di Milano, Dipartimento di Medicina Veterinaria e Scienze Animali. Dipartimento di Medicina Veterinaria e Scienze Animali, 2025 Mar 21. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13628_1.pdf","fileformat":"Adobe PDF","fileversion":"contratto","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1151235/2705288/phd_unimi_R13628_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/829077"},"title":"PATHOLOGY OF ROUND CELL TUMORS AND SARCOMAS: A DIAGNOSTIC AND CLINICALLY-ORIENTED APPROACH, WITH A FOCUS ON BASIC INVESTIGATION","internalauthor":"GAMBINI, MATTEO","type":"Tesi di dottorato","year":"2021","abstract":"Neoplasms represent a constantly increasing threat for companion animals, requiring fast and reliable diagnostic techniques. In this context, cytology is a diagnostic tool widely applied to preliminarly investigate the nature of lesions observed in daily veterinary practice. Nevertheless, considered the limitations of cytology as well as the key role that a cytological diagnosis might cover for the clinical approach to each patient, estimation of the reliability of this technique represents a fundamental step. With this in mind, diagnostic accuracy studies can provide a proof of reliability of cytological results, when the latter are compared to the histopathological gold standard. With these premises, the main aim of the current Thesis was to evaluate the diagnostic accuracy of cytology applied to different round cell tumors and sarcomas currently representing a serious threat for the canine and feline species. Chapter 1 describes a study investigating the diagnostic accuracy of cytology in the evaluation of canine splenic neoplasm. To the best of our knowledge, our work was the first study conjunctively reporting overall accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of cytology in the diagnosis of these lesions. Diagnostic accuracy indexes identified limitations of negative cytological results in excluding a dog to be truly free from neoplasia; however, high specificity and positive predictive value still highlighted cytology as a valuable tool in the diagnostic approach to splenic neoplasms. In Chapter 2 is described a study investigating interobserver agreement and diagnostic accuracy of cytology in the immunophenotype prediction of feline nodal lymphoma. Our results revealed a low inter-observer agreement and a low diagnostic accuracy in immunophenotype prediction, thus highlighting potential marked differences among laboratories and even among different cytologists within the same laboratory, and consequently the mandatory need of histopathology and immunohistochemistry for a correct interpretation of feline nodal lymphoma immunophenotype.  Chapter 3 describes two studies focusing on the application of cytology in the evaluation of nodal metastasis of canine mast cell tumor (MCT). The preliminary investigations described in Section 1 focused on the quantification of mast cells in cytological nodal samples obtained from both non oncological dogs and MCT-bearing dogs, revealing that mast cell (MC) quantification in lymph node (LN) cytological samples obtained from the latter might be useful to determine the nodal metastatic status. Our findings further suggested that neither the sampling technique applied to collect cytological samples nor the quantification method applied to estimate the number of MCs, influence the number of nodal MCs observed. Section 2 describes a study investigating interobserver agreement and diagnostic accuracy of cytology in the evaluation of the metastatic status of lymph nodes obtained from MCT-bearing dogs. Specifically, the study investigated the diagnostic performance of the cytological interpretative system currently available in literature as well as that of 2 amendments of the latter (AM1 and AM1.2 system). Our results revealed that the AM1.2 system, which include MC quantification besides the cytological criteria reported in the previously published cytological interpretative system, could represent a valid alternative to the latter, being characterized by an almost overlapping interrater agreement, and sensibly higher accuracy and sensitivity without substantial changes of the other diagnostic accuracy indexes. Besides studies focusing on the diagnostic accuracy of cytology, the Addendum briefly describes the results of 2 research projects investigating viral oncolysis in a cell culture model of canine histiocytic sarcoma, performed by the Ph.D. candidate during his externship at the University of Veterinary Medicine of Hannover (TiHo Hannover, Germany).","language":"eng","citation":"PATHOLOGY OF ROUND CELL TUMORS AND SARCOMAS: A DIAGNOSTIC AND CLINICALLY-ORIENTED APPROACH, WITH A FOCUS ON BASIC INVESTIGATION / M. Gambini ; tutor: C. Giudice ; phd course coordinator: V. Grieco. Dipartimento di Medicina Veterinaria, 2021 Mar 30. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12036.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/829077/1750671/phd_unimi_R12036.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1201955"},"title":"DATA GOVERNANCE FRAMEWORK FOR ML-BASED, DATA-INTENSIVE DISTRIBUTED SYSTEMS","internalauthor":"POLIMENO, ANTONGIACOMO","type":"Tesi di dottorato","year":"2025","abstract":"The data processing landscape has been fundamentally transformed in recent decades, evolving from monolithic systems to complex distributed architectures where multiple services operated by different parties collaborate to deliver sophisticated analytics capabilities. Machine Learning (ML) and Internet of Things (IoT) technologies are increasingly integrated into these systems, enabling advanced data processing pipelines that span multiple organizational boundaries. Modern distributed data processing systems support critical operations across various domains, from healthcare analytics to financial services, making their trustworthiness and compliance with data protection regulations a concern.    This transformation has created significant challenges for data governance, particularly in balancing data quality preservation with privacy protection requirements. Current approaches suffer from fundamental limitations: existing governance frameworks focus primarily on static privacy configurations, neglecting the dynamic nature of distributed service environments and failing to optimize quality-privacy trade-offs systematically. Traditional access control models are inadequate for multi-dimensional optimization scenarios where data utility must be maximized while ensuring regulatory compliance. Despite increasing regulatory requirements and organizational needs for privacy-preserving data processing, there is a lack of governance frameworks that can systematically optimize quality-privacy trade-offs in modern distributed systems while maintaining computational tractability and industrial applicability.    In this thesis, we propose a data governance framework that addresses this impasse. Our framework operates at the service composition layer, providing policy-driven optimization for data processing pipelines built as compositions of distributed services. It implements a multi-dimensional approach that balances data quality preservation with privacy protection through systematic service selection and dynamic adaptation mechanisms. The framework integrates seamlessly with existing distributed data processing platforms and has been validated through industrial deployment and experimental evaluation.    Our contribution is manifold. First, we design and implement a policy-driven service selection framework. The framework defines three complementary quality metrics that capture different aspects of data utility preservation: a quantitative metric based on weighted Jaccard coefficients ($M_J$), a qualitative metric using Jensen-Shannon divergence ($M_{JSD}$), and an entropy-based metric ($M_H$) that quantifies information content retention. Then, we develop sliding window heuristic algorithms that address the NP-hard problem of optimal service selection by employing moving optimization windows that balance local and global objectives. Moreover, we provide a methodology for integrating our governance framework within existing distributed data processing platforms, demonstrating practical deployment through successful integration with the ALIDA (Advanced Laboratory for Interactive Data Analytics) platform. To validate our framework and demonstrate its industrial applicability, we conduct experimental evaluation across multiple datasets and deployment scenarios, proving the framework's effectiveness in maintaining data quality while ensuring privacy compliance with acceptable operational overhead.","language":"eng","citation":"DATA GOVERNANCE FRAMEWORK FOR ML-BASED, DATA-INTENSIVE DISTRIBUTED SYSTEMS / A. Polimeno ; tutor: C. A. Ardagna ;  co-tutor: M. Anisetti ;  coordinatore: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2025 Dec 05. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13812.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1201955/3202229/phd_unimi_R13812.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1161580"},"title":"APPLICATION OF CARBON CREDITS IN THE ITALIAN AND PAKISTANI AGRI-FOOD SECTOR","internalauthor":"AHMAD, ANEES","type":"Tesi di dottorato","year":"2025","abstract":"The Italian agri-food sector, famous for its diverse and high-quality production in Europe, is increasingly under pressure to address its greenhouse gas (GHG) emissions, particularly from methane (CH₄) and nitrous oxide (N₂O), which contribute significantly to climate change. Pakistan’s agri-food sector plays a considerable role in the economy, supporting livelihoods and food security. Key activities, such as rice cultivation and cattle farming, are the primary sources of these emissions. CH₄ is emitted from rice paddies due to anaerobic conditions created by flooded fields, while cattle farming generates CH₄ through digestion and manure decomposition. Reliable data on GHG emissions from this sector in Pakistan is scarce and inconsistent, making it difficult to design effective policies. Therefore, it is essential to identify and implement sustainable strategies to reduce these emissions and highlight how they can be integrated into carbon credit systems to achieve both economic and environmental benefits.  In rice farming, practices such as alternate wetting and drying (AWD), and midseason drainage are shown to effectively lower CH₄ emissions by altering soil conditions and breaking the anaerobic cycle. Additionally, organic farming methods, such as the use of compost and biofertilizers, reduce dependency on synthetic fertilizers, thereby minimizing nitrous oxide emissions and improving soil health. Precision agriculture tools optimize fertilizer application, enhancing efficiency and further reducing emissions. These strategies present an opportunity for the Italian agri-food sector to leverage carbon credit systems like the Gold Standard (GS) and the American Carbon Registry (ACR). By documenting and verifying reductions in emissions through improved water and nutrient management, farmers can generate carbon credits. These credits can be traded in voluntary carbon markets or used to offset emissions in other industries, fostering a circular economy and supporting Italy’s climate objectives.  This research emphasizes the dual advantages of adopting sustainable agricultural practices, significantly lowering GHG emissions while benefiting from carbon credit opportunities. Through innovative resource management methods, the Italian agri-food sector can reduce its carbon footprint, enhance economic sustainability, and contribute to global climate mitigation efforts. These measures not only position Italy as a leader in sustainable agriculture but also provide a replicable framework for other nations aiming to balance environmental responsibility with agricultural productivity.  Additionally, this thesis also dwells on sustainable high-altitude expeditions and discusses the recent Italian team K2 expedition in 2024, where the use of solar panels and recycled materials marked a shift toward sustainable practices in extreme environments. This expedition can serve as a model for how clean energy technologies can significantly reduce environmental footprints in high-impact activities, illustrating the potential for sustainable practices across diverse sectors. Additionally, it highlights the application of sustainable technologies, such as leveraging satellite data from platforms like Sentinel-1 and Sentinel-2, to monitor glacier dynamics. This includes tracking glacier retreats, analyzing melt patterns, and assessing changes in ice mass in regions impacted by GHG emissions, such as Pakistan. Advanced remote sensing techniques offer a more efficient, cost-effective, and resource-light alternative to conventional methods, minimizing the need for carbon-intensive fieldwork and fossil fuel-powered equipment. These technologies also enable continuous, real-time monitoring, enhancing climate models' accuracy and supporting more effective GHG mitigation policies. By using these advanced techniques, we gain critical insights into the impacts of climate change on glaciers, water resources, and ecosystems while minimizing the carbon footprint associated with traditional data collection methods.  By bridging the fields of agricultural science and cryosphere studies, this thesis presents a comprehensive approach to GHG mitigation, underscoring the importance of technological innovation and environmental sustainability. The first part of the research involves a thorough review of life cycle assessments (LCA) in rice production and mitigating the potential of anaerobic digestion plants (ADP) in beef cattle farming. It evaluates various GHG mitigation strategies, highlighting the effectiveness of ADP technology for biogas production as a means to reduce CH4 emissions fagri-foodock manure and enhance energy efficiency on farms. The second part of this thesis explores how climate change affects glaciers and the hydrological cycle and focuses on sustainable practices in high-altitude expeditions to lower carbon emissions. By quantifying the environmental impacts of both agri-food production and high-altitude expeditions, this study provides a foundation for sustainable practices that can help lower GHG emissions and lead to carbon credit generation. The findings advocate for policy frameworks that encourage the adoption of carbon credit mechanisms within the agri-food sector while simultaneously addressing the urgent need for glacier monitoring and conservation efforts in the face of climate change.","language":"eng","citation":"APPLICATION OF CARBON CREDITS IN THE ITALIAN AND PAKISTANI AGRI-FOOD SECTOR / A. Ahmad ; tutor: G. A. Diolaiuti, J. Bacenetti, coordinator: D. Fugazza. Dipartimento di Scienze e Politiche Ambientali, 2025 May 06. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13650.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 28-OTT-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1207095"},"title":"STRATEGIES TO TARGET HUMAN D-ASPARTATE OXIDASE AND MODULATE ENDOGENOUS D-ASPARTATE LEVELS IN SCHIZOPHRENIA","internalauthor":"CAVINATO, MIRIAM","type":"Tesi di dottorato","year":"2026","abstract":"D-aspartate (D-Asp) is abundant in mammal brain at embryonal level while it rapidly decreases   at post-natal stages due to the enhanced activity of D-aspartate oxidase (DASPO). D-Asp   participates to glutamatergic neurotransmission and alterations of physiological metabolism are   linked to pathologies. Depletion of D-Asp observed in post-mortem brain samples of   schizophrenia patients has been correlated with excessive degradation by DASPO and causes the   typical reduction of neurotransmission. D-Asp administration improves neurotransmission,   synaptic plasticity and dendritic length, therefore the modulation of endogenous levels of D-Asp   is interesting to develop potential therapies. To this aim, DASPO is a significant target in the   absence of evidence for key regulators in the synthesis of D-Asp.   5-aminonicotinic acid (5-ANA) and olanzapine are mild inhibitors of human DASPO (hDASPO),   thus new potential inhibitors were synthetised starting from the latter and their efficacy was tested   in the Amplex UltraRed inhibition assay. While 5-ANA derivatives resulted inactive on hDASPO   and were later repurposed on alternative targets, olanzapine derivatives showed interesting   activity. Among a panel of 20 molecules, six paired the inhibition activity of olanzapine and   X-ray crystallography was used to investigate molecular interactions and understand how to   improve inhibition. The structure of wild type hDASPO was solved for the first time by molecular   replacement and two out of six derivatives were modelled in the structures as non-competitive   inhibitors in possible allosteric sites.    Alongside, we would like to promote DASPO degradation via the proteasomes. To this aim,   PROTAC molecules were synthetised linking olanzapine to either lenalidomide or (VH032)-Me   designed to recruit Cereblon or Von Hippel–Lindau (VHL) E3 ligases, respectively. These   compounds were tested both in vitro and in cell lines for the interaction with DASPO and E3   ligases, and for the formation of ternary complexes necessary for DASPO proteasomal   degradation. Among them, PROTAC 1 showed ternary complex formation with a KD = 1.6 μM   and induced hDASPO degradation in a neuroblastoma cell line after 48 hours of treatment.   Ternary complex formation will be further investigated by NMR and SPR assays to enable   complex isolation and facilitate future X-ray crystallography studies.  In conclusion, on one side, inhibitor development and their structural characterisation can allow   more specific modification of hit compounds to obtain potent molecules against hDASPO   activity; on the other side, PROTAC technology was applied successfully for the first time to an   enzymatic target and demonstrates the suitability of degradation strategy to target hDASPO. Both   approaches open new avenues to regulate endogenous D-Asp levels, which may ultimately benefit   patients by improving neurotransmission.","language":"eng","citation":"STRATEGIES TO TARGET HUMAN D-ASPARTATE OXIDASE AND MODULATE ENDOGENOUS D-ASPARTATE LEVELS IN SCHIZOPHRENIA / M. Cavinato ; autore: M. Cavinato ; tutor: M. Nardini ; phd coordinator: S. Ricagno. - Dipartimento di Bioscienze, Università degli studi di Milano, Milano. Dipartimento di Bioscienze, 2025 Jan 16. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13893.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 09-GEN-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1222035"},"title":"SYNTHESIS AND STRUCTURAL DESIGN OF CARBOHYDRATE-BASED ARCHITECTURES: FROM VACCINE ADJUVANTS TO GLYCAN FOLDAMERS","internalauthor":"SCHIVARDI, SIMONE","type":"Tesi di dottorato","year":"2026","abstract":"Carbohydrates are complex molecules currently under deep investigation for the multiple roles they have in Nature: from source of energy, bricks of cell surface to several biological processes1. In the past years carbohydrates have been used in many applications: in the pharmaceutical field they are found in drug discovery2, design and synthesis of glycomimetics structures3, vaccine adjuvants4. Polyglycan structures have been used both for biology and for material chemistry purpose5.  The first chapter of this PhD thesis focus the attention on vaccine adjuvant semi-synthesis. Vaccines are one of the oldest treatments in medicine prevention, since the first vaccination was performed in the 1790s by Edward Jenner for the cowpox prevention6. Science has made great strides over the last two centuries however, for many years vaccination relied on whole-pathogen approach exploiting: viral vector, live-attenuated vector or inactivated/killed vector to generate immunological response7. Although whole-pathogen vaccines elicit long-lasting immunity, safety issues related to administering these complex mixtures, prevent their universal application8; therefore, in the early 2000s, modern subunit vaccination were deeply investigated due to their improved safety and more precise targeting compared to whole-pathogen vaccination, as possible alternative9. Nevertheless, immunization with purified protein antigen (subunit) are inherently less immunogenic, typically resulting in a modest antibody response with little or no T cell response10.  Adjuvants, in the context of vaccines, are defined as substances capable to enhance antigen-specific immune responses by triggering and modulating both the innate and acquired immunity: memory of long-lasting10. However, despite many years of improvements and developments, only few adjuvants are currently included in vaccination approved for human use: aluminium salts, emulsions (e.g. squalene), liposomes/virosomes and microparticles just to mention a few11. In this scenario, new classes of adjuvants are currently under investigation to offer an alternative and overcome this issue. Among them QS-21, an immunostimulatory saponin natural product extracted form Quillja Saponaria tree bark9, has emerged as a noteworthy alternative. The semi-synthesis of QS-21 and its main components will be faced in the first chapter of this thesis.","language":"eng","citation":"SYNTHESIS AND STRUCTURAL DESIGN OF CARBOHYDRATE-BASED ARCHITECTURES: FROM VACCINE ADJUVANTS TO GLYCAN FOLDAMERS / S. Schivardi ; tutor: A. Bernardi (UNIMI) ;  co-tutor: L. Senaldi  (INDENA S.p.A.) coordinator: D. Passarella (UNIMI). Dipartimento di Chimica, 2026 Mar 02. 38. ciclo, Anno Accademico 2022/2023.","filename":"phd_unimi_R13921_1.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 04-SET-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/951892"},"title":"UNVEILING CARDIAC IL-33/ST2L PATHWAY DEREGULATION IN ANIMAL MODEL OF OBESITY AND CARDIOVASCULAR DISEASE","internalauthor":"SITZIA, CLEMENTINA","type":"Tesi di dottorato","year":"2023","abstract":"Obesity has become an increasing public health issue worldwide; it is estimated than over 65% of American adult population is overweight and 35% are actually obese. Criteria for obesity definition is traditionally linked to Body Mass Index (BMI). Although an important correlation exists between BMI and body fat deposit, the BMI criteria cannot actually predict body composition in any given individual due to variability determined by age, sex, race and ethnicity. Besides the weight of an individual, both fat localization and type represent more important estimators of cardiovascular disease. Importantly, the accumulation of visceral fat – more than subcutaneous fat – is linked to cardiovascular disease severity and mortality. Among ectopic fat depots, pericardial and epicardial fat accumulation are intriguingly important. Epicardial adipose tissue (EAT) represents a biological active tissue that secretes adipokines known to promote low-grade inflammation and diabetic vascular complications. The cause is due to the shared blood supply between EAT and myocardium, as indeed EAT provides the 50–70% of the energy used for contraction trough the release of free fatty acids (FFAs). It is intuitive that molecular/metabolic alteration of EAT will be reflected on its secretome and on cardiac metabolism. EAT thickness seems to be associated to ventricular myocardial mass and importantly to myocardial steatosis. A plethora of works highlighted the role of IL-33 and its receptor ST2 within cardiac dysfunction and inflammation associated with obesity. Once secreted in activated or damaged cells, IL-33 modulates the functions of various immune cells through ST2 binding, affecting the proliferation of T cells, macrophages, and innate lymphoid cells. Accordingly, IL-33/ST2 pathway is involved in lipid metabolic diseases and - following its role as immune sensor to infection and stress – it is linked to pro-fibrotic remodeling of myocardium and more in general in cardiovascular diseases. Our group demonstrated in coronary artery disease (CAD) a direct correlation between EAT thickness and IL-33/ST2 signalling imbalance further highlighting a role for EPAC protein involved in cAMP signal transduction  In this PhD Project we aimed to further investigated the IL-33/ST2 effects on cardiac remodeling in obesity, focusing on the molecular pathway that links adipose/cardiac-derived IL-33 to development of fibrosis or hypertrophy. We choose Zucker Fatty rats (ZF) and Zucker Diabetics Fatty rats (ZDF) to overcome the problems linked to tissue availability and to the homogeneity of human EAT samples that need to be collected during cardiac surgery. Since genetic animal models do not fully recapitulate human pathology, we developed in vitro models to mimic adipose and myocardial relationship in vitro. Indeed, we evaluated the effects of visceral adipose tissue (VAT)-derived cellular medium in the modulation of adipose secretome and how they affect myocardial gene expression. Finally, we compared obtained results with those derived from Diet induced obesity (DIO) mice, a naturally occurring model of obesity that reliably resembles human disease. Following both molecular and proteomic analysis, we demonstrated a dysregulation of IL-33/ST2 signalling in both adipose and cardiac tissue, where they affected myocardial gene expression and determined a pro-fibrotic signature. In Zucker rats, pro-fibrotic effects were counteracted by ghrelin-induced IL-33 secretion, whose release influenced transcription factor expression (such as MEF2a), but also increased sST2 and not cardioprotective ST2L form. In this context we observed a reduction of EPAC signalling, that is promoted by VAT secretome and linked to ST2 isoforms balancing regulation. Similar results were obtained in ZDF rats, as both models did not develop evident alteration of cardiac architecture, although we described the increase of the pro-fibrotic signature. To avoid the genetic bias linked to leptin mutation and ghrelin up-regulation we repeated our analysis in DIO mice that fully recapitulates human obesity and presents gradual appearance of hyperglycaemia and progression of metabolic syndrome. Thanks to the analysis of cardiac proteome, we observed an enrichment in proteins and networks involved in extra-cellular matrix remodeling and ventricular function. Interestingly, IL-33 was considered among the possible up-stream regulators of this process.  In conclusion, this PhD project demonstrated a dysregulation of IL-33/ST2 signalling in obesity, that directly correlate with Epac expression in ZF rats. The alteration of these pathways in adipose tissue could influence IL-33/ST2 expression and hypertoric/fibrotic response in cardiac tissue. Importantly the effect of IL-33 signalling could be modulated by hormones (such as Ghrelin) and other stimuli.   Importantly, the final effect of IL-33 signalling activation is dependent on several factor, as cell types’ origin and balancing of ST2 isoforms. Noteworthy, extreme importance has to be ascribed to the animal models used in in vivo experiments, the chronic or acute condition as such as the time of IL-33 secretion. This way, it is reasonable that to define a unique protective role of IL-33 is over-simplistic and further studies are needed to confirm and unveil mechanisms of IL-33 as a gene expression regulator in cardiac obesity.","language":"eng","citation":"UNVEILING CARDIAC IL-33/ST2L PATHWAY DEREGULATION IN ANIMAL MODEL OF OBESITY AND CARDIOVASCULAR DISEASE / C. Sitzia ; tutor: MM. Corsi-Romanelli; supervisor: E. Vianello ; coordinatore N. Landsberger. Università degli Studi di Milano, 2023 Jan 31. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12718.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/951892/2126402/phd_unimi_R12718.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/816685"},"title":"L'ASSICURAZIONE ISLAMICA (CD. TAKAFUL): LEGAL TRANSPLANT E MODELLI A CONFRONTO","internalauthor":"BENARAFA, JIHANE","type":"Tesi di dottorato","year":"2021","abstract":"For a long time, the notion of insurance has been considered incompatible with the principles and rules of the Muslim community. In Islam, in fact, every aspect of life is governed by Allah’s teaching which abhor uncertainty and risk in stark contrast with the legal and economic characteristics of traditional insurance. In addition to the risk of occurrence of the event for which insurance is sought, other aspects conflict with the principles of Islamic law such as the difference between premiums paid to and the payouts by the insurance company, the use of premiums in fruit-bearing instruments, delays in payment of premiums with interests and penalties, uncertainty as to the object and duration of the contracts and so forth. That being said, in Islam and other communities bound by different religious beliefs, the need for protection and stability is strong and demands an effective answer by the legal framework.   The takaful has been such answer by Islamic law experts to traditional insurance to respond to the need for protections which is a primary need for all human beings, even if obliged to follow the precepts of Islam. It is a fully shari’ah-compliant alternative to provide coverage against risk and is based on solidarity, mutuality and the prohibition of riba (interest), gharar (uncertainty) and maysir (speculation).   The takaful model was first developed in 1985 and has ever since established itself within the Muslim community. It is recently new and, therefore, the questions which we must answer are: is there a possibility to transplant the model in a non-religious system of law? Is the takaful architecture compatible with the structure of traditional insurance. What are the solutions to offer shari’ah-compliant instruments to respond to the need of protection in specific territories and which have been neglected by traditional insurance operators?  Undoubtedly there is a measure of convergence between traditional insurance and takaful such as the function (i.e. to insure against risk), payment of a premium or a sum of money and the payout in case an event occurs. However, the structure is quite different as takaful requires the creation of two funds and a management role which differs from traditional insurance. In addition, a shari’ah board is often included within the takaful model which does not exist in traditional insurance. It is from this starting point, made of similarities and differences, that the following dissertation moves in order to answer the questions above.","language":"ita","citation":"L'ASSICURAZIONE ISLAMICA (CD. TAKAFUL): LEGAL TRANSPLANT E MODELLI A CONFRONTO / J. Benarafa ; tutor: R. E. Cerchia ; coordinatore: G. Ludovico. Dipartimento di Diritto Privato e Storia del Diritto, 2021 Feb 24. 33. ciclo, Anno Accademico 2020. [10.13130/benarafa-jihane_phd2021-02-24].","filename":"phd_unimi_R11846.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/816685/1710094/phd_unimi_R11846.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/957476"},"title":"METFORMIN, CLIC1 AND TRANSCRANIAL STIMULATION: THE BASIS OF A NEW TARGETED THERAPY AGAINST GLIOBLASTOMA RELAPSE","internalauthor":"CANNAVALE, GAETANO","type":"Tesi di dottorato","year":"2023","abstract":"Glioblastoma (GBM) is the most prevalent type of brain tumor and has a very poor prognosis. The current standard of care includes surgery to remove the mass of the tumor, followed by chemoradiation therapy. However, this technique is neither effective nor specific, and tumor recurrence occurs frequently, often fatally. As a result, new techniques for preventing glioblastoma relapse and increasing patients' life expectancy should be developed. GBM stem-like cells (GSCs) are primarily responsible for the high level of aggressiveness and recurrence. GSCs drive tumorigenesis and self-renewal, confer resistance to the tumor and guide tumor relapse. Recent publications proposed the transmembrane CLIC1 protein (tmCLIC1) as a potential pharmacological target since it is crucial for GSCs proliferation. tmCLIC1 inhibition shows tumor growth impairment both in vitro and in vivo. Recently, tmCLIC1 has been proposed to be one of metformin’s targets. In this work, we show molecular and functional evidence of the direct metformin-CLIC1 interaction, by NMR, MicroScale Thermophoresis, and single-channel patch-clamp experiments.  However, due to the blood brain barrier, the high concentration of metformin (10mM) required to inhibit tumor progression, which has been beneficial in other types of tumors, cannot be reached in the brain. As a result, the primary goal of this study is to improve metformin antitumoral activity on glioblastoma by lowering its operative concentration to a level that allows it to enter the brain. Our strategy is to induce repetitive membrane depolarizations to the tumor to promote metformin-tmCLIC1 binding. In fact, interaction between the two only occurs when tmCLIC1 is in the open state. Pulsed depolarizing electromagnetic field (EMF) stimulation should increase tmCLIC1 close-to-open transitions and, consequently, the availability of metformin binding sites. The application of EMF stimulation resulted in a 10-fold decrease of metformin concentration (1mM) needed to have the same antiproliferative effect in vitro on GSCs cultures and spheroids. To see if the impact was sustained in vivo, zebrafish embryos were orthotopically injected with GSCs, and the tumor mass was measured after 72 hours in absence or presence of 1mM metformin diluted in embryos’ water and of EMF stimulation. GSCs were orthotopically implanted into zebrafish embryos, and tumor mass was assessed after 72 hours in the absence or presence of 1mM metformin diluted in embryo water and EMF stimulation. The findings were comparable with those obtained in vitro, demonstrating that combining 1mM metformin and EMF decreases tumor growth in zebrafish embryos to the same level as metformin 10mM alone.  In addition, we provide data showing that stimulation increases tmCLIC1 open probability by both imaging techniques and electrophysiological experiments. GSCs were transfected to encode a green-fluorescent chloride sensor that can be monitored in living cells under fluorescent microscope. We found that chloride flux increases upon EMF stimulation in wild-type GSCs while the increase is way lower in cells Clic1-/-, suggesting that CLIC1 activity is effectively stimulated by EMF application. For the same purpose, we performed single channel recordings of tmCLIC1 current in the same GSCs in control condition and consecutively switching on EMF stimulation. The outcome was that tmCLIC1 open probability increased significantly with stimulation.  The long-term goal of the project is to combine transcranial stimulation and metformin administration to patients as adjuvant therapy to target chemotherapy-resistant cells that drive tumor relapse.","language":"eng","citation":"METFORMIN, CLIC1 AND TRANSCRANIAL STIMULATION: THE BASIS OF A NEW TARGETED THERAPY AGAINST GLIOBLASTOMA RELAPSE / G. Cannavale ; tutor: M. Mazzanti. Dipartimento di Bioscienze, 2023 Mar 16. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12555.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/957476/2155436/phd_unimi_R12555.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1132260"},"title":"MODELLING RIBOFLAVIN TRANSPORTER DEFICIENCY (RTD) USING IPSC-DERIVED MODELS TO TEST GENE THERAPY EFFICACY","internalauthor":"MEI, CECILIA","type":"Tesi di dottorato","year":"2025","abstract":"Riboflavin transporter deficiency syndrome (RTD) is a rare childhood-onset neurodegenerative disorder caused by mutations in SLC52A2 and SLC52A3 genes, encoding the riboflavin (RF) transporters RFVT2 and RFVT3. In the present study we focused on RTD Type 2, which is due to variants in SLC52A2 gene. There is no cure for RTD patients and, although studies have reported clinical improvements with administration of RF, an effective treatment is still unavailable.   Herein, we developed three disease models through 2D motoneurons, spinal cord and retinal organoid differentiation of RTD patients-specific induced pluripotent (iPSC) line carrying several mutations in SLC52A2 gene.   First, we tested gene replacement therapy on RTD type 2 patient-derived motoneurons using an adeno-associated viral vector 2/9 (AAV9) carrying the human codon optimized SLC52A2 cDNA. We optimized the in vitro transduction of motoneurons using Sialidase treatment. Our results proved that treated RTD motoneurons showed a significant increase in neurites’ length when compared to pathological untreated samples demonstrating that AAV9-SLC52A2 gene therapy can rescue RTD motoneurons. This leads the path towards more complex in vitro as well as in vivo studies offering a potential treatment for RTD patients.  Therefore, RTD iPSC-derived spinal cord organoids were generated. This model displayed similar features of the 2D model of motoneurons, including motoneurons cytoskeletal defects and motoneurons degeneration confirming the hallmarks of the disease. These results showed the feasibility of the 3D model to test AAV9 gene therapy.   Additionally, since very little is known regarding the RTD retina and the mechanism leading to patients’ blindness, retinal organoids have been generated. This study started to clarify some of the pathogenesis in RTD retina. Both photoreceptors and retinal ganglion cells seems to be involved in the mechanism leading to the blindness of RTD patients.  These results allowed us to consider retinal organoids as a feasible model to further indagate the RTD pathomechanism in retina.  This thesis highlights the successful applications of 2D and 3D iPSC-derived models in RTD disease modelling, confirming the suitability of these in vitro models for testing novel therapeutics.","language":"eng","citation":"MODELLING RIBOFLAVIN TRANSPORTER DEFICIENCY (RTD) USING IPSC-DERIVED MODELS TO TEST GENE THERAPY EFFICACY / C. Mei ; tutor: S. P. Corti; co-tutor: C. Compagnucci ; co-tutor: A.Gonzalez-Cordero ; coordinatore: C. Sforza, M. S. Clerici. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2025 Jan 24. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13245.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1132260/2627533/phd_unimi_R13245.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1246256"},"title":"BEES, HONEY AND TERRITORY: A COMPLEX NETWORK OF INTERACTIONS BETWEEN LANDSCAPE, BEEKEEPING AND HONEY QUALITY","internalauthor":"HOLZER, ERICA","type":"Tesi di dottorato","year":"2026","abstract":"From ecological, economic and cultural perspectives, bees are among the most important groups of insects. This is due to their central role in pollination pro-cesses and the production of numerous hive products. The genus Apis and the tribe Meliponini, which includes stingless bees, are fundamental components of natural and agricultural systems. Through pollination, they contribute to main-taining plant biodiversity and ensuring stable food production worldwide.   However, bee populations have become increasingly exposed to multiple stressors in recent decades, including climate change, agricultural intensifica-tion, habitat loss, pollution, and the spread of pathogens. Many of these stress-ors are closely associated with human activities and beekeeping practices.  Against this backdrop, the thesis entitled “Bees, Honey and Territory: A Complex Network of Interactions between Landscape, Beekeeping and Honey Quality”, aims to analyse the relationships between bees, floral resources, land-scape structure, and honey quality. The research takes an integrated approach, combining ecological, sanitary, productive and territorial considerations.   The main objective is to understand how interactions between pollinating in-sects, environmental conditions and beekeeping management influence the composition of honey and the health of bee communities. Particular attention is given to the interactions between domesticated and wild pollinators, and to the role of territory in shaping the characteristics of apicultural products.  Bees of the genus Apis are among the most extensively studied pollinators worldwide, playing a crucial role in plant reproduction and agricultural produc-tivity. Apis mellifera in particular has undergone a long process of domestication and is now distributed across almost all continents, providing valuable ecologi-cal and economic pollination services. However, the growing number of man-aged colonies, particularly in urban and semi-natural environments, has given rise to new ecological concerns. These include the competition with wild polli-nators for floral resources and the transmission pathogens between managed and wild species, which could alter pollination networks and affect the stability of native communities.  Meanwhile, stingless bees (Meliponini) are among the most important polli-nator groups in tropical and subtropical regions. They play a vital role in the functioning of natural ecosystems and the pollination of numerous tropical crops. Despite their ecological and cultural importance, they face similar threats to honeybees, including habitat degradation, exposure to agrochemicals and transmission of pathogens. Furthermore, despite the long-standing tradition of meliponiculture in many tropical countries, scientific knowledge of the charac-teristics of stingless bee honeys is limited, particularly in highly biodiverse re-gions such as Bolivia. This highlights the need for integrated studies linking honey composition to ecological and territorial factors.  Within this framework, the thesis explores the intricate connections between pollinators, plant resources, landscape structure, and the characteristics of hon-ey.  Not only is honey a food product resulting from the biological activity of bees, it is also a reflection of the ecological context in which it is produced. By collecting nectar and pollen from various plant species across diverse land-scapes, bees combine floral resources on a territorial scale. This results in honeys with specific chemical, physical, and sensory characteristics that are closely linked to their botanical and geographical origin. Consequently, honey can be interpreted as a territorial product reflecting environmental conditions and bee-keeping practices.  A central theme of the thesis is the interaction between domesticated honey-bees and wild pollinators. The intensification of beekeeping and the global spread of Apis mellifera have altered pollination networks and the availability of floral resources. In certain contexts, high densities of managed colonies can re-duce the availability of resources for wild species and increase the likelihood of pathogens being transmitted across different taxa. These processes, often re-ferred to as competition and pathogen spillover, pose significant challenges to pollinator conservation. Therefore, understanding these dynamics is essential for developing sustainable management strategies that balance apicultural pro-duction with biodiversity protection.  Another key aspect of the research relates to the connection between honey and territory. Bees forage over spatially variable areas, collecting nectar and pol-len from a variety of plant species. The resulting honeys have distinctive chemi-cal compositions and sensory properties that reflect the botanical and geograph-ical characteristics of the area in which the bees foraged. By analysing pollen content and physicochemical parameters, foraging patterns can be reconstructed and honey can be interpreted as an ecological indicator of the landscape ex-plored by bees. In this sense, honey acts as a biological archive, capable of re-cording information about plant communities, environmental conditions, and land use.  The thesis also addresses the broader issues of pollinator conservation and the sustainability of beekeeping practices. Anthropogenic pressures, including climate change, habitat fragmentation, pesticide exposure and pathogen spread, are increasingly endangering bee populations worldwide. These stressors often act synergistically, compromising both managed colonies and wild pollinator communities.   Overall, the thesis takes a systemic approach to examining the relationships between bees, the landscape and honey production. It emphasises that the quali-ty and characteristics of honey are influenced by the intricate interplay of eco-logical processes, geographical features and management practices. By linking pollinator ecology, pathogen dynamics and honey characterisation, the research improves our understanding of the connections between biodiversity, apiculture and food quality.  By emphasising the role of territory in shaping honey characteristics and pol-linator health, the thesis supports the development of sustainable management practices that consider interactions between environmental conditions, beekeep-ing strategies, and product quality.","language":"eng","citation":"BEES, HONEY AND TERRITORY: A COMPLEX NETWORK OF INTERACTIONS BETWEEN LANDSCAPE, BEEKEEPING AND HONEY QUALITY / E. Holzer ; tutor: D. Lupi ; co-tutor: S. Savoldelli ; coordinatore: D. Mora. