Archivio Istituzionale della Ricerca - Università degli Studi di Pavia
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Breaking More Than Bones: Systemic Marker Dysregulation in a Mouse Model of Osteogenesis Imperfecta
No full textThis thesis asks how a single change in type I collagen can unsettle organ biology outside the skeleton. Using the Brtl mouse, I examined the cerebellum at eighteen months and the liver and kidney at twelve months with a mixed toolkit: routine histology, Picrosirius in bright field and polarized light, Picro Mallory, quantitative whole-field image analysis in CellProfiler, targeted immunolabeling with optical density and cell counts, and transmission electron microscopy. In the cerebellum the three layers remain in place, yet the molecular and internal granular layers hold fewer cells, and small hemorrhages appear in males. Collagen signals are weaker in meninges and choroid plexus. Endothelial readouts suggest sex specific barrier remodeling: ZO-1, VE-cadherin and VEGF shift in opposite directions in males and females. Autophagy markers point to different control points by sex. In males, p62 is lower while LC3B rises and cathepsin B falls, consistent with brisk autophagosome formation and limited degradative capacity; in females, LC3B is lower while cathepsin B and p62 patterns fit reduced initiation with relatively active clearance. PINK1 and Parkin are both reduced, with PINK1 more affected in females and Parkin in males. Mitochondrial and redox indicators converge on organelle strain: cytochrome c increases, COX4 falls, SOD2 and NRF2 increase, and GPX4 is broadly reduced. Calbindin, a calcium buffer, increases in males and stays near baseline in females.
In the viscera, related themes recur with different weight. In the liver, p62 and LC3B rise in males and fall in females; p53 increases in both sexes and PARP1 is markedly higher in males. Electron microscopy in male liver shows thinner, disorganized collagen fibrils, dilated rough endoplasmic reticulum and enlarged mitochondria. Picro Mallory confirms a thinning of endothelial associated fibrous structures in liver and a milder change in kidney. Renal autophagy shifts are modest, while p53 and PARP1 again separate by sex. Together, the data support a matrix to mitochondria cascade buffered by antioxidant responses, selective autophagy, mitophagy and DNA repair, with failure points set by tissue and sex.This thesis asks how a single change in type I collagen can unsettle organ biology outside the skeleton. Using the Brtl mouse, I examined the cerebellum at eighteen months and the liver and kidney at twelve months with a mixed toolkit: routine histology, Picrosirius in bright field and polarized light, Picro Mallory, quantitative whole-field image analysis in CellProfiler, targeted immunolabeling with optical density and cell counts, and transmission electron microscopy. In the cerebellum the three layers remain in place, yet the molecular and internal granular layers hold fewer cells, and small hemorrhages appear in males. Collagen signals are weaker in meninges and choroid plexus. Endothelial readouts suggest sex specific barrier remodeling: ZO-1, VE-cadherin and VEGF shift in opposite directions in males and females. Autophagy markers point to different control points by sex. In males, p62 is lower while LC3B rises and cathepsin B falls, consistent with brisk autophagosome formation and limited degradative capacity; in females, LC3B is lower while cathepsin B and p62 patterns fit reduced initiation with relatively active clearance. PINK1 and Parkin are both reduced, with PINK1 more affected in females and Parkin in males. Mitochondrial and redox indicators converge on organelle strain: cytochrome c increases, COX4 falls, SOD2 and NRF2 increase, and GPX4 is broadly reduced. Calbindin, a calcium buffer, increases in males and stays near baseline in females.
In the viscera, related themes recur with different weight. In the liver, p62 and LC3B rise in males and fall in females; p53 increases in both sexes and PARP1 is markedly higher in males. Electron microscopy in male liver shows thinner, disorganized collagen fibrils, dilated rough endoplasmic reticulum and enlarged mitochondria. Picro Mallory confirms a thinning of endothelial associated fibrous structures in liver and a milder change in kidney. Renal autophagy shifts are modest, while p53 and PARP1 again separate by sex. Together, the data support a matrix to mitochondria cascade buffered by antioxidant responses, selective autophagy, mitophagy and DNA repair, with failure points set by tissue and sex
Reconstructing the ancestry and history of populations through ancient and modern genomes
No full textPopulation genetics has been a fundamental discipline in the study of human history since the early 20th century. Over the decades, researchers have employed a range of approaches — beginning with classical markers, followed by uniparental systems such as mitochondrial DNA (mtDNA) and the Y chromosome, and more recently, whole-genome sequencing — to investigate the genetic composition of populations and uncover clues about their past dynamics.
More recently, the advent of archaeogenomics has been a game-changer, enabling scientists to unlock the genetic information preserved in ancient skeletal remains and offering unprecedented insights into the origins, evolution, and interactions of human groups across time.
Human populations have been shaped by complex processes, including migrations, admixture, and demographic shifts, that occurred over thousands of years. While specialists in archaeology, history, and linguistics have long sought to reconstruct these events, archaeogenomics now provides a powerful complementary tool, allowing for a more integrated and data-driven reconstruction of human history.
In this framework, the main aim of my PhD project was to reconstruct the genetic history of populations, as well as of single individuals, through the analysis of ancient human remains. This involved the processing of a total of 60 skeletal elements recovered from different archaeological contexts in Europe, specifically Italy and Greece (Chapters 8-11). In most cases, sampling was performed using a minimally invasive approach to preserve bone integrity while still obtaining sufficient material for genomic analysis.
In addition, one project focused on mitogenome variability to elucidate the origin of modern North Africans from a maternal perspective (Chapter 12). This study, recently published in Scientific Reports, contributed 238 newly generated complete modern mitogenomes from North Africa, substantially enriching the available genetic data for this region.