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2026 May 22. 38. ciclo","filename":"phd_unimi_R13859_1.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 18-NOV-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/966823"},"title":"PRIVILEGE LOST: THE COUNTRY HOUSE, ARISTOCRACY AND ENGLISHNESS IN NANCY MITFORD'S NOVELS","internalauthor":"PRINA, FEDERICO","type":"Tesi di dottorato","year":"2023","abstract":"\"This thesis explores the connections between Englishness and the English aristocracy in Nancy Mitford’s novels through a detailed analysis of their symbolic-cultural representation: the English country house. The main purpose of the present work, which combines literary, biographical, historical, geographical, architectural and social analysis, is the re-evaluation of Mitford’s undervalued literary production, which has been relegated to the category of conservative mass entertainment – also due to the thin veil of humour, satire, irony and sarcasm that characterises it – and its claims to cultural and historical relevance in interwar British fiction. Mitford's biography clearly influenced her narrative choices in terms of characters, settings and themes: her upper-class background, that of an English noblewoman who describes in detail, carefully examines and, at the same time, subtly lampoons her own social class, constructing her fictional characters as the perfect caricatures of aristocratic types, has been taken into consideration in the analysis of her novels since it not only lies at the basis of her literary output, but it also constitutes a unicum among the interwar English writers of country-house novels. The present thesis is structured in two main parts. The first introductory one pinpoints a few methodological directions, a specifically angled recognition of the studies that have so far dealt with Englishness, the myth of the English countryside and country house-fiction, and offer a detailed examination of the historical background to the decline of English country houses and of the landed classes in Britain in the interwar period. The second section features close reading and close observation, with the aim to explore the connections between the country house, aristocracy and Englishness in Mitford’s novels. Such connections characterise almost all her works, and trigger reflection on the reasons why and on the ways in which they are implicated in the narration: the declining English country house as a former repository of essential Englishness, the interwar English countryside still considered by the old aristocracy as a symbol of traditional values and as a bucolic refuge from the chaos of the modern world, the opposition between the declining Victorian and Edwardian nobility that hides behind the curtains of its country mansions, unwilling to accept the loss of its former power and prestige and the young, modern aristocrats and members of the Bright Young People of the 1920s and ’30s, who enjoy the pleasures of life between London and rural England, seen by them only as “commodified” landscape ready to be consumed, but which they are generally unable to fit into. Albeit a crude version of her more mature ones, her interwar novels in the strict sense, which are the object of analysis in chapter one and two, already reveal many similarities in the rural settings – a castle in the Scottish Highlands in \"\"Highland Fling\"\" (1931), small cottages and grand country houses in the Cotswolds both in \"\"Christmas Pudding\"\" (1932) and in \"\"Wigs on the Green\"\" (1935) –, and in the upper- and upper-middle-class characters (members of the old British nobility and of the Bright Young People). Mitford’s most famous novels, \"\"The Pursuit of Love\"\" (1945) and its companion volume, \"\"Love in a Cold Climate\"\" (1949), which were written during and after World War II, mainly focus “on the powerful cultural image of the English country house”, celebrating on the surface “a conservative, largely upper-class view that appealed to a nation devastated by war and to later generations holding fast to a particular notion of Englishness amid great historical and social change”, but in fact concealing “a sharply critical study of a declining upper class, incapable of maintaining its traditional feudal role as legal and moral authority” (Kawano 2017: 13). The fourth chapter, which takes into account Mitford’s two post-war ‘French’ novels, \"\"The Blessing\"\" (1951) and \"\"Don’t Tell Alfred\"\" (1960), accesses a seemingly different field of analysis, at the cross-road between the English and the French cultural spheres. However, as I show, the remarkable shift from England to France, from Englishness to Frenchness, from the English to the French nobility, which coincides with Mitford’s move to Paris (and later to Versailles), is only apparent, since, besides the presence of some very English characters of her previous novels, the accurately portrayed country houses and estates of the French aristocracy in Provence still present a great deal of fictional similarities with their English counterparts, thereby becoming a sort of literary transposition onto French soil of England’s great mansions. Finally, it can be observed that the thread of connections between Englishness, the aristocracy and its ancestral element, the country house, runs through all Mitford’s novels, which, despite being largely ignored by the academic world, have come closest to the best-selling romances in their use of the “shimmering gauze of that aristocratic myth” (Wessels 1992: 320): a myth, which still holds and commands the attention of the modern reading public due to the idea that the upper-classes manage, in a way, to “answer a universal desire for personification of the heroic” (Ibidem, 360), and which is never objectified by Mitford thanks to her piercing humour.\"","language":"ita","citation":"PRIVILEGE LOST: THE COUNTRY HOUSE, ARISTOCRACY AND ENGLISHNESS IN NANCY MITFORD'S NOVELS / F. Prina ; tutor: N. Brazzelli ; coordinator: M.V. Calvi. Dipartimento di Lingue, Letterature, Culture e Mediazioni, 2023 May 05. 35. ciclo","filename":"phd_unimi_R12489.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/966823/2191247/phd_unimi_R12489.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/943799"},"title":"ANTIGONES D'AFRIQUE SUR LA SCENE FRANCOPHONE. LES PARADOXES CULTURELS ET POLITIQUES DE LA CREATION THEATRALE FRANCO-AFRICAINE","internalauthor":"LACIRIGNOLA, DONATO","type":"Tesi di dottorato","year":"2022","abstract":"At the crossroads of cultural, political and anthropological issues, this thesis analyses the  transposition of a Greek myth into the African universe. It focuses on the figure of Antigone  and her representation, questioning contemporary Francophone theatrical production through  the study of ten «Antigones of Africa», on a chronological arc going from the end of the 1980s  to the present. This work is based on a corpus composed of textual re-readings, but also and  above all on research into peri-textual materials (performances, adaptations, photographs,  dramaturgical projects, interviews, etc.), most of which have never been published.  Considering theatrical productions as artistic objects where the relations between cultures and  power are manifested, this thesis questions the way in which coloniality and the contemporary  world affect the revival of a «classic» in the reverberation of Franco-African relations. By  turning to the theatre to rethink the whole of cultural products in terms of performance and  forms of domination, the analysis of the corpus shows the relationships between theatrical  creation, cultural institutions, and economic and political logics. The analysis shows, on the  one hand, the ways in which artistic productions convey representations that can favour the  fabrication of an aestheticization of difference, notably in the form of the exoticism of the body  and the imaginary; on the other hand, it highlights the strategies that make it possible to thwart  identity assignments and deconstruct stereotypes relating to these pre-established and dominant  frameworks, either to subvert them or to redeploy them for «counter-exotic» purposes.","language":"fre","citation":"ANTIGONES D'AFRIQUE SUR LA SCENE FRANCOPHONE. LES PARADOXES CULTURELS ET POLITIQUES DE LA CREATION THEATRALE FRANCO-AFRICAINE / D. Lacirignola ; sotto la direzione di S. Riva e S. Chalaye. Università degli Studi di Milano, 2022 Oct 14. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12204.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/943799/2089548/phd_unimi_R12204.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/958032"},"title":"DECISION MAKING IN LIFE CHOICES","internalauthor":"SAVIONI, LUCREZIA","type":"Tesi di dottorato","year":"2023","abstract":"\"The project stems from the desire to better understand how decisions are made in “real life contexts”, with the aim of focusing on health and mainly on how cancer patients and survivors decide to participate in psychological interventions that aim to improve the quality of life.  Three studies have been designed to understand how decisions are made, changed and maintained in “real life” and the factors that may influence the decision to take part in psychological interventions, as well as to maintain commitment to them.  The project identifies that there are several factors that come into play when we find ourselves having to make \"\"real\"\" decisions that can have effects and repercussions on the entire life ahead, for example the context in which the decision is made, social interactions and individual differences.  Focusing on participation in psychological interventions aimed at improving well-being and quality of life in cancer patients, we have seen how the issue of participation, engagement and adherence is paramount.  The studies highlight the importance for patients that their needs are taken into consideration during both the design and the implementation of health interventions. Another aspect that emerges from the studies is that patients’ motivation may fluctuate and change during an intervention experience, with possibly unpredictable consequences on the maintenance of positive change.  In order to reduce the risk of non-participation or drop out it is important that the activities of interventions take into consideration patients’ daily life, future plans and obligations, and the subjective representation of illness.\"","language":"eng","citation":"DECISION MAKING IN LIFE CHOICES / L. Savioni ; supervisor: G. Pravettoni ; add supervisor: S. Triberti ; internal advisor: I. Cutica. Dipartimento di Oncologia ed Emato-Oncologia, 2023 Apr 13. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12412.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/958032/2159112/phd_unimi_R12412.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/914697"},"title":"DESIGN AND SYNTHESIS OF PHOTOLUMINESCENT PT(II) AND IR(III) COMPLEXES FOR LIFE SCIENCE AND OLEDS APPLICATION","internalauthor":"DE SORICELLIS, GIULIA","type":"Tesi di dottorato","year":"2022","abstract":"The remarkable versatility and the outstanding photophysical properties of heavy transition metal complexes prompted towards the design of innovative cyclometalated Pt(II) and Ir(III) complexes with enhanced luminescence. Indeed, the long life-time of the excited states and the possibility to finely tune the phosphorescence phenomenon through minor modifications of the organic backbone makes them attractive for bioimaging, photodynamic therapy and OLEDs application.     In this context, the introduction of sterically hindered substituents and of biologically relevant substrates such as glucose and tryptophan on the organic framework was successfully achieved, thus obtaining excellent emitters characterized by increased brightness and selectivity towards tumorous cells.   The present thesis provides an extensive discussion concerning the theoretical basis underlying the design of the developed luminophores, the synthetic pathways followed, and the remarkable results obtained.   Notably, the designed Pt(II) complexes exhibited extraordinary photophysical properties that have never reported in literature before.","language":"eng","citation":"DESIGN AND SYNTHESIS OF PHOTOLUMINESCENT PT(II) AND IR(III) COMPLEXES FOR LIFE SCIENCE AND OLEDS APPLICATION / G. De Soricellis ; tutor: A. Colombo ; co-tutor: C. Dragonetti. Dipartimento di Chimica, 2022 Mar 25. 34. ciclo, Anno Accademico 2021. [10.13130/de-soricellis-giulia_phd2022-03-25].","filename":"phd_unimi_R12348.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/914697/1997971/phd_unimi_R12348.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1215215"},"title":"IL PRINCIPIO DI SUSSIDIARIETÀ. TRA LIMITI TEORICI E DEGENERAZIONI PRATICHE DELLA LEGISLAZIONE IN MATERIA PENALE","internalauthor":"ALMA, FEDERICA","type":"Tesi di dottorato","year":"2026","abstract":"This doctoral dissertation aims to analyse, from both a theoretical and practical perspective, the principle of subsidiarity as the foundation and limitation of the ius puniendi.  Starting from the liberal assumption that punishment should represent the extrema ratio of the legal system, the research seeks to determine whether this principle still retains an effective capacity to guide and constrain legislative expansion in criminal matters.  The work is divided into three main sections. The first chapter reconstructs the theoretical origins and systematic scope of the principle of subsidiarity, identifying its role as an overarching metaprinciple of the criminal law system and its connections with the principles of harm, proportionality, necessity and fragmentation. From this perspective, subsidiarity emerge sas a criterion of rationality and legitimacy of criminal law, intended to ensure balance between social defence and the protection of individual freedom. As such, it may serve not only as a guiding principle in the design of criminal policy, but also as a potential parameter in assessing the constitutional legitimacy of legislative choices.  The second chapter shifts the focus to the systemic level, deepening the distinction between physiological expansions and pathological manifestations of criminal intervention. While the former correspond to a reasonable adaptation of law to social and technological change, the latter take the form of penal populism and symbolic legislation, in which punishment assumes a primarily communicative and reassuring function within the social body.  The third chapter provides an empirical assessment of Italian legislative production from the XVI to the XIX legislature, with the aim of verifying whether the national legal system can truly be said to suffer from a condition of penal hypertrophy, as argued by much of the legal scholarship. The quantitative and qualitative analysis of the legislative measures reveals, however, that the expansion of criminal law does not display the features of an endemic or irreversible pathology, but rather those of an episodic and contingent deviation,  linked to specific political or emergency-driven interventions. Alongside these, the research identifies a physiological increase in criminal regulation, representing a natural response to the evolution of society, the emergence of new legally protected interests and the appearance of novel forms of criminal conduct.  The conclusions depict a framework in which the Italian criminal system, although marked by phases of disordered expansion, cannot be deemed irreversibly degenerated. Pena hypertrophy appears not as a chronic disease, but as an episodic and manageable phenomenon. In this light, the principle of subsidiarity emerges not only as a theoretical canon but as a potentially operative and legal remedy: on the one hand, as a guiding criterion for legislative choices, aiming to restore punishment to its proper function as extrema ratio; and on the other, as a constitutional standard, capable of guiding judicial review of such choices.  The research ultimately concludes that contemporary criminal law, if properly governed by the principle of subsidiarity, can still preserve it coherence with the fundamental values of the rule of law and with the guarantee-based function that defines its very raison d’être.","language":"ita","citation":"IL PRINCIPIO DI SUSSIDIARIETÀ. TRA LIMITI TEORICI E DEGENERAZIONI PRATICHE DELLA LEGISLAZIONE IN MATERIA PENALE / F. Alma ; tutor: G.L. Gatta ; cotutor: A.P.A. Della Bella ; coordinatore: E. Damiani. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2026. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14098.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1215215/3249491/phd_unimi_R14098.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/945228"},"title":"NEW FINDINGS INTO TARGET-DIRECTED MICRORNA DEGRADATION MECHANISM","internalauthor":"RUBOLINO, CARMELA","type":"Tesi di dottorato","year":"2022","abstract":"MiRNAs are a class of small non-coding RNAs that function in post-transcriptional gene silencing by interacting with target RNAs. A novel mechanism in control of miRNA levels, called Target-Directed miRNA degradation (TDMD), has been described, which involves specific transcripts able to interact with miRNAs and induce miRNA degradation. We showed that an endogenous RNA transcript, Serpine1, uses TDMD to control levels and activity of miR:30b/c in murine fibroblasts. It is unknown how many other TDMD transcripts exist; therefore, we developed TDMDfinder, a computational pipeline and free webtool, that identifies “high confidence” TDMD interactions in the Human and Mouse transcriptomes by combining sequence alignment and feature selection approaches. Our predictions suggested that TDMD is widespread, with potentially every miRNA controlled by endogenous targets. We experimentally tested 37 TDMDfinder predictions, of which 17 showed TDMD effects as measured by RT-qPCR and small RNA sequencing, linking the miR-17, miR-19, miR-30, miR-221, miR-26 and miR-23 families to novel endogenous TDMD triggers. Computational analyses performed using the multiomic TCGA platform substantiated the possible involvement of many TDMD transcripts in human cancer and highlighted 36 highly significant pan-cancer interactions, suggesting TDMD as a new potential oncogenic mechanism. Focusing on the SERPINE1:miR30b/c pair as a model, we applied molecular and genetic approaches to manipulate TDMD and investigate the effects afforded by miRNA degradation in breast cancer. Our results suggested that TDMD is used by breast cancer cells to keep low miRNA activity and provide a selective advantage in various cancer phenotypes. In order to identify all TDMD-regulated miRNAs in breast cancer, we inhibited the TDMD mechanism by knocking down a critical player of the pathway, the ZSWIM8 culling-RING ubiquitin ligase substrate adapter. We repressed ZSWIM8 by CRISPR interference in a set of 8 different breast cancer (BC) cell lines, representing the entire spectrum of BC subtypes. Our analyses showed that loss of ZSWIM8 caused significantly increased accumulation of 31 miRNAs, without any evidence of transcriptional regulation, thus expanding the role of endogenous TDMD in sculpting miRNA levels. Finally, to identify the TDMD triggers in BC, we designed a strategy based on the combined use of TDMDfinder predictions and experimental CRISPR-based tools. We performed a proof-of-concept validation of the approach by identifying the endogenous TDMD trigger (NREP) for miR-29b-3p in SUM159PT and BT549, proving that this can be an effective strategy to quickly identify TDMD substrates and triggers.","language":"eng","citation":"NEW FINDINGS INTO TARGET-DIRECTED MICRORNA DEGRADATION MECHANISM / C. Rubolino ; coordinator: S. Minucci ; tutor: F. Nicassio; supervisor: M.J. Marzi. Dipartimento di Oncologia ed Emato-Oncologia, 2022 Dec 16. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12438.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/945228/2094713/phd_unimi_R12438.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1227104"},"title":"GENETIC DISSECTION OF PINE1 CONTROLLED STEM ELONGATION AND NEW INSIGHTS INTO LONG DAY FLOWERING IN ORYZA SATIVA","internalauthor":"BERTAGNON, GRETA","type":"Tesi di dottorato","year":"2026","abstract":"Rice flowering is promoted by exposure to short days (SD) and occurs through the coordination of two   developmental processes:  the shoot apical meristem (SAM) produces an inflorescence while, along the stem,   internodes elongate to allow heading. Recently, PREMATURE INTERNODE ELONGATION1 (PINE1), a C2H2 zinc   f  inger transcription factor, was described as the responsible for stem elongation during flowering and under   submergence in deepwater rice. PINE1 is highly expressed when the stem is compact and it is rapidly   downregulated as the plant needs to elongate internodes, which occurs during flowering induction in normal   paddy rice as well as under submergence in deepwater rice. pine1 mutants shows constitutive internode   elongation since germination. In this thesis, morphological studies with EdU staining assay were performed,   revealing that the premature internode elongation is due to intercalary meristem (IM) development followed   by cell elongation. Premature internode elongation was associated with pine1 mutants of wheat and maize   as well, thus showing a conserved role of PINE1 among these species.    Rice pine1 mutants are highly responsive to gibberellins (GA) as their internodes rapidly elongate   proportionally to the exogenous GA concentration, contrary to WT stems whose growth is unaffected. To   understand how PINE1 may be involved in the GA signalling pathway, we have generated single and double   knockout mutants with CRISPR-Cas9 of pine1 and four well-characterized genes belonging to GA biosynthesis,   perception and signalling pathways: GIBBERELLIN INSENSITIVE DWARF1 (GID1), GIBBERELLIN INSENSITIVE   DWARF2 (GID2), SEMI-DWARF (SD1) AND SLENDER RICE1 (SLR1). Two novel gain-of-function dominant   mutations in SLR1 were also identified. The novel dominant slender mutants (named slrD) lacks two   aminoacids close to the DELLA motif and might be crucial for its degradation, causing SLR1 overaccumulation   and dwarf phenotype. Double mutants pine1-gid1, pine1-gid2 and pine1-slrD, even preserving an overall   dwarf aspect similarly to gid1, gid2 and slrD respectively, can develop an active IM similarly to pine1 single   mutants, as demonstrated with EdU staining assay. RNA sequencing of slrD and slr1 revealed that when a   loss-of-function of PINE1 is also present, the transcriptomic profile radically changes. These results suggest   that PINE1 activity is crucial for complete silencing of IM, and that PINE1 may act synergistically with SLR1 for   chromatin remodelling and repression of its target genes. PINE1 ability to remodel chromatin was assessed   by the demonstration of the existence of a trimeric complex between PINE1, a TOPLESS protein and a histone   deacetylase.    Rice is short-day plant, but in temperate regions, the selection of loss-of-function alleles of some long-day   f  lowering repressors allows rice cultivation even where growing season is limited and characterized by long  day (LD) photoperiod. In the present study, we took advantage of a mutagenized Volano (a typical Italian rice   variety) population to identify novel genes or alleles associated with the regulation of flowering time in LD.   MutMap is a rapid gene identification method based on whole-genome resequencing of pooled DNA from F2   segregating populations. In this study, it was applied to one F2 population derived from an early-flowering   5   line and to two additional populations derived from late-flowering lines. MutMap revealed that the early  f  lowering line resulted from a loss-of-function of PHOTOPERIOD SENSITIVITY 13 (OsSE13). The delay of   f  lowering was indeed caused by an aminoacidic substitution, not yet described, in the rice long day flowering   promoter RICE FLOWERING LOCUS T 1 (OsRFT1) in one late flowering line, whereas the second late-flowering   line presented a premature stop codon in the gene DROUGHT AND SALT TOLERANCE (OsDST), a gene whose   loss-of-function mutant has already been previously reported to regulate drought and salt tolerance.","language":"eng","citation":"GENETIC DISSECTION OF PINE1 CONTROLLED STEM ELONGATION AND NEW INSIGHTS INTO LONG DAY FLOWERING IN ORYZA SATIVA / G. Bertagnon ; tutor: S.Pierce ; co-tutor: V. F. Brambilla ; coordinatore: S. R. Pilu. - Via celoria 2, aula Molon. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2026 Mar 27. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13778.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 20-SET-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/957202"},"title":"EPIGENETIC MECHANISMS OF POLYCOMB REPRESSIVE COMPLEX 1 IN INTESTINAL LINEAGE COMMITMENT","internalauthor":"DEL VECCHIO, ANNACHIARA","type":"Tesi di dottorato","year":"2023","abstract":"Polycomb group proteins are key transcriptional repressive complexes involved in cell fate decisions during development and cell identity maintenance during homeostasis (1).   Polycomb group proteins primarily assemble into two different complexes: Polycomb repressive complex 2 (PRC2) with the catalytic subunit EZH1/2 which can mono, di, and tri- methylase the histone H3 at lysine 27 (H3K27); and Polycomb Repressive Complex 1 (PRC1) with the catalytic subunits RING1A/B, which catalyze the monoubiquitylation of histone H2A at lysine 119 (H2AK119) (1,2). In PRC1, the RING1A/B subunits form a core heterodimer with one of the 6 mutually exclusive PCGF (1-6) proteins, thus creating six subcomplexes (PRC1.1 – PRC1.6). Simply put, PRC1 subcomplexes can be divided into canonical PRC1 (PRC1.2 and PRC1.4) and variant PRC1 (PRC1.1, PRC1.3, PRC1.5 and PRC1.6) (1,2).   Polycomb Repressive Complexes are essential for the transcriptional repression of developmental genes, such as germ-line related genes in embryonic stem cells (ESCs) (3).  During intestinal homeostasis, chromatin modifiers play important roles in maintaining transcriptional signatures of specific cell types. Our group has already demonstrated that RING1A/B are necessary to maintain normal tissue homeostasis by preservation of the WNT/B-catenin activity (4).   However, the contribution of PCGFs in adult intestinal homeostasis is unclear. To address this, we evaluated the role of six different PRC1 subcomplexes in transcriptional repression maintenance in intestinal cells by using several inducible PCGFs knockout mouse models.   Our data suggest that the lack of single PCGF proteins does not alter intestinal homeostasis due to the compensatory effects of PRC1 subcomplexes in chromatin binding and in transcriptional repression maintenance.   In fact, we observed that PRC1.1, PRC1.2 and PRC1.4 share binding sites on chromatin in intestinal cells. The simultaneous depletion of PCGF1, PCGF2, PCGF4 affects not only RING1b binding, but also its activity and H2AK119ub deposition. This leads to a transcriptional de-repression in adult intestinal cells, and so to a disrupted intestinal homeostasis.   Interestingly, we observed that the Tuft cell number increases remarkably following PCGF6-deletion. Tuft or Brush cells are a very rare cell population with chemosensory activity in the intestinal epithelium (5). However, the Tuft cell differentiation program is under investigation.","language":"eng","citation":"EPIGENETIC MECHANISMS OF POLYCOMB REPRESSIVE COMPLEX 1 IN INTESTINAL LINEAGE COMMITMENT / A. Del Vecchio ; internal advisor: S. CASOLA, D. PASINI ; external advisor: F. X REAL ; PHD coordinator: S. MINUCCI. Dipartimento di Scienze della Salute, 2023 Apr 13. 34. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12408.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/957202/2153921/phd_unimi_R12408.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1023131"},"title":"MES-DERIVED CARDIOMYOCYTES AS CELLULAR MODEL TO STUDY CARDIAC DISEASES: ALTERATIONS IN STRN AND GNB5 GENES","internalauthor":"COSPITO, ALESSANDRO","type":"Tesi di dottorato","year":"2024","abstract":"Striatin (Strn), a scaffold protein expressed in many tissues, among which in cardiomyocytes (CMs), whose altered expression has been found in various cardiac diseases. Here we studied the role(s) of cardiac STRN by comparing the electrophysiological properties of CMs, generated from STRN-KO and isogenic WT mouse embryonic stem cell (mESC) lines. 10-12-day old beating  mESC-CMs were analyzed by Patch-clamp, motion video tracking, Ca2+ dynamics and immunofluorescence analysis. STRN-KO cells have a higher spontaneous beating rate and faster action potential depolarization (dV/dt) than WT, correlated with a larger fast INa conductance. Since in HEK cells downregulation of STRN was reported to destabilize microtubules and increase INa, immunofluorescence analysis confirmed the higher Na+ channel expression and a more dynamic microtubule network in KO CMs. Motion video tracking analysis highlighted an altered contraction in STRN-KO CMs, and this was associated with a global increase in intracellular Ca2+. This was likely due to an increased late Na+ current (INaL) and a reduction of Ca2+extrusion through the Na+/Ca2+ exchanger (NCX). Other currents such as ICaL, If and IKr were not altered in STRN-KO cells. Incubation of STRN-KO CMs with the microtubule stabilizer Taxol, induced a reduction of INa conductance toward WT levels. In conclusion, loss of STRN alters CMs electrical and contractile profile and affects cell functionality by a disarrangement of multi-protein complexes leading to the impairment of microtubules dynamics and trafficking of Na+ channels.","language":"eng","citation":"MES-DERIVED CARDIOMYOCYTES AS CELLULAR MODEL TO STUDY CARDIAC DISEASES: ALTERATIONS IN STRN AND GNB5 GENES / A. Cospito ; tutor: A. Barbuti ; phd school coordinator: R. Mantovani. Dipartimento di Bioscienze, 2024 Jan 24. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13006.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1023131/2342421/phd_unimi_R13006.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1153055"},"title":"DEVELOPMENT OF AN INTEGRATED METHODOLOGY TO ASSESS THE PRESENCE AND THE IMPACT OF (MICRO)PLASTICS ON THE RIVER BENTHIC COMMUNITY","internalauthor":"SBARBERI, RICCARDO","type":"Tesi di dottorato","year":"2025","abstract":"Plastic pollution is one of the main environmental issues of the modern society since the development of synthetic polymers with exceptional chemical/physical characteristics in the 20th century led to a continuous production and use of these materials with a great increase in plastic wastes. Consequently, the mismanagement of the end-of-life plastic products induces a constant flux of these materials into the environment, especially in aquatic ecosystems. In this context, rivers are the main collectors of plastics from the continental areas, representing also an important sink of these contaminants in the sediments, with a possible affection of benthic communities.  Since most of the studies about plastic pollution in freshwaters primarily deals with water matrix, the main aim of this project was to develop an integrated methodology to monitor the plastic pollution in several freshwater ecosystems, considering the impact of some variables, as the environmental matrix selection and the temporal variation of the contamination, associated to their toxicity evaluation on the benthic macroinvertebrate Chironomus riparius.  Firstly, the method setting was crucial to determine the best sampling and analytical setup for plastic monitoring in sediments. This preliminary step was performed in the Lambro River (Northern Italy), which represents an excellent site for the method development due to its high plastic pollution. In detail, plastics were separated from the collected sediments through two density extraction methods, comparing the efficiency of sodium chloride (NaCl) and zinc chloride (ZnCl2) solutions. Results showed a significant difference (p < 0.05) in the extraction performance, with ZnCl2 extracting more plastics (53.3 ± 16.1 plastics/kg sediments wet weight - w.w.) than NaCl (8.3 ± 10.4 plastics/kg sediments w.w.; see manuscript 1).  The study moved subsequently to the comparison of plastic pollution in both waters and sediments in four of the main Po River tributaries (Ticino, Adda, Oglio, and Mincio Rivers), using the ZnCl2 solution in the separation processes. Results showed that contamination in sediments was four times higher than in waters, highlighting heterogeneous pollution from both quantitative and qualitative point of view, with the highest levels in Mincio River (62.9 ± 53.9 plastics/m³ in waters and 26.5 ± 13.3 plastics/kg dry weight - d.w. - in sediments) and the lowest in Ticino River (0.9 ± 0.5 plastics/m3 in waters and 6.8 ± 4.5 plastics/kg d.w. - in sediments; see manuscript 2). This study suggested that the monitoring of both matrices provide complementary information: waters offer a picture of an instantaneous contamination, while sediments, representing a sink of plastics, a “historical” pollution. Since waters represent a snapshot of plastic contamination in a water body, the temporal variation of these contaminants in the water matrix was also assessed. Lake Maggiore, from which Ticino River is the main emissary, was selected as reference site due to the highest plastic contamination compared to the other great sub-alpine Lakes. This work revealed a monthly variation in plastic content, from  0.02 plastics/m3 in September to 0.29 plastics/m3 in December (see manuscript 3). These findings underscore the importance of comprehensive monitoring plans considering both abiotic matrices (waters and sediments), as well as multi-sampling campaigns throughout the year, to better understand the plastic contamination in freshwater ecosystems.  Since the most of studies investigated the toxicity of virgin standard plastic particles, ignoring the wide plethora of shapes, sizes and polymers detected in the environment, in this project the sampled plastics in the abovementioned freshwater lotic environments were used in the exposures of Chironomus riparius. Since no normalized methods for the Chironomid exposure to plastics were available, a modification of the Chironomid Life-Cycle Toxicity Test (OECD 233) was performed, and both apical and molecular/cellular multigenerational effects on two generations were evaluated. The toxicity of sampled plastic mixtures from the Po River tributaries (40 plastics/kg d.w. for Ticino, 68 plastics/kg d.w. for Adda, 58 plastics/kg d.w. for Oglio and 420 plastics/kg d.w. for Mincio) were tested in comparison to virgin polystyrene microbeads of 1 μm (PS; 22,400 plastics/kg sediment d.w., 112,000 plastics/kg d.w., 224,000 plastics/kg d.w.). No significant multigenerational effects (p > 0.05) were observed for virgin plastics, despite the highest tested concentrations compared to those used for sampled plastics, while plastics from Adda River significantly decreased (p < 0.05) the Emergence Rate (ER) in the 2nd generation of Chironomus riparius (see manuscript 4). These results suggested that the toxicity of these contaminants could be also related to the physical/chemical characteristics, from shape to polymer composition, instead of the simple plastic concentration.  This project contributes to filling the knowledge gap associated to the impact of plastics in water body sediments, suggesting that the monitoring integrated with an ecotoxicological assessment can provide a more complete view of the potential hazardousness of these pollutants.","language":"eng","citation":"DEVELOPMENT OF AN INTEGRATED METHODOLOGY TO ASSESS THE PRESENCE AND THE IMPACT OF (MICRO)PLASTICS ON THE RIVER BENTHIC COMMUNITY / R. Sbarberi ; tutor: S. Magni, co-tutor: A. Binelli ; coordinator: M. P. M. Guarino. Dipartimento di Bioscienze, 2025 Apr 07. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13537.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1153055/2710268/phd_unimi_R13537.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1217956"},"title":"RESPONSIBLE AI GOVERNANCE: BALANCING THE GOALS OF BIAS MITIGATION AND PRIVACY PROTECTION THROUGH TRANSPARENCY","internalauthor":"NAVDARASHVILI, TAMAR","type":"Tesi di dottorato","year":"2026","abstract":"Amid increasing societal reliance on artificial intelligence (AI), this thesis begins by establishing a foundational understanding of AI systems, their capabilities, applications, and social implications, before turning to its central focus: the interplay between the goals of   debiasing AI systems and safeguarding privacy. While the development and use of AI systems offer significant benefits, they also present serious risks, including data-driven bias that reinforces social inequalities and improper data handling that compromises privacy. Addressing these dual challenges is central to the European Union’s (EU) framework for responsible AI governance.    Against this backdrop, the study critically engages with the technical and ethical dimensions of how these pressing concerns intersect. It then examines two key regulatory pillars—the General Data Protection Regulation (GDPR) and the Artificial Intelligence Act   (AIA)—recognizing their foundational roles while also exposing regulatory blind spots that warrant greater attention. The analysis highlights the significance of proper data strategies, suggesting the critical role of proportionality, contextual, and evidence-based approaches. The central argument of this thesis is that the EU’s responsible AI governance framework should be rooted in transparent and accountable decision-making, where technical, ethical, and regulatory strategies are coherently aligned. In the quest to balance bias mitigation and privacy protection, the thesis proposes dynamic transparency as both a bridging principle and an internal governance approach. When initiatives are driven by strong internal commitment and reinforced by externally coordinated efforts among relevant actors through diverse transparency-oriented mechanisms, the groundwork is laid for AI systems that are not only   innovative but also developed and deployed responsibly.","language":"eng","citation":"RESPONSIBLE AI GOVERNANCE: BALANCING THE GOALS OF BIAS MITIGATION AND PRIVACY PROTECTION THROUGH TRANSPARENCY / T. Navdarashvili ; tutor: L. Cominelli ; co-tutor: I. Pellizzone ; coordinator: D. U. Galetta. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2026 Mar 09. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14003.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 24-AGO-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1202230"},"title":"L¿IMPATTO DELL¿INTELLIGENZA ARTIFICIALE E DEI NUOVI PROCESSI DI TRATTAMENTO DEI DATI PERSONALI SULLA VITA MORALE DELL¿UOMO E SULLA SUA DIGNITÀ","internalauthor":"BRAMBILLA, EMANUELE","type":"Tesi di dottorato","year":"2025","abstract":"\"The thesis, after outlining the notion of technology, reflects on the concept of intelligence and its different meanings, starting from the definition proposed by Turing and the way functionalism understands it. Then, it goes on to examine the relationships and differences between natural and artificial intelligence. Thanks to the results achieved, an attempt is made to clarify whether there is a new anthropology brought about by digital technology and its influence. To answer, the thesis focuses both on personal aspects in the relationship with the virtual world and on the moral capacity of users to live in it, emphasizing the transformation of relationships that it produces. The analysis highlights the importance of human dignity and its ontological interpretation, which is the only one capable of justifying and promoting the role of the human person in relation to artificial intelligence. The second section explores the concepts of \"\"infosphere\"\" and \"\"docusphere\"\", outlining their convergences and differences. Then, it considers how the digital environment is experienced and governed from the point of view of the relevance of personal data. Afterwards, the analysis explores the role of algorithms, presenting their technical aspects and ethical issues, to which it attempts to provide possibile answers. The third chapter deals with the relationship and difference between personal and digital identity, highlighting how the latter is not a mirror of the former, but a simplified and datafied version of it. Specifically, it examines the history of concept of \"\"electronic body\"\" and the problem of its composition, asking whether it is a sum of data or something more. The results achieved highlight the need to revisit the issue of dignity, linking it to that of the electronic body and demonstrating the need for legislation to recognize and protect it as already present in the human being, and not as something to be legally conferred upon him.\"","language":"ita","citation":"L¿IMPATTO DELL¿INTELLIGENZA ARTIFICIALE E DEI NUOVI PROCESSI DI TRATTAMENTO DEI DATI PERSONALI SULLA VITA MORALE DELL¿UOMO E SULLA SUA DIGNITÀ / E. Brambilla ; tutor: G. Ziccardi ; co-tutor: P. Perri ; coordinatrice: F. Poggi. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2025 Dec 19. 38. ciclo, Anno Accademico 2025.","filename":"phd_unimi_R13999.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1202230/3203329/phd_unimi_R13999.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/886506"},"title":"EUROPEANIZATION VERSUS DEMOCRATIZATION IN GEORGIA, MOLDOVA AND UKRAINE. INTERNAL AND EXTERNAL CHALLENGES TO DEMOCRATIC CONSOLIDATION","internalauthor":"POPSOI, MIHAIL","type":"Tesi di dottorato","year":"2021","abstract":"There is a growing disconnect between Europeanization and democratization in the immediate neighborhood of the European Union.  Often overlooked by euro-centric academic research, Georgia, Moldova and Ukraine are a litmus test for the challenges facing democratic consolidation in a geopolitically contested region.  The study dissects the relationship between Europeanization and Democratization processes in the three countries; scrutinizes the internal and external challenges to democratic consolidation and critically assesses the effectiveness of EU’s normative power projection in the region. In the process, the author challenges Huntington’s concept of ‘snowballing’, disconfirming his one directional democratic cascade theory in the specific condition of the countries comprising the case study. The unique condition of these countries is epitomized by the European Union’s facilitation of democracy, on the one hand, and, on the other hand, Russia’s facilitation of the status quo, while also encouraging undemocratic practices. This challenges the neofunctionalist democratic spillover expectation and accredits a path-dependent neo-institutionalist account of democratization in the region. Moreover, the author finds robust evidence in support of the modernization theory of democracy, while also confirming the negative effects of active geopolitical competition on the battleground countries. The study questions the efficacy of EU’s democracy promotion efforts and argues in favor of anchoring the three countries on the European integration track as an imperative mechanism for boosting the chances of democratic consolidation.","language":"eng","citation":"EUROPEANIZATION VERSUS DEMOCRATIZATION IN GEORGIA, MOLDOVA AND UKRAINE. INTERNAL AND EXTERNAL CHALLENGES TO DEMOCRATIC CONSOLIDATION / M. Popsoi ; advisor: F. Franchino. Universita' degli Studi di MILANO, 2021 Dec 10. 32. ciclo, Anno Accademico 2020. [10.13130/popsoi-mihail_phd2021-12-10].","filename":"phd_unimi_R11774.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/886506/1922173/phd_unimi_R11774.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1097129"},"title":"BEYOND DESERT AND MORAL RESPONSIBILITY: RETHINKING JUSTICE","internalauthor":"BERAHA, MARINA","type":"Tesi di dottorato","year":"2024","abstract":"This research conducts a comprehensive critique of retributive justice, understood pragmatically as a system for addressing the complex social challenges stemming from reciprocal violence. Starting from an exploration of violence management in pre-State societies, particularly through the scapegoating victimisation mechanisms and the ensuing emergence of religious constructs as elucidated by Girard, the intricate interplay among violence, justice, and religion will be scrutinized. Subsequently, the focus will shift to analysing the modern State’s monopolisation of violence and its fundamental role in violence management. Within this context, the traditional justifications for retributive practices will be examined and criticised, alongside an exploration of the relationship between retribution and emotions considered in their adaptive function. Furthermore, the conceptual evolution of retributive justice, in its connection to the notions of free will, desert, and individual moral responsibility, will be traced, commencing from the analysis conducted by 17th-century philosophers. Having ascertained the moral inadequacy of the retributive conception of justice, the possibility of replacing the retributive paradigm with a transformative and restorative justice system, underpinned by utilitarianism and a redefined conception of shared moral responsibility, will be investigated.","language":"eng","citation":"BEYOND DESERT AND MORAL RESPONSIBILITY: RETHINKING JUSTICE / M. Beraha ; tutor: G. Mormino, P. Saltel ; coordinatore del dottorato: N.  G Guicciardini ;  directeur de l’école doctorale : T.  Mènissier. Università degli Studi di Milano, 2024 Sep 13. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12839.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1097129/2529578/phd_unimi_R12839.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1241499"},"title":"THE LOCATION OF DAMAGE IN THE EU CONFLICT OF LAWS: THE CASE OF FINANCIAL LOSS IN THE CONTEXT OF BLOCKCHAIN TRANSACTIONS","internalauthor":"MARESCA, CARLOTTA","type":"Tesi di dottorato","year":"2026","abstract":"Starting from a technical reconstruction of the blockchain, understood as a distributed ledger, and an analysis of the regulatory initiatives proposed at international, European and national level to regulate its use, the thesis analyses the case of pure financial loss that may occur when financial investments are made using these new technologies and the resulting impact from an international private law perspective.  Part I introduces blockchain technology and the private international legal regime developed so far. Title I examines blockchain technology from a historical and technical perspective. It starts with the analysis of its evolution and then focuses on concepts such as distributed ledger technology (DLT), block, node, consensus, cryptocurrencies, smart contracts and initial coin offerings (ICOs). Title II investigates the existing regulatory framework, which at the international level consists of soft-law initiatives (i.e. the UNIDROIT Principles on Digital Assets and Private Law, the UNCITRAL Model Law Texts and Taxonomy, the HCCH Digital Tokens Project and the HCCH–UNIDROIT Joint Project on Digital Assets and Tokens), and at the European level of Regulation No 2023/1114 on markets in crypto-assets (MiCA) and Regulation No 2022/858 on a pilot regime for market infrastructures based on distributed ledger technology (the DLT Pilot Regime). At the national level, it examines the legislative texts and case law in eighteen States, including Italy, France, Germany, Switzerland, Spain, Liechtenstein, the United Kingdom, the United States and Singapore, with particular attention paid to the (limited) conflict-of-laws rules provided therein.  Part II is dedicated to private international law issues arising from the Court of Justice of the European Union (CJEU) case law concerning pure financial loss. Title I analyses the CJEU’s rulings, illustrating the tortuous development of the interpretation of Article 7(2) of Brussels I bis Regulation from Marinari (C-364/93), through Kolassa (C-375/13), Kronhofer (C-168/02), Universal Music (C-12/15), Löber (C-304/17), to VEB (C-709/19). In these judgments, albeit not autonomously characterising pure financial loss as falling within the scope of non-contractual liability rules, the Court of Justice has excluded – on factual grounds – the contractual route as well as the consumer-investor protective forum.  Accordingly, for the purpose of determining jurisdiction, it becomes essential to locate the damage, which, as above stated, in the present context is immaterial and potentially multi-localised. For these reasons, Part II, Title II deals with the issues of characterisation of the claims (if contractual or non-contractual), the possible characterisation of the investor as a consumer, the problems of collective redress, the location of damage and the conceivable solution of a forum actoris. Although the CJEU’s judgments have been delivered in relation to jurisdiction, similar implications arise for the determination of the applicable law under the Rome II Regulation.  Problems relating to the location of damage are particularly evident in cases where financial loss occurs in a wallet managing crypto-assets, which are addressed in Part III. Starting with a brief introduction of English jurisdictional rules, Title I analyses UK rulings concerning jurisdiction and applicable law in cases of pure financial loss resulting from investments carried out through the use of blockchain. These judgments have been delivered by the English High Court of Justice, which has generally identified the place where the damage occurred as the claimant’s domicile, sometimes stressing that this is the place where the claimant is able to exercise control over their assets. Mirroring Part II, Title II of Part III investigates private international law issues arising from the case law, such as claim characterisation, investor-consumer protection, collective redress, location of damage, liability under MiCAR, possible new heads of jurisdiction de lege ferenda, the forum actoris solution, and, lastly, the repercussions on the applicable law.  In light of the difficulties encountered both in the characterisation of pure financial loss and in the location of damage, the thesis reflects on the desirability of amending the existing instruments of EU private international law governing jurisdictional grounds and connecting factors for the determination of the applicable law (respectively, Brussels I bis and Rome II Regulations), in order to adapt the normative framework to the challenges posed by current developments and by the increasing use of new technologies in the future.","language":"eng","citation":"THE LOCATION OF DAMAGE IN THE EU CONFLICT OF LAWS: THE CASE OF FINANCIAL LOSS IN THE CONTEXT OF BLOCKCHAIN TRANSACTIONS / C. Maresca ; tutor: S. Bariatti ;  co-tutor: P. de Vareilles-Sommières,  F. C. Villata ;  coordinator: F. Biondi. Dipartimento di Diritto Pubblico Italiano e Sovranazionale, 2026. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13737.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1241499/3319435/phd_unimi_R13737.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/920111"},"title":"CHALLENGES AND OPPORTUNITIES OF MAYTANSINOL, CANNABIDIOL AND CALLYSPONGIOLIDE IN NATURAL PRODUCT CHEMISTRY","internalauthor":"MARZULLO, PAOLA","type":"Tesi di dottorato","year":"2022","abstract":"The development of new drugs has long been inspired by Nature as the main source of the biologically active compounds. This practice has motivated total synthesis and diversity-oriented synthesis in the drug discovery and drug design process because natural products offer great opportunities to find new low molecular weight structures active against a wide range of assay targets. Obtaining a synthetic source and creation of derivative analogs would allow a greater understanding of the biologocal effects because natural products has tipically been extracted in complex mixture with other compounds making isolation impossible with useful quantities.   With this in mind, the enantioselective syntheses carried out to obtain maytansinol-based conjugates as microtubule modulators, cannabidiol-C4, and two fragments of callyspongiolide are described in this thesis.","language":"eng","citation":"CHALLENGES AND OPPORTUNITIES OF MAYTANSINOL, CANNABIDIOL AND CALLYSPONGIOLIDE IN NATURAL PRODUCT CHEMISTRY / P. Marzullo ; tutor: D. Passarella ; co-tutor:  S. Pieraccini ;  coordinatore: D. Passarella. Dipartimento di Chimica, 2022 Apr 06. 34. ciclo, Anno Accademico 2021. [10.13130/marzullo-paola_phd2022-04-06].","filename":"phd_unimi_R12394.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/920111/2013521/phd_unimi_R12394.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/818993"},"title":"RATIONAL DESIGN, SYNTHESIS AND NANOTECHNOLOGIES AS TOOLS IN EARLY DRUG DISCOVERY: CANCER AND NEURODEGENERATION AS TARGETS","internalauthor":"COLOMBO, ELEONORA","type":"Tesi di dottorato","year":"2021","abstract":"Rational design, synthesis and nanotechnologies as tools in early drug discovery: cancer and neurodegeneration as targets    The rubric “multifactorial” has been applied to several diseases spanning multiple therapeutic areas, e.g. schizophrenia, autism, depression, epilepsy, diabetes, rheumatoid arthritis, hypertension, cancer, Alzheimer's and Parkinson's disease, multiple sclerosis and probably hundreds of other conditions; such label entails that the disease is influenced by multiple genetic and environmental factors, and that its progression is also influenced by a plethora of elements.1 Diseases may earn this label either if they are clearly heritable/familial although influenced by environmental factors (as is the case for diabetes); alternatively also if genetic liabilities are insufficient to predict whether a person will actually develop the disease, while environmental/sporadic factors are (much) more relevant for disease development and progression (as is mostly the case for amyotrophic lateral sclerosis/ALS).  The terms complex and multifactorial are also commonly used to describe the architecture of the genetic component of disease liability. In these cases, these terms are usually at least implicitly equated with the trait being polygenic; in fact, 'complex', 'multifactorial' and 'polygenic' are commonly used as synonyms. It is important here to make a distinction in how the term polygenic is used: the implication is that a given disorder arises in each individual due to the combined effects of a large number of genetic variants (multiple causative factors for a single pathology).2 This definition is distinct from a model of genetic heterogeneity, in which many different variants are involved across the population, but where each case is caused by a single variant, or a few (a single, or few causative factors for a multiplicity of closely related pathologies).  Multifactorial disorders are difficult to study and treat because the most relevant causative factors that mostly influence the establishment and the progression of these disorders have not yet been identified. Although many technologies and strategies can be used to detect molecular factors influencing complex diseases, these technologies and strategies have inherent limitations.3 In fact, the very name “complex disease” suggests that the results from relevant studies will not be simple to decipher.  The absence of a univocally recognized, disease-determining mechanism makes it difficult to develop any target-focused drug to treat these diseases, or to rationally improve the therapeutic potential of biologically active compounds that have an unknown mode of action.   The first part of my Ph.D. thesis deals with this issue, that is the synthesis of photoactivatable probes (PAPs)4 to help with the identification of molecular targets for the treatment of neurodegenerative diseases. More in details:  • Chapter 1 (pp. 19-85) deals with the synthesis of chemical probes built on edaravone, a known anti-oxidant with strong radical-scavenging activity5. Edaravone is commercialized in Japan and the US for the treatment of ALS, and was recently identified by an ISS research group in Rome (Dr. Agresti) as a remyelinating agent in oligodendrocytes progenitor cells (OPCs) with possible MS reverberations6. Several edaravone analogues, including PAL moieties, were synthetized in order to investigate together with ISS the existence of a putative molecular target specific for the MS-targeted activity.  • Chapter 2 (pp. 87-152) regards Sephin1, a mono-chlorinated Guanabenz analogue that was introduced as a potent inhibitor of inducible PP1-GADD34/PPP1R15A phosphatase complex.7 However, recent literature8 seems to question such target identification; and recent studies performed in collaboration between my research group and Trento University (Prof. Piccoli) hypothesized its interaction with actin, a completely unrelated protein. Thus, several Sephin1-derived chemical probes were synthetized, including azides and diazirines as PAPs and biotin-functionalized derivatives for pull-down, affinity chromatography9 experiments.  The treatment of complex, multifactorial diseases often requires a targeted delivery of active compounds to the site of action to avoid unwanted side effects. In particular, my efforts refer to neurodegenerative diseases, that require permeation of the blood brain barrier (BBB) in order to reach their site of action; and to multiple cancer types, where only mutated/hyperproliferating/immortalized cancer cells need to be targeted while limiting drug exposure for healthy cells.  The second part of my Ph.D. thesis will thus deal with the targeted delivery of drug candidates, in particular suggesting their formulation as self-assembled nanoparticles as a possible solution. More in details:  • Chapter 3 (pp. 179-216) concerns the use of betulinic acid as self-assembly inducer for the formation of nanoparticles.10 Among its biological activities, betulinic acid is known as a cytotoxic agent. Thus, we wanted to investigate its use not only as a self-assembly inducer but also as an anticancer drug, hoping to take advantage of both these abilities. In particular, several betulinic conjugates were synthetized with cytotoxic drugs acting on microtubules dynamics.  • Chapter 4 (pp. 217-258) regards the synthesis of trehalose-based, self-assembled nanoparticles.11 Trehalose is a disaccharide known to induce autophagy and to reduce protein misfolding and aggregation.12 Unfortunately, high mM trehalose concentrations are needed in vivo for efficacy, due to its high hydrophilicity and due to trehalase enzymes in the gut of humans that inactivate it by hydrolysing it to glucose.13 To improve its bioavailability by both preventing its hydrolysis and masking its hydrophilicity, we thought that squalene-trehalose conjugates and their self-assembled nanoparticles could be a promising approach towards the use of trehalose as an autophagy-inducing, neuroprotective drug.  • Chapter 5 (pp. 259-339) addresses a different aspect of nanoparticles in nanomedicine, that is drug targeting. The need to discriminate between healthy and tumoral cells to reduce side effects of cytotoxic drugs is among the main issues in the treatment of cancer. We exploited folate targeting14 by preparing hetero-nanoparticles bearing both folic acid and an anticancer drug in order to have folate recognition/receptor targeting, followed by selective internalization of folate-drug conjugates inside tumoral cells.   While the first two parts of my thesis mostly deal with medicinal chemistry approaches, during my Ph.D. I dealt also with total synthesis and chemical methodologies. Total synthesis is important both to confirm the structure of largely complex natural products and to obtain them and their analogues in significant amounts, expanding the pool of pharma-focused chemical diversity. That’s why the third part of my Ph.D. thesis concerns some of these aspects, in particular:  • Chapter 6 (pp. 357-435) covers the total synthesis of triazole analogue of epothilones. Epothilones are a class of macrolides presenting different biological activities, among which the stabilization of microtubules that makes them good candidates for cancer treatment.15 However, since they present issues related to stability, we modified their structure using a triazole as bioisostere of their amidic function to improve their physiological stability.  • Chapter 7 (pp. 437-495) reports the results I obtained during my period abroad, spent at the University of Barcelona from April to July 2019. There I obtained some preliminary results in the total synthesis of Schoberine B, a polycyclic alkaloid extracted from Myrioneuron faberi,16 and I performed a methodological study on the main reaction involved in its total synthesis - in particular, the stereoselective cyclocondensation of trisubstituted 2,4,6-cyclohexanone derivatives.  Each Chapter in this Ph.D. thesis is divided in five Sections:  1) A short introduction on the targeted molecular pathway, and in particular the molecular targets involved;   2) A description of the chemical routes used for the preparation of all target compounds, and their key intermediates;  3) Their virtual and tangible characterization (in-silico docking, in vitro and sometimes in vivo profiling);   4) A critical evaluation of project results, and planned future activities;   5) An experimental part reporting in details the synthesis, the purification and the analytical characterization of each intermediate and of each final, targeted molecule.     Bibliography  1 K. J. Mitchell, Genome Biol., 2012, 13, 237–247.  2 R. Plomin, C. M. A. Haworth and O. S. P. Davis, Nat. Rev. Genet., 2009, 10, 872–878.  3 N. J. Schork, Am. J. Respir. Crit. Care Med., 1997, 156, S103–S109.  4 E. Smith and I. Collins, Futur. Med Chem, 2015, 7, 159–183.  5 M. P. Cruz, Pharm. Ter., 2018, 43, 25–28.  6 C. Eleuteri et al., Sci. Rep., 2017, 7, 45780–45794.  7 I. Das et al., Science, 2015, 348, 239–242.  8 A. Crespillo-Casado, J. E. Chambers, P. M. Fischer, S. J. Marciniak and D. Ron, Elife, 2017, 6, 1–29.  9 C. Mulder, N. Leijten and S. Lemeer, Curr. Opin. Syst. Biol., 2018, 10, 9–18.  10 E. Colombo et al., ACS Med. Chem. Lett., 2020, 11, 895–898.  11 E. Colombo et al., Pharmaceutics, 2019, 11, 422.  12 A. B. Richards et al., Food Chem. Toxicol., 2002, 40, 871–898.  13 S. Maicas, J. P. Guirao-Abad and J.-C. Argüelles, Biochim. Biophys. Acta - Gen. Subj., 2016, 1860, 2249–2254.  14 M. Fernández, F. Javaid and V. Chudasama, Advances in targeting the folate receptor in the treatment/imaging of cancers, Royal Society of Chemistry, 2018, vol. 9.  15 K. Gerth, N. Bedorf, G. Höfle, H. Irschik and H. Reichenbach, J. Antibiot. (Tokyo)., 1996, 49, 560–563.  16 M. M. Cao et al., RSC Adv., 2016, 6, 10180–10184.","language":"eng","citation":"RATIONAL DESIGN, SYNTHESIS AND NANOTECHNOLOGIES AS TOOLS IN EARLY DRUG DISCOVERY: CANCER AND NEURODEGENERATION AS TARGETS / E. Colombo ; tutor: P. Seneci ; co-tutor: D. Passarella ; coordinatore.: D. M. Roberto. Dipartimento di Chimica, 2021 Mar 04. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11914.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/818993/1716922/phd_unimi_R11914.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1150637"},"title":"ECO-SUSTAINABLE PACKAGING MATERIALS FOR THE FOOD INDUSTRY (ECOPACKMAT)","internalauthor":"BELLESIA, TOMMASO","type":"Tesi di dottorato","year":"2025","abstract":"This PhD thesis focused on developing an eco-sustainable packaging material for the food industry, addressing the growing environmental, social, and economic challenges posed by the increased plastic consumption and generation of associated wastes.  Aligning with global efforts to transition to a circular economy model, this work explored the use of cellulose as a “backbone” for the generation of biodegradable and high-performance packaging materials. At first, cellulose from underexploited agri-food wastes and plant residues (i.e., giant cane, Posidonia oceanica seagrass, coffee silverskin, and brewer’s spent grain) was obtained using a standardized process reliant on soft chemicals and solvents. Native cellulose was subsequently miniaturized to micro- and nano-forms, namely microfibrillated cellulose (MFC) and cellulose nanocrystals (CNCs), using physical (i.e., high pressure homogenization, HPH) and chemical (i.e., sulfuric acid hydrolysis) methods, respectively. All these products were thoroughly characterized and further tested - both internally (UNIMI) and at the industrial partner’s site (Fedrigoni S.p.a) – in different packaging configurations.  Remarkably, a strong correlation between the size of the extracted cellulose and its derivatives, and the functionality of the obtained materials was recorded, demonstrating that it is possible to obtain materials with different functional properties as a function of the miniaturization degree. For instance, the freshly extracted cellulose, that is, in its native macro-form, is suitable for creating both 3D objects through wet molding processing and common paper sheets (Chapter Ⅲ). The combination of high surface area, UV-shielding behavior, high stiffness, and excellent oxygen barrier performance makes microfibrillated cellulose the ideal substrate for producing eco-friendly stand-alone films for the preservation of oxygen-sensitive foods (Chapter Ⅳ). At last, cellulose nanocrystals can be expediently used as nanobuilding blocks for the generation of bionanocomposite films and coatings, again for food packaging applications (Chapter Ⅳ).   Overall, the basic approach set in this thesis work has a great potential to reduce agricultural wastes and their environmental impact, whilst offering green innovation in the food packaging sector. Nonetheless, room is left for further research activities aimed to i) validate the tested materials through shelf-life and life cycle assessment (LCA) studies, ii) assess the toxicological risk for humans associated with the potential migration to foods of nanoparticles (e.g., cellulose nanocrystals) from packaging materials (such as nanocomposite coatings), and ultimately iii) verify the up-scaling feasibility of the technologies employed in this PhD work through a techno-economic analysis.","language":"eng","citation":"ECO-SUSTAINABLE PACKAGING MATERIALS FOR THE FOOD INDUSTRY (ECOPACKMAT) / T. Bellesia ; tutor: S. Farris, D. Romano ; coordinatore: D. Mora. - Via Celoria 2. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2025 Mar 03. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13631.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1150637/2701910/phd_unimi_R13631.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1120937"},"title":"A FRAMEWORK FOR NETWORK EVOLUTION","internalauthor":"GALDEMAN, ALESSIA","type":"Tesi di dottorato","year":"2024","abstract":"The digital transformation has fundamentally reshaped how organizations operate, leading to an unprecedented flood of data across all sectors. With the global digital transformation market projected to reach 3.4 trillion by 2026, the need to understand and leverage this data has become critical. Network science has emerged as a powerful approach for analyzing complex systems, offering tools to understand interconnected entities through the lens of nodes and edges.  Network science has demonstrated its effectiveness across numerous domains. In social science, the field evolved from early sociograms to sophisticated analyses of social media behavior, polarization, and user migration patterns. Financial applications include the analysis of market stability, interbank relationships, and fraud detection through transaction networks. In biology and medicine, network approaches have revolutionized our understanding of protein interactions and disease mechanisms, while ecological applications have enhanced our grasp of species interactions and ecosystem dynamics.  While initial research focused primarily on static networks, recent attention has shifted toward temporal networks that incorporate time-varying relationships. This evolution reflects the inherently dynamic nature of most complex systems. For instance, urban mobility networks capture changing traffic patterns throughout the day. Brain networks map the temporal progression of neural impulses. Social networks track the spread of information and trends over time. Financial networks reveal patterns in transaction timing and market responses. Disease transmission networks highlight the temporal aspects of outbreak patterns. Current research has primarily focused on describing network changes over time from a macroscopic perspective, leaving a significant gap in understanding the underlying mechanisms driving these evolutionary patterns.  By extracting the mechanisms, named rules, of evolution from a temporal graph, we can reveal the general mesoscopic mechanisms governing network dynamics. This means understanding how mesoscopic network structures evolve over time.   This thesis addresses this gap by developing a comprehensive framework, named GERANIO, for modeling, mining, and analyzing network evolution rules. Graph evolution rules (GER) mining is a frequency-based pattern discovery method used to examine the dynamics of networks as they evolve over time. GERs are designed to identify recurring local changes throughout the network's evolution. Drawing inspiration from the notion of association rules in the context of data mining, GERs consist of two essential components: a precondition and a set of postconditions. These rules indicate that a subgraph matching (being isomorphic to) the precondition is likely to evolve into one of the configurations represented by the postconditions, with the corresponding probability.  Despite their potential, existing approaches face significant challenges, particularly in the complexity of identifying and analyzing GERs and the difficulties associated with isomorphism checks.  The GERANIO framework makes several key contributions to address these challenges. First, it introduces a universal taxonomy for modeling evolving networks, applicable across various domains. Second, it provides a categorization method for isomorphic subgraphs through canonical coding, ensuring universal applicability of results. Third, it proposes ad-hoc null models to extract statistically significant rules. Fourth, it introduces the TULIP algorithm, which mines graph evolution rules from a broader perspective than existing approaches. Finally, it develops the concept of evolutionary profiles – probability distributions of rule frequencies that enable immediate visual feedback on evolving network behavior and network comparison.  The framework distinguishes between stand-alone rules and general graph evolution rules. Stand-alone rules excel at identifying specific evolutionary processes, such as cycles in financial networks, while general rules capture the complete evolutionary behavior of a network. Both approaches benefit from the framework's canonical coding method, which provides a unique representation of graphs for easy comparison and analysis.  This thesis is structured in four main parts: a comprehensive background on temporal networks modeling and theoretical foundations; an exploration of the GERANIO framework's stand-alone rules component; and an introduction to broader graph evolution rules through the TULIP algorithm.  Finally, this thesis explores an evolutionary aspect typical of Web3 networks that cannot be fully captured by graph evolution rules alone: user migration. This phenomenon is particularly relevant in the context of blockchain-based online social networks (BOSNs) and presents unique challenges for network analysis.    Through these contributions, this thesis aims to enhance our understanding of network dynamics and provide powerful tools for comparing different networks and analyzing changes over time.","language":"eng","citation":"A FRAMEWORK FOR NETWORK EVOLUTION / A. Galdeman ; tutor: S. Gaito ; co-relatore: M. Zignani ; coordinatore: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2024 Dec 05. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13320.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1120937/2596256/phd_unimi_R13320.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1197539"},"title":"MULTI-OMIC LINEAGE TRACING PREDICTS THE MOLECULAR DRIVERS OF CANCER STEM CELLS IN TRIPLENEGATIVE BREAST CANCER EVOLUTION.","internalauthor":"PIRRA PISCAZZI, MARIA","type":"Tesi di dottorato","year":"2025","abstract":"Triple-Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype, and patients still rely primarily on chemo-neoadjuvant therapy (NACT). Their poor prognosis is largely driven by extensive phenotypic heterogeneity, sustained by complex genetic and epigenetic interactions that are difficult to dissect without perturbing the native cellular context in which multiple phenotypically distinct subpopulations coexist.  Recent advances integrating single-cell omics with different clonal barcoding have begun to uncover features linked to the aggressive behavior of cancer clones. However, the intricate gene regulatory mechanisms that define their identity and govern their fate remain insufficiently resolved.  In this work, we developed GALILEO, a single-cell multiomic framework that combines lineage tracing with transcriptomic and chromatin accessibility profiling (via snRNA-seq and snATAC-seq) and integrates these with phenotypic assays. Applying GALILEO to the intrinsically heterogeneous and highly tumorigenic TNBC cell line SUM159PT, we identified two distinct subpopulations: drug-tolerant cells (DTCs) and tumor-initiating cells (TICs). DTCs are marked by a genomic alteration on chromosome 11 that confers reduced sensitivity to cytotoxic treatment. Conversely, TICs exhibit two baseline transcriptional states and share a set of co-accessible chromatin regions, indicative of a pre-existing epigenetic basis for tumor initiation. Their behavior is orchestrated by specific gene regulatory networks driven by a set of transcription factors that regulate the epithelial-to-mesenchymal transition (EMT) program.  To validate these findings, we performed prospective isolation using TM4SF1 as a TIC-specific surface marker. TM4SF1high cells were confirmed to be enriched for tumor-initiating capacity through in vivo orthotopic transplantation. We further generated high-resolution transcriptional and epigenetic profiles of TM4SF1high cells via bulk RNA-sequencing and CUT&Tag, enabling precise annotation of the active regulatory elements underlying the networks reconstructed with GALILEO.  Overall, this study elucidates the coexisting genetic, epigenetic, and transcriptional determinants shaping TNBC evolution and reveals the molecular architecture of rare, pre-encoded tumor phenotypes.","language":"eng","citation":"MULTI-OMIC LINEAGE TRACING PREDICTS THE MOLECULAR DRIVERS OF CANCER STEM CELLS IN TRIPLE NEGATIVE BREAST CANCER EVOLUTION / M. Pirra Piscazzi ; supervisor: F. Nicassio ; co-supervisor: M. Marzi ; coordinator: D. Pasini. - IFOM Campus. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Dec 17. 36. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13147.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 21-NOV-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1133297"},"title":"BIOMECHANICAL RISK FACTORS FOR ANTERIOR CRUCIATE LIGAMENT INJURY: WHAT DO LANDING TASKS TELL US?","internalauthor":"BRUNETTI, CLAUDIA","type":"Tesi di dottorato","year":"2025","abstract":"The anterior cruciate ligament (ACL) injury is the most debilitating among the knee structure injuries, in terms of severity and economic burden. It mostly occurs in non-contact situations, during cutting, landing, and pivoting manoeuvres, when the impact to the ground exacerbates the knee load and the tibial shear force. Laboratory tests are commonly adopted to identify athletes predisposed to such injuries, but the results are often inconsistent. The overall aim of this dissertation was to explore the use of landing tasks to assess biomechanical risk factors associated with ACL injuries. The presented protocols included landing tasks with varying features to compare different groups of athletes or to assess the impact of task type on injury-related biomechanics and performance.  Sex-related kinematic differences were evaluated in 30 male and 30 female athletes, who were asked to perform a battery of landing tasks. A key aspect was the customization of jump characteristics based on the athletes' anthropometrics and performance levels, minimizing potential confounding factors. A similar approach was adopted to assess sport-related kinematic differences between 22 soccer and 19 volleyball players; in this case, the customized task battery included uniplanar and multiplanar landings, to simulate the sport-specific ACL injury mechanisms. In both projects, statistical models were used to assess the main kinematic variables, considering the instant of ground contact and the peak reached while landing, which are commonly associated with ACL injury. Sex-related kinematic differences emerged, although tasks were customized, but we found non-significant sport-related differences.  The multiplanar tasks, included in these projects and in other past studies, are often characterized by combined jumps, but the impact of the secondary jump direction had not been fully analysed yet. For this purpose, the same participants were involved to analyse the entire time series of landing kinematics using the Statistical Parametric Mapping. Thanks to this approach, the observed direction-related differences highlighted how important it is to consider the task type before drawing conclusions about an athlete's risk.  Another aspect of ACL injury considered in this thesis was the influence of cognitive abilities on anticipated and unanticipated landing tasks. The cognitive abilities of 10 athletes were assessed using a novel motor-cognitive test battery, allowing the evaluation of athletes’ ability to apply these skills in sport gestures. Motor-cognitive scores seemed to be associated with potentially detrimental movements and the cognitive loads in unanticipated tasks affected lower limb biomechanics, reinforcing the importance of evaluating cognitive performance to mitigate injury risks during athletic performance.  Finally, the conflict between ACL injury prevention and jump performance was investigated including 31 athletes, evaluating the effect of a cushioned (soft) landing on both kinematics and jumping metrics, with respect to unrestricted and fast techniques. The findings confirmed that a soft landing was beneficial, as the increased knee flexion protects the ACL from excessive loads, but highlighted its potential drawbacks on jump height and contact time, underlining a plausible trade-off between preventing ACL injuries while improving performance.  The fil rouge connecting the conclusions of each section of this dissertation was that not all tests are suitable for every individual, and several factors must be considered, such as sex, sport, test characteristics, and cognitive aspects. Although we are still far from having standardized methods for identifying athletes at risk, advancements in research and technology are improving, making ACL injury rate reduction increasingly achievable.","language":"eng","citation":"BIOMECHANICAL RISK FACTORS FOR ANTERIOR CRUCIATE LIGAMENT INJURY: WHAT DO LANDING TASKS TELL US? / C. Brunetti ; tutor: C. Sforza ; coordinator: C. Sforza. Dipartimento di Scienze Biomediche per la Salute, 2025 Jan 23. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13255.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1133297/2630300/phd_unimi_R13255.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/955633"},"title":"STUDIES OF COHERENT FREE-ELECTRON LASERS DRIVEN BY COMPACT LINACS OR BY PLASMA WAKEFIELD ACCELERATORS","internalauthor":"OPROMOLLA, MICHELE","type":"Tesi di dottorato","year":"2023","abstract":"Free-Electron Lasers (FELs) constitute the last generation of synchrotron light sources: they are conventionally driven by a radio-frequency linear electron accelerator (LINAC), where the electron beam is accelerated to relativistic energies, followed by a chain of undulator magnets, which force the electron beam to oscillate and emit radiation. High brightness, tunable and transversely coherent radiation pulses with unique properties are finally delivered to the downstream experimental stations for a wide range of applications in the fields of physics, biology, medicine and chemistry.  External seeding techniques aimed at improving the intrinsically poor temporal coherence and shot-to-shot stability of a FEL starting from shot noise have been proposed and experimentally demonstrated.  State-of-the-art fully coherent FELs make use of an external coherent signal, which is basically a high-power laser system seeding and imprinting its coherence properties on the electrons at the undulator entrance, and exploit seeded schemes based on frequency up-conversion to increase the low frequency of the seed laser and generate fully coherent radiation at shorter wavelengths.  Independently of the specific seeded scheme, the output FEL radiation properties, such as wavelength and repetition rate, strongly depend on those of the seed laser.  In particular, the repetition rate capability of conventional high-power lasers is limited to few kHz at maximum, which is incompatible with the MHz-class ones of a superconducting LINAC, while their wavelength limits the minimum output wavelength that can be achieved with reasonable harmonic up-conversions: the study of alternative seeding sources and FEL configurations overcoming this limitation, thus exploiting the potentials of superconducting LINACs, is the new frontier of FEL science.   Such research line has synergies with another ambitious and innovative frontier of accelerator science, the study and development of plasma-based accelerators as well as advancements towards their application in light sources, whose ultimate goal is to make advanced radiation sources available to a wide range of users with the realisation of compact user facilities that could be built in small-scale laboratories.     \\par This thesis deals with theoretical and numerical studies of novel schemes for a fully coherent FEL driven by a compact LINAC at high repetition rate or by a plasma-wakefield accelerator.  Coherent and high repetition rate FEL pulses would enable high resolution experiments and more data collection in shorter experimental times respectively, greatly improving the ongoing science at FELs by supporting new experiments.  In this scenario and in the framework of the MariX and BriXSinO projects in Milan, Italy, I investigated the FEL oscillator (FELO) configuration in different spectral regions from the THz down to the X-rays by means of a simulation code, written in Fortran, which iterates the required simulation steps for its study. \\\\  Based on the acquired knowledge of the FELO scheme, producing high-power coherent pulses suitable for FEL seeding, this thesis proposes two novel FEL oscillator-amplifier setups capable of generating high repetition rate and coherent radiation at short wavelengths in the tender X-ray range ($0.3-0.5$ nm).   In these two schemes, the seed pulses are provided by an Extreme-Ultra-Violet (EUV) FELO equipped with Molibdenum/Silicium multilayer mirrors and frequency up-conversion based on the electron beam phase space manipulation is performed.  The first proposed scheme, seeded by the EUV FELO, similarly to a fresh bunch High-Gain Harmonic Generation (HGHG) FEL scheme, is a three-stage harmonic FEL cascade made of different undulator sections, where the seed modulates the electron bunches inducing non-linear phase space motions and the emission of higher harmonics in the following undulators. FEL emission in the final radiator up to the 35th harmonics of the FELO wavelength has been predicted by simulations, with the generaton of $10^9-10^{10}$ coherent photons per shot in the tender X-ray range at 0.5 MHz.   The same EUV FELO has been considered for seeding an Echo-Enhanced Harmonic Generation (EEHG) FEL cascade: the generation of intense ($10^8-10^{10}$ photons per shot), ultra-short (down to 1 fs) and coherent FEL pulses up to the 50th harmonics of the seed has been simulated, demonstrating a higher versatility, tunability and efficiency.  %has been proposed in literature for overcoming the limits posed by the incoherent energy spread and to reach higher harmonic orders: the seed is split in two pulses seeding the electron beam in two different modulators followed by two dispersive sections for harmonic bunching generation and a final radiator stage.   %Another option for the MariX X-ray FEL is a FELO based on an X-ray cavity as direct source of coherent X-rays. The design study of a cavity made of four diamond crystal mirrors has been carried out in collaboration with Politecnico di Milano. Based on the simulated performances of this source, fs-scale pulses with $10^10$ coherent photons per shot at 3-3.5 keV at 1 MHz are produced.  %The simulated performances of these schemes, driven by the MariX electron beam, show increased stability conditions with respect to the FEL start-up from shot noise, these studies have been published in peer-reviewed international journals and contributed to the MariX Conceptual Design Report.  %In the FELO configuration, high-power coherent pulses suitable for FEL seeding are generated and amplified by the passage of successive electron bunches through an undulator embedded in an optical cavity for radiation recirculation: the pulses’ wavelength and repetition rate are only linked to the availability of suitable cavity mirrors and to the cavity and electron beam repetition rate respectively, giving the possibility to provide high-frequency and coherent seed pulses at high repetition rate.   %I developed a simulation code for the FELO design and model, written in Fortran, which iterates the required simulation steps, automatically launching the 3D time-dependent FEL simulation code GENESIS 1.3 after each cavity round trip and accounting for the effects of propagation and mirrors. I have been studying the FELO configuration in different spectral regions.  %During the first year of PhD and in the framework of the MariX project, I studied advanced schemes for its X-ray seeded FEL. After the injector of the MariX accelerator complex, the electron beam is accelerated up to 3.8 GeV in a compact two-way Superconducting radio-frequency Linac, which operates in continuous-wave mode at 1 MHz and is equipped with an arc compressor reinjecting the beam in the Linac.  %The MariX novel and compact accelerator scheme, based on the two-pass two-way Superconducting Linac and an arc for electron beam compression and reinjection in the Linac, will be demonstrated in the MariX demonstrator, called BriXSinO, to be built at the LASA laboratory in Segrate. The electron bunches are generated using a DC gun driven by an Yitterbium laser, at a maximum repetition rate of about 93 MHz. After compression, the electrons are boosted by three Superconducting cavities and then injected into the two-pass two-way Linac, where the beam passes twice with alternate verse. The last element of the device is the arc, which allows the beam to come back to the two-way main Linac and hosts an Inverse Compton Source and a THz FEL.  %In this framework, I contributed with the study of the BriXSinO FEL source; named TeRra and operating in the short-THz frequency range (6-30 THz): thanks to the properties of the electron beam and due to space constraints, a FELO scheme with a two-mirror near concentric cavity hosting two short undulator modules with different periods has been chosen for the THz FEL. Source performances in both one and two-color operation, producing up to 1 kW of average power, were simulated. In this short-frequency emission range, the design study mainly focused on the definition of optimal stable oscillator parameters and working points.   %Such study contributed to the BriXSinO Technical Design Report and has been recently published.    \\par The second topic of this thesis is the ongoing collaboration with the SPARC\\\\ \\_LAB laboratory of INFN in Frascati in the framework of the EuPRAXIA project: objects of this collaboration are the demonstration of FEL lasing with a compact beam-driven plasma-wakefield accelerator at SPARC, whose plasma module is made of a cm-scale, 3D-printed capillary, and the design study of the EuPRAXIA FEL beamlines. \\\\  I contributed to the analysis of the experimental data obtained in two experiments at SPARC and the connected simulation of the FEL process. Single-spike FEL amplification at about 827 nm from shot noise with up to tens-nJ energy, characterized by high shot-to-shot energy fluctuations, has been measured and observed from both the experiment and simulations.  A second experiment with the same FEL, driven by the plasma-accelerated electron beam and seeded by a portion of the same laser used for the electron photo-emission, has shown increased energy levels and stability conditions.   %The result has been recently published in Nature and is promising for the future implementation of the EuPRAXIA@SPARC\\_LAB FEL.  This cumulative thesis finally presents the still ongoing design study of the second beamline of the EuPRAXIA@SPARC\\_LAB project, a compact and seeded low-energy beamline in the standard HGHG configuration, which can be driven by either the plasma accelerator or the EuPRAXIA X-band LINAC.  Simulations of its performances in the whole spectral range of operation and in the two electron beam modes are compared, showing the production of fully coherent single-spike pulses in the Vacuum-UV range from 50 to 180 nm starting from a long wavelength state-of-the-art laser pulse.","language":"eng","citation":"STUDIES OF COHERENT FREE-ELECTRON LASERS DRIVEN BY COMPACT LINACS OR BY PLASMA WAKEFIELD ACCELERATORS / M. Opromolla ; supervisor: V. Petrillo ; co-supervisor: G. Rossi ; director of the school: M. Paris. Università degli Studi di Milano, 2023 Jan 24. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12628.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/955633/2145578/phd_unimi_R12628.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/866538"},"title":"BONE TURNOVER AND FRACTURE RISK IN POSTMENOPAUSAL WOMEN WITH TYPE 2 DIABETES","internalauthor":"CAIROLI, ELISA","type":"Tesi di dottorato","year":"2021","abstract":"Introduction. Bone fragility is increasingly recognized as a complication of type 2 diabetes (T2DM). However, the underestimation of fracture (Fx) risk in T2DM using the classical assessment tools pointed out the need of clinical recommendations for the evaluation of bone health in T2DM. The multidisciplinary expert panel chaired by Chiodini suggested the diagnostic approaches for the detection of T2DM patients worthy of bone-active treatment (Chiodini I et al, Nutr Metab Cardiovasc Dis. 2021).  Aims. The aim of the study was to apply these algorithms to a well characterized cohort of postmenopausal women with T2DM to validate them in clinical practice.   Materials and methods. The presence of the major T2DM-specific Fx risk factors (a disease duration ≥10 years, one or more chronic T2DM complications, the use of insulin or thiazolidinediones and persistent poor glycaemic control) was ascertained at baseline in 107 female subjects with T2DM. They were conservatively followed-up. At baseline and after follow-up we evaluated bone mineral density (BMD) and the presence of clinical and morphometric vertebral Fx.   Results. Following the flow-charts, 34 (31.8%) and 73 (68.2%) patients would have been pharmacologically and conservatively treated, respectively. Among the 49 patients without both clinical Fx and major T2DM-related risk factors, who would have been, therefore, conservatively followed-up, only one subject showed a prevalent vertebral Fx (sensitivity 90%, negative predictive value 98%). After the follow-up the BMD variation in T2DM patients who would have been pharmacologically treated did not differ from that observed in T2DM patients who would have been conservatively followed-up. Two patients experienced an incident Fx and both would have been pharmacologically treated at baseline.   Conclusions. The clinical consensus recommendations established by the Italian multidisciplinary expert panel performed well in our sample of postmenopausal women with T2DM. Indeed, among those subjects with bone-active treatment indication as many as 15.3% of patients experienced an incident Fx fracture (incident rate 30 Fx per 1000 patient-years), thus confirming a high Fx risk worthy of specific treatment and, conversely, among those subjects without bone-active treatment indication no incident Fx were observed.","language":"eng","citation":"BONE TURNOVER AND FRACTURE RISK IN POSTMENOPAUSAL WOMEN WITH TYPE 2 DIABETES / E. Cairoli ; tutor: L. Fugazzola: supervisor: I. Chiodini ; coordinatore: E. Berti. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2021 Sep 09. 33. ciclo, Anno Accademico 2020. [10.13130/cairoli-elisa_phd2021-09-09].","filename":"phd_unimi_R12030.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/866538/1865205/phd_unimi_R12030.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1128516"},"title":"ELUCIDATING THE ROLE OF HET0016 IN AMELIORATING 20-HETE INDUCED OXIDATIVE STRESS AND LIVER INJURY IN B-THALASSEMIA: A NOVEL THERAPEUTIC TARGET","internalauthor":"BOU FAKHREDIN, RAYAN","type":"Tesi di dottorato","year":"2025","abstract":"Background: Reactive oxygen species (ROS) are one of the main contributors to pathological outcomes in β-thalassemia, with their generation being a consequence of iron overload and abnormal red blood cell metabolism. We have previously shown that CYP450 mediates ROS production in the liver of a mouse model of β-thalassemia through an increase in 20-hydroxyeicosatetraenoic acid (20-HETE) activity.  Aim: The aim of this study is to assess the efficacy of N-Hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016), an inhibitor of 20-HETE formation, in reducing 20-HETE-mediated oxidative stress and injury in the livers of mice affected by β-thalassemia.  Methods: Hbbth3/+ mice (The Jackson Laboratory) were used as a model of non-transfusion dependent thalassemia (NTDT) and were divided into 3 groups: a control group (N=11) treated intraperitoneally (IP) with a 1:1 solution of dimethyl sulfoxide (DMSO) and phosphate-buffered saline (PBS), Hbbth3/+ mice treated with a 1:1 solution of DMSO and PBS (N=14), and Hbbth3/+ mice treated with HET0016 (N=7). HET0016 was administered in the form of a daily IP injection at a dose of 5mg/kg/day for a total duration of four weeks. Enzymatic activity of NADPH oxidases was assessed using the NADPH oxidase assay. mRNA expression levels of two isoforms of CYP4A, as well as CYP4A protein levels, were measured in the liver using Real-time Polymerase Chain Reaction (PCR) and western blot, respectively. Degree of expression of CYP4A was also evaluated in the liver by immunohistochemistry (IHC). Formalin-fixed paraffin-embedded liver tissues were also sectioned and stained with Pearl’s Prussian blue stain to detect ferric iron (Fe3+). Sirius red stain and measurement of hepatocyte growth factor (HGF) mRNA expression levels were performed to detect signs of liver injury. To assess the degree of lipid peroxidation, an IHC staining for 4-hydroxynonenal (4-HNE) in addition to a malondialdehyde (MDA) colorimetric assay was performed. IHC staining for Caspase-3 was conducted to assess apoptosis. Finally, the effects of 20-HETE inhibition on the ferroptosis pathway were examined by measuring the mRNA and protein expression levels of glutathione peroxidase 4 (GPX4) in addition to measuring total glutathione (GSH) levels.   Results: In Hbbth3/+ mice, there was an increase in intracellular ROS levels and NADPH oxidase enzymatic activity. At both mRNA level and protein level, in addition to IHC staining, a significant increase was observed in the expression of CYP4A in Hbbth3/+ mice compared to control. This significantly decreased after HET0016 administration. Moreover, Hbbth3/+ mice showed an increase in the lipid peroxidation markers MDA and 4-HNE, which decreased after HET0016 administration. HET0016 also ameliorated liver injury in Hbbth3/+ mice treated with HET0016 as shown by a significant decrease in HGF mRNA expression levels and collagen fiber content. Increased tissue iron levels were detected in the liver of Hbbth3/+ mice compared to controls and this decreased with HET0016 administration. Caspase 3 levels also decreased following treatment with HET0016. Finally, HET0016 treated Hbbth3/+ mice showed a significant increase in GPX4 at both mRNA and protein level in addition to increased GSH levels, when compared to their non-treated counterparts.   Conclusion: Our preclinical study is the first to assess the efficacy of HET0016 in reducing 20-HETE-mediated oxidative stress and injury in the livers of mice affected by β-thalassemia. These findings lay the groundwork for future and further investigations on the role of 20-HETE induced oxidative stress in β-thalassemia and may pave the way for a new novel therapeutic target in the field.","language":"eng","citation":"ELUCIDATING THE ROLE OF HET0016 IN AMELIORATING 20-HETE INDUCED OXIDATIVE STRESS AND LIVER INJURY IN B-THALASSEMIA: A NOVEL THERAPEUTIC TARGET / R. Bou Fakhredin ; tutor: I. Motta   co-tutor: F. Peyvandi PhD program coordinator: C. Sforza. Dipartimento di Scienze Cliniche e di Comunità, 2025 Jan 23. 37. ciclo","filename":"phd_unimi_R13252.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1128516/2618783/phd_unimi_R13252.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/958034"},"title":"ROLE OF ASGR1 IN METABOLIC SYNDROME, OBESITY, AND ATHEROSCLEROSIS","internalauthor":"SVECLA, MONIKA","type":"Tesi di dottorato","year":"2023","abstract":"Background and aim: Asialoglycoprotein receptor 1 (ASGR1), is primarily expressed on the surface of the hepatocytes where it recognizes glycoproteins with exposed galactose or N-acetylgalactoseamine as terminal glycan moiety. Following recognition, the receptor binds to the glycoproteins and removes them from circulation through endocytosis. ASGR1 loss-of-function mutations have been linked to a lower cardiovascular risk of 34%. Thus, the aim of this Ph.D. project was to investigate, in vivo, the impact of ASGR1 deficiency on modulating glycans and glycoproteins and lipid metabolism on cardiometabolic disorders such as obesity and atherosclerosis.    Methods:  Male mice, 2-month-old WT and ASGR1 knockout (ASGR1-/-), were fed with a high-fat diet for 20 weeks (HFD). In those mice, extensive metabolic analysis and immunophenotyping were performed. Furthermore, total plasma N-glycome and untargeted liver proteomics were carried out for functional analysis. Second, to evaluate the lipid metabolism and atherosclerosis, we backcrossed ASGR1-/- with LDL-R-/- and ApoE-/- mice, generating DKO mice lacking ASGR1-/-/LDL-R-/- or ASGR1-/-/ApoE-/-. Female and male, 2-month-old LDL-R-/- and ApoE-/- mice were fed with a high-cholesterol diet (WTD, western-type diet) for 16 weeks. In DKO mice models lipid profile, plaque formation, and composition were assessed. Additionally, the circulating immunophenotype was measured.    Results: ASGR1-/- present similar trends with the WT mice for galactosylation in complex glycans as well as α-2,3-linked sialylation, on mono-/diantennary glycans and in tri-/tetrantennary glycans while they present an increased sialic acid O-acetylation. Upon HFD, the circulating metabolic profile of ASGR1 deficient was similar to the WT mice, in terms of lipid, glucose, and immunoinflammatory profile. However, ASGR1-deficient mice presented an inflamed liver and adipose tissue compared to WT. Additionally, the main ATP-production pathways such as β-oxidation, glycolysis, and gluconeogenesis were dysfunctional in ASGR1-/- compared to the controls. DKO mice ASGR1-/-/LDL-R-/- and ASGR1-/-/ApoE-/- compared to their controls, upon WTD diet present a significantly lower level of cholesterol with increased collagen content and without any change in immunoinflammatory profile. Those mice do not show changes in liver morphology.    Conclusion and discussion: Total plasma N-glycome remains stable in ASGR1 deficient mice suggesting that there is no increase in circulating glycoproteins. Thus, other redundant mechanisms should take over the glycoprotein endocytosis. ASGR1 deficiency upon high fat diet is associated with liver and adipose tissue inflammation without modulating the systemic one. In contrast, in high-cholesterol diet, ASGR1 deficiency lowers the lipid profile, reduces the plaque area size, and increases the collagen content, compared with the WT mice. These results indicate that the improved lipid profile reduces plaque progression and increases plaque stability. These changes did not alter liver morphology, nor the immunoinflammatory profile in circulating in DKO compared to their counterparts LDL-R-/-, ApoE-/- mice, respectively. These results indicate that ASGR1 might be a potential pharmacological target as target lowering therapy.","language":"eng","citation":"ROLE OF ASGR1 IN METABOLIC SYNDROME, OBESITY, AND ATHEROSCLEROSIS / M. Svecla ; supervisor: G. D. NORATA. Dipartimento di Scienze Farmacologiche e Biomolecolari, 2023 Apr 04. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12596.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/958034/2159117/phd_unimi_R12596.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1036168"},"title":"DENKMALER UND SACRARI FUR DIE HELDEN DES FASCHISMUS IN ITALIEN 1922 - 1943","internalauthor":"TOMESANI, MARTA","type":"Tesi di dottorato","year":"2024","abstract":"Questo elaborato di tesi intitolato Denkmaeler und sacrcari fuer die Helden des Faschismus in Italien 1922-1943 si prefigge di indagare le opere architettoniche e scultoree ideate o realizzate su iniziativa del partito fascista durante il ventennio 1922-1943, al fine di commemorare i caduti per la causa del regime, presentando le strategie adottate in ambito architettonico e scultoreo per ottemperare a direttive ed esigenze del culto del littorio. Innanzitutto è necessario premettere che si tratta di un lavoro di ricerca scientifico, che prende le distanze da qualsiasi posizione politica, basato sulla ferma convinzione che sia doveroso occuparsi della storia e comprenderla appieno, con il fine ultimo di impegnarsi a tutelare la democrazia.  Per il movimento fascista il culto dei caduti fu “probabilmente il più espressivo del suo senso di religiosità secolare” (Gentile, 1993, p. 47) e svolse fin dai primordi un ruolo chiave nella sua ideologia, costituendo una fra le manifestazioni più durature e meno soggette a variazioni, caratterizzato da una dimensione locale e al contempo capillarmente presente su tutto il territorio nazionale. Attingendo, come noto, alle forme e ai linguaggi del primo dopoguerra, così come al repertorio cristiano, il regime dedicò monumenti e sacrari ai caduti per la causa del regime (Suzzi Valli 2008; Masseroni, 2017) al fine di legittimare il proprio culto. Appuratone il carattere sincretico, i riferimenti alla religione cristiana, al contesto militare del secolo precedente ed alla romanità, questa tesi si propone di analizzare le architetture, il repertorio iconografico e il rapporto tra modernità e classicità adottati dal regime per definire architettonicamente e figurativamente la sacralità dei suoi luoghi sacri.   Con questo elaborato si offre quindi un contributo alla riflessione relativa alla definizione del concetto di sacrale nell’architettura e nell’arte del culto del littorio, suggerendo strumenti e chiavi di lettura di questo fenomeno, a partire dall’analisi delle fonti primarie – edite ed archivistiche – risalenti al ventennio. Considerati il carattere capillare di diffusione dei monumenti – che rimanda a quello della monumentomania del primo dopoguerra – e il numero di progetti e realizzazioni all’interno delle case del fascio, stimato a circa 25.000 (Mangione, 2006), risulta evidente come numerosi siano i monumenti e sacrari per i caduti per la causa fascista ad oggi non compiutamente approfonditi dalla ricerca. Nell’indagare quest’ambito, si palesa l’ulteriore difficoltà della definizione terminologica di sacrario e della tipologia in cui questi si inquadrano. Definito il sacrario come “Cappella o ambiente in cui sono raccolti i resti o i ricordi di persone benemerite della patria” (Treccani, enciclopedia), i luoghi sacri dedicati ai caduti fascisti si differenziano dai monumentali progetti di sacrari militari in quanto i primi si caratterizzano per un contesto di realizzazione più ampio, che spazia da ambienti ricavati all’interno di edifici istituzionali – fra cui appunto le case del fascio –, inseriti in punti nevralgici del tessuto urbano, a quelli previsti all’interno di edifici religiosi, in cimiteri così come include quelli allestiti in contesti espositivi. Ad oggi la ricerca riconduce, correttamente, i numerosi progetti di sacrari alle forme e ai linguaggi del noto modello del sacrario liberiano della Mostra della Rivoluzione Fascista. Tale tesi viene supportata dalla dimensione prescrittiva della realizzazione di un ambiente dedicato ai caduti all’interno delle case del fascio, contenuta nel foglio d’ordini promulgato dal partito il 20 novembre 1932. Si ritiene tuttavia che – considerando l’eterogeneità dei differenti contesti di realizzazione, la varietà di forme, stili e linguaggi impiegati nei vari progetti – la tipologia di monumenti e sacrari nel suo complesso vada ulteriormente indagata, soprattutto contestualizzandola nei diversi ambiti di realizzazione e alla luce dei dibattiti teorici sulla modernità e sulla romanità, così come in relazione alla definizione di un edificio religioso moderno finalizzato al culto. Inoltre si constata ad oggi la mancanza di uno studio sistematico che analizzi lo sviluppo architettonico ed artistico delle opere commemorative nell’intero arco cronologico della storia del fascismo, approfondendone i modelli architettonici, i rimandi iconografici e stilistici, contemplandone la presenza in riviste e periodici sia divulgativi che scientifici, ed andando a studiare le scelte artistiche operate dal regime per la realizzazione di un carattere sacrale precipuo del culto del littorio. A differenza di altre opere del regime a carattere rappresentativo, si conferma per i monumenti e i sacrari dedicati ai caduti per la causa fascista una evidente mancanza di linee guida, con un’inevitabile ricaduta sulla definizione delle opere stesse sia a livello progettuale sia di realizzazione. Sullo sfondo di tale complessa interazione tra esigenze politiche ed aneliti religiosi, si delinea una caratterizzazione artistica tutt’altro che lineare, bensì spesso contraddittoria ed imprecisa tanto nelle direttive quanto nelle aspettative del regime, che portò il monumento ad evolversi in luogo percorribile per il visitatore e il sacrario ad aprirsi da ambiente di raccoglimento personale a palcoscenico della messa in scena della liturgia del littorio, a scopo propagandistico dell’ideologia e della fede politica del regime.","language":"ita","citation":"DENKMALER UND SACRARI FUR DIE HELDEN DES FASCHISMUS IN ITALIEN 1922 - 1943 / M. Tomesani ; tutor:  I. Herklotz, S. G. Bignami ; coordinatore: F. Slavazzi. Dipartimento di Beni Culturali e Ambientali, 2024 Mar 14. 35. ciclo [10.13130/tomesani-marta_phd2024-03-14].","filename":"phd_unimi_R13291_2.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1036168/2601101/phd_unimi_R13291_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1233175"},"title":"PREPARATION OF NANO- AND MOLECULAR COMPOUNDS FOR ANTITUMORAL APPLICATIONS TRIGGERED BY LIGHT","internalauthor":"SCHIFANO, VERONICA","type":"Tesi di dottorato","year":"2026","abstract":"The PhD thesis comprises 5 research projects, all dealing with the preparation of compounds for antitumoral applications, involving different types of compounds: nanocomposite materials, organometallic complexes, and organic compounds. The antitumoral action of most of these systems was based on the photodynamic therapy (PDT), often to combine it with a secondary antitumoral strategy to enhance its efficiency. A smaller part of the thesis was instead devoted to the preparation of a luminescent metformin derivative to investigate the antitumoral activity of this antidiabetic drug.   In the first project, the surface of gold nanostars (GNS) was functionalized with a polyamidoamine-Ru(II) complex to increase the PDT efficiency of the complex, i.e. to produce ROS upon irradiation, due to the metal-enhanced 1O2 generation promoted by GNS. Another possible advantage of such functionalized nanostructures that has not been studied yet is the possibility to combine PDT with plasmon photothermal therapy (PTT) promoted by the same GNS. Differently, in the second project, GNS were employed to decorate the external surface of HNT, aiming to obtain a nanocomposite carrier for small molecules loaded into the HNT tubular structure, whose release would be triggered by the local hyperthermia produced by GNS. The action of the released drug is combined with the PTT. The antitumoral drug selected in this thesis (mitoxantrone) can be replaced with an organic photosensitizing agent to introduce an additional PDT treatment. In the third project HNT were functionalized in their inner lumen to serve as carriers for hydrophobic photosensitizers, such as perfluorinated porphyrins (in their non-coordinated and Zn-coordinated form), well known for their PDT action.  The second part of the thesis focuses on the preparation of organometallic and organic compounds and includes the last two projects. One concerns the preparation of a bioconjugate between a tris-cyclometalled Ir(III) complex and a peptide nucleic acid (PNA). This work aimed to obtain a multifunctional compound with anticancer activity based on a possible synergic effect between PDT, promoted by the Ir complex, and an antisense/antigene strategy induced by specific PNA sequences that can target RNA or DNA chains and interfere with their transcription. Finally, the last project was dedicated to the preparation of a luminescent molecule containing a terminal biguanide group to study how this moiety interacts with tumoral cells and can be related to the activity of the anti-diabetic drug metformin in inhibiting the proliferation of various types of tumors.   Moreover, for three of these projects, a biological investigation at the cellular level was carried out, confirming their efficacy for antitumoral therapies.","language":"eng","citation":"PREPARATION OF NANO- AND MOLECULAR COMPOUNDS FOR ANTITUMORAL APPLICATIONS TRIGGERED BY LIGHT / V. Schifano ; tutor: D. Maggioni ; co-tutor: S. Cauteruccio ; co-supervisore: A. Salvati ; coordinatore: L. Prati. Dipartimento di Chimica, 2026 Apr 16. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13888.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1233175/3299128/phd_unimi_R13888.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1126539"},"title":"UNVEILING HUMAN NATURAL KILLER CELLS ONTOGENESIS IN HOMEOSTATIC CONDITIONS AND DURING THE IMMUNE RECONSTITUTION AFTER HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION","internalauthor":"FRIGO, ALESSANDRO","type":"Tesi di dottorato","year":"2025","abstract":"Natural Killer (NK) cells are potent members of the innate immune system, as they are endowed with the capacity of sensing and eliminating tumor-transformed and viral infected cells by integrating a plethora of inhibitory and activating signals coming from a repertoire of germline encoded receptors whose expression is finely tuned throughout NK cell differentiation and licensing. For ontological reasons and similarities in terms of transcription factors and secreted cytokines, NK cells have been grouped in the family of innate lymphoid cells (ILCs), a recently identified heterogeneous cell population now divided into cytotoxic, by means of NK cells, and helper ILCs, further subdivided in subclusters mimicking helper T cells.   Despite advances in the classification of ILCs, their ontogenesis remains to date uncertain. Many notions come from murine models, but precise orthologous phenotypical markers often lack, as well some developmental intermediates, likely stimulus microenvironment driven. In fact, the generation of ILCs mostly occurs in the bone marrow niche, in contact with specific soluble and cellular components, but secondary lymphoid tissues and peripheral stimuli are involved in the most advanced phases. Additionally, ILCs are characterized by a huge plasticity, the capacity of transdifferentiating in other subsets NK cells included upon stimulations, further entangling the topic. h-ILC are mainly involved in homeostatic and metabolic processes but act as first line mediators in the tissues where they localize as a prompt source of pro-inflammatory stimuli. Recent evidence also reported ILCs contribution in different solid and hematologic malignancies, with both anti and pro-tumorigenic effects. Often, especially in the case of hematologic tumors an underlying aspect favoring tumor expansion is characterized by alterations in the ontogenetic pathways of both NK cells and h-ILCs, that result in the accumulation of undifferentiated, hypofunctional cells characterized by unconventional phenotypes, that are poorly investigated.  Additionally, NK cells concur in granting of a favorable outcome after hematopoietic stem cell transplantation (h-HSCT) being the first lymphocytic population to complete immune reconstitution(IR), thus providing immune-compromised individuals with a certain degree of protection from opportunistic pathogens, still representing the major cause of morbidity and mortality of this potent curative procedure. On the contrary, a little is known regarding h-ILC IR kinetics.   Given these premises, in this study we carried out a multi methodologic dissection of human NK cell ontogenesis to evaluate the contribution of rare subsets and h-ILCs. We started by FACS sorting and differentiating in vitro precursors, h-ILCs and NK cell subsets from the BM in presence of an autologous feeder layer of MSC that could help us to recapitulate the interactions occurring within the BM niche. To enlarge our data power and include also the stimuli occurring in the periphery, we performed a scRNA-seq experiment on 6 healthy subjects to characterize rare subsets from a transcriptomic point of view and to perform a pseudotime trajectory analysis that could infer differentiation trajectories based on transcriptional similarities. Last, a consistent part of this study was carried out on HSCT patients, a unique setting reported as a reliable model to study the ontogenesis of immune populations in vivo. This study was carried out by manual gating and applying a novel pipeline capable of processing FACS data as single cell ones.  Altogether our data confirm the involvement of h-ILCs in the differentiation pathway from precursors to mature NK cells. These h-ILCs mostly belong to the h-ILC3/p subset, confirming their nature of precursors also for NK cells. additionally, we highlight cCD56bright NK cells as driver of NK cell differentiation both in vitro and in silico. This is true also for the process of IR after h-HSCT, where cCD56bright are accompanied by expanded unCD56dim that concur to the generation of more differentiated NK cell subset few months after h-HSCT. However, in silico data hints that HCs unCD56dim NK cells differ from the unCD56dim identified after transplantation, suggesting the heterogeneity of NK cells with similar CD56 and CD16 expression. This is valid also for the unCD56bright NK cells, seemingly compatible with a more differentiated nature as hinted by our in vitro differentiation but characterized by an early appearance during IR and transcriptional and phenotypic features that make them indistinguishable from cCD56bright or cCD56dim. Another interesting aspect that we observed regards the relationship between NK cell activation, differentiation and licensing. If cells in vitro are uncapable of generating terminally differentiated subsets, circulating NK cells display an activated profile both in silico and ex vivo related with the acquisition of a terminal differentiated, fully licensed phenotype, highlighting the interplay of other stimuli and immune mediators in the homeostatic differentiation of NK cells and during their IR after h-HSCT.","language":"eng","citation":"UNVEILING HUMAN NATURAL KILLER CELLS ONTOGENESIS IN HOMEOSTATIC CONDITIONS AND DURING THE IMMUNE RECONSTITUTION AFTER HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION / A. Frigo ; tutor: D. Mavilio ; supervisor: C. Di Vito ; coordinatore: N. Landsberger. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2025 Jan 15. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13378.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1126539/2614142/phd_unimi_R13378.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1066288"},"title":"THE OBSCENE DEVICE. ARCHAEOLOGY OF IMMERSIVE PORNOGRAPHIES","internalauthor":"MALASPINA, ROBERTO PAOLO","type":"Tesi di dottorato","year":"2024","abstract":"This dissertation is devoted to examining the interplay between immersive devices and erotic-pornographic images. Employing a media archaeological approach, the research delves into technologies of the past to shed light on contemporary phenomena. Specifically, the stereoscope, in its various material forms, has served as the focal point of this exploration into erotic archaeology.   The initial segment of this study elucidated conceptual frameworks and interpretive paradigms essential for understanding the processes of immersion in the image. Posture and inclination were thus examined both as symbolic forms that co-partecipate in the immersion process and as metaphorical models underlying the transfer of meaning that attributes moral and social qualities to the bodies that perform it and the devices with which they come into contact.   Subsequently, the historical evolution of the stereoscopic apparatus and the philosophical discourse surrounding it have been examined. This investigation laid the groundwork for a theoretical trajectory exploring the stereoscopic devices both in their ergonomic conformations and rhetoric communication.   This structure was then applied to the more properly erotic-pornographic sphere. This section examined the functioning and compositional strategies of the stereopornographic image, focusing on the second half of the nineteenth century. One of the main aims was to demonstrate the non-coincidental synchronicity between the emergence of these machines of the visible and the definition of the pornographic in the modern sense. Indeed, it has been argued that the ambiguous relationship with technically reproduced reality inaugurated by the stereoscope has contributed to the ever-unstable definition of the ontology of the pornographic, beyond its genealogy related to cinema.  In keeping with the intention to propose the most situated analysis possible, we then proceeded to outline the relations – theoretical, scopic, social and political – between the female figure and erotic-immersive spectatorship in the same years, hypothesising a form of female resistance to the paradigms of the male gaze.   Finally, the dissertation returned to the present. Maintaining the perspectives used so far – posture and female spectatorship – the final chapter focused on the re-emergence of immersive pornography through Virtual Reality (VR), highlighting its main compositional, aesthetic and political characteristics.","language":"eng","citation":"THE OBSCENE DEVICE. ARCHAEOLOGY OF IMMERSIVE PORNOGRAPHIES / R.p. Malaspina ; tutor: A. Pinotti; co-tutor: S. Paasonen ; coordinatore del dottorato: N. Guicciardini Corsi Salviati. - Milano. Dipartimento di Filosofia Piero Martinetti, 2024 Jun 17. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12916.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1066288/2450472/phd_unimi_R12916.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1128522"},"title":"LIQUID BIOPSY IN GLIOBLASTOMA (GBM)CHARACTERIZATION OF PLASMA EXTRACELLULAR VESICLES CONCENTRATION, SIZE AND CARGO FOR NON-INVASIVE GBM DIAGNOSIS, MONITORING AND IDENTIFICATION OF CIRCULATING BIOMARKERS","internalauthor":"ZACCHERONI, ELENA","type":"Tesi di dottorato","year":"2025","abstract":"Glioblastoma (GBM) is a highly aggressive brain tumor that presents extensive heterogeneity and high recurrence rates. Current diagnostic and monitoring approaches, primarily relying on MRI and tissue biopsies, have limitations. MRI sensitivity is limited, and tissue sampling is invasive and may not accurately reflect tumor heterogeneity. Thus, the need for a non- invasive strategy to complement MRI and tissue profiling is critical to implement GBM management.  Liquid biopsy, particularly through the analysis of Extracellular Vesicles (EVs), offers a promising avenue. We isolated EVs from 2 mL of plasma using Size Exclusion Chromatography and assessed their concentration and size with Tunable Resistive Pulse Sensing. We observed increased plasma EV levels in GBM patients compared to healthy controls and patients with other CNS malignancies, with a predominance of medium-sized EVs in GBM plasma. Post-surgery, EV levels decreased, suggesting their potential for monitoring disease progression.  EV-associated DNA and total plasma exDNA analysis yielded limited insights into parental GBM mutations. Accordingly, shallow WGS of plasma exDNA revealed limited tumor- derived information. However, fragmentation patterns in total plasma exDNA showed differences between GBM patients and healthy controls.  Proteomic analysis of plasma EVs effectively distinguished GBM samples from healthy and matched GBM post-surgery samples, allowing the identification of potential companion biomarkers to implement the specific diagnosis of GBM and its longitudinal monitoring.","language":"eng","citation":"LIQUID BIOPSY IN GLIOBLASTOMA (GBM)CHARACTERIZATION OF PLASMA EXTRACELLULAR VESICLES CONCENTRATION, SIZE AND CARGO FOR NON-INVASIVE GBM DIAGNOSIS, MONITORING AND IDENTIFICATION OF CIRCULATING BIOMARKERS / E. Zaccheroni ; tutor: G. Pelicci ; supervisore: S. Santaguida ; curatori: S. El Andaloussi, J. Nordin (external advisors) ; phd coordinator: D. Pasini. Università degli Studi di Milano, 2025 Jan 21. 36. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13142_3.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1128522/2618821/phd_unimi_R13142_3.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1206436"},"title":"IS B4GALT5 DEFICIENCY A NEW CONGENITAL DISORDER OF GLYCOSYLATION?","internalauthor":"MONTAVOCI, LINDA","type":"Tesi di dottorato","year":"2026","abstract":"Glycosphingolipids (GSLs) are relevant components of mammalian cell membranes where they play multiple roles. Many specific glycosyltransferase enzymes are responsible for the synthesis of the different oligosaccharide chains of GSLs. Knock-out mouse models lacking single or multiple glycosyltransferases were generated in the past elucidating the role of individual GSLs in mouse brain. Inactive variants of two specific glycosyltransferases were found responsible for two human congenital disorders of glycosylation (CDG) characterized by clinical pictures not really predicted by the corresponding mouse KO models. Previous studies showed that two similar galactosyltransferases, B4GALT5 and B4GALT6, are both responsible for the synthesis of lactosylceramide (LacCer), the precursor of many GSLs. B4GALT5 appeared more relevant, but B4GALT6 was still able to rescue B4GALT5 KO in mice.  Genome analysis of a patient revealed a compound heterozygous mutation in B4GALT5 gene (DECIPHER Patient ID: 412221) opening the question if a novel human CDG exists not predicted by mouse models.   The aim of this thesis is to investigate if the above B4GALT5 variants are actually inactive and if human B4GALT6 is unable to compensate for the lack of B4GALT5 activity, indicating the possibility of such a novel CDG.  Cell models were constructed trough KO of either B4GALT5 or B4GALT6, or both together in HEK-293T cells using CRISPR/Cas9 genome editing. Transfections were performed with either coding cDNAs placed in expression vectors without or with N-terminal (Halo) or C-terminal (C-myc) tagging. Transcript levels by qPCR, protein expression by western blotting, galactosyltransferase activity by in vitro assay, and cell GSL biosynthesis by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) were then determined. Similar analyses were also performed on patient’s serum and dermal fibroblasts.   Results showed that the mutations do not impair transcript levels or protein expression, while both variants are totally unable to use their substrates in vitro and to restore LacCer and GM3 ganglioside expression upon transfection in double KO HEK-293T cells. In silico studies of mutated proteins revealed pronounced conformational instability compared to the wildtype, affecting both protein backbone and UDP-Gal binding. ΔStability calculations confirmed strong destabilizing effects, particularly for G274R.  Moreover, the GSL profile of patient serum and fibroblasts displayed  an accumulation of GlcCer and a strong reduction of LacCer, GM3 and globoside Gb3. These findings together indicate that both variants have lost their functional activity.  While B4GALT6 KO clones maintain almost unchanged the GSL pattern of HEK-293T cells, B4GALT5 KO clones retain less than 20% of the above GSLs, despite the transcript level of B4GLT6 is about 10-fold higher than that of B4GALT5. Moreover, upon transfection of B4GALT6 cDNA untagged or tagged at the C-terminus, no protein is detectable by western blotting, despite the high levels of B4GALT6 transcript achieved. Protein expression becomes evident only upon Halo tagging at the N-terminus, allowing detection of LacCer synthase activity in vitro and GSL rescuing in dKO clones. In particular, B4GALT6 ability to restore GSL expression is comparable to that of B4GALT5. However, detection of Halo-tagged B4GALT6 by western blotting is not comparable with that of Halo-tagged B4GALT5, since it requires much higher transcript levels to achieve comparable expression levels, as confirmed by transfecting the cDNAs placed under the control of weaker promoters. Hypothesizing a reduced efficiency of B4GALT6 translation, we constructed and transfected B4GALT6 chimeras where B4GALT5 N-terminal tail and transmembrane domain, or those plus the entire stem region, replaced the corresponding sequence of the native cDNA. Western blot analysis reveals detectable B4GALT6 protein with both chimeras, confirming the hypothesis.  In conclusion, the evidence that: (1) B4GALT5 variants reported in a patient are totally inactive; (2) human B4GALT6 is not efficiently translated being able to drive relevant GSL biosynthesis only at extremely high levels of its transcripts, suggest that the amounts of brain GSLs, probably gangliosides, could not be sufficient, at least in some cell types, to assure proper brain development and function. It is possible that a novel CDG exists, although additional patients and/or studied on differentiated neural cells or organoids are necessary for definitive proof.","language":"eng","citation":"IS B4GALT5 DEFICIENCY A NEW CONGENITAL DISORDER OF GLYCOSYLATION? / L. Montavoci ; tutor: A. Caretti ; co-tutor: M. Trinchera ; coordinatore: M. Clerici. Dipartimento di Scienze della Salute, 2026 Jan 22. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13861.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 07-LUG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1228016"},"title":"AN ENGINEERED POTASSIUM CHANNEL FOR THERMOGENETICS","internalauthor":"MERCURIO, CHIARA AGNESE","type":"Tesi di dottorato","year":"2026","abstract":"Pain, a complex sensory and emotional experience, is essential for protection against environmental threats but becomes maladaptive when chronic, as seen in neuropathic pain. This condition involves pathological hyperexcitability in nociceptive circuits, where ion channels play critical roles in action potential (AP) generation and propagation. While targeting endogenous ion channels offers therapeutic potential, their distinct expression patterns and compensatory mechanisms pose significant challenges. To address these limitations, we developed a synthetic potassium (K⁺) channel, TICK (Temperature-Induced Channel K⁺), designed for selective expression and activation via external thermal stimuli, enabling long-term membrane voltage hyperpolarisation to inhibit nociceptive signalling.   TICK was engineered by combining the temperature-sensitive domain of the bacterial BacNavAe1 channel with the viral KcvNTS channel pore. Through single-point mutations in the coiled-coil region, the prototype channel was optimised to activate within the physiological temperature range. Additionally, trafficking and export signals were introduced at the C-terminus to enhance plasma membrane expression. Electrophysiological analyses demonstrated a 3.3-fold increase in current density between 25°C and 40°C, and robust thermosensitivity, with a half-activation temperature (T1/2) of 38.95°C, and a Q10 value of \uf07e16. Confocal imaging revealed a >6-fold reduction in endoplasmic reticulum retention compared with earlier constructs, consistent with improved trafficking to the plasma membrane.  In vivo validation initially focused on the central nervous system, where viral delivery to the anterior cingulate cortex confirmed neuronal expression but indicated that infrared stimulation through the skull achieved only partial activation of the channel (maximum intracerebral ΔT of +1.68 °C). This limitation prompted the transition to the peripheral nervous system, where AAV-mediated delivery of TICK2.1 to dorsal root ganglia and sensory afferents successfully enabled peripheral expression. Upon localized heating of the hind paw, TICK2.1 activation significantly reduced inflammatory mechanical hypersensitivity in the Complete Freund’s Adjuvant (CFA) pain model, decreasing withdrawal responses by 73% in males and 33–44% in females compared with non-heated controls. These results represent the first demonstration that thermogenetic silencing of peripheral nociceptors can modulate pain behaviour in vivo.  Collectively, these findings establish TICK2.1 as a functional prototype for temperature-controlled neuronal inhibition and introduce thermogenetics as a viable strategy for gene-based analgesia. The project also integrated a technology transfer and translational development framework, outlining the preclinical, regulatory, and industrial pathways required to advance TICK2.1 towards clinical application. Future work will focus on refining viral vector design, optimising delivery and stimulation methods, and validating efficacy in chronic neuropathic pain models to support first-in-human studies.","language":"eng","citation":"AN ENGINEERED POTASSIUM CHANNEL FOR THERMOGENETICS / C.a. Mercurio ; scientific supervisor: A. Moroni ;  industrial supervisor: S. Gay ;  PhD school coordinator: S. Ricagno. Dipartimento di Bioscienze, 2026 Mar 25. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R14075.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 23-SET-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/852692"},"title":"STUDY AND EXPERIMENTAL ANALYSIS OF AN INNOVATIVE METHOD FOR QUENCH LOCALIZATION IN SUPERCONDUCTING HIGH ORDER MAGNETS","internalauthor":"MARIOTTO, SAMUELE","type":"Tesi di dottorato","year":"2021","abstract":"This Ph.D. thesis concerns the study of the quench propagation in the new High Order corrector superconducting magnets for the Large Hadron Collider upgrade project, called High Luminosity LHC, and the development of a magnetic field measurement system for their characterization. To better introduce the work performed on these types of superconducting magnets, a brief introduction to particle accelerators, and in particular particle accelerator colliders, is reported in Chapter 1. The introduction describes the basic concepts to further understand particle physics at high energy scales and the rules which govern particle interactions and their properties. It focuses mainly on the description of the magnetic field produced by a superconducting magnet and how the magnetic field quality can be measured and qualified. The new magnetic field measurement system, which has been used to measure and characterize the High Order corrector magnets, has been developed in a collaboration framework between INFN Milan and the CERN magnetic field measurement system department. This device is based on the classical rotating coil measuring system design with 5 PCB coils to achieve high levels of accuracy. A brief description of the theoretical frame of the rotating coil method for the magnetic measurement system is introduced in Chapter 1 highlighting the correlation between the magnetic field harmonics and the Fourier decomposition of the voltage induced in the rotating coil PCB. An introduction to the High Luminosity LHC upgrade project is reported in Chapter 2 to better describe the motivation and the requirements for the development of these new NbTi superconducting magnets on which this thesis work is performed. A detailed analysis of the magnet electromagnetic and mechanical designs is reported together with the description of the development of the new magnetic measurement system installed at the INFN-LASA laboratories in Milan. Being able to measure different types of HO corrector magnets in parallel during the same cryogenic test, the high rotational order of the magnets represents a challenge both for the calibration of the measurements and their accuracy. To optimize the design of the new magnetic measurement system, a set of electromagnetic 3D simulations have been performed on the final magnet configuration and assure that the cross-talking between the magnet during the cryogenic powering tests is negligible. The same set of simulations has been performed also for the configuration of the magnet when installed in the LHC lattice, to evaluate the performances in the final configuration, giving the same negligible cross-talking result. Finally, examples of real data of magnetic field quality, taken during the last phase of the prototype development and the first batch of the magnet series, are compared with the 3D electromagnetic simulations showing very good performances of the produced magnets. The quench protection study of the HO corrector magnets is reported in Chapter 3. A brief introduction to superconductivity is reported together with the description of the main problems which have to be faced during a quench development inside a superconducting magnet. The quench development and propagation inside the superconducting coils of the magnets have been studied focusing, at first, on the analysis of the coil material properties to reproduce experimental data. The superconductor wire and all the coil properties are described together with the comparison of the calculated differential inductance of the magnet with real data taken from the powering of corrector magnet prototypes. The simulations of the real quench that happened during both the prototype development phase and the series production, are in very good agreement with the simulated data, thus demonstrating high accuracy of the models used. The results obtained from the comparison have been used to model and evaluate the quench protection system requirements during the powering tests of the magnets and the final working condition in the LHC lattice. All the simulations have been firstly performed with the program QLASA, developed at LASA in Milan, and then improved with the combination of QLASA and the STEAM package, developed at CERN, to identify the real behaviour of the magnet internal voltages. The main innovative aspect of this thesis, reported in Chapter 4, concerns the use of the developed magnetic field quality measurement system to evaluate and locate the development of a quench inside the superconducting coils of the magnet. Even if different magnetic measurement system has been already used to detect the development of the quench inside superconducting magnets, like for example quench antennas, the presented method is based on the measurement of the residual magnetic field which is strongly influenced by the number and the position of the coils quenched in the magnet. We can precisely identify the quenched coil in the magnet through the analysis of the magnetic field harmonics produced by the sum of the magnetization of the superconductor inside the not-quenched coils and the residual magnetization of the ARMCO Iron, which composes the main structure of the magnets. A brief introduction on the observed behaviour of the residual magnetic field measured in the HO corrector magnets is reported. An analytical model of the expected behaviour of the superconductor coil magnetization contribution is reported together with the comparison with experimental data. A detailed FEM model and 2D simulations have been also developed and compared with experimental data showing the possibility to locate exactly the quenched coil inside the superconducting magnet for any rotational order of the main harmonic produced. After the magnet discharge, the presented method can reconstruct the exact location of the quench and it does not aim to detect the development of the quench inside a superconducting magnet nor to help triggering the protection system. The exact quenched coil reconstruction can help during the construction processes of a superconducting magnet prototype, as it helps identifying weak points, and it can also help during the series production to highlight possible superconductor degradation which limits the performances of the magnets. Finally, the conclusion of this Ph.D. work is reported with discussed future perspectives for additional analysis of this new type of investigation of the quench development inside superconducting magnets.","language":"eng","citation":"STUDY AND EXPERIMENTAL ANALYSIS OF AN INNOVATIVE METHOD FOR QUENCH LOCALIZATION IN SUPERCONDUCTING HIGH ORDER MAGNETS / S. Mariotto ; supervisor: M. Sorbi ; coordinator: M. Paris. Università degli Studi di Milano, 2021 Mar 23. 33. ciclo, Anno Accademico 2020. [10.13130/mariotto-samuele_phd2021-03-23].","filename":"phd_unimi_R12062.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/852692/1827514/phd_unimi_R12062.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1127843"},"title":"INVESTIGATING THE BASES OF THE SPECIFICITY OF THE RESTRICTOR COMPLEX FOR THE TERMINATION OF NONCODING TRANSCRIPTION","internalauthor":"MANDANA, GAURAV MADAPPA","type":"Tesi di dottorato","year":"2025","abstract":"Rampant transcription initiation occurring at the tens of thousands of cis-regulatory regions in the genome can be detrimental to the normal functioning of the cell. Several transcription termination mechanisms act to keep the initiation of non-productive transcription in check. The Restrictor complex, composed of the adaptor protein WDR82 and the RNA-binding protein ZC3H4, suppresses processive transcription of thousands of noncoding RNAs (ncRNA) in mammalian genomes. The mechanism of Restrictor-mediated termination is not known but does not involve cleavage of the nascent RNA, setting it apart from known mammalian termination machineries. Furthermore, it is uniquely specific for noncoding transcription.  Here, we show that ZC3H4 binds its non-coding RNA targets with high specificity, thereby bringing about Restrictor termination activity. We show that ZC3H4 RNA binding occurs at the very 5’ end of the transcript, to a specific RNA consensus sequence. We found that the activity of the Restrictor complex is more widespread than previously thought, with its depletion resulting in processive transcription at a vast number of previously undetectable ncRNAs.   Further, we show that PNUTS, a protein implicated in transcription termination and also in the Restrictor-mediated pathway, directly binds to nascent RNA originating from different genomic loci where PNUTS’ phosphatase binding partner PP1 is known to act. We show that among the PNUTS-bound RNAs are Restrictor-sensitive ncRNAs, thereby providing a basis for the Restrictor-PNUTS synergy recently reported. Finally, I show evidence of sequence specificity of PNUTS’ RNA binding, suggesting that the underlying RNA sequence facilitates recruitment of PNUTS-PP1 for targeted dephosphorylation events.","language":"eng","citation":"INVESTIGATING THE BASES OF THE SPECIFICITY OF THE RESTRICTOR COMPLEX FOR THE TERMINATION OF NONCODING TRANSCRIPTION / G.m. Mandana ; tutor: G. Natoli ; internal advisor: B. Amati ; co-tutor: D. Pasini. Università degli Studi di Milano, 2025 Jan 21. 36. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13159_2.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1127843/2616971/phd_unimi_R13159_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1221575"},"title":"USE OF GAS EMISSION BY BIOELECTROCHEMICAL APPROACHES FOR POWER-TO-X","internalauthor":"SOGGIA, GABRIELE","type":"Tesi di dottorato","year":"2026","abstract":"The transition toward a climate-neutral energy system requires technologies capable of con-verting surplus renewable electricity into valuable products within a circular and sustainable framework. Among these, Power-to-X (PtX) is emerging as a promising solution for energy conversion and storage. Bioelectrochemical systems (BESs) offers the possibility to couple renewable electricity storage with microbially catalysed carbon and nitrogen capture. Their mild operating conditions, renewability and tolerance to impurities of the biocatalyst could enable the valorisation of industrial side-streams and CO2-rich emissions.  This PhD project explored bioelectrochemical PtX pathways, focusing on Power-to-Methane (PtM) and Power-to-Protein (PtP), with the goal of improving their efficiency, cost-effectiveness, and feasibility. Both approaches were investigated as strategies for capturing natural and industrial CO2 emissions.  Within the PtM framework, a comprehensive review was conducted to assess reactor config-urations, CO2 sources, key operational parameters, and current barriers limiting the scaling up of this system. Experimentally, low-cost terracotta bioreactors were developed to capture CO2 in natural degassing areas. Although methane productivity remained low (8.5 ± 4.9 mL L-1 d-1) due to gas leakage, salt precipitation, sulphate-reducing bacteria competition, and CO2 dosing inefficiencies, the systems achieved a Coulombic efficiency of 45 ± 13%. The results confirmed the suitability of terracotta as a porous material capable of maintaining an anoxic environment for methanogenesis paving its possible application directly in-situ after improvements.  PtP was investigated as a route to couple renewable electricity storage with the valorisation of biogas-derived CO2 and NH3-rich digestate liquid fraction from anaerobic digestion, es-tablishing a circular economy loop. Single-cell protein production was tested in double-chamber microbial electrosynthesis cells (MES) at different cathode polarizations (−0.6 and −1.0 V vs Ag/AgCl), alongside an unpolarized control. Carbon-cloth electrodes functional-ized with wood-derived biochar were used as cathodes. More negative cathodic polarization enhanced CO2 and N capture (up to 39 ± 2% and 6.7 ± 0.8%, respectively) and protein con-tent (69.1 ± 1.0% at −1.0 V vs 43.2 ± 0.6% at −0.6 V and 33.1 ± 1.3% in the unpolarized control). No significant differences were observed between the amino acid profiles obtained using the two cathode polarizations. Microbial community analysis revealed a shift toward autotrophic and electrotrophic taxa at −1.0 V, whereas heterotrophs predominated in the con-trol.  A second set of experiments assessed the effect of different biochar post-treatments under -1.2 V vs Ag/AgCl cathode polarization. Biochar-enriched electrodes outperformed bare car-bon cloth. CO2-activated biochar exhibited the best performance, attributed to its higher sur-face area, abundance of functional groups, and amorphous structure offering more suitable pore dimensions for microorganisms interactions and thus electron transfer. N-impregnated and post-pyrolyzed biochars led to slightly lower protein yields due to their smoother and more graphitic structures. Single-cell proteins produced in this experiment displayed protein contents of 42-49%, similar to or slightly higher than soybean meal, and essential amino ac-ids content representing 39–41% of total amino acids.   Overall, the achieved nutritional value demonstrated the potential of PtP as a sustainable bi-otechnological pathway for feed and food production. Combined with insights from PtM, this work advances the development of bioelectrochemical PtX technologies as enabling tools for the energy transition within a circular and bio-based economy.","language":"eng","citation":"USE OF GAS EMISSION BY BIOELECTROCHEMICAL APPROACHES FOR POWER-TO-X / G. Soggia ; tutor: F. Adani ; co-tutor: P. Cristiani ; phd coordinator: R. S. Pilu. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2026 Mar 27. 38. ciclo, Anno Accademico 2025.","filename":"phd_unimi_R14144.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1221575/3266447/phd_unimi_R14144.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/953993"},"title":"STATISTICAL LEARNING FOR STANDARD MODEL PHENOMENOLOGY","internalauthor":"STEGEMAN, ROY","type":"Tesi di dottorato","year":"2022","abstract":"The focus of this thesis is the accurate determination of parton distribution functions (PDFs), with a particular emphasis on modern machine learning tools used within the NNPDF approach. We first present NNPDF4.0, currently the most recent and most precise set of PDFs based on a global dataset. We then provide suggestions for improvements to the machine learning tools used for the NNPDF4.0 determination, both in terms of parametrization and model selection. We discuss different sources of PDF uncertainty. First, we elucidate the nontrivial aspects of averaging over the space of PDF determinations by explicitly calculating the data-driven correlation between different sets of PDFs. Then, we lay out certain fundamental properties of the sampling as performed within NNPDF methodology through explicit examples, and discuss how one may gain insight into the results of a neural network fit despite it being a black box model. Finally, we show how the flexibility of the NNPDF methodology allows for it to be applied to problems other than PDF determination, in particular we present a determination of neutrino inelastic structure functions.","language":"eng","citation":"STATISTICAL LEARNING FOR STANDARD MODEL PHENOMENOLOGY / R. Stegeman ; supervisore: S. Forte ; coordinatore: M. Paris. Università degli Studi di Milano, 2022 Dec 19. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12724.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/953993/2137715/phd_unimi_R12724.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/899089"},"title":"ASTROPHYSICAL NUCLEAR REACTIONS ON NEON ISOTOPES AT LUNA","internalauthor":"MASHA, ELIANA","type":"Tesi di dottorato","year":"2022","abstract":"This thesis reports the direct measurements of the 22Ne(α,γ)26Mg and  20Ne(p,γ)21Na  reactions at astrophysical energies of interest.   The 22Ne(α,γ)26Mg reaction competes with the 22Ne(α,n)25Mg reaction which is the main source of neutrons for the s-process in low-mass Asymptotic Giant Branch and massive stars. At temperatures T < 300 MK where the (α,γ) channel becomes dominant, the rate of the 22Ne(α,γ)26Mg reaction is influenced by several resonances studied only indirectly. The first part of this thesis concerns the direct measurement of one of these resonances, Er = 334 keV, which so far was studied only indirectly leading to six orders of magnitude range of possible values for its resonance strength. The experiment has been performed at LUNA (Laboratory for Underground Nuclear Astrophysics) using the intense alpha beam of the LUNA 400 kV accelerator and a windowless gas target combined with a high-efficiency BGO detector. In the present study, an upper limit of 4.0·10−11 eV has been determined for the resonance strength. Taking into account these results, an up-dated 22Ne(α,γ)26Mg thermonuclear reaction rate was obtained and its role on the predicted 25Mg/26Mg ratio of a 5M⊙ AGBs was investigated. The data show a decrease by a factor of 15 of the intershell 25Mg/26Mg ratio.  The 20Ne(p,γ)21Na is the slowest reaction of the NeNa cycle. It determines the velocity of the cycle and defines the final abundances of the isotopes synthesized in this cycle. The uncertainties on the NeNa cycle are affected by the  20Ne(p,γ)21Na reaction rate. The main goal of the second part of this thesis was the direct measurement of the Ecm = 366 keV resonance which dominates the total rate in the temperature range between 0.2 GK and 1 GK. The measurement has been performed at LUNA using the windowless gas target and two high-purity germanium detectors placed at different positions. This measurement allowed to reduce the uncertainty on the strengths of the 366 keV resonance from 18% to 7%. These results were used to update the 20Ne(p,γ)21Na reaction rate.","language":"eng","citation":"ASTROPHYSICAL NUCLEAR REACTIONS ON NEON ISOTOPES AT LUNA / E. Masha ; supervisor: A. Guglielmetti; co-supervisor: A. Caciolli; director of the school: M. Paris. Dipartimento di Fisica Aldo Pontremoli, 2022 Jan 21. 34. ciclo, Anno Accademico 2021. [10.13130/masha-eliana_phd2022-01-21].","filename":"phd_unimi_R12368.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/899089/1958103/phd_unimi_R12368.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/890348"},"title":"THE DARK SIDE OF THE FORCE: SQUARE-TORSION GRAVITY AND DARK MATTER","internalauthor":"MEGIER, ELIAS ARAWI SOL","type":"Tesi di dottorato","year":"2021","abstract":"The present work explores the possibility that dark matter be described by spacetime geometry. This is achieved using a special instance of the so called square-torsion theories of gravity. Theories in this class extend the Einstein-Hilbert action with terms quadratic in the torsion tensor. The theory hereby studied seems to have hitherto been neglected due to the fact that the torsion tensor is not totally fixed by the equations of motion. Some torsional degrees of freedom remain to be fixed a priori as though they were external sources. The present work uses this analogy with matter and shows that it becomes mathematically exact for a spacetime with vanishing spin density. The free degrees of freedom then appear in the Einstein equations as a dark stress-energy tensor due to torsion. This tensor can take the exact form of dust, which is one of the most successful models for dark matter.  Square-torsion gravity is then applied to the long standing dark matter problem under the simplifying assumption of spherical symmetry. The dark stress-energy tensor satisfies an anisotropic structure equation. In vacuum this is equivalent to a wave equation with sources. A natural class of exact solutions is found which explicitly perturbs any seed spacetime metric by a conformal factor. This leads to the concept of dark coating. Static solutions are then used to construct structures that model dark matter halos surrounding baryonic bodies.  In the Newtonian régime the baryonic mass m_b and the flat rotation curve velocity v_f are shown to be related by the baryonic Tully-Fisher relation, where m_b is proportional to v_f^4, a hitherto purely empirical result.  The example of a dark halo on the Schwarzschild geometry is made as a toy model for a galaxy. Qualitative and quantitative features of galactic rotation curves are recovered. In this setting, a boundary of staticity is found, called torsion sphere, placed between the photon sphere and the event horizon. The phenomenon of dark radiation is briefly exposed.","language":"eng","citation":"THE DARK SIDE OF THE FORCE: SQUARE-TORSION GRAVITY AND DARK MATTER / E.a.s. Megier ; supervisors: S. L. CACCIATORI, L. PIZZOCCHERO; coordinator: V. MASTROPIETRO. Dipartimento di Matematica Federigo Enriques, 2021. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11862.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/890348/1933403/phd_unimi_R11862.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/961276"},"title":"METABOLIC ADVERSE EFFECTS INDUCED BY SECOND GENERATION ANTIPSYCHOTIC DRUGS IN PEDIATRIC PATIENTS: PHARMACOGENETIC PROFILING AND MECHANISTIC ANALYSIS OF GENETIC VARIANTS EFFECT IN VITRO MODELS","internalauthor":"NAPOLI, ALESSANDRA","type":"Tesi di dottorato","year":"2023","abstract":"Second-generation antipsychotics (SGAs) are increasingly used in pediatric patients both in and offlabel. The rise in SGA prescription rates may be due to the perception of improved safety compared with first-generation antipsychotics. However, SGA use is often associated with rapid weight gain and metabolic syndrome as adverse drug reactions (ADRs). Interestingly, these side effects are not observed in all SGA-treated children, suggesting that some underlying genetic factors may predispose an individual to develop these adverse conditions. Recent studies have identified single nucleotide polymorphisms (SNPs) in genes encoding for enzymes involved in drug metabolism (CYP450) and SGA receptors in the central nervous system (CNS), which partly explain the inter-patient variability in ADR development. With this project, we intend to define the role of SNPs in genes related to the pharmacodynamics of SGA, expressed in peripheral tissues, to evaluate their involvement in the mechanisms responsible for weight change and metabolic ADRs. To this end in a cohort of 209 paediatric patients affected by disruptive behavioural disturbance who are prescribed SGAs (risperidone and aripiprazole), we have assessed the association of pharmacodynamics genetic variants with the occurrence of changes in body mass index (BMI) Zscore. This allows us to evaluate if the presence of specific variant alleles increases or decreases the risk of weight changes and metabolic adverse events. Tested SNPs will be selected from a comprehensive meta-analysis by Zhang e al (2016) of associated gene variants with antipsychotic-related weight gain. Between the 15 SNPs studied, the variants statistically significant associated with BMI changes are rs6318, rs3813929, rs5181147 in 5- Hydroxytryptamine Receptor 2C (HTR2C), rs1799732, rs6275, rs7131056 in D2 dopamine receptor (DRD2) and rs489693 in melanocortin-4-receptor (MCR4). We consider that the identification of these SNPs might provide useful input for personalized and individualized early intervention. Another goal of this project is to examine the direct effect of SGAs and validate the role of selected SNP at the peripheral level by performing in vitro experiments. Dysregulation in adipose tissue homeostasis has been suggested as a plausible mechanism by which antipsychotics induced metabolic alteration. To investigate the impact of SGAs on dysfunctional adipose tissue we decided to use the SW872 liposarcoma cell model. 6 First, we performed a detailed characterization of the model establishing the cell culture condition for the adipogenic differentiation process. Then, to clarify the mechanisms by which SGAs induce weight gain we studied the risperidone effect on the adipogenesis of SW872. We observed that risperidone directly promoted adipocyte differentiation and lipid accumulation. To better understand the phenotype of risperidone-induced adipocytes, next we assess its impact on some mitochondria parameters. We observed that risperidone's effect on mitochondrial phenotype can more faithfully recapitulate the white adipocyte profile observed in human adipose tissue. In line with this, our data also showed that Hoxc4, a key marker of white adipocytes, is highly expressed in risperidone adipocytes. From these results, we hypothesize that the induction of white adipocytes may be a possible mechanism by which risperidone induces weight gain as a side effect. Finally, to validate in the adipocyte cell line the impact of SNPs on differentiation, we have set up an in vitro model system for the expression of the genetic variants, by choosing the site-directed mutagenesis approach to modified the DNA sequence of the genes of interest . We selected two SNPs: rs6318 for the 5-HT2C gene and rs6275 for the DRD2 gene, identified in our population study as related to BMI changes after SGAs administration and already evaluated in correlation with weight gain, metabolic ADRs, and antipsychotic treatment with a focus on SNC expression . Using our adipocyte differentiation protocol, we showed that the modified cells could be differentiated into adipocytes therefore providing a relevant model for studying the SNP role in SGAs-induced adipogenesis.","language":"eng","citation":"METABOLIC ADVERSE EFFECTS INDUCED BY SECOND GENERATION ANTIPSYCHOTIC DRUGS IN PEDIATRIC PATIENTS: PHARMACOGENETIC PROFILING AND MECHANISTIC ANALYSIS OF GENETIC VARIANTS EFFECT IN VITRO MODELS / A. Napoli ; tutor: E. Clementi ; correlatrice: C. Perotta, S. Zecchini, S. Cheli. Dipartimento di Scienze Biomediche e Cliniche, 2023 Apr 04. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12615_2.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/961276/2167972/phd_unimi_R12615_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/979908"},"title":"A DOCTRINAL VIEW OF LOGIC","internalauthor":"GUFFANTI, FRANCESCA","type":"Tesi di dottorato","year":"2023","abstract":"The general framework of this thesis is Categorical Logic, more precisely the one of Doctrines, introduced by Lawvere in 1969. Doctrines are a categorical tool that allows the analysis of both syntax and semantics of logical theories — in particular first-order theories — using the same mathematical structure.  The thesis begins with a thorough analysis of Henkin’s Theorem for first-order logic (“every consistent theory has a model”), with the aim of interpreting it in the language of existential implicational doctrines. The thesis also considers how to describe free constructions in algebra in the context of elementary doctrines.  At first, we study the meaning of “adding a constant to a language” for any doctrine, and “adding an axiom to a theory” for a primary doctrine.  These constructions are used to find a possible interpretation of Henkin’s Theorem. Starting from a consistent doctrine, we construct a new doctrine which is rich, where a theory is rich when for every valid formula of the kind ∃xφ(x) there exists a witness constant c such that φ(c) holds. We then show that a rich doctrine admits an appropriate morphism towards the doctrine of subsets. Henkin’s Theorem for doctrines follows from these two results, and our proof in the context of existential implicational doctrines is modeled on the main lines of the original theorem.  Finally, the thesis proposes a further analysis of the procedure for adding structure and axioms to a theory, this time in the context of elementary doctrines. It is well-known in universal algebra that adding structure and equational axioms generates forgetful functors between varieties, and such functors all have left adjoints. Given a morphism of elementary doctrines, we prove the existence of a left adjoint of the functor induced by precomposition in the doctrine of subobjects of a Grothendieck topos. It is then shown how the existence of free functors in universal algebra follows from a more general result that lives in the theory of doctrines.","language":"eng","citation":"A DOCTRINAL VIEW OF LOGIC / F. Guffanti ; coordinatore: D. Bambusi ; tutor: S. Mantovani ; co-tutor: G. Rosolini. Dipartimento di Matematica Federigo Enriques, 2023 Jul 17. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12543.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/979908/2231751/phd_unimi_R12543.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1123315"},"title":"IMPACT OF CHOLINE SUPPLEMENTATION ON GENETICALLY MODIFIED MICE: NEW INSIGHTS IN THE MODULATION OF CARDIOVASCULAR RISK","internalauthor":"COLOMBO, ALICE","type":"Tesi di dottorato","year":"2024","abstract":"Atherosclerotic cardiovascular disease is the leading cause of death globally. In recent years, scientific evidence has suggested a role of the gut microbiota in the modulation of cardiovascular risk and a major focus has been directed on trimethylamine-N-oxide (TMAO), a gut microbiota-derived metabolite of dietary choline, whose plasma levels are positively correlated with an increased risk of cardiovascular events.  This project was aimed at investigating whether different amounts of dietary choline administered to genetically modified mice, prone to atherosclerosis development, would result in further metabolic changes, beyond TMAO production, and to assess whether the gut microbiota shaped by diets with different choline content maintained an intrinsic ability to induce atherosclerosis in mice.  Ten-weeks-old atherosclerosis-prone, apolipoprotein E-deficient (EKO) female mice were divided in two groups of 20 animals each and fed for 16 weeks two standard low-fat diets, only differing for their choline content (STD, containing 0.09% choline and HC, containing 1.2% choline). At the end of the dietary treatment, atherosclerosis development, targeted plasma metabolomics, hepatic transcriptome and gut microbiota composition were evaluated. Furthermore, the cecal content of STD and HC mice was transplanted into antibiotic-treated EKO female mice (10 animals/group), which were subsequently fed STD for 16 weeks. At sacrifice, the same analyses performed in STD and HC mice were carried out. Additionally, specific regulatory mechanisms driven by the two choline metabolites, betaine and TMAO, were investigated in vitro, in HepG2 cells.  HC diet worsened atherosclerosis development. Interestingly, metabolomic analysis revealed that HC diet, besides increasing TMAO plasma levels, lowered those of homocysteine and increased those of methionine, sarcosine, glycine, carnitine, propionylcarnitine and butyrylcarnitine. Liver transcriptomic analysis supported these metabolic findings, showing that the genes upregulated in HC mice enriched pathways mainly involved in the amino acid and one-carbon metabolism. HC diet mildly modulated gut microbiota composition, and these moderate differences between the microbiota of HC and STD did not differently affect atherosclerosis development in microbiota transplanted mice. However, metabolomic analysis showed a decrease of several plasma triglyceride species in mice that received the microbiota from HC mice, and this result was in line with liver transcriptomic data. In vitro experiments on HepG2 cells suggested a direct modulatory effect of betaine and TMAO on choline-homocysteine-related pathways never described before.  In conclusion, the supplementation of dietary choline worsened the development of atherosclerosis, and, additional to TMAO, modified plasma levels of several metabolites playing a role in cardiovascular disease. HC diet mildly modulated gut microbiota, which did not show an increased pro-atherogenic potential, but affected the levels of several plasma lipids, mainly triglycerides. Finally, choline metabolites, tested in vitro, exerted a direct effect on the one carbon metabolism pathway, suggesting new choline-mediated mechanisms implied in atherosclerosis development, which will deserve further investigation.","language":"eng","citation":"IMPACT OF CHOLINE SUPPLEMENTATION ON GENETICALLY MODIFIED MICE: NEW INSIGHTS IN THE MODULATION OF CARDIOVASCULAR RISK / A. Colombo ; tutor: G. Chiesa ; coordinatore: G. D. Norata. Dip. di Scienze Farmacologiche e Biomolecolari Rodolfo Paoletti, 2024 Dec 19. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13232.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1123315/2604975/phd_unimi_R13232.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/819652"},"title":"PALLADIUM CATALYZED REACTIONS: REDUCTIVE CYCLIZATION OF NITROARENES, AND OXIDATIVE CARBONYLATION OF ANILINE","internalauthor":"RAMADAN, DOAA REDA MOHAMED","type":"Tesi di dottorato","year":"2021","abstract":"Palladium Catalyzed Reactions: Reductive Cyclization of Nitroarenes, and Oxidative Carbonylation of Aniline      Abstract:  The thesis is divided into two main chapters: reductive cyclization of nitroarenes, and oxidative carbonylation of aniline.     The first chapter involves developing a catalytic system for carbazoles synthesis through reductive cyclization of 2-nitrobiphenyls employing phenyl formate as an in-situ source of CO. Thus, the synthetic chemist can avoid handling pressurized CO lines and perform the reaction in a pressure tube, a cheap and readily available tool for any laboratory. Moreover, the developed protocol can tolerate both air and moisture and can be performed using undried and undistilled commercial DMF. Several carbazoles bearing a wide range of substituents were synthesized in good to excellent yields including some with valuable pharmaceutical or thermo/electrical applications. The reaction could be performed on the grams scale affording carbazole in a very good yield (85%) without the need for chromatographic purification, making our synthetic strategy even more attractive and economically advantageous.            The second chapter deals with the palladium/iodide couple which is the most investigated catalytic system for the oxidative carbonylation of amines to give ureas or carbamates. In reinvestigating it, we found that the most prominent role of iodide is to etch the stainless steel of the autoclave employed in most of previous works, releasing in solution small amounts of iron salts. The latter are much better promoters than iodide itself. Iron and iodide have a complex interplay and, depending on relative ratios, can even deactivate each other. The presence of a halide is beneficial, but chloride is better than iodide in this respect. The ideal Fe/Pd ratio is around 10, but even an equimolar amount of iron with respect to palladium (0.02 mol% with respect to aniline, corresponding to 12 ppm Fe with respect to the whole solution) is sufficient to boost the activity of the catalytic system. Such small amount may also come from Fe(CO)5 impurities present in the CO gas when stored in steel tanks. The role of the solvent has also been investigated. It was found that the reason for the better selectivity in some cases is at least in part due to a hydrolysis of the solvent itself, which removes the coproduced water.","language":"eng","citation":"PALLADIUM CATALYZED REACTIONS: REDUCTIVE CYCLIZATION OF NITROARENES, AND OXIDATIVE CARBONYLATION OF ANILINE / D.r.m. Ramadan ; COORDINATOR: E. LICANDRO ; ADVISOR: F. RAGAINI. Dipartimento di Chimica, 2021 Mar 09. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11990.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/819652/1718871/phd_unimi_R11990.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1205210"},"title":"BIOLOGICAL AND CLINICAL MARKERS IN PSYCHOPATHOLOGY: FROM VULNERABILITY TO CATEGORICAL DISORDERS","internalauthor":"COLLI, CHIARA","type":"Tesi di dottorato","year":"2026","abstract":"Studying risk factors, trajectories, and outcomes of psychiatric disorders is crucial for improving their  management and clarifying their causal links. Ultimately, the goal is to develop early intervention strategies  that can mitigate the impact of clinically established conditions later in life. This requires a comprehensive  understanding of the underlying psychopathological processes.  Adolescence to early adulthood represents a particularly critical phase of vulnerability, during which the  intertwined relationship between genetic and environmental factors shapes both brain development and  behavioral patterns, potentially leading to the onset of psychiatric disorder.  Within this developmental framework, my research aims to disentangle the extent to which genetic and  environmental factors drive brain and behavioral differences in a young sample, employing twin analysis as  a powerful method to explore these influences.  Specifically, my thesis focuses on the early detection and prevention of severe psychiatric disorders,  adopting a transdiagnostic approach and integrating genetic, environmental, biological, and economic  perspectives.  Through twin models, I investigated the genetic and environmental determinants of susceptibility states,  employing both specifically designed questionnaires and potential biological biomarkers (i.e., L1  retrotransposons). Moreover, I examined the clinical and economic implications of implementing MRI in  the routine evaluation of first-episode psychosis to rule out the “organic” form of psychosis.  The psychopathological process was thus addressed at different stages and from multiple perspectives, with  the common aim of better characterizing vulnerability states, facilitating early identification, and supporting  timely interventions to modify illness trajectories.","language":"eng","citation":"BIOLOGICAL AND CLINICAL MARKERS IN PSYCHOPATHOLOGY: FROM VULNERABILITY TO CATEGORICAL DISORDERS / C. Colli ; supervisor: P. Brambilla ;  program coordinator: S. M. Clerici. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2025. 38. ciclo, Anno Accademico 2025/2026.","filename":"phd_unimi_R13864.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 29-GIU-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1165817"},"title":"RECYCLED MANURE SOLIDS AS DAIRY COW BEDDING SUBSTRATES: MICROBIOLOGICAL ASPECTS RELATED TO MAMMARY GLAND HEALTH","internalauthor":"FUSAR POLI, SARA","type":"Tesi di dottorato","year":"2025","abstract":"Recycled manure solids (RMS) have emerged as a sustainable alternative to conventional bedding   materials in dairy farming, in line with the principles of circular economy and environmental   sustainability. However, its adoption poses challenges, particularly in terms of microbiological risks   and effects on udder health. This thesis investigates the use of RMS, with a particular focus on the   use of separated raw manure solids (SRMS) and anaerobically digested manure solids (ADMS) as   bedding substrates. Comparative analyses of RMS with conventional materials such as sand and   sawdust were also conducted to explore their advantages and disadvantages in greater detail. The   first study evaluated the effect of refrigeration and freezing prior to microbiological analysis on the   bacteriological counts of SRMS, ADMS, and new sand, and showed that storage conditions impacted   on the recovery of some bacterial populations, particularly Gram-negative bacteria. These findings   underscore the importance of proper storage to ensure reliable microbiological analysis and valid   comparisons across materials. The second study examined the effects of different concentrations of   a lime-based bedding conditioner (LBC) on the physicochemical properties and microbial counts of   RMS. The results showed that LBC was effective in increasing pH and dry matter (DM) content, with   higher concentrations resulting in higher reductions in bacterial counts. This study highlights the   potential of stabilization treatments in mitigating the microbiological risks associated with RMS. The   third study evaluated the in vitro efficacy of LBC in inhibiting the growth of specific environmental   mastitis-associated pathogens (Escherichia coli, Klebsiella pneumoniae, Streptococcus uberis, and   Enterococcus faecium) in different bedding substrates, including RMS, sand, and sawdust. LBC   reduced pathogen loads in all substrates, but its effectiveness depended both on the substrate and   on the pathogen characteristics. These findings suggest that LBC is a promising but contextdependent solution for pathogen control. Overall, RMS shows potential as a cost-effective and   sustainable bedding option. However, their microbiological risks require attention through   appropriate management and stabilization treatments. Comparative analyses with conventional   materials highlight the need for rigorous on-farm evaluations to assess long-term effects on dairy   cow health, welfare, and milk quality under different management conditions. This research   provides practical insights for dairy farmers seeking sustainable bedding strategies while maintaining   high standards of hygiene and productivity.","language":"eng","citation":"RECYCLED MANURE SOLIDS AS DAIRY COW BEDDING SUBSTRATES: MICROBIOLOGICAL ASPECTS RELATED TO MAMMARY GLAND HEALTH / S. Fusar Poli ; tutor: M. F. Addis ;  coordinator: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2025 Jun 13. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13632.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1165817/3075149/phd_unimi_R13632.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/933253"},"title":"STRUMENTI GIURIDICI DI CONTRASTO ALLA CRIMINALITA' ORGANIZZATA NELLA PROSPETTIVA DELLE POLITICHE EUROPEE","internalauthor":"VILASI, FELICIA","type":"Tesi di dottorato","year":"2022","abstract":"Analysis of the process of European harmonization of criminal law and European judicial cooperation in the fight against organized crime, with specific regard to the establishment of the European Public Prosecutor’s Office.","language":"ita","citation":"STRUMENTI GIURIDICI DI CONTRASTO ALLA CRIMINALITA' ORGANIZZATA NELLA PROSPETTIVA DELLE POLITICHE EUROPEE / F. Vilasi ; tutor: F. Basile ; coordinator: F. Basile. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2022 Jul 11. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12286.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/933253/2049915/phd_unimi_R12286.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/978211"},"title":"EPIDEMIOLOGICAL AND FUNCTIONAL APPROACHES TO EVALUATE THE EFFECTS OF PARTICULATE MATTER EXPOSURE IN INFANTS WITH VIRAL BRONCHIOLITIS","internalauthor":"CAFORA, MARCO","type":"Tesi di dottorato","year":"2023","abstract":"According to the World Health Organization (WHO), environmental air pollution is currently among the leading causes of death and disease globally. Particulate matter (PM) exposure has been linked to the exacerbation of acute respiratory diseases, especially in the most susceptible population’s subgroups, such as infants and chil\\dren. Acute bronchiolitis, a common clinical condition characterized by inflammation and obstruction of bronchioles, is generally caused by a viral infection of the lower airways and is estimated to be the leading cause of hospitalization of infants worldwide. At present, the severity of the disease is only partially explained by current known predisposing risk factors but recent evidence suggests that short-term exposure to PM causing airway inflammation, might result in increased susceptibility to viral infections and bronchiolitis severity.  Due to its anatomical location, the upper respiratory tract (URT) is persistently exposed to PM, which affects the airway microbiome: recent evidence has linked the effects of PM10 and PM2.5 to microbiota structure and composition. In this context, innate immunity plays a fundamental role in the first response to both exogenous agents and commensal/pathobionts components of microbiota. In particular, bacterial-derived Extracellular vesicles (bEVs) are emerging as essential interregnum messengers that could play a crucial role in communication with mammalian cells, by modulating the host immune system.  The main aim of the work is to investigate how PM exposure might modulate the relation that occurs between the severity of acute bronchiolitis, the respiratory microbiota, and the host immune response mediated by bEVs. First, we showed that the exposure to PM2.5 from the Milan metropolitan area impaired the innate immunity response following an acute infectious stimulus in a zebrafish (Danio rerio) embryo model. In particular, PM induced a pro-inflammatory effect, which leads to a dampened leukocytic response to a subsequent inflammatory stimulus. In the second part of the thesis, we investigated the relationship between short-term exposure to PM (PM2.5 and PM10) and the severity of viral bronchiolitis through a population study involving infants with bronchiolitis (with and without Respiratory Syncytial Virus, RSV, infection) aged less than one year living in the area of Milan. A positive association was observed between the severity of the disease and PM2.5 and PM10 exposure levels in the third week before the bronchiolitis peak. Moreover, we performed a metataxonomic analysis, comparing the composition of the bacterial portion of the nasal microbiome (bNM) of infants with bronchiolitis and matched it to healthy controls, to unveil a plausible interplay of the URT microbiota in this framework. We observed a respiratory dysbiosis in bNM of infants with bronchiolitis. Furthermore, Haemophilus influenzae (Hi) was predicted as the most represented species and also positively modulated by PM exposure during bronchiolitis. Last, the immunomodulatory potential of Hi-deriving bEVs was investigated using the zebrafish embryo. With this model, we showed that Hi-bEVs promote a pro-inflammatory response by altering leukocyte trafficking in particular in the neutrophil population.  Overall, our data support the role of PM exposure in influencing the interplay between respiratory viruses, such as RSV, and specific microbiota components of the URT, such as Hi, in modulating the host immune response, potentially determining the pathogenesis and severity of acute bronchiolitis.","language":"eng","citation":"EPIDEMIOLOGICAL AND FUNCTIONAL APPROACHES TO EVALUATE THE EFFECTS OF PARTICULATE MATTER EXPOSURE IN INFANTS WITH VIRAL BRONCHIOLITIS / M. Cafora ; tutor: V. Bollati ; coordinatore: F. Ficetola. Dipartimento di Scienze Cliniche e di Comunità, 2023 Jul 11. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12618.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/978211/2226222/phd_unimi_R12618.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1168135"},"title":"TOOLS AND STRATEGIES FOR THE SYNTHESIS OF PHARMACEUTICAL ACTIVE COMPOUNDS","internalauthor":"ORLANDO, PAOLO","type":"Tesi di dottorato","year":"2025","abstract":"This dissertation presents an overview of three years of research aimed at applying novel tools and strategies for the synthesis of potential pharmaceutical active compounds.   In this context, I commenced my research at the University of Milano under the supervision of Professor Daniele Passarella. My work centered on two main projects involving the design, synthesis, and characterization of new pharmaceutical compounds with potential therapeutic applications. These projects focus on convenience and cost-effective synthetic strategies, as detailed in Chapters 1 and 2.   I also had the opportunity to spend six months abroad at ICIQ (Tarragona, Spain) in the laboratory of Professor Arjan Kleij. During this time, I worked on the enantioselective synthesis of chiral γ-amino alcohols, which is presented in Chapter 3, as well as the utilization of carbon dioxide as a green starting material to create novel drug-containing macromolecules for future drug-delivery applications, outlined in Chapter 4. In the final part of my Ph.D. program, I moved to Indena SpA (Settala, Italy) to complete my industrial internship, which was a part of my Ph.D. funding. The research conducted during this period focused on the extraction and purification of a component of vaccine adjuvant mixtures, discussed in Chapter 5.  Chapter 1 explores the safracin family, a class of alkaloids known for their significant antibacterial and antitumor properties, which were first isolated from bacteria such as Pseudomonas species. This chapter begins with a detailed NMR characterization of Safracin B, an important intermediate in the synthesis of commercially available anticancer drugs. We then report on the synthetic conversion of Safracin B into Cyanosafracin B and Safracin A, two additional components of the safracin family, along with their structural elucidation achieved through NMR spectroscopy. The findings presented will enhance the overall understanding of the chemical profile of safracins and provide a foundation for further chemical and structural investigations into their biological activities and potential applications in drug discovery. Chapter 2 focuses on the design and synthesis of novel tubulin binders in the frame of the European Joint Doctorate TubInTrain program, which examines microtubule dynamics and their relationship to neurodegenerative diseases. The designed scaffolds, created using time- and cost-efficient synthetic methods, feature an amide core with various warheads intended for covalent targeting of tubulin. Biochemical evaluations and X-ray crystallography structure determinations have revealed promising candidates that can covalently bind to the Todalam site. These encouraging results motivate us to continue optimizing these molecules.  Chapter 3 discusses the first project I undertook at ICIQ in the laboratory of Professor Arjan Kleij. Specifically, we present the first general enantioselective synthesis of γ-amino alcohols that contain a tertiary carbon center through a Cu-based propargylic amination reaction. Our protocol features user-friendly reaction conditions for the initial oxidation step, and we have established a reasonable scope for both alkynyl oxetanes and functional aromatic amines. Furthermore, the further derivatization of selected γ-amino alcohols demonstrates the synthetic potential of these chiral building blocks, which could diversify the range of chiral intermediates valuable for future drug discovery and development programs.   Chapter 4 deals with the development of an effective method for synthesizing drug-modified six-membered cyclic carbonates. These can subsequently be advanced to polycarbonates through organocatalytic ring-opening polymerization (ROP), allowing for a controllable amount of the drug in   the resulting polymer-drug conjugates. Preliminary depolymerization studies conducted by Arjan Kleij’s research group indicate that the free acid form of the drug can be released at elevated temperatures, while the polycarbonate selectively degrades into a bicyclic triol. These encouraging results lead us to further investigate this area for future drug release applications.  Finally, Chapter 5 addresses a project aimed at the extraction and purification of squalene from vegetable sources. Squalene is a natural triterpene used as an adjuvant in vaccine formulations. In this context, we aimed to develop an efficient and scalable extraction method that could be applied in an industrial setting to yield the desired target quantitatively.","language":"eng","citation":"TOOLS AND STRATEGIES FOR THE SYNTHESIS OF PHARMACEUTICAL ACTIVE COMPOUNDS / P. Orlando ; tutor: D. Passarella ;  co-tutor: P. Allegrini ;  coordinatore: D. Passarella. Dipartimento di Chimica, 2025 Jun 05. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13636.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 02-DIC-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/843343"},"title":"QUASI EX CONTRACTU TENERI: RICERCHE SULL¿ORIGINE DELLA CATEGORIA DEL QUASI CONTRATTO.","internalauthor":"SANTORU, PIETRO GIOVANNI ANTONIO","type":"Tesi di dottorato","year":"2021","abstract":"The purpose of this thesis is to make a contribution to the reflection on quasi-contracts by surveying the most problematic aspects of the subject. In particular, through the analysis of the evolutionary path made starting from the classification of the sources of obligation, it will be attempted whether the quasi-contract is already attested in the classical Roman jurisprudential thought and, at the same time, to understand what is the process that led to the development of the same.  The analysis is structured in four chapters. In the first one, it is outlined a brief historical evolutionary framework of the quasi-contract that starts from the reflections made by Roman jurists, in the main historical periods, and then reaches, passing through the discipline of common law and the doctrine of the seventeenth and eighteenth centuries, the reasons that led to its non-acceptance within the current regulatory framework of the Italian Civil Code of 1942. In the second part, starting from the summa divisio obligationum contained in the Institutiones of Gaius, the first question is why a partition that is originally presented as basically complete, is not in fact so, and then what can be, following the close relationship between mutuum and solutio indebiti, the perspective from which the jurist moves in the elaboration of his partition. All of this, trying to establish whether, starting from the proper juridical foundation on which the obligationes ex variis causarum figuris are based, there is any clear dialectical purpose between what Gaius asserts in his multifunctional institutional manual and the subsequent elaboration envisaged in the Libri rerum cottidianarum sive aureorum.  In the third one, after that, an attempt will be made to demonstrate both the truthfulness and completeness of what has been transmitted to us in the Res cottidianae, about the tripartition of the sources of obligations and the figures that can be traced back to it, especially in the light of what was the subsequent elaboration expressed in Justinian’s Institutions, and then, questioning the relationship between obligatio and actio in personam, to establish whether, before and during the period in which Gaius lived, the cases listed among the obligationes ex variis causarum figuris were known, and likewise to ascertain whether they were treated in the same way as obligations that did not come within the category of contracts, but could, however, be approached analogically to them.  Finally, in the fourth chapter, taking its cue from Justinian’s systematization, in which the threefold division of the sources of obligations was replaced by a fourfold division in which, in addition to obligations under contract and delict, there are obligations quasi ex contractu and those quasi ex delicto, a review is made of the individual obligationes quasi ex contractu contained in the Iustiniani Institutiones, in relation to those provided for in the Res cottidianae, and concludes with an analysis of the relevant passages, devoted to quasi contractus, in the Greek Paraphrase to the Imperial Institutions of Theophilus.","language":"ita","citation":"QUASI EX CONTRACTU TENERI: RICERCHE SULL¿ORIGINE DELLA CATEGORIA DEL QUASI CONTRATTO / P.g.a. Santoru ; coordinatore: C. R. Luzzati ; relatore: I. Fargnoli. Dipartimento di Diritto Privato e Storia del Diritto, 2021 Jun 04. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11904.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/843343/1799927/phd_unimi_R11904.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1135579"},"title":"MAFIE E IMPRENDITORIA. ANALISI CRITICA DELLA VIGENTE NORMATIVA DI CONTRASTO PATRIMONIALE E PROPOSTE DI REVISIONE.","internalauthor":"FURCINITI, GIUSEPPE","type":"Tesi di dottorato","year":"2025","abstract":"The present work proposes a critical analysis of the ablative models provided for  in our legal system (criminal and preventive confiscations) through which it is  possible to ‘sanction’, from a patrimonial point of view, illicit conducts ascertained  in the context of interaction, infiltration or instrumentality between entrepreneurial  activities and mafia organisations.  In fact, it is considered necessary, in view of the progressive evolution of the  mechanisms and strategies with which mafia organisations make their entry into the  economic fabric by liaising with the legal business community, to carry out an  accurate verification of the actuality and adequacy of such models more than 40  years after their entry into force.  In this context, starting from a systematic framing of the principal anti-mafia  patrimonial measures provided for by the criminal and prevention legislation  (finalized to highlight the different legal nature and the different prerequisites  required for their adoption) and through an in-depth jurisprudential exploration,  the principal application criticalities have been identified with reference to the  business realities, for the solution of which, in a de jure condendo perspective, specific  proposals of modification of the current regulations are hypothesized with the  pertinent technical-legal motivations.  The above-mentioned reform project aims to overcome the traditional  insufficiency of the conceptual tools of criminal law in the field of confiscation  related to business crime, by making the anti-mafia legislation acquire considerable  progress on a technical level and improving its ability to address one of the most  ‘thorny’ and complex interpretative and applicative issues, i.e. the delimitation of  the object of the ablatory measures against companies.  Moreover, on a more general level of criminal policy, this model would have the  effect of improving and adapting prevention and countermeasures to the  increasingly modern manifestations of organised crime in the economic sector,  according to a logic of effective proportionality and progressiveness of sanctions  and, at the same time, through a synergic and complementary use of the available  regulatory instruments.","language":"ita","citation":"MAFIE E IMPRENDITORIA. ANALISI CRITICA DELLA VIGENTE NORMATIVA DI CONTRASTO PATRIMONIALE E PROPOSTE DI REVISIONE / G. Furciniti ; tutor: F. Basile ; coordinatore: F. Basile. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2025. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13377_2.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1135579/2637989/phd_unimi_R13377_2.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/959316"},"title":"A SEMANTIC APPROACH FOR CONSTRUCTING KNOWLEDGE GRAPHS EXTRACTED FROM TABLES","internalauthor":"BONFITTO, SARA","type":"Tesi di dottorato","year":"2023","abstract":"Knowledge graphs (KGs) are networks of real-world entities with their relationships and properties and are  more and more used as a means for the integration of heterogeneous sources of information in a common  model that facilitates the interoperability of different applications and generates a huge quantity of information  that can be exploited for machine learning predictions.  Many approaches were proposed for the construction of KGs starting from tables extracted from spreadsheets,  Web tables, or tables contained in digital documents, that entail the location and segmentation of the table  in the source document, the extraction of its components, the identification of the function of different areas  and the discrimination of relationships between attributes. However, the semantic characterization of the table  content in terms of a domain ontology and the generation of the KG are still open research problems because  of the heterogeneity of the table contents, the eventual presence of mistakes, and the lack of standardization.  The goal of this thesis is the development of an approach for supporting the user in the construction of a  knowledge graph, which is compliant with a domain ontology, starting from tabular data presenting a complex  structure and syntactic and semantic mistakes. We believe that a completely automatic approach that exploits  sophisticated machine learning (ML) techniques cannot properly be used in this context. A semi-automatic  approach can be devised in the process of data cleaning, semantic characterization of the table content, and  translation in the KG representation. Users need to be supported by easy-to-use graphical interfaces for  correcting mistakes and improving the system’s overall performances.  For these reasons, in this thesis, we have devised a three phases approach. The first phase focuses on the  semantic characterization of table columns in terms of the basic types and/or properties of a domain ontology.  In this phase, a table is extracted from a spreadsheet and different cleaning activities are carried out (like  removal of headers and footers, removal of blank and semi-blank rows, and detection of table rows that are  correlated using a declarative pattern-based language). Then, through the identification of basic types of table  columns, syntactic mistakes are identified and the user can correct them by exploiting different interfaces. This  process improves the characterization of the semantic concepts contained in the table. The second phase of  the approach focuses on the definition of a semantic description of the table content w.r.t. a domain ontology.  The description is created starting from the result of the previous phase and exploits a graph neural network  model for the identification of the relations that bind the concepts contained in the table. The third phase  focuses on the generation of the triples of the KG starting from the table content and the semantic description.  In this activity, we have developed interfaces for the identification of semantic mistakes occurring in the data  and for the specification of identifiers of the KG instances. Different experiments have been conducted for  validating the three phases of the approach proposed in the thesis and the usability of the entire system.","language":"eng","citation":"A SEMANTIC APPROACH FOR CONSTRUCTING KNOWLEDGE GRAPHS EXTRACTED FROM TABLES / S. Bonfitto ; advisor: M. Mesiti ; coordinator: R. Sassi. Dipartimento di Informatica Giovanni Degli Antoni, 2023 Apr 27. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12571.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/959316/2162034/phd_unimi_R12571.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1161955"},"title":"NOVEL SUSTAINABLE STRATEGIES FOR THE SYNTHESIS OF ACTIVE PHARMACEUTICAL INGREDIENTS (APIS) AND BIOACTIVE MOLECULES THROUGH THE EXPLOITATION OF ISOLATED ENZYMES AS BIOCATALYSTS","internalauthor":"TOGNOLI, CHIARA","type":"Tesi di dottorato","year":"2025","abstract":"Green chemistry is a chemical concept, condensed in 12 principles, which aims at directing chemical industries and academic researchers to paths of sustainability, supporting the efforts in the context of the ecological transition. A valuable strategy widely recognized to fulfill most of the 12 principles is the exploitation of biocatalytic methods.  Biocatalysis, at the intersection of chemistry and biology, delineates the family of catalytic processes operating in a living biological system to perform chemical modifications on organic compounds. It involves the exploitation of enzymes as highly specialized proteins to be used in vitro to transform selected substrates into valuable products. As molecular catalysts, enzymes are proteins which provide precision and efficiency, enabling these transformations with outstanding stereo- and regioselectivity, working under significantly mild and ecofriendly conditions, thus allowing greener and more efficient synthesis of complex molecules.   Biocatalyzed reactions can be performed by exploiting either purified isolated enzymes or lyophilized crude cell lysates. The wide availability of commercial synthetic genes suggests that, at least theoretically, any enzyme with a known amino acid sequence can be obtained recombinantly, thus expanding the range of applications for these catalysts.  The first part of this PhD, carried out in the laboratories of SCITEC-CNR, focused on the development of sustainable entries to bioactive compounds, small molecules, and chiral synthons of pharmaceutical and industrial interest, by combining the ability of various biocatalysts alongside traditional organic synthetic protocols. Both commercially available and in-house expressed, recombinant enzymes were considered, exploiting their activities as isolated proteins to produce scaffolds of pharmaceutical interest and compounds endowed with potential antiprotozoal properties and/or cytotoxicity. Chapters I to III provide an overview of the enzymes used and the results obtained. A detailed study on the substrate promiscuity and selectivity features of a panel of alcohol dehydrogenases, including the functional characterization of a newly identified ketoreductase named Is2-SDR, is presented. Additionally, novel chemo-enzymatic strategies were developed to prepare compounds potentially endowed with antiprotozoal activity. An innovative approach, comprising two biocatalyzed step coupled with a chemical oxidation one, was applied to synthesize the promising antiplasmodial scaffolds linear diarylpirazines. Further investigations involved the application of laccases for various purposes: specifically, to study the oxidation of a series of aromatic amines; to prepare enantiopure terpene derivatives and their corresponding atropisomeric C-C dimers; and, finally, to propose an enzymatic approach for the synthesis of biologically active riminophenazines.  The third year of my PhD program was spent at Dipharma Francis Srl, co-funder of the doctoral fellowship. The experimental work carried out during this period, described in Chapter IV, involved the design and development of a novel synthetic protocol to prepare a pharmaceutical precursor of industrial interest, starting from a metabolite byproduct of intestinal bacteria.","language":"eng","citation":"NOVEL SUSTAINABLE STRATEGIES FOR THE SYNTHESIS OF ACTIVE PHARMACEUTICAL INGREDIENTS (APIS) AND BIOACTIVE MOLECULES THROUGH THE EXPLOITATION OF ISOLATED ENZYMES AS BIOCATALYSTS / C. Tognoli ; tutor: M. De Amici ;  co-tutors: S. Riva, I. Bassanini ;  coordinator: G. Vistoli. Dipartimento di Scienze Farmaceutiche, 2025 May 13. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13555.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1161955/2993160/phd_unimi_R13555.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1204537"},"title":"INNOVATIVE MARKETING STRATEGIES AND TOOLS FOR THE WINE SECTOR - A FOCUS ON SPARKLING WINE FIRMS IN THE HO.RE.CA. CHANNEL","internalauthor":"SARACINO, RICCARDO","type":"Tesi di dottorato","year":"2025","abstract":"The wine sector is undergoing significant transformations, with consumption declining across most wine categories except for sparkling wines. Within this context, fine dining restaurants emerge as one of the most value-adding channels for wineries. Wine lists, often curated by sommeliers, serve not only as tools for sales but also as instruments to shape the dining experience. Given the central role of wine in restaurants, successful establishments tend to achieve different levels of consumer satisfaction. However, wine lists are not the sole determinant of customer perceptions: other factors, such as the quality of the food offering and the restaurant’s location, also play a crucial role in influencing overall satisfaction. Therefore, this thesis targets several intersected topics, with different complementary studies. On a general perspective, the overarching aim is to provide insights into how the change in consumption can be faced in the hospitality sector towards wine list management, and how it can enhance both wineries performance and consumer experience in the context of sparkling wine and fine dining. While, in detail, the aims are several. The first aim is to individuate trends and gaps in the literature in relation to wine brands, to set the stage for the following parts. The second aim addresses directly the dynamics of the Sparkling wine industry in terms of territorial responses to globalization standards. The third aim is to investigate the role of restaurant location in city context in terms of effect on consumer satisfaction. The fourth aim is to investigate how consumers satisfaction is influenced by wine list features in the fine dining sector. The fifth aim it to depict the role of wine list in shaping the experts’ evaluation of upscale restaurants. The sixth and last aim is to investigate the reasons behind the choice of sommelier in terms of Sparkling wines to list in upscale restaurants. Moreover, this thesis includes six chapters and the conclusions. The first chapter presents a bibliometric analysis of wine branding research published between 1998 and 2024. By examining 579 academic articles, this study identifies leading contributors, thematic clusters, and emerging research trajectories. Findings reveal how collective branding, consumer segmentation, and winery branding for tourism have evolved as central research themes, with regional identity and experiential marketing playing an increasingly prominent role. Along with these findings, in this chapter are illustrated the gaps in the literature. The second chapter focuses on differentiation strategies in Classic Method sparkling wine production in three different areas. Survey data on vineyard management, vinification practices, and distribution highlight convergences in agronomy but divergences in cellar techniques, pricing strategies, and market orientation. These differences illustrate how value chain practices of the three territories are rooted in the response to globalization, and how the three areas set their value chain to be competitive. The third chapter investigates competition among restaurants in Milan by applying spatial econometric models to 4,108 establishments. The results show that restaurant ratings exhibit positive spatial autocorrelation, while neighbouring ratings exert a negative competitive effect. This indicates that spatial dynamics and proximity influence consumer evaluations, providing useful insights for positioning strategies in the Ho.Re.Ca. channel. The fourth chapter examines Michelin Guide restaurants in Italy, with a particular focus on how wine list elements, such as price ranges and origins, affect consumer ratings. Findings show that while higher menu prices and Michelin stars are positively correlated with ratings, excessively high wine prices or an overly localized selection may reduce consumer satisfaction. The fifth chapter extends the analysis to Germany, where a Seemingly Unrelated Regression model jointly considers consumer and expert evaluations. While both groups value similar features, although in different ways, experts are more sensitive to wine list composition, particularly price extremes and countries of origin, whereas consumers respond more broadly to menu characteristics. The sixth chapter investigates the role of sommeliers in curating wine lists, based on interviews with 20 professionals in German Michelin restaurants. The analysis highlights how sparkling wine selection reflects a balance between product quality, experiential value, and brand prestige, positioning the sommelier, along with chefs, as a central figure in shaping the dining experience and reinforcing symbolic value in the Ho.Re.Ca. channel. Finally, the conclusive chapter sums up the findings and discuss the theoretical contribution of this thesis. Along with the theoretical contributions, this thesis also offers several managerial implications. In the last part of the chapter, are addressed the limitations and the future research trends.","language":"eng","citation":"INNOVATIVE MARKETING STRATEGIES AND TOOLS FOR THE WINE SECTOR - A FOCUS ON SPARKLING WINE FIRMS IN THE HO.RE.CA. CHANNEL / R. Saracino ; tutor: S. Corsi ; co-tutor: C. Mazzocchi ; coordinatore: S. R. Pilu. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2025 Dec 15. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13743.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 22-DIC-26"}
,{"handle":{"url":"https://hdl.handle.net/2434/1021029"},"title":"CLINICAL VALIDATION OF 371 MICRO-RNA USE IN SMALL TESTICULAR MASSES AND IN STAGE IIA AND IIB<3CM TESTICULAR GERM CELL TUMORS","internalauthor":"NAZZANI, SEBASTIANO","type":"Tesi di dottorato","year":"2024","abstract":"Background and Objectives     Testicular Germ-cell Tumour (TGCT) is the most frequent tumour in the young male and its occurrence is increasing in Europe. Prognosis is favourable, and TGCT basically represents a model of curability of solid tumours. However, clinical management and follow-up of both localized and locally advanced TGTCs is still complex and the risk of treatment delay or, conversely, of overtreatment is high. According to this assumption we focused on two different TGCTs patients categories to test a new biomarker that may allow to improve TGCTs management. 371a-p microRNA showed the ability to identify vital cancer in GCTs and its performance in term of sensitivity and specificity exceed the available markers. We tested its diagnostic accuracy in small testicular masses and in low volume retroperitoneal disease (Stage IIA or IIB). In the first setting we know that up to 70% of small testicular lesions (&lt;20 mm) are benign. Conversely, in the second setting we know that from 9 to 20% of patients who have retroperitoneal lymphnode dissection RPLND for stage IIA or IIB TGCTs have no nodal disease at definitive pathology. Given this data, new diagnostic biomarkers that may allow to discriminate between the presence or not of TGCTs is needed.     Material and Methods    We selected patients with small testicular masses between 5 and 20 mm or with low volume retroperitoneal disease. Analysis of 371a-p miRNA in serum will be performed by dedicated biologists. In case of small testicular masses 371a-p miRNA was tested before surgery. Conversely, in low volume retroperitoneal disease it was tested before surgery and at 30 days after surgery.     Results     371a-p miRNA was tested in all patients with small testicular masses before surgery. The proposed cut-off for presence of GCTs is 15 as Relative Quantity (RQ). In SGCTs the RQ ranged from 17 to 1857. Of note the patients with the highest value was pT2. In mixed GCT the RQ was 17. Finally, considering all GCTs, the patient with mixed germ cell tumors with burn-out component had an RQ of 8. Conversely, the expression of 371a-p miRNA in patients with no GCT was 5 and 9 (RQ) in Leydig cell tumors, 1 in burn-out tumor, 2 in leiomyoma and 16 in capillary hemangioma. The overall sensitivity is 88% and the overall specificity is 75%.  371a-p miRNA was tested in all small retroperitoneal disease patients before surgery and in 8 of 9 patients at thirty days. The proposed cut-off from the producer (Gold Standard Diagnostics) for presence of GCTs is 15 as RQ. All patients with vital cancer had 371a-p miRNA values over the cut-off. Conversely, 2 on 3 patients with negative specimen for vital cancer had negative 371a-p miRNA values. 371a-p miRNA RQ was higher in patients with larger metastatic depots.    Two patients experienced relapse. One patient with elevated tumor markers at 30 days (R.Q. 144.70) who was classified at pathological stage IIB at RPLND. The relapse was retroperitoneal outfield and pulmonary. The other patient was the one with marker elevation after RPLND (Definitive specimen: Burn-out), this patient experienced a 6 months relapse with beta-HCG elevation.    Conclusion    In patients with small testicular mass and low volume retroperitoneal disease 371a-p miRNA showed a promising role in determining the presence or not of GCTs and in predicting relapse.","language":"eng","citation":"CLINICAL VALIDATION OF 371 MICRO-RNA USE IN SMALL TESTICULAR MASSES AND IN STAGE IIA AND IIB<3CM TESTICULAR GERM CELL TUMORS / S. Nazzani ; relatore: E. Montanari ; correlatore: G. Albo, N. Nicolai. Dipartimento di Scienze Cliniche e di Comunità, 2024 Jan 23. 36. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R13027.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1021029/2334159/phd_unimi_R13027.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1124265"},"title":"ADVANCED AAV-MEDIATED LIVER-DIRECTED GENE THERAPIES FOR HAEMOPHILIA A AND MUCOPOLYSACCHARIDOSIS TYPE VI","internalauthor":"ESPOSITO, FEDERICA","type":"Tesi di dottorato","year":"2024","abstract":"Liver-directed gene therapy using adeno-associated viral (AAV) vectors holds  significant promise for providing long-term transgene expression following a  single systhemic administration. However, both the limited cargo capacity (~4.7  kb) and the non-integrative nature of AAV vectors prevent their application to  conditions caused by either mutations in large genes (i.e. F8 whose coding  sequence exceeds ~ 4.7 kb) or to those that require early stage of intervention,  such as early-onset inborn errors of metabolism. My PhD project aims to  overcome these shortcomings and broaden the therapeutic applications of AAVs.  To overcome the issue of limited cargo capacity, I explored an AAV-mediated  protein trans-splicing (PTS) strategy utilizing split inteins. PTS is a natural  mechanism employed by organisms across all domains of life to reconstitute large  proteins from shorter precursors. Split inteins facilitate this process by selfexcising  from the host protein in an energy-independent manner. I used this  approach for haemophilia A (HemA), the most common X-linked bleeding  disorder (affecting 1 in 5,000 males), caused by a deficiency of clotting factor 8  (F8, ~7 kb). I first demonstrated the successful full-length reconstitution of the  large (~5 kb) and highly active B-domain deleted (B-DD) N6-F8 variant in vitro.  Subsequently, I designed two separate AAV vectors, with regular size genomes,  each encoding for half of the N6-F8, flanked by split inteins. The AAV-N6 intein  system led to successful reconstitution of functional full-length N6-F8 in the  mouse liver, achieving therapeutic F8 activity in haemophilic mice without  eliciting anti-F8 immune responses.  In parallel, I developed an AAV-mediated CRISPR/Cas9 homology-independent  targeted integration (AAV-HITI) platform to achieve stable transgene integration  at the 3’ end of the mouse Albumin locus, which is highly expressed in  hepatocytes. This approach mitigates the loss of episomal AAV genomes in  proliferative tissues, thereby preserving therapeutic efficacy over time.  14  I demonstrated AAV-HITI efficacy, in mouse models of HemA and  Mucopolysaccharidosis type VI (MPS VI), a lysosomal storage disorder,  achieving stable therapeutic levels of systemic proteins even at low AAV doses.  Importantly, I performed comprehensive molecular analyses to characterize the  AAV-HITI outcomes within the target site confirming successful targeted  integration. Moreover, in AAV-HITI treated livers nor gross chromosomal  rearrangements or significant off-target insertions/deletions were observed 1-year  post neonatal delivery. Furthermore, I demonstrated the effectiveness of this  platorm in adult MPS VI and HemA mice, using vector doses that are within the  safe range for human translation.  Overall, my findings support two distinct AAV-mediated liver-directed platforms  to address major limitations of current AAV-based therapies. The AAV-intein  N6-F8 system holds promise as a potential therapeutic option for HemA, while  the AAV-HITI platform could serve as a durable therapeutic option for livertargeted  diseases, particularly those requiring early intervention.  These innovations represent significant advancements in overcoming challenges  related to cargo capacity, stable transgene expression, and long-term efficacy in  gene therapy.","language":"eng","citation":"ADVANCED AAV-MEDIATED LIVER-DIRECTED GENE THERAPIES FOR HAEMOPHILIA A AND MUCOPOLYSACCHARIDOSIS TYPE VI / F. Esposito ; tutor:  A. Auricchio ; internal supervisor: N. Brunetti-Pierri ; external supervisor: A. Follenzi ; coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2024 Dec. 36. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13154_1.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1124265/2607877/phd_unimi_R13154_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1053929"},"title":"THE INTEGRATION OF SECOND - GENERATION MIGRANTS: EXPLORING LABOUR MARKET DYNAMICS IN ITALY.","internalauthor":"DI GASPARE, SILVIA","type":"Tesi di dottorato","year":"2024","abstract":"The socioeconomic integration of second generation migrants into host labour markets poses  significant challenges characterized by a wide gap when compared to their native counterparts. While extensively examined in old migration destinations, this issue remains largely unexplored in new host countries. Italy, with its recent migration history and regional disparities, offers a compelling yet understudied context for investigation. This study seeks to fill this research lacuna by analysing data from the ISTAT Labour Force Survey spanning from 2018 to 2022. Through the application of statistical methodologies, the research endeavours to elucidate the disparities in employment access and job arrangments among natives, mixed, and second generation migrants. This dissertation aims to enhance our comprehension of the divergent labour market outcomes between Italians and second generation migrants, exploring their integration trajectories in the frame of the regional disparities within the country.","language":"eng","citation":"THE INTEGRATION OF SECOND - GENERATION MIGRANTS: EXPLORING LABOUR MARKET DYNAMICS IN ITALY / S. Di Gaspare ; supervisor: M. Ambrosini ; directors of doctoral program: P. Rebughini, G. Semi. Dipartimento di Scienze Sociali e Politiche, 2024 Jul 09. 35. ciclo, Anno Accademico 2022.","filename":"phd_unimi_R12783.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1053929/2419432/phd_unimi_R12783.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1197904"},"title":"A SEARCH FOR EPIGENETIC VULNERABILITIES OF AML CELLS PERFORMED BY A CDK INHIBITOR¿BASED CRISPR SCREENING","internalauthor":"VALZELLI, RICCARDO","type":"Tesi di dottorato","year":"2025","abstract":"Acute myeloid leukemia is an aggressive hematologic malignancy characterized by uncontrolled proliferation and impaired differentiation of hematopoietic progenitors. Epigenetic dysregulation plays a central role in AML pathogenesis, and targeting chromatin-modifying enzymes has emerged as a promising therapeutic strategy. Among these, the histone demethylase LSD1/KDM1A has been extensively studied, yet clinical responses to LSD1 inhibition remain variable. Work from our group demonstrated that pharmacological prolongation of the G1 phase of the cell cycle through sub-optimal doses of CDK4/6 inhibitors reprograms the chromatin landscape of fast-cycling AML cells resistant to LSD1 inhibition, rendering them more similar to slow-cycling counterparts that are intrinsically sensitive to LSD1 inhibition. This finding suggested that cell cycle dynamics critically influence the response to epigenetic therapies.  The present study employed CRISPR-Cas9 dropout screenings to systematically identify chromatin-related vulnerabilities emerging upon cell cycle manipulation. Using a Cas9-expressing AML cell line, we screened more than 600 epigenetic regulators in the context of CDK targeting. The optimized pipeline reliably uncovered known dependencies, validating its robustness, and revealed novel candidates whose loss synergizes with low-dose CDK inhibitors to impair leukemic cell proliferation. Genetic and pharmacological validation provided proof of principle that, in AML models unresponsive to LSD1 inhibition, cell cycle manipulation can unmask alternative chromatin-related dependencies such as DOT1L. Extending the screening to AML models where cell cycle manipulation does not result in sensitivity to LSD1  17  inhibition further identified additional context-dependent vulnerabilities unmasked by cell cycle lengthening.  Nuclear phospho-proteomics studies (ongoing) revealed that Palbociclib treatment rewires kinase signaling in the nucleus and chromatin-associated phosphorylation networks, setting the ground for the discovery of mechanistic insights into how cell cycle modulation primes AML cells for epigenetic intervention.  Following a similar experimental approach, but following a different line of research in our group, we have combined the CRISPR-screening platform with metabolic drugs, to uncover functional crosstalk between chromatin regulation and metabolic pathways.  Overall, our studies demonstrates that cell cycle manipulation exposes epigenetic vulnerabilities that can be exploited pharmacologically. These findings propose a generalizable framework in which chromatin reprogramming through cell cycle modulation enhances the therapeutic potential of epigenetic interventions in AML.","language":"eng","citation":"A SEARCH FOR EPIGENETIC VULNERABILITIES OF AML CELLS PERFORMED BY A CDK INHIBITOR-BASED CRISPR SCREENING / R. Valzelli ; tutor: S. Minucci ; coordinator: D. Pasini. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Dec 17. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13505.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 24-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1125896"},"title":"AUTONOMOUS VEHICLES: LEGAL IMPLICATIONS AND POSSIBLE SOLUTIONS.","internalauthor":"CINQUE, ALBA","type":"Tesi di dottorato","year":"2024","abstract":"The dissertation represents an attempt to enlighten the legal issues that the spread of automated vehicles imposes to jurists to face.","language":"eng","citation":"AUTONOMOUS VEHICLES: LEGAL IMPLICATIONS AND POSSIBLE SOLUTIONS / A. Cinque ; tutor: A. Maniaci, S. Navas coordinatore: A. Maniaci; S. Navas. Dipartimento di Diritto Privato e Storia del Diritto, 2024 Oct 31. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13668.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1125896/2613735/phd_unimi_R13668.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1141329"},"title":"NETWORKS OF GROUP EQUIVARIANT NON-EXPANSIVE OPERATORS FOR ARTIFICIAL INTELLIGENCE. MODELS, APPLICATIONS AND INTERPRETABILITY.","internalauthor":"BOCCHI, GIOVANNI","type":"Tesi di dottorato","year":"2025","abstract":"Artificial Intelligence (AI) and Machine Learning (ML) are increasingly integrated into our daily lives, yet we often encounter opaque, black-box algorithms driving these systems, which can be deceptive or counterfeit. The pursuit of eXplainable Artificial Intelligence (XAI) aims to develop methods that clarify the decision-making processes of black-box AI systems, making them more understandable and trustworthy for end users, in line with regulatory and policy demands.    Another significant challenge facing XAI is creating algorithms that are intrinsically explainable by design. In this context, the mathematical theory of Group Equivariant Non-Expansive Operators (GENEOs) has all the credentials to be at the base of a new generation of ML models with desirable geometric properties. This thesis aims to support this claim by investigating GENEO networks from both an application and theoretical perspective, demonstrating their effectiveness as building blocks for competitive networks in terms of performance and explainability. In essence, a GENEO is an operator between two functional spaces that satisfies two important properties: firstly, there is equivariance, which prescribes that the operator must commute with all the elements of a certain group of transformations of the functional data domain, and secondly, non-expansivity, which requires that the distance between the outputs of a GENEO must be always smaller than the original distance between the inputs, when measured with the appropriate distance.       From the point of view of applications, I will present in particular GENEOnet, which is the principal implementation of a GENEO network and that was developed during an industrial collaboration with experts in medicinal chemistry on the problem of protein pocket detection. More generally, I will present and analyze several GENEO networks designed to tackle various types of data and problems. These networks outperform other state-of-the-art domain-specific models while also featuring enhanced explainability and robustness properties. The primary experimental finding is that such networks can deliver strong results relying on a minimal number of learnable parameters, making them easier to interpret and study, while moving towards intrinsically explainable models. Furthermore, the reduced number of parameters helps to maintain the model structure simple and decreases computational costs, compared to more complex models like deep neural networks.    From a theoretical perspective, I will introduce new techniques for generating linear GENEOs within the context of graph theory, yielding GENEOs that can commute with the group of graph isomorphisms. These methods are based on the concept of permutant and generalize previously developed results, particularly by using input-dependent permutants to embed specific subgraphs into the graph of interest. Using aggregation results for GENEOs, these subgraph search operators enable the definition of a novel isomorphism test for graphs. I compared this test with other conventional approaches in terms of accuracy and computational cost, and it was found to be superior when considering both criteria simultaneously.    The findings in this thesis establish the basis and initial experimental evidence for GENEOs as tools for creating networks that belong to the class of models explainable by design. The ultimate objective of this research is to further substantiate this claim by constructing a library of GENEOs easily used for various use cases.","language":"eng","citation":"NETWORKS OF GROUP EQUIVARIANT NON-EXPANSIVE OPERATORS FOR ARTIFICIAL INTELLIGENCE. MODELS, APPLICATIONS AND INTERPRETABILITY / G. Bocchi ; tutor: A. Micheletti, P. Frosini, C. Talarico ; coordinatore: G. Ciraolo. - Milano, Dipartimento di Matematica. Dipartimento di Scienze e Politiche Ambientali, 2025 Feb 18. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13235.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1141329/2655505/phd_unimi_R13235.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/839459"},"title":"PROS AND CONS OF NANOMATERIALS: STUDY OF HALLOYSITE-BASED NANOCOMPOSITES FOR BIOMEDICAL OR CATALYTIC PURPOSES AND EVALUATION OF ENVIRONMENTAL AQUATIC TOXICITY OF CEO2 NANOPARTICLES","internalauthor":"HAMZA, HADY AHMED IBRAHIM","type":"Tesi di dottorato","year":"2021","abstract":"My Ph.D. dealt mainly with the study of halloysite nanotubes (HNT), and their interaction with molecules and nanoparticles as potential for potential applications either in biomedicine or in catalysis. A minor part of my Ph.D work was dedicated to the preparation and characterization of Ceria nanoparticles stabilized with polymers of different charge, to investigate, in collaboration with the group of prof Della Torre and Binelli, their effect on various animal and bacterial models relative to their possible toxic effects especially in the aquatic environment.  I started the first part of my thesis by introducing the clay material HNT. HNT is a unique natural nanomaterial composed of double-layered aluminosilicate with a hollow tubular structure in the micro range. A preliminary literature survey revealed that HNT, due to their physical and chemical features, could be suitable for many application fields like medicine and catalysis (Chapter 1). We started our aim by synthesizing some HNT adducts possibly suitable for hyperthermia applications by selectively load superparamagnetic iron oxides (SPIONs) into the inner lumen of HNT. The magnetic properties of the loaded SPIONs did not change after their trapping inside the HNT lumen. The SPION-in-HNT nanocomposite was synthesized through the pre-modification of the HNT inner lumen such that it becomes suitable to be suitable to load the apolar SPION as synthesized by thermal decomposition method without a further step of ligand exchange (Chapter 2). To extend the loading to another kind of NP for hyperthermia applications, we tried to load gold nanoparticles. The gold NPs can be synthesized in various shapes; we synthesized spherical and star shapes of gold for our purpose. Gold can be loaded inside the inner lumen in the studied shapes, but the low concentration of gold suspension hampered a massive loading into the HNT lumen. (Chapter 3). The second part of the work with Halloysites was devoted to the preparation and characterization of HNT adducts with luminescent molecules able to act as photosensitizers for photodynamic therapy (PDT). For this purpose, we were interested in loading perfluorinated porphyrin, in their non-coordinated- and Zn-coordinated form, inside the lumen of HNT. The release of the photosensitizer by the inner lumen was slowed down compared to the release of the perfluorinated drugs adsorbed in the outer surface of HNT. (Chapter 4). To use HNT as a dual vector for drug delivery, we synthesized HNT-Ru photosensitizer. The photosensitizer was covalently bonded to the silica part of the outer surface of HNT, leaving the inner lumen free for potentially an extra loading with another drug. The photophysical properties of synthesized nanocomposite were then tested (Chapter 5). Finally, concerning HNT, we aimed to synthesize a new synthetic Au-Pt nanoparticle supported over HNT with different Au-to-Pt molar ratios via a sol immobilization method for catalytic purposes. The synthesized catalyst showed that the activity toward hydrogenation of C=O of cinnamaldehyde increased with increasing the molar ratio of Au/Pt (Chapter 6).   Unfortunately, the product potentially useful for biomedical purposes were not tested at least at cellular level, and this lack to the work was essentially due to the COVID-19 pandemic situation that slowed down a lot of collaboration especially with biologist collaborators.  The last part of my thesis was devoted to synthesizing nanoceria and covering it with natural polymer available in the aquatic system as alginate and chitosan. Ceria NPs surrounded by both Alginate and Chitosan showed no acute toxicity effects at the average environmental concentration level of the two tested natural macromolecules (Chapter 7).","language":"eng","citation":"PROS AND CONS OF NANOMATERIALS: STUDY OF HALLOYSITE-BASED NANOCOMPOSITES FOR BIOMEDICAL OR CATALYTIC PURPOSES AND EVALUATION OF ENVIRONMENTAL AQUATIC TOXICITY OF CEO2 NANOPARTICLES / H.a.i. Hamza ; supervisor: D. MAGGIONI ; coordinatore: D. ROBERTO. Dipartimento di Chimica, 2021 May 11. 33. ciclo, Anno Accademico 2020. [10.13130/hamza-hady-ahmed-ibrahim_phd2021-05-11].","filename":"phd_unimi_R11988.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/839459/1787938/phd_unimi_R11988.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/800834"},"title":"THE EFFECT OF TANNINS FROM CASTANEA SATIVA MILL. ON INFLAMMATION INDUCED BY HELICOBACTER PYLORI IN GASTRIC EPITHELIAL CELLS","internalauthor":"PIAZZA, STEFANO","type":"Tesi di dottorato","year":"2021","abstract":"The eradication therapy against Helicobacter pylori (H. pylori) accounts for the reduction of IL-8 levels in gastric mucosa and the related risk of gastric cancer and ulcer onset. However, the current therapeutic approach has being challenged by antibiotic resistance. The discovery of natural compounds from edible plants with anti-inflammatory and anti-bacterial activities may contribute to the control of the disease and improve the safety profile of eradication. Plants producing tannins, including ellagitannins, have already shown pre-clinical gastroprotective evidences, but pharmacological validations are still required. Accordingly, Castanea sativa Mill. (sweet chestnut) is a well-known source of tannins, traditionally used for gastro-intestinal and respiratory diseases.  On the base of the traditional indication, extracts from sweet chestnut are currently allowed as botanical ingredients by several European countries; however, their phytochemical composition and biological activity are poorly investigated, thus limiting the substantiation of health claims.  The aim of the phD project was to characterize hydroalcoholic extracts from fruit and leaves of sweet chestnut, with a particular attention to tannin composition. In parallel, extracts were evaluated as potential candidates against gastritis and H. pylori through a multidisciplinary approach, including in vitro pharmacological and microbiological experiments. In the view of nutraceutical application, the work took into account the importance of the botanical origin of the extracts and evaluated the impact of gastric digestion on the stability of natural compounds.  The results obtained on the fruit (chestnut) have been published by the research group (Sangiovanni and Piazza et al. 2018): in brief, following a bio-guided approach, hydroalcoholic extracts from chestnut of five different varieties were screened for their ability to impair TNFα-induced IL-8 release in human gastric epithelial cells (AGS). Two varieties (Venegon and Verdesa) emerged for their promising inhibitory activity (IC50s less than 10 μg/mL) and further characterized for their polyphenolic content. HPLC-MS analysis revealed the presence of condensed tannins (oligomeric proanthocyanidins) in extracts from the outer part of chestnut (pericarp and episperm), which correlated with IL-8 impairment (IC50s less than 0.5 μg/mL); on the contrary, the edible part (endosperm) was devoid of proanthocyanidins and inactive. Of note, hydrolysable tannins typical of the bark of sweet chestnut, namely gallotannins and ellagitannins, were absent in chestnut.  In line with the literature on tannins, extracts maintained their inhibitory activity after the simulation of gastric digestion. Moreover, the bioactivity was modestly affected by the application of brief thermal treatments (till 100 °C for 30 min), thus suggesting the possibility of recovering chestnut shell for the enrichment of a bioactive chestnut flour. Consequently, an episperm-fortified flour was prepared respecting the original composition of chestnut, then extracted and assayed again for IL-8 impairment (IC50 = 16.35 μg/mL), thus demonstrating the potential application of chestnut by- products in nutraceuticals.  Following a similar approach, hydroalcoholic extracts from leaf belonging to the most promising varieties (Venegon and Verdesa) were investigated. Contrarily to the fruit, the ellagitannins castalagin and vescalagin were revealed (1-2%) in leaf, thus prompting further studies on the anti-H. pylori effect.  In particular, the antibacterial and anti-inflammatory activity was evaluated in a co-culture model of gastric epithelial cells infected with the bacteria (tumoral AGS in comparison with non-tumoral GES- 1). Leaf extracts inhibited IL-8 release in both the infected cells with IC50s lower than 30 μg/mL and  impaired the bacterial growth at 100 μg/mL. After simulated gastric digestion, these bioactivities were moderately impaired (2 folds); in paralleled, a slight decrease in total phenols content was observed, thus suggesting their possible stability at gastric level after oral consumption. Ellagitannins castalagin and vescalagin exhibited the same inhibitory effects (IC50 on IL-8 less than 16 μM; MIC = 25 μM), but at concentrations unable to completely explain the effect of the whole extract; therefore, the synergy with other polyphenols could play a role.  The experimental work sustained for the first time the potential anti-gastritis application of by- products from sweet chestnut, such as chestnut shell and leaf, pointing out the role of tannins for the biological activity.","language":"eng","citation":"THE EFFECT OF TANNINS FROM CASTANEA SATIVA MILL. ON INFLAMMATION INDUCED BY HELICOBACTER PYLORI IN GASTRIC EPITHELIAL CELLS / S. Piazza ; tutor: M. Dell'Agli ; coordinatore:  A. L. Catapano. Dipartimento di Scienze Farmacologiche e Biomolecolari, 2021 Jan 13. 33. ciclo, Anno Accademico 2020. [10.13130/piazza-stefano_phd2021-01-13].","filename":"phd_unimi_R11981.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/800834/1661966/phd_unimi_R11981.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/844784"},"title":"TRANSCRIPTOMIC ANALYSIS OF HUMAN CIRCULATING MONOCYTES: FOCUS ON MEMBRANE-SPANNING 4A GENE FAMILY MEMBERS.","internalauthor":"RIGAMONTI, ALESSANDRA","type":"Tesi di dottorato","year":"2021","abstract":"Within the mononuclear phagocyte system (MPS), monocytes represent the unique population able to operate as both effector and precursor cells. These incredibly plastic cells, mainly present in peripheral blood, are essential components of the innate immune system and play central roles both in homeostatic and pathological conditions. Monocytes are key determinants for the surveillance of endothelial integrity and repair, regulation of wound healing and replenishment of tissue resident macrophages (TRMs). Moreover, they serve as first line of defence against infections and hold a key position in several human diseases. Despite the fact that current classification distinguishes three major subsets (classical, intermediate and non-classical), monocytes represent an extremely heterogeneous population in terms of phenotype and specialized functions.  To overcome the remarkable lack of consensus on the identity and interrelationship of monocyte subsets, we have performed a single cell RNA sequencing analysis on circulating mononuclear cells of healthy donors. We identified 8 cluster of monocytes. C0 and c2 resembled neutrophil-like monocytes (NeuMo) and, together with c1, displayed distinct inflammatory programs and activation states. Of the two other clusters of classical monocytes, c7 significantly expressed high levels of antiviral genes, including IFN-related genes, while c12 corresponded to circulating monocyte-platelet aggregates (MPA). C6 and c3 resembled the intermediate and non-classical monocyte populations, respectively. Finally, a small cluster of CD16+ cells (c13) was characterized by the specific expression of genes of the complement system. We then moved to the analyses of a public transcriptomic dataset obtained from peripheral blood mononuclear cells (PBMCs) of gastrointestinal cancer patients at 3 time points of treatment. We were able to identify all previously defined monocyte subsets. Preliminary data showed the specific expansion of the IFN-related cluster c7 exclusively in responder patients after treatment with immunotherapy, suggesting a potential role of this population in response to therapy.  Analyses of the Membrane-Spanning 4-domain subfamily A (MS4A) protein family, representing a set of proteins whose roles in regulating myeloid cell function are now emerging, identified MS4A4A as potential markers for the commitment to circulating non-classical monocytes in humans. The expression of MS4A4A on a fraction of CD16+ monocytes was further confirmed at the protein level by flow cytometry. Given the selective expression of this protein on CD16+ cells and based on solid preliminary data from our laboratory, we  3  hypothesized that MS4A4A may play a role in the biology of this subset of cells. Interestingly, bulk RNA sequencing of CD16-MS4A4A-, CD16+MS4A4A- and CD16+MS4A4A+ monocytes revealed enrichment of the Fc gamma receptor (FcγR) and Fc epsilon receptor (FcεR) pathways in MS4A4Apos cells. Implementation of these findings with functional assays is in program and will be essential to deeper investigate a possible role of MS4A4A as modulator of FcRs function in monocytes.","language":"eng","citation":"TRANSCRIPTOMIC ANALYSIS OF HUMAN CIRCULATING MONOCYTES: FOCUS ON MEMBRANE-SPANNING 4A GENE FAMILY MEMBERS / A. Rigamonti ; directors of studies: F. Marchesi, M. Locati ; coordinatore: M. Locati. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, 2021 Jun 11. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R12093.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/844784/1804638/phd_unimi_R12093.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/902991"},"title":"RADIOMICS-BASED MACHINE LEARNING CLASSIFICATION OF BONE CHONDROSARCOMA","internalauthor":"GITTO, SALVATORE","type":"Tesi di dottorato","year":"2022","abstract":"The aim of this thesis is to determine diagnostic performance of machine learning in differentiating between atypical cartilaginous tumor (ACT) and high-grade chondrosarcoma (CS) based on radiomic features derived from magnetic resonance imaging (MRI) and computed tomography (CT). In chapter 2, the concept of radiomics of musculoskeletal sarcomas is introduced and a systematic review on radiomic feature reproducibility and validation strategies is conducted. In chapter 3, a preliminary study is performed to investigate the performance of MRI radiomics-based machine learning in discriminating ACT from high-grade CS, using a single-center cohort, in comparison with an expert radiologist. In chapter 4, the influence of interobserver segmentation variability on the reproducibility of CT and MRI radiomic features of cartilaginous bone tumors is assessed. In chapter 5, the performance of CT radiomics-based machine learning in discriminating ACT from high-grade CS of long bones is determined and validated using independent data from a multicenter cohort, compared to an expert radiologist. In chapter 6, the performance of MRI radiomics-based machine learning in differentiating between ACT and grade II CS of long bones is determined and validated using independent data from a multicenter cohort, in comparison with an expert radiologist. Finally, in chapter 7, the main results and implications of this thesis are summarized and discussed.","language":"eng","citation":"RADIOMICS-BASED MACHINE LEARNING CLASSIFICATION OF BONE CHONDROSARCOMA / S. Gitto ; tutor: L.M. Sconfienza, J.L. Bloem (Leiden University Medical Center, The Netherlands) ; coordinatore: E. Berti. Dipartimento di Scienze Biomediche per la Salute, 2022 Feb 16. 34. ciclo, Anno Accademico 2021. [10.13130/gitto-salvatore_phd2022-02-16].","filename":"phd_unimi_R12376.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/902991/1968860/phd_unimi_R12376.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/819434"},"title":"THE EFFECTS OF BI-LITERACY ON PHONOLOGICAL AWARENESS AND READING ABILITY IN L2 ITALIAN AND L3 ENGLISH - A STUDY ON YOUNG HERITAGE SPEAKERS OF ROMANIAN IN ITALY","internalauthor":"STAN, IRINA SUZANA","type":"Tesi di dottorato","year":"2021","abstract":"If it holds that L3 learners are influenced by the general cognitive effects of bilingualism  (Bialystok, 2001) and that bilingualism provides better opportunities for the growth of  cognitive, linguistic, and academic skills provided bilinguals develop literacy in their first  language (Cummins, 2000), it could be hypothesised that bi-literacy translates into benefits  not only in L2 but also in L3 learning. This dissertation aims at determining the effects of  bi-literacy (versus bilingualism alone) on young bilingual children’s phonological awareness  and reading ability. The study specifically looks for the possibility of metalinguistic  awareness benefit on the level of phonology and word-level decoding by having Romanian  acquired as a first and heritage language and Italian as a second language and medium of  instruction. It also examines the possibility of transfer of these benefits into the third  language, English, which is learnt formally at school as a foreign language. Finally, it seeks  to determine whether this possible metalingual benefit can manifest differently in L2 with  respect to L3.  Sixty-one 8 to 10-year-old Romanian-Italian bilingual children who met the exclusionary  criterion of having Romanian as first and dominant language in the home were selected from  different public primary schools in Northern Italy that were hosting Romanian language  courses for young heritage speakers. Next, they were further divided into two groups, namely  the bi-literate bilingual group that were participating in these courses of Romanian as a  heritage language and therefore had literacy skills in Romanian, and the mono-literate  bilingual group that was not attending any such course nor had literacy knowledge in  Romanian. Finally, a group of Italian monolingual children, matched on demographic and  socio-economic characteristics, were selected from the same schools as the bilingual groups.  All participants were first assessed for their non-verbal intelligence. Then bilingual  children’s language proficiency was measured through three vocabulary tests, each in  Romanian, Italian and English, and were assessed for their daily (passive and active) spoken  language use in Romanian and Italian through a parental questionnaire. They were also  assessed for their phonological awareness abilities that included phoneme segmentation and  blending, syllable blending and onset-rime oddity in the three languages. Finally, the  participants were assessed for their Italian and English word reading abilities through a list   of both real and pseudo-words arranged in increasing difficulty level. The monolingual  children completed the vocabulary, phonological awareness and reading tests in Italian and  English only.  Results from the above tests generated four important findings. Firstly, it is clear that the  bi-literate bilinguals develop better phonological awareness skills in Romanian, their L1, as  they outperformed the mono-literate bilinguals on all phonological awareness tasks.  Secondly, the superiority of the bi-literates over mono-literate bilinguals is also visible in L2  Italian, at least as pseudo-word reading, phoneme segmentation, onset-rime oddity and  syllable blending are concerned. Moreover, being Romanian-Italian bi-literate can also  translate into benefits over Italian monolinguals as tests on L2 Italian onset-rime, syllable  and pseudo-words have shown; at the same time, as far as L2 Italian testing is concerned,  being mono-literate bilinguals does not result in advantages over monolinguals. Thirdly, the  results supported the prediction that Romanian (L1) literacy skills would have a positive  impact on English (L3) phonological awareness and literacy acquisition. This conclusion  derives from the superiority of the bi-literate bilingual group over both the mono-literate  bilingual and monolingual groups on all four phonological awareness tests and on the word  decoding task. On the other hand, being bilingual mono-literates results in leverage over  monolinguals only on phoneme and onset-rime testing. Finally, these results would seem to  put forward that L3 acquisition is different from L2 acquisition and cannot be considered a  simple variation of it, since the development of phonological and reading skills resulted to  manifest themselves differently in the two languages. Therefore, it could be suggested that  L2 and L3 acquisition should represent a distinct research domain.  This study contributes to early heritage language literacy learning in the Italian and  European context, especially learning to read in English as a foreign language. My study  provides evidence that among bilingual children, the phonological processing skill and  reading ability skills can be elevated through teaching the orthographic knowledge of the  first language.","language":"eng","citation":"THE EFFECTS OF BI-LITERACY ON PHONOLOGICAL AWARENESS AND READING ABILITY IN L2 ITALIAN AND L3 ENGLISH - A STUDY ON YOUNG HERITAGE SPEAKERS OF ROMANIAN IN ITALY / I.s. Stan ; tutor: P. Catenaccio; coordinatrice del dottorato: M. V. Calvi. Dipartimento di Scienze della Mediazione Linguistica e di Studi Interculturali, 2021 Mar 02. 33. ciclo, Anno Accademico 2020. [10.13130/stan-irina-suzana_phd2021-03-02].","filename":"phd_unimi_R12022.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/819434/1718244/phd_unimi_R12022.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1156137"},"title":"THE ACQUISITION OF PHRASAL VERBS THROUGH ENHANCED AUDIOVISUAL CAPTIONS. IMPLICATIONS FOR THE DEVELOPMENT OF A SUBTITLING TOOL FOR EFL LEARNERS","internalauthor":"VERDINO, ANDREA","type":"Tesi di dottorato","year":"2025","abstract":"Since their introduction in the late 1980s, captioned audiovisual materials have increasingly gained attention in Second Language Acquisition (SLA) research (Gottlieb 1994; Danan 2004; Caimi 2006; Pavesi &amp; Perego 2008). These materials, initially conceived as tools for accessibility, have demonstrated a potential to enhance language learning, making them increasingly relevant for educators and researchers. Recent studies have underscored the effectiveness of textual input enhancement (TIE) techniques, which can highlight particular linguistic elements in audiovisual input to draw learners’ attention and facilitate learning. Research by MacDonald and Comeaux (2018), Montero-Perez et al. (2015, 2018), Lee and Révész (2018, 2020), and Cintrón-Valentín and Garcia-Amaya (2021) suggests that TIE applied to captioned videos can significantly impact learners’ ability to notice and retain linguistic forms. Yet, despite these positive findings, the relationship between attention, noticing, and retention remains insufficiently understood (Zhang 2022).  Moreover, while the consensus supports that TIE favours attentional processes, it is less clear whether different forms of TIE (such as colouring, highlighting, or keyword captioning) lead to differential outcomes in noticing and retention. This gap in the literature is particularly evident concerning more complex lexico-grammatical items, such as English phrasal verbs (PVs). Although TIE techniques have been successfully employed to enhance learning of linguistic features like individual words and grammatical structures, the application of these methods for phrasal verb acquisition via subtitled videos remains under-researched (Fu 2021).  English phrasal verbs represent a particularly challenging linguistic feature for learners, as they often involve a combination of both literal and idiomatic meanings. Studies have consistently shown that learners, especially those at lower proficiency levels, tend to avoid using phrasal verbs due to their perceived complexity (Dagut &amp; Laufer 1985). This avoidance persists even as learners become more proficient, suggesting that traditional teaching methods may not effectively address the cognitive difficulties associated with phrasal verb acquisition (Natsumi 2021).  Thus, this doctoral project seeks to address several key gaps in the current research. First, it investigates the impact of different TIE techniques on learners’ ability to notice and retain phrasal verbs in captioned videos. Second, it explores the role of high-quality captioning materials, as the availability of pre-prepared and accurately captioned videos remains a significant challenge for educators (Romero-Fresco 2020). Lastly, it aims to develop a learning tool, “SubTeachMe,” to simplify the process of creating and using enhanced captioned materials, thereby bridging the gap between research findings and pedagogical practice. The primary objective of this study is to determine whether specific TIE techniques can enhance the acquisition of phrasal verbs through captioned audiovisual materials. In doing so, it also aims at providing insights into the broader implications of input enhancement strategies in multimedia learning. By combining empirical investigation with the development of a pedagogical tool, this research contributes to both theoretical interpretations of SLA and practical approaches to language teaching.  To achieve these goals, the study is divided into two main components. The first is an experimental study that evaluates the effects of different captioning conditions (no enhancement, colouring, and keyword captioning) on learners’ noticing and retention of English phrasal verbs. Preliminary results suggest that coloured captions may significantly enhance learners’ ability to notice phrasal verbs, although further research is required to determine the impact on retention. The second component involves the creation of a software tool, “SubTeachMe,” designed to assist educators in producing high-quality, TIE-enhanced captioned materials. This tool represents an innovative contribution to the field, facilitating the integration of audiovisual input into language classrooms and addressing the practical challenges faced by teachers.  The first chapter of the thesis establishes the theoretical foundations of this research. It explores key concepts like input salience, noticing, and input enhancement within the framework of SLA theories. This introductory part also delves into the role of working memory in language processing, drawing connections between cognitive capacity and learners’ ability to notice and retain linguistic features.  The second chapter provides a thorough review of audiovisual studies in SLA, focusing on how subtitles and captions have been used in language learning contexts. It reviews contemporary research on different types of subtitles (intralingual and interlingual) and enhanced captions, outlining their effects on learners’ noticing and retention of linguistic forms.  The third chapter is dedicated to a detailed analysis of phrasal verbs, their complexity in English as a second language, and how learners often struggle to acquire them. It introduces key theoretical perspectives on the cognitive challenges of acquiring phrasal verbs and discusses how audiovisual input and TIE techniques might address these challenges. The fourth chapter presents the empirical core of the research. It details the experimental design and methodology used to investigate the effects of different captioning conditions (no enhancement, colouring, and keyword captioning) on the noticing and retention of phrasal verbs among EFL learners. The results are discussed in relation to both existing literature and the research questions.  In the fifth and final chapter, the research turns practical, focusing on the development of the “SubTeachMe” tool, a software designed to help teachers and learners create and use enhanced captions for language learning. This part discusses the rationale behind the tool, its key features, and how it can be integrated into educational practice to optimise phrasal verb acquisition through audiovisual input.  By offering a comprehensive investigation into the impact of TIE techniques on phrasal verb learning and the creation of a tailored subtitling tool, this doctoral project aims to contribute both to the field of applied linguistics and to the practical resources available for educators in EFL contexts.","language":"eng","citation":"THE ACQUISITION OF PHRASAL VERBS THROUGH ENHANCED AUDIOVISUAL CAPTIONS. IMPLICATIONS FOR THE DEVELOPMENT OF A SUBTITLING TOOL FOR EFL LEARNERS / A. Verdino ; tutor: L. Pedrazzini ; co-tutor: A. Nava ; coordinatrice: L. Pinnavaia. Dipartimento di Lingue, Letterature, Culture e Mediazioni, 2025 Apr 07. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13203.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1156137/2728014/phd_unimi_R13203.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1050394"},"title":"THERMO-HYDRO-MECHANICAL NUMERICAL MODELLING TO ASSESS THE ROLE OF CLIMATIC FACTORS IN THE STABILITY OF ALPINE ROCK SLOPES","internalauthor":"MORCIONI, ANDREA","type":"Tesi di dottorato","year":"2024","abstract":"This work aims at increasing the knowledge of climate impacts on the stress-strain evolution of rock slopes, through the adoption of a multi-disciplinary approach and the development of multiphysics numerical analyses. Several case studies of past and active rockslide events in the Alpine region were analyzed, for which the effects of different couplings were explored. By means of a methodological process that includes geological and geomechanical characterization of rock slopes, the definition of a geological conceptual model, and the development of numerical stress-strain analysis, this work is intended to be a valid reference for the analysis of rock slope evolution in response to climate inputs.  Concerning the hydro-mechanical (HM) couplings, two case histories in which exceptionally heavy rainfall events led to slope failure are discussed. In particular, the Piuro landslide (Bregaglia Valley, Sondrio, Italy), which occurred in 1618, and the 2012 Cimaganda rockslide (San Giacomo Valley, Sondrio, Italy) were back-analyzed with a focus on their triggering mechanisms related to the distribution of pore pressure, resulting from extreme rainfall events. The results confirmed the dominant role of HM couplings in defining slope instability processes.  Next, the effects of surface temperature variations on slope stability were analyzed along the Cimaganda rock slope, with particular focus on a large historical rockslide. The combined effect of long- and short-term thermal evolution were numerically explored, overlapping the late-Pleistocene/Holocene warming trend to the seasonal temperature oscillations. It was shown that although slope failure events do not appear to be directly triggered by thermal cycles, the latter over a long period can lead to considerable mechanical slope degradation and strain accumulation. Moreover, a thermal monitoring system placed along the Cimaganda slope provided some preliminary evidences on the impact of current environmental loadings (from daily to seasonal) on the distribution of temperature inside the monitored rock-mass and the resulting rock-joint deformations.  Then, to assess the relationship between climate variables and the evolution of an active rockslide, the Ruinon case study (Frodolfo Valley, Sondrio) was analyzed. In particular, after a careful assessment of the factors controlling rockslide evolution via numerical stress-strain analysis and hydrogeological modelling, coupled thermo-poro-mechanical modelling was carried out. Once calibrated, the model allowed to simulate the recently measured velocity history of the rockslide and was then adopted to explore the impact of forthcoming climate changes on rockslide activity. This allowed to gain further insight into the link between climate inputs and rockslide activity, providing the basis for the development of a physics-based warning system.  The presented research allowed to:  •Correctly simulate the evolution of the analyzed Alpine rock slopes, by considering the mainpredisposing and triggering factors.  •Gain deeper understanding on the quantitative relationships between temperature, pore pressuresand strain rates in Alpine rockslides via numerical modeling.  •Provide advice on the development and calibration of physics-based numerical models thatinclude climate scenarios in the prediction of future landslide activity.  The presented multi-disciplinary approach (geological characterization, conceptual modeling, numerical analysis) has proven to be a valid method for the investigation of rock slopes exhibiting gravitational instability phenomena. It can be deduced that multiphysical approaches should no longer be overlooked in slope stability analyses, as their role in forecasting and predictive applications is of paramount importance.","language":"eng","citation":"THERMO-HYDRO-MECHANICAL NUMERICAL MODELLING TO ASSESS THE ROLE OF CLIMATIC FACTORS IN THE STABILITY OF ALPINE ROCK SLOPES / A. Morcioni ; autore: A. Morcioni ; tutor: T. Apuani; co-tutor: F. Cecinato ; coordinatore: I. Spalla. Dipartimento di Scienze della Terra Ardito Desio, 2024 May 29. 36. ciclo","filename":"phd_unimi_R12840.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1050394/2411513/phd_unimi_R12840.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1047301"},"title":"IL CONFLITTO DI DECISIONI NELLO SPAZIO GIUDIZIARIO EUROPEO","internalauthor":"DOCAJ, DENISA","type":"Tesi di dottorato","year":"2024","abstract":"In the transnational context we traditionally refer to conflict of decisions when the effects of two (or more) decisions, given between the same parties and, in some cases, involving the same cause of action, entail legal consequences that are mutually exclusive. Such scenarios undermine legal certainty in the European area of justice along with the procedural guarantees of the right of action and defense that are confirmed by the principle of due process – as enshrined in Art. 6 of the ECHR – and the right of access to civil justice. Conversely, the practical implementation of these guarantees should be coordinated with the need to ensure an undemanding circulation of decisions in the European judicial area,  consistent with the line taken by the European legislator to abolish as much as possible controls on decisions rendered in the Member States and marked by the principle of mutual trust between judicial authorities. According to the simplified circulation regime currently outlined by the European regulations, in fact, decisions falling within the material scope of the regulations, given by a Member State in compliance with the principle of adversarial proceedings between parties and, in wider terms, with the generally provided procedural guarantees, may circulate. The effects of such decisions may be invoked in any other Member State, behind the constraint on the court of the requested Member State to comply with the findings of the court of origin. Based on these premises, the thesis, after retracing the dynamics of transnational litigation that could lead to irreconcilable decisions, aims to examine the discipline of the conflict of decisions provided for by the European legislator by looking, firstly, at the rules on coordination of parallel proceedings. As is common knowledge, in fact, in order to ensure the harmonious administration of justice, a series of procedural instruments are provided for to prevent, to the extent possible, the occurrence of irreconcilable decisions from the outset. This is, precisely, the rationale behind the provisions on lis pendens and related actions. In such a perspective, the requirements of the lis pendens rule – then recalled by the legislator also to define the assumptions of conflicting decisions – are, therefore, examined. Attention thus shifts, in the second part of the dissertation, to the rules intervening at a later stage, looking beyond the coincidence of the requirements mentioned above in order to verify whether there are additional assumptions likely to give rise to conflicting decisions and, having clarified this, whether the provisions on the conflict of decisions are compatible with the principle of mutual recognition of judgments that informs the European area of justice. The analysis is conducted by adopting a cross-sectional perspective and thus looking at civil and commercial matters, according to  the provisions set forth in Regulation (EU) No 1215/2012, family disputes, notably, in light of Regulation (EU) 2019/1111, Regulation (EU) 2016/1103, Regulation (EU) 2016/1104, Regulation (EC) No 4/2009, and succession matters as set forth in Regulation (EU) No 650/2012, having regard to the interpretation given by the Court of Justice of the European Union and national case law of Member States.","language":"ita","citation":"IL CONFLITTO DI DECISIONI NELLO SPAZIO GIUDIZIARIO EUROPEO / D. Docaj ; tutor: F.C. Villata ; co-tutor: M. Zulberti ; coordinatore: F. Biondi. Dipartimento di Studi Internazionali, Giuridici e Storico - Politici, 2024 May 07. 36. ciclo","filename":"phd_unimi_R13074.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1047301/2403992/phd_unimi_R13074.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/939050"},"title":"LEGAL RECOGNITION OF POLYAMOROUS FAMILIES: A CLAIM FOR DESIRABILITY","internalauthor":"MICCOLI, FRANCESCA","type":"Tesi di dottorato","year":"2022","abstract":"The aim of this work is twofold. Firstly, to investigate the feasibility of the legal recognition of polyamorous families from a socio-legal perspective. To achieve this purpose, in the first part of the work I outline an empirical and legal discussion of the phenomena of new families. This premise helps me deal with the issue of the feasibility of polyamorous families’ legal recognition in the long and short run. Furthermore, I point out the relevance of polyamorous relationships as a case study, by assessing their statistical prevalence, and visibility, problematising possible definitions and enumerating their main features and values. The socio-legal context of increasing visibility and social acceptance of new families, including polyamorous ones, grounds my argument in favour of the feasibility of the legal recognition of polyamory, at least in the long run. Moreover, the empirical framework further supports my normative argument in favour of the desirability of the legal recognition of polyamory.  The second aim of this work is to argue in favour of the desirability of the legal recognition of polyamorous families on an equal basis, with a political-philosophical approach. Accordingly, the second part of the dissertation addresses normative questions about the legitimacy and the desirability of liberal states’ intervention in recognizing families. I argue that, both from the perspective of political and perfectionist liberalism, the law can legitimately recognize families as relationships of care. Furthermore, I foreground that states’ intervention in the matter of family is desirable as well. However, in order to be legitimate, family law should recognize all different kinds of families, including polyamorous ones. To conclude, I advocate the desirability of the legal recognition of polyamorous families both from a neutralist and a perfectionist perspective, and I suggest a necessity to look for new legal institutions, more suitable than marriage in regulating all families on an equal basis. Adopting both a socio-legal and a political-philosophical perspective, I aim to offer a systematic review of the topic of the legal recognition of polyamorous families, which has been addressed very scarcely and fragmentarily so far.","language":"eng","citation":"LEGAL RECOGNITION OF POLYAMOROUS FAMILIES: A CLAIM FOR DESIRABILITY / F. Miccoli ; tutor: N. Riva ; coordinatore: M. Jessoula. Dipartimento di Scienze Sociali e Politiche, 2022. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12205.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/939050/2099606/phd_unimi_R12205.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/831873"},"title":"CYBER ORGANIZED CRIME. LA REPRESSIONE DELLA CRIMINALITÀ ORGANIZZATA CIBERNETICA: UN CONFRONTO TRA ITALIA E USA","internalauthor":"PICARELLA, LORENZO","type":"Tesi di dottorato","year":"2021","abstract":"\"The doctoral thesis assesses the application of the criminal association offence and the mafia-type offence of the Italian criminal code and the conspiracy offence and the RICO offences of the US federal criminal code to criminal groups operating online. The first chapter summarizes the criminological literature on cyber organized crime. The second and the third chapters focus on the features of the offences taken into consideration in this research, also from an historical point of view. The fourth chapter analyzes the jurisprudence related to cyber organized crime which allowed to identify two types of criminal associations: criminal associations that operate entirely online (\"\"cyber criminal associations\"\") and criminal associations that operate only partially online (\"\"cyber-hybrid criminal associations\"\"). The last chapter highlights the main features of the jurisprudence on cyber organized crime and critically assess the legal and criminological concept of organized crime in the light of the new cyber phenomenon.\"","language":"ita","citation":"CYBER ORGANIZED CRIME. LA REPRESSIONE DELLA CRIMINALITÀ ORGANIZZATA CIBERNETICA: UN CONFRONTO TRA ITALIA E USA / L. Picarella ; tutor: F. Basile; coordinatore: F. Basile. Dipartimento di Scienze Giuridiche Cesare Beccaria, 2021 Apr 19. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11842.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/831873/1760749/phd_unimi_R11842.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1118136"},"title":"OPEN-SOURCE MIDDLEWARE FOR QUANTUM COMPUTING","internalauthor":"PASQUALE, ANDREA","type":"Tesi di dottorato","year":"2024","abstract":"Quantum computing has the potential to greatly surpass classical computing for specific tasks. Despite the noise challenges in current quantum devices, NISQ (Noisy Intermediate-Scale Quantum) devices are becoming more accessible to research groups and institutions.  To successfully deploy quantum computing algorithms on hardware or through simulations, specialized middleware software is crucial for transitioning from theoretical research to practical experiments. This thesis introduces an open-source framework for quantum simulation, hardware control, and characterization: Qibo.  Simulation tools are vital for designing and benchmarking quantum algorithms before deploying them on quantum hardware. In this thesis, we demonstrate circuit-based quantum simulation using just-in-time compilation on multiple hardware accelerators, achieving performance on par with state-of-the-art full-state vector simulators.  Deploying quantum algorithms on hardware requires a distinct software layer, provided by Qibolab. This library offers a unified framework for controlling the various electronics needed to operate a quantum computer. Additionally, Qibolab handles all necessary tasks to prepare quantum circuits for execution on a fully characterized device, including circuit transpilation and compilation.  However, controlling the electronics alone is insufficient for deploying algorithms on quantum hardware, as current devices are noisy and prone to decoherence, leading to parameter drifts. To address these issues, this framework includes Qibocal, a package for calibrating quantum devices, which eases the burden on experimentalists dealing with noisy devices.  Finally, to demonstrate the framework’ capabilities, we present applications achieved using Qibo, including a novel approach to enhancing ground state preparation with Variational Quantum Eigensolvers and Double Bracket algorithms.","language":"eng","citation":"OPEN-SOURCE MIDDLEWARE FOR QUANTUM COMPUTING / A. Pasquale ; coordinatore. A. Mennella ; supervisore: S. Cazza. Dipartimento di Fisica Aldo Pontremoli, 2024 Dec 04. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13299.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1118136/2587888/phd_unimi_R13299.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1205209"},"title":"PRIMING STRATEGIES TO ENHANCE THE EFFECT OF THE SECRETOME OF MESENCHYMAL STEM/STROMAL CELLS IN COUNTERACTING OSTEOARTHRITIS THROUGH THE ACTION OF THE EVS","internalauthor":"CADELANO, FRANCESCA","type":"Tesi di dottorato","year":"2026","abstract":"Osteoarthritis (OA) is the most prevalent form of joint disease, affecting millions worldwide and leading to chronic pain, stiffness, and functional disability due to progressive degeneration of articular cartilage, synovial inflammation, and exposure of subchondral bone and nervous terminals. Further, OA is increasingly recognized as being influenced by “inflammaging”, an emerging  oncept describing the chronic, low-grade inflammation associated with aging that contributes to tissue degeneration and impaired repair mechanisms. Despite its multifactorial pathophysiology, current OA treatments primarily address symptoms without targeting the underlying biological processes, ultimately necessitating surgical intervention. Additionally, OA can affect any individual since its early stages of aging, and considering the increasing average lifespan, disease-modifying or even disease-reverting approaches are urgently required, to overcome this social and economic burden.  Among emerging therapeutic strategies, mesenchymal stem cell (MSC)-derived conditioned medium (CM) has gained significant attention for its ability to recapitulate many of the regenerative, immunomodulatory, and anti-inflammatory properties of stem cells through its complex cargo of cytokines, growth factors, and extracellular vesicles. However, translating CM into clinical practice is hindered by production variability and the absence of preclinical models and guidelines to test its efficacy, safety and dosage. With this project, we established a standardized protocol to produce CM from adipose-derived MSC (ASCs) and characterized it comprehensively. CM was then evaluated into increasingly complex OA models, both bidimensional (2D) and three-dimensional (3D), where the pathology was recapitulated by the exposure to inflammatory cytokines, namely TNFα and/or IL-1β. These platforms were used to test the effects of both naïve and primed CM on cellular and tissue responses, focusing on key molecular markers related to inflammation, matrix degradation, and tissue remodelling. CM treatment resulted in a significant downregulation of catabolic enzymes such as MMPs in cartilage representative models, moreover it demonstrated anti-inflammatory properties in both cartilage and synovial membrane representative ones.  Importantly, in ex vivo settings, the response to CM varied among donors, with some explants exhibiting marked improvement while others showed minimal modulation, revealing inter-individual differences in therapeutic responsiveness. These findings not only confirm the potential of MSC-derived CM as a promising disease-modifying agent in OA but also underscore the value of patient-specific ex vivo models as predictive tools for therapeutic screening and for stratifying patients based on their molecular response profiles, paving the way toward personalized approaches in OA management.","language":"eng","citation":"PRIMING STRATEGIES TO ENHANCE THE EFFECT OF THE SECRETOME OF MESENCHYMAL STEM/STROMAL CELLS IN COUNTERACTING OSTEOARTHRITIS THROUGH THE ACTION OF THE EVS / F. Cadelano ; tutor: A. T. Brini ;  supervisor: S. Niada ;  director: N. Landsberger. Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, 2026 Jan 30. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13934.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1205209/3213354/phd_unimi_R13934.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/850498"},"title":"FORMA E NULLITÀ DI PROTEZIONE NEI CONTRATTI FINANZIARI","internalauthor":"GIULIANI, SAMUELE","type":"Tesi di dottorato","year":"2021","abstract":"This study aims to analyze the new formal requirements of contracts introduced by special legislation, together with the connected remedy of “protective nullity”, in the perspective of their respective functions.  Through the regulation of relationships with disparity of contractual power, the legislator acknowledged the needs emerging from the changed economic context, where real estate property is no longer central, given the rise of a dynamic, competitive market of products and services, where asymmetric contracts prevail; in this context, the most relevant asset is information, held by the “strong” professional party, towards which the other party is in a position of structural weakness.  In this situation, the form of the contract is no longer only aimed at guaranteeing certainty in the circulation of property: it becomes an instrument for reducing information asymmetries and ensuring the transparency of the contractual contents, with consequent promotion of the order, the efficiency and the competitiveness of the relevant market. The same protection purpose inspires the nullity provision, which limits the right of action to the weaker party only.  Therefore, the “protective” form and nullity of the contract will be analyzed in a joint and interconnected study, carried out with specific reference to the financial sector, which represents a fertile field of investigation for the examination of the critical issues regarding the connection between special legislation and general rules set forth under the Italian Civil Code. This analysis, to be carried out by doctrine, proceeds together with the process of gradual review of the general categories of civil law.  In such perspective, this study investigates how the enhancement of the function of law can contribute to evolve legal categories, in order to provide adequate answers to the problems arising in the modern economic reality. This approach is also endorsed by a recent ruling of the Italian Supreme Court, which seems an expression of a renewed “jurisprudence of interests”.  The above-mentioned analysis starts from the study, in the first chapter, of the evolution of the functions of the form of contract.  The second chapter is dedicated to the in-depth study of the form of financial contracts, carried out by analyzing the characteristics and limits of formal protection in such field, as well as its integration through the provision of specific information and conduct duties of financial intermediaries. Among the issues which arise from the formal requirement, particular attention is paid to the validity of financial contracts signed only by the investor.  The third chapter focuses on the protective nullity provided for investment contracts; it is dedicated, in particular, to the issue of possible abuses of the advantages granted by the legal system to the weaker party, with specific regard to the so-called “selective” claims. The study tries to suggest solutions aimed at avoiding a dysfunctional use of the protective legislation, which occurs when such rules are exploited for purposes other than those envisaged by the legislator.  On the one hand, the enhancement of the specific functions of special legislation is useful in order to guarantee a consistent interpretation and a renovation of the traditional legal categories of form and nullity of the contract; on the other hand, such approach allows to prevent an opportunistic use of the rules aimed at protecting the weaker party, which would have disruptive effects not only on individual contractual relationships, but also on the system as a whole.  In the specific field of financial intermediation, the considerations above demonstrate the unfairness of legal actions based on the nullity of the financial contract, when proposed in the absence of a real information harm, for the sole purpose of obtaining the return of the sums used for disadvantageous investment transactions, regardless of an actual lack of information or inadequacy to the investor’s risk profile.  Lastly, the analysis carried out offers a contribution to the study of the limits of formal protection, especially in sectors such as the financial one, characterized by an intrinsic high complexity of the products and services under offer. In light of the evolution of legislation and regulation, it is now clear that information transparency, conveyed by the contractual document, is necessary but not sufficient to ensure a substantial protection of the weaker party. This outcome inevitably requires the effective compliance with the behavioural duties of the professional party.","language":"ita","citation":"FORMA E NULLITÀ DI PROTEZIONE NEI CONTRATTI FINANZIARI / S. Giuliani ; tutor: E. Panzarini ; referente del curriculum: C. Tenella Sillani ; coordinatore del corso di dottorato: G. Ludovico. Dipartimento di Diritto Privato e Storia del Diritto, 2021 Jun 15. 33. ciclo, Anno Accademico 2020.","filename":"phd_unimi_R11901.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/850498/1821672/phd_unimi_R11901.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1195301"},"title":"ADVANCING IN SITU CRYO-ET TO THE NEXT DIMENSION: TOMOGRAPHY ON 3D ORGANOIDS","internalauthor":"NGUYEN, HO THUY DUNG","type":"Tesi di dottorato","year":"2025","abstract":"Interpreting how molecular organization supports cell and tissue function remains a central challenge in biology. In situ cryo-electron tomography (cryo-ET) can help to address this challenge by providing high-resolution, three-dimensional visualization of macromolecules in near-native, minimally disturbed conditions. With its broad resolution, cryo-ET enables us to study the organization and architecture of macromolecules across different spatial scales. Hence, this capacity to bridge molecular and cellular levels offers a unique opportunity to connect structural biology with medical research.   However, for a long time, cryo-ET has been mainly applied to simple biological systems, such as viruses, bacteria, and two-dimensional cell cultures. While these systems are technically feasible, they lack the interaction information, resulting in poor translation from cellular to tissue-level biology. To more precisely capture the molecular landscape, ideally, we should extend studies to tissue samples. Yet, they pose significant ethical and methodological challenges.   A promising alternative is the use of three-dimensional organoids, which present a balance between physiological relevance and technical capabilities. Organoids recapitulate key aspects of tissue architecture and physiology, thus bridging the gap between cellular and tissue contexts. Additionally, they are simpler and easier to manipulate and access than tissue samples. Combining organoids with in situ cryo-ET creates new opportunities for conducting structural biology in physiologically relevant models.  This thesis presents the first applications of cryo-ET to organoid samples, specifically human forebrain organoids and mouse thyroid organoids, enabling in situ structural analysis at subcellular scales within tissue-like environments. To overcome challenges posed by these samples, we developed several methodological advances: (i) Serialized On-grid Lift-In Sectioning for Tomography (SOLIST), an optimized cryo-lift-out technique improving sample stability and lamella production efficiency; (ii) a generalized in situ cryo-ET workflow applicable to a variety of organoids, embedding with or without extracellular matrix; and (iii) a targeted cryo-ET pipeline facilitating precise imaging of defined regions within these organoids. Using these advances, together with other complementary imaging techniques, we successfully resolved the molecular landscape in human forebrain organoids and characterized the follicular organizations in mouse thyroid organoids.   By integrating the structural resolution of in situ cryo-ET with the physiological relevance of organoids, this work has established a methodological framework for in-depth investigations at the molecular level in complex and medically relevant systems. The outcome of this study sets the foundations for future approaches, where organoids and patient samples become the preferred choice in structural biology, thereby permitting the validation of simpler model systems and advancing our understanding of research and disease treatment.","language":"eng","citation":"ADVANCING IN SITU CRYO-ET TO THE NEXT DIMENSION: TOMOGRAPHY ON 3D ORGANOIDS / H.t.d. Nguyen ; supervisor: P. Erdmann ;  coordinator: F. Coscia, G. Pigino, A. de Marco, D. Pasini. Dipartimento di Oncologia ed Emato-Oncologia, 2025 Nov 10. 37. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13511.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open from 11-MAG-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1040537"},"title":"DISSECTING THE ROLE OF NEDD4 HECT E3 LIGASE AND ITS ISOFORMS IN CANCER","internalauthor":"LOMBARDO, LIERIN","type":"Tesi di dottorato","year":"2024","abstract":"NEDD4 is a E3 ubiquitin ligase belonging to the HECT family and is composed by a N-terminal C2 domain, four WW domains and the catalytic C-terminal HECT domain. Different studies evidenced a correlation between NEDD4 overexpression and tumor progression and in some cases its proto-oncogenic activity has been ascribed to the ubiquitination-mediated degradation of the tumor suppressor PTEN. The proto-oncogenic role of NEDD4 seems to be cellular context dependent and interesting data linked K-RAS activation to NEDD4 overexpression and subsequent PTEN degradation in human colorectal cancer. Since NEDD4 is overexpressed in Non-Small Cell Lung cancer (NSCLC), and high percentage of these tumors show K-RAS mutation, we decided to verify the proto-oncogenic role of NEDD4 in a genetic context characterized by K-RAS mutation in NSCLC. Unfortunately, our attempt to functionally link these events or to validate the phenotype associated to NEDD4 failed. Conducting the experiments, we noticed the presence of few putative NEDD4 isoforms recognized by anti-NEDD4 antibody, and, hypothesizing a possible contribute to the proliferation phenotype, we decided to characterize them.  The existence of alternative splice variants of NEDD4 has been reported in online databases, but their relevance is largely unknown. Experiments of siRNA interference followed by western blot together with RT-PCR and sequencing confirmed the identity of NEDD4 isoforms, heterogeneously expressed in cancer cells representative of various tumors.  Among the alternative versions of NEDD4, isoform 3 is reported to be one of the mainly expressed across different tissues. Interestingly, this putative isoform, compared to the canonical isoform 1 protein, exhibits a unique domain of 516-amino acid at the N-terminus together with a consistent deletion of the C2 domain. The presence of the N-terminal additional domain, together with the well-known relevance of the C2 domain for the regulation of the catalytic activity of NEDD4, suggests that isoform 3 may promote cellular processes different from the ones exerted by isoform 1. In order to unveil biological and biochemical features of NEDD4 isoform 3, we started analyzing its cellular localization and ubiquitination activity. In addition, co-immunoprecipitation coupled with proteomic experiment led to the identification of exclusive NEDD4 isoform 3 interactors, of which the mitochondrial carrier SLC25A13. To date, significant observations linking NEDD4 E3 ligase to mitochondria are not reported, thus the functional relevance arising from this interaction was explored. In this context, the observed mitochondrial membrane potential dependency upon NEDD4 isoform 3 may provide first evidences of the isoform’s involvement in undisclosed pathways, shedding light on its potential impact on novel cellular functions, different from the ones ascribed to canonical NEDD4.","language":"eng","citation":"DISSECTING THE ROLE OF NEDD4 HECT E3 LIGASE AND ITS ISOFORMS IN CANCER / L. Lombardo ; tutor: G. Scita ; co-tutor: S. Polo ; added supervisor: C. Mercurio ; phd coordinator: S. Marinucci. Dipartimento di Oncologia ed Emato-Oncologia, 2024 Apr 11. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12771.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1040537/2386489/phd_unimi_R12771.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1232683"},"title":"NUTRITION ECOLOGY IN THE LIVESTOCK PRODUCTION SYSTEM - ALGAE POTENTIAL AS SUSTAINABLE FEED INGREDIENTS","internalauthor":"FRAZZINI, SARA","type":"Tesi di dottorato","year":"2026","abstract":"The transition towards more sustainable livestock production systems represents one of the major challenges for contemporary animal production. The growing demand for animal-derived food, combined with the need to reduce environmental impact and limit antibiotic use, requires the development of innovative and circular nutritional strategies. In this scenario, algae emerge as a highly promising resource, due to their high productivity, ability to grow in marginal environments without competing with arable land used for human food production, and rich content of bioactive compounds with documented functional properties.  This doctoral research aimed to provide a multidimensional assessment of the potential of algae as sustainable and functional feed ingredients, integrating in vitro, ex vivo, and in vivo approaches. In the first phase, several algal species were characterized from a chemical, nutritional, and functional perspective, with particular focus on the presence of bioactive compounds with antioxidant, antimicrobial, and immunomodulatory activities. In vitro studies investigated the stability and bioavailability of algal bioactive compounds during simulated digestion, highlighting the preservation of relevant biological activities.  Subsequently, ex vivo studies explored the mechanisms of interaction between algal extracts and immune cells derived from mice and pigs models, demonstrating significant effects in modulating inflammatory responses and regulating macrophage functions under chemical stress conditions. These findings confirmed the potential of algae not only as alternative nutrient sources but also as genuine functional ingredients capable of supporting immune health.  In vivo trials, carried out on weaned piglets and neonatal calves, evaluated the impact of algal supplementation under real farming conditions. The results showed positive effects on gut health, with a reduction in the incidence and severity of post-weaning and neonatal diarrhea, which represent a serious health and economic problem for farmers and are conditions in which antibiotics are often extensively used, though frequently with limited effectiveness, as well as improvements in growth parameters and overall health status. Moreover, the use of algae demonstrated potential in reducing antibiotic reliance, thereby promoting more sustainable farming practices.  Overall, the outcomes of this project highlight the strategic role of algae in the future of animal nutrition, combining environmental sustainability, food security, animal welfare, and production resilience. This research contributes to strengthening the applicability of the nutritional ecology framework within modern livestock systems, outlining innovative scenarios in which algae can represent a cornerstone of functional and circular diets. However, their practical application is still limited by factors such as the relatively high production costs and the heterogeneity in composition among different algal species and cultivation systems, which may affect consistency, scalability, and economic feasibility.","language":"eng","citation":"NUTRITION ECOLOGY IN THE LIVESTOCK PRODUCTION SYSTEM - ALGAE POTENTIAL AS SUSTAINABLE FEED INGREDIENTS / S. Frazzini ; tutor: L. Rossi ; co-tutor: R. Resca ; coordinatore: F. Ceciliani. Dipartimento di Medicina Veterinaria e Scienze Animali, 2026 Apr 15. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13764.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open from 09-OTT-27"}
,{"handle":{"url":"https://hdl.handle.net/2434/1156227"},"title":"FROM CLOCKS TO EXERCISE, FROM METABOLISM TO PERFORMANCE: A CHRONOPHYSIOLOGICAL APPROACH","internalauthor":"CIORCIARI, ANDREA MICHELE","type":"Tesi di dottorato","year":"2025","abstract":"This doctoral thesis aims to explore the relationship between rhythmic behavior of selected variables and exercise, examining their impact on athletic performance and physiology. The first part of the thesis provides a comprehensive introduction to chronobiology, highlighting its role in regulating physiological processes such as sleep-wake cycles, hormonal rhythms, and metabolic functions. The second part examines how chronobiological factors affect physical performance, emphasizing the role of sleep quality, chronotype, and social jetlag in shaping endurance, strength, and balance. The final section of this introduction delves into molecular aspects, investigating the influence of temperature regulation, metabolism, and clock genes in determining exercise physiology. The complex interaction between the central biological clock and peripheral clocks is described, with a focus on clock genes such as Cry1 and Cry2, which are crucial in regulating metabolic processes and circadian rhythms. Then, experimental studies are presented, which demonstrate the effects of sleep impairments, circadian misalignment, and chronotype on aerobic capacity, motor skills, and postural control in athletes. Additionally, studies on mice show how exercise can synchronize core body temperature and metabolism, and offer insights into the role of clock genes in modulating energy metabolism and physical performance in Cry1/2 muscle-specific knockout mice models. This research contributes to the emerging field of exercise chronophysiology, offering novel perspectives on how biological rhythms and exercise can be leveraged to optimize both health outcomes and peak athletic performance.","language":"eng","citation":"FROM CLOCKS TO EXERCISE, FROM METABOLISM TO PERFORMANCE: A CHRONOPHYSIOLOGICAL APPROACH / A.m. Ciorciari ; tutor: A. Montaruli ; coordinatore: F. Esposito, C. Gozzoli. Dipartimento di Scienze Biomediche per la Salute, 2025 Mar 26. 37. ciclo, Anno Accademico 2023/2024.","filename":"phd_unimi_R13437.pdf","fileformat":"Adobe PDF","fileversion":"postprint","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1156227/2731322/phd_unimi_R13437.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/821732"},"title":"CT- AND MRI-DERIVED BIOMARKERS FOR CARDIOVASCULAR DISEASE","internalauthor":"MONTI, CATERINA BEATRICE","type":"Tesi di dottorato","year":"2021","abstract":"Cardiac computed tomography (CT) and magnetic resonance imaging (CMR) have shown potential in providing new insights concerning different cardiovascular pathologies. More recently, the focus of such studies has shifted from a simple qualitative evaluation of imaging, to a more objective approach, which includes the assessment of quantitative biomarkers. In particular, late gadolinium enhancement (LGE), myocardial strain and extracellular volume fraction (ECV) could be used to aim for a more tailored approach to the study of different diseases. The main applications for LGE discussed in this study include the definition of a more appropriate gadolinium-based contrast dosage for the assessment of myocardial infarction at CMR, and the appraisal of LGE patterns and roles in patients with Tetralogy of Fallot (ToF), the most common cyanogen congenital heart defect. The analysis of myocardial strain focused on the detection of subclinical contractility anomalies in patients with ToF, and with myocarditis, aiming for a quantitative approach which could help highlight early cardiac disease before myocardial function is irreversibly altered. The study of ECV, conversely, focused on the early detection of subclinical cardiotoxicity stemming from anthracycline treatment for breast cancer. Overall, the use of such quantitative biomarkers in imaging studies could help pave the way for a more tailored patient treatment, and towards personalized medicine.","language":"eng","citation":"CT- AND MRI-DERIVED BIOMARKERS FOR CARDIOVASCULAR DISEASE / C.b. Monti ; tutor: F. Sardanelli ; co-tutor: F. Secchi. Università degli Studi di Milano, 2021 Feb 23. 33. ciclo, Anno Accademico 2020. [10.13130/monti-caterina-beatrice_phd2021-02-23].","filename":"phd_unimi_R11879.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/821732/1726070/phd_unimi_R11879.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1172116"},"title":"GOSSIP AS SOCIAL EXCHANGE IN NETWORKS","internalauthor":"MUNOZ SCHUFFENEGGER, ESTEBAN NICOLAS","type":"Tesi di dottorato","year":"2025","abstract":"This thesis is about gossip. This concept is understood as a conversation between two or more individuals about absent third parties (i.e., behind their backs). Gossip has not been free of controversy. In fact, it has been condemned and considered an undesirable activity by various groups and communities because it fails to follow some basic social norms, such as solidarity. However, socialization through gossip has been compared to grooming in primates. Not only does gossip allow individuals to share information, but these conversations have been shown to have several social functions. One problem with the literature on gossip is the lack of a common framework and definition of the concept. In this dissertation, we use social exchange theory for two main purposes. First, as a way to understand the social functions of gossip. Second, as a mean to clarify the more recent developments of the goal-framing theory of gossip. These approaches provide a better way to understand the definition of gossip. Similarly, they allow for potential explanations for its use. In three empirical chapters, we used social network analysis methods to study gossip networks in organizations. In the first two, we focused on the association of the gossip networks between senders and receivers and their cooperation and affective relationship networks. In the third, we focused on the same associations, but between their senders and targets. Our findings provide empirical support that gossip can be useful to consolidate instrumental and affective relationships between those who share it. Similarly, we found that instrumental relationships do not prevent individuals from gossiping about those with whom they must cooperate. These results suggest that gossip can be used as a social bonding and control mechanisms in small groups. Similarly, we found that individuals are less likely to gossip about those with whom they feel affectively connected. These findings also suggest that the use of gossip is not necessarily detrimental to organizations, given that individuals can also benefit from it by providing opportunities to form and strengthen positive relationships in these environments.","language":"eng","citation":"GOSSIP AS SOCIAL EXCHANGE IN NETWORKS / E.n. Munoz Schuffenegger ; tutor: F. Squazzoni ; coordinator: M. Guerci. Dipartimento di Scienze Sociali e Politiche, 2025 May 19. 36. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R12890.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1172116/3095364/phd_unimi_R12890.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1036168"},"title":"DENKMALER UND SACRARI FUR DIE HELDEN DES FASCHISMUS IN ITALIEN 1922 - 1943","internalauthor":"TOMESANI, MARTA","type":"Tesi di dottorato","year":"2024","abstract":"Questo elaborato di tesi intitolato Denkmaeler und sacrcari fuer die Helden des Faschismus in Italien 1922-1943 si prefigge di indagare le opere architettoniche e scultoree ideate o realizzate su iniziativa del partito fascista durante il ventennio 1922-1943, al fine di commemorare i caduti per la causa del regime, presentando le strategie adottate in ambito architettonico e scultoreo per ottemperare a direttive ed esigenze del culto del littorio. Innanzitutto è necessario premettere che si tratta di un lavoro di ricerca scientifico, che prende le distanze da qualsiasi posizione politica, basato sulla ferma convinzione che sia doveroso occuparsi della storia e comprenderla appieno, con il fine ultimo di impegnarsi a tutelare la democrazia.  Per il movimento fascista il culto dei caduti fu “probabilmente il più espressivo del suo senso di religiosità secolare” (Gentile, 1993, p. 47) e svolse fin dai primordi un ruolo chiave nella sua ideologia, costituendo una fra le manifestazioni più durature e meno soggette a variazioni, caratterizzato da una dimensione locale e al contempo capillarmente presente su tutto il territorio nazionale. Attingendo, come noto, alle forme e ai linguaggi del primo dopoguerra, così come al repertorio cristiano, il regime dedicò monumenti e sacrari ai caduti per la causa del regime (Suzzi Valli 2008; Masseroni, 2017) al fine di legittimare il proprio culto. Appuratone il carattere sincretico, i riferimenti alla religione cristiana, al contesto militare del secolo precedente ed alla romanità, questa tesi si propone di analizzare le architetture, il repertorio iconografico e il rapporto tra modernità e classicità adottati dal regime per definire architettonicamente e figurativamente la sacralità dei suoi luoghi sacri.   Con questo elaborato si offre quindi un contributo alla riflessione relativa alla definizione del concetto di sacrale nell’architettura e nell’arte del culto del littorio, suggerendo strumenti e chiavi di lettura di questo fenomeno, a partire dall’analisi delle fonti primarie – edite ed archivistiche – risalenti al ventennio. Considerati il carattere capillare di diffusione dei monumenti – che rimanda a quello della monumentomania del primo dopoguerra – e il numero di progetti e realizzazioni all’interno delle case del fascio, stimato a circa 25.000 (Mangione, 2006), risulta evidente come numerosi siano i monumenti e sacrari per i caduti per la causa fascista ad oggi non compiutamente approfonditi dalla ricerca. Nell’indagare quest’ambito, si palesa l’ulteriore difficoltà della definizione terminologica di sacrario e della tipologia in cui questi si inquadrano. Definito il sacrario come “Cappella o ambiente in cui sono raccolti i resti o i ricordi di persone benemerite della patria” (Treccani, enciclopedia), i luoghi sacri dedicati ai caduti fascisti si differenziano dai monumentali progetti di sacrari militari in quanto i primi si caratterizzano per un contesto di realizzazione più ampio, che spazia da ambienti ricavati all’interno di edifici istituzionali – fra cui appunto le case del fascio –, inseriti in punti nevralgici del tessuto urbano, a quelli previsti all’interno di edifici religiosi, in cimiteri così come include quelli allestiti in contesti espositivi. Ad oggi la ricerca riconduce, correttamente, i numerosi progetti di sacrari alle forme e ai linguaggi del noto modello del sacrario liberiano della Mostra della Rivoluzione Fascista. Tale tesi viene supportata dalla dimensione prescrittiva della realizzazione di un ambiente dedicato ai caduti all’interno delle case del fascio, contenuta nel foglio d’ordini promulgato dal partito il 20 novembre 1932. Si ritiene tuttavia che – considerando l’eterogeneità dei differenti contesti di realizzazione, la varietà di forme, stili e linguaggi impiegati nei vari progetti – la tipologia di monumenti e sacrari nel suo complesso vada ulteriormente indagata, soprattutto contestualizzandola nei diversi ambiti di realizzazione e alla luce dei dibattiti teorici sulla modernità e sulla romanità, così come in relazione alla definizione di un edificio religioso moderno finalizzato al culto. Inoltre si constata ad oggi la mancanza di uno studio sistematico che analizzi lo sviluppo architettonico ed artistico delle opere commemorative nell’intero arco cronologico della storia del fascismo, approfondendone i modelli architettonici, i rimandi iconografici e stilistici, contemplandone la presenza in riviste e periodici sia divulgativi che scientifici, ed andando a studiare le scelte artistiche operate dal regime per la realizzazione di un carattere sacrale precipuo del culto del littorio. A differenza di altre opere del regime a carattere rappresentativo, si conferma per i monumenti e i sacrari dedicati ai caduti per la causa fascista una evidente mancanza di linee guida, con un’inevitabile ricaduta sulla definizione delle opere stesse sia a livello progettuale sia di realizzazione. Sullo sfondo di tale complessa interazione tra esigenze politiche ed aneliti religiosi, si delinea una caratterizzazione artistica tutt’altro che lineare, bensì spesso contraddittoria ed imprecisa tanto nelle direttive quanto nelle aspettative del regime, che portò il monumento ad evolversi in luogo percorribile per il visitatore e il sacrario ad aprirsi da ambiente di raccoglimento personale a palcoscenico della messa in scena della liturgia del littorio, a scopo propagandistico dell’ideologia e della fede politica del regime.","language":"ita","citation":"DENKMALER UND SACRARI FUR DIE HELDEN DES FASCHISMUS IN ITALIEN 1922 - 1943 / M. Tomesani ; tutor:  I. Herklotz, S. G. Bignami ; coordinatore: F. Slavazzi. Dipartimento di Beni Culturali e Ambientali, 2024 Mar 14. 35. ciclo [10.13130/tomesani-marta_phd2024-03-14].","filename":"phd_unimi_R13291_1.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1036168/2376989/phd_unimi_R13291_1.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1121115"},"title":"CHARACTERIZATION OF AGROBIODIVERSITY PRODUCTS FOR THE ENHANCEMENT OF MARGINAL AND MOUNTAIN ENVIRONMENTS","internalauthor":"LEONI, VALERIA","type":"Tesi di dottorato","year":"2024","abstract":"Marginal and mountain territories are important for the conservation of environment and biodiversity (and agrobiodiversity). “Marginal” and “rural” adjectives are frequently used together to describe specific territories. Marginal/rural areas host great part of tangible and intangible heritage for humanity that is always at risk of being lost and then “fragile”. On the other hand, the natural, unique resources of marginal territories, which are often unknown and underutilized, could be central for their recovery: value chains, in the agriculture, agroforestry and tourism sectors, are often the backbones of marginal areas economies and deliver essential ecosystem services to society. The pristine habitats are spaces to enhance the production of high-quality food, agricultural products and non-timber goods (as spices or medicinal plants). Very often agrifood products turn into a gastronomic portrayal of landscapes, as in the case of honey, that is also a useful tool to monitor (further than a unique agrifood product) the conditions of special habitats in marginal territories. The environments defined as “marginal”, “mountain”, “rural” and “fragile” deserve the attention of Environmental Sciences. These territories could offer for sure many fields of scientific investigations for the correct management of their resources and the conservation of the environment and its (agro)biodiversity. This thesis is the result of the research activities realized at the Department of Agricultural and Environmental Sciences - Production, Landscape, Agroenergy (DISAA), at the Centre of Applied Studies for the Sustainable Management and Protection of Mountain Areas (CRC Ge.S.Di.Mont.) and at the Swiss Federal Research Center for Agri-food and Environment (Agroscope), in the framework of the PhD in Environmental Sciences (PhD ES), XXXVII cicle, Department of Environmental Science and Policy. The thesis, presented as collection of publications, relates to the main research lines followed during the doctoral thesis: i) “Honeybee products as representation of marginal territories, their peculiarities and changes” ii) “Agricultural agrobiodiversity and minor crops for the renaissance of marginal and mountain territories: landraces, saffron and minor cereals” Considering the first point, honey is strongly linked to the area where it is produced, especially for its relation to the vegetation. Beekeeping can be a secondary activity to help economically vulnerable communities, such as the ones of marginal and mountain territories, through honey production, as well as with other economic benefits such as pollination services. Additionally, honeybees are not only agents of biodiversity maintenance, but also sentinels of the conditions of agroecosystems and possible ongoing alterations. These concepts are at the base of the research works presented in chapter 3. Many plants, also rare or endemic, rely on cross pollination for their reproduction, and they could become special foraging resources for honeybees and other pollinators in certain environments. This is the case of the endemic plant Sanguisorba dodecandra Moretti, which resulted also a resource for other agricultural activities (as pastoralism), contributing to build unique agroecosystems (chapter 3.1 and 3.2). Beekeeping products are identified with special protection labels for their representativity of special territories, as the honey produced in the high lands (chapter 3.3) or dune habitats (chapter 3.4) and, other than being very specific and unique, these products often portray features and variations of these fragile areas. Finally, some honey from these special territories are excellences which still need an in-depth characterization, as raspberry honey (chapter 3.5). The floral origin of honeys, other than being valuable to describe their organoleptic features and to valorize them, is useful to protect these products against food frauds (very common for honey and pollen). Finding reliable analytical techniques to define honey botanical origin becomes then pivotal for many reasons, as food analysis and bee ecology and ethology (chapter 3.6). In the second research line of chapter 4, instead, other “niche” products which could be focal to revitalize agroecosystems in marginal territories are considered. In specific, they are one show case of ancient plant variety (Caigua or Ciuenlai, chapter 4.1), saffron (chapter 4.2 and 4.3) and minor cereals (chapter 4.4). A special focus is reserved to the socio-economic and cultural dimension as another important component of agrobiodiversity (chapter 4.3 and 4.4), also considering the scientific validation of traditional good production practices (chapter 4.2). the body of the thesis is followed by a final discussion of the work through a Strengths, Weaknesses, Opportunities, and Threats (SWOT) analysis which can help in summarizing what was learnt about agrobiodiversity in marginal and mountain territories during the research work and to draw successful strategies for further studies and projects. In the SWOT analysis the strengths and opportunities resulted more than the weaknesses and threats, and technical and scientific knowledge could have an important role in overcoming the limits. The focal points for future research are individuated in a scientific, multidisciplinary and participatory approach, based on sustainability and on the exceptionality of the resources of agrobiodiversity of marginal territories.","language":"eng","citation":"CHARACTERIZATION OF AGROBIODIVERSITY PRODUCTS FOR THE ENHANCEMENT OF MARGINAL AND MOUNTAIN ENVIRONMENTS / V. Leoni ; tutor: L. Giupponi. Dipartimento di Scienze Agrarie e Ambientali - Produzione, Territorio, Agroenergia, 2024 Dec 19. 37. ciclo, Anno Accademico 2024.","filename":"phd_unimi_R13360.pdf","fileformat":"Adobe PDF","fileversion":"altro","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1121115/2597204/phd_unimi_R13360.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/1226656"},"title":"CAUSES AND CONSEQUENCES OF TELOMERE LENGTH VARIATION IN TWO WILD BIRD POPULATIONS","internalauthor":"NOVELLI, ANDREA","type":"Tesi di dottorato","year":"2026","abstract":"Understanding the physiological and molecular mechanisms that generate interindividual variation in survival and reproductive success is a central goal in evolutionary ecology. In this context, telomeres may be particularly relevant, as their length (TL) and attrition rate (ΔTL) may reflect somatic state and maintenance, and thus individual conditions/quality, while also capturing environmentally driven variation that may play a key role in life-history evolution. However, studies from wild populations are still limited and have yielded mixed results, especially those integrating multiple environmental, physiological and parental sources of interindividual variation in early-life TL/ΔTL, and those examining whether this variation translates into different performance over the entire lifespan. Therefore, the present thesis investigated the potential environmental, physiological and parental sources of interindividual variation in early-life TL and ΔTL, as well as the possible fitness consequences of such variation, on two wild bird species, the lesser kestrel (Falco naumanni) and the barn swallow (Hirundo rustica). Chapter 1 tested the effects of thermal stress and growth on ΔTL in lesser kestrel nestlings. ΔTL was slower in nestlings experiencing experimentally decreased nest temperature, while was faster under heatwaves and in faster-growing nestlings, indicating that both thermal stress and growth may accelerate telomere loss during development. Chapter 2 investigated, in barn swallow nestlings, the possible link between hypothalamus-pituitary-adrenal (HPA) axis activity (i.e. corticosterone release), stimulated through a handling-induced stress, and TL/ΔTL, while also testing the influence of developmental conditions and growth. TL and ΔTL were negatively associated with body mass and mass gain in males but not in females, pointing to sex-specific telomeric costs of growth. Moreover, higher corticosterone levels at the end of handling-induced stress were associated with faster ΔTL in smaller broods, but the opposite pattern emerged as brood size increased, suggesting HPA axis activity as a possible proximate mechanism through which stressful developmental conditions may influence telomere dynamics. In barn swallows, Chapter 3 examined environmental and parental sources of interindividual variation in early-life TL and whether this translated into differences in long-term survival. Nestling TL was negatively associated with brood size and paternal age, indicating that both competitive family environment and parental aging may contribute to nestlings’ TL variability. Notably, nestlings with longer telomeres showed higher probability of surviving beyond the first reproduction, suggesting that interindividual variation in TL established early in life can translate into differences in long-term survival, and longer telomeres at this stage may be favored by natural selection even in a species characterized by high annual mortality. The possible association between TL and fitness was further investigated by Chapter 4 in adult barn swallows. Consistent with TL measured during development, longer telomeres at recruitment (i.e. 1-year old) were associated with both longer lifespan and higher lifetime reproductive success, indicating that TL at the onset of adulthood may capture variation in individual quality, and be therefore still exposed to selection at the beginning of adult life. Furthermore, TL and ΔTL covaried with secondary sexual traits in a sex- and trait-specific manner, pointing to a potential role of telomere dynamics in sexual selection processes. Therefore, the thesis identifies multiple environmental, physiological and parental sources of interindividual variation in TL/ΔTL early in life, and shows that such variation can persist across life stages and be associated with survival, reproduction and ornament expression. Moreover, the presence of sex-specific relationships highlights the importance of considering species-specific traits when investigating both the possible causes and consequences of telomere variation. Overall, these results support the idea that telomeres may contribute to linking developmental conditions with later-life performance and suggest that telomere dynamics may represent one of the molecular mechanisms underlying life-history variation in wild populations.","language":"eng","citation":"CAUSES AND CONSEQUENCES OF TELOMERE LENGTH VARIATION IN TWO WILD BIRD POPULATIONS / A. Novelli ; tutor: A. Romano; co-tutor: D. Rubolini; coordinatrice: M. P. M. Guarino. - Università degli Studi di Milano. Dipartimento di Scienze e Politiche Ambientali, 2026 Mar 25. 38. ciclo, Anno Accademico 2024/2025.","filename":"phd_unimi_R13871.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1226656/3279271/phd_unimi_R13871.pdf"},"license":"Creative commons - http://creativecommons.org/licenses/by-sa/4.0/"}
,{"handle":{"url":"https://hdl.handle.net/2434/1014208"},"title":"PORPHYROMONAS GINGIVALIS CONTRIBUTES TO COLON CANCER PROGRESSION BY ENHANCING INKT CELL PRO-TUMORIGENIC FUNCTIONS","internalauthor":"DIAZ BASABE, ANGELICA","type":"Tesi di dottorato","year":"2023","abstract":"Colorectal cancer (CRC) is characterized by a complex tumor microenvironment. Invariant Natural Killer T (iNKT) cells are a CD1d-restricted, lipid-specific, T cell population known to be pro-tumorigenic in CRC. On the other hand, the microbiota has gained importance for its infuence over cancer cells and, most importantly, the immune system. Porphyromonas gingivalis is a member of the oral microbiota linked to CRC. Although the pro-tumor functions of iNKT cells in CRC are known, how they acquire these features is not well understood. Hence, we aimed at understanding if iNKT cells become pro-tumorigenic due to signals given by CRC-associated bacteria, in particular P. gingivalis. For this, we used two murine models and functional assays with human iNKT cell lines. We observed that CRC cells did not induce IL-17, GM-CSF and IL-10 production, known to be secreted by pro-tumorigenic iNKT cells, but activated iNKT cell cytotoxicity via the perforin/granzyme pathway. P. gingivalis enhanced the expression of pro-tumor cytokines and neutrophil chemoattractant activity on tumor-infiltrating iNKT cells in vivo. Furthermore, we found that iNKT cells are necessary for the pro-tumorigenic effects of P. gingivalis in the AOM/DSS model. In vitro experiments revealed that P. gingivalis-primed cells have a neutrophil chemotactic signature and diminished cytotoxicity. Moreover, we showed that Toll-like receptor 2 and 4 signaling mediates the increase in IL-10 and GM-CSF production, whereas chitinase 3-like protein 1 is responsible for the impaired killing activity. These results identified a novel mechanism of P. gingivalis in CRC pathogenesis, by acting on unconventional T cell activities.","language":"eng","citation":"PORPHYROMONAS GINGIVALIS CONTRIBUTES TO COLON CANCER PROGRESSION BY ENHANCING INKT CELL PRO-TUMORIGENIC FUNCTIONS / A. Diaz Basabe ; tutor: F. Facciotti ; co-tutor: S. Santaguida ; phd coordinator: S. Minucci. Dipartimento di Oncologia ed Emato-Oncologia, 2023. 35. ciclo, Anno Accademico 2023.","filename":"phd_unimi_R12770.pdf","fileformat":"Adobe PDF","fileversion":"editoriale","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/1014208/2316689/phd_unimi_R12770.pdf"}}
,{"handle":{"url":"https://hdl.handle.net/2434/925248"},"title":"IL MULTICULTURALISMO NEL RAPPORTO DI LAVORO","internalauthor":"CASSANO, GIULIA","type":"Tesi di dottorato","year":"2022","abstract":"The research conducted in this doctoral thesis aims to investigate the protection offered by labour law to multicultural workers. The problem is analysed from the angle of the prohibitions of discrimination. It first reconstructs the regulatory framework, at an international, European and Italian level, with particular reference to the analysis of the risk factors directly connected with the phenomenon of multiculturalism (ethnic origin, language, race, religion). It then goes on to study the structure of the prohibitions of discrimination, dwelling on the possible configurability of a right to equal treatment. Having affirmed the existence of such a right, its characteristics are analysed, also in the light of the traditional debates of interpreters and scholars of anti-discrimination law. Subsequently, the study focuses on the search for the limits – internal and external – of the right to equal treatment. With reference to the external limits, in particular, the discussion is articulated by reasoning on the basis of two different declinations of the right to equal treatment, for which the point of balance is sought with respect to other rights worthy of protection: the constitutionally protected rights of third parties and the right to freedom of enterprise under Article 41 of the Italian Constitution. With this in mind, a number of hypotheses are analysed that have been the focus of attention of anti-discrimination law scholars as well as national and supranational courts. In this context, the nature of the obligation of “reasonable accommodation”, provided for by law for discrimination on the grounds of disability, is also reconstructed, and its possible extension to all other hypotheses of discrimination is investigated by way of interpretation.","language":"ita","citation":"IL MULTICULTURALISMO NEL RAPPORTO DI LAVORO / G. Cassano ; tutor:  M.T. Carinci ; coordinatore:  G. Ludovico. Dipartimento di Diritto Privato e Storia del Diritto, 2022 May 16. 34. ciclo, Anno Accademico 2021.","filename":"phd_unimi_R12287.pdf","fileformat":"Adobe PDF","fileversion":"tesi","fileaccess":"Open","fileurl":{"url":"https://air.unimi.it//retrieve/handle/2434/925248/2026928/phd_unimi_R12287.pdf"}}]