My research also extended to the analysis of DNA samples recovered from the Turin Shroud (Chapter 13), adding a unique case study to the broader framework of ancient DNA investigations.
Beyond population-level analyses, I also contributed to the development of an R package for the management of huge amounts of ancient DNA metadata (Chapter 14). This tool was designed to streamline data organisation and enhance reproducibility in the study of ancient genomes.
Overall, my research encompassed five main projects and two side projects, carried out in collaboration with different institutions, as detailed in the respective chapters
Improving psychosis detection and management using precision medicine.
No full textPsychosis is a debilitating disorder that imposes substantial societal costs and disrupts the lives of predominantly young people. Comprehensive management across all clinical stages—including indicated prevention during the prodromal phase, early intervention in first-episode psychosis, and long-term care for chronic patients—is essential to improve prognosis, symptoms, and functioning. Advances in precision medicine have shown promise in enhancing detection of at-risk individuals and optimizing treatment selection. This thesis expands current knowledge on precision psychiatry by introducing scalable dynamic detection methods for individuals at risk (Part A) and novel approaches to integrating shared decision-making into precision treatment rules for first-episode psychosis (Part B).
Part A focuses on improving identification of individuals at risk of psychosis using dynamic survival modelling. Chapter 1 introduces indicated prevention and the concept of Clinical High Risk for Psychosis, outlining the need for effective detection strategies and key challenges. It also reviews clinical prediction modelling in psychiatry, emphasizing dynamic survival models and their clinical relevance. Chapter 2 presents a study developing and internally-externally validating a dynamic risk calculator using electronic health records from 158,139 patients in secondary mental health care. A Cox Landmark model was constructed and compared with a static approach using multi-level meta-regression methods. The dynamic model improved discrimination performance by 0.035 in Harrell’s C (95% CI 0.031–0.043, p < 0.001), corresponding to a 20% error reduction. Calibration and clinical utility also improved, particularly for later predictions. These findings advance scalable and systematic detection strategies and enhance the translational potential of risk calculators.
Part B develops precision medicine methods incorporating shared decision-making to improve treatment selection in first-episode psychosis. Chapter 3 reviews psychopharmacological treatment in early psychosis, compares existing decision support systems for antipsychotic selection, and discusses barriers to individualized care. It introduces pragmatic precision psychiatry and causal inference methods for observational data to optimize treatment decisions. Chapter 4 presents the first development and validation of precision treatment rules that integrate patient preferences. Using electronic health records from 1,709 patients in early intervention services, innovative rules were constructed combining causal forest methods with rankings of patient preferences, effectiveness, and side effects. Across preference scenarios, aripiprazole was recommended as optimal for 80% to 98% of patients. Implementation of these rules would significantly reduce most side effects, although extrapyramidal symptoms may increase. No significant effects were observed for hospitalization rates or medication changes.
Part C summarizes the findings, discusses their implications for psychiatry and precision medicine, and highlights future research directions.Psychosis is a debilitating disorder that imposes substantial societal costs and disrupts the lives of predominantly young people. Comprehensive management across all clinical stages—including indicated prevention during the prodromal phase, early intervention in first-episode psychosis, and long-term care for chronic patients—is essential to improve prognosis, symptoms, and functioning. Advances in precision medicine have shown promise in enhancing detection of at-risk individuals and optimizing treatment selection. This thesis expands current knowledge on precision psychiatry by introducing scalable dynamic detection methods for individuals at risk (Part A) and novel approaches to integrating shared decision-making into precision treatment rules for first-episode psychosis (Part B).
Part A focuses on improving identification of individuals at risk of psychosis using dynamic survival modelling. Chapter 1 introduces indicated prevention and the concept of Clinical High Risk for Psychosis, outlining the need for effective detection strategies and key challenges. It also reviews clinical prediction modelling in psychiatry, emphasizing dynamic survival models and their clinical relevance. Chapter 2 presents a study developing and internally-externally validating a dynamic risk calculator using electronic health records from 158,139 patients in secondary mental health care. A Cox Landmark model was constructed and compared with a static approach using multi-level meta-regression methods. The dynamic model improved discrimination performance by 0.035 in Harrell’s C (95% CI 0.031–0.043, p < 0.001), corresponding to a 20% error reduction. Calibration and clinical utility also improved, particularly for later predictions. These findings advance scalable and systematic detection strategies and enhance the translational potential of risk calculators.
Part B develops precision medicine methods incorporating shared decision-making to improve treatment selection in first-episode psychosis. Chapter 3 reviews psychopharmacological treatment in early psychosis, compares existing decision support systems for antipsychotic selection, and discusses barriers to individualized care. It introduces pragmatic precision psychiatry and causal inference methods for observational data to optimize treatment decisions. Chapter 4 presents the first development and validation of precision treatment rules that integrate patient preferences. Using electronic health records from 1,709 patients in early intervention services, innovative rules were constructed combining causal forest methods with rankings of patient preferences, effectiveness, and side effects. Across preference scenarios, aripiprazole was recommended as optimal for 80% to 98% of patients. Implementation of these rules would significantly reduce most side effects, although extrapyramidal symptoms may increase. No significant effects were observed for hospitalization rates or medication changes.
Part C summarizes the findings, discusses their implications for psychiatry and precision medicine, and highlights future research directions
Sedimentation across a coastal plain to deep-water system: Insights from a Carboniferous succession, northern England
No full textDisrupting illusion in ancient Greek comedy: a cognitive perspective
No full textThis paper applies a modern, cognitive model, the conceptual blending theory, to ancient Greek comic fragments, with the aim of shedding light on the relationships between actor and audience. The theory maintains that spectators blend an actor and his character into one new concept of identity during a performance. In particular, I shall investigate the model in relation to a way of disrupting the dramatic illusion found in ancient Greek comedy, namely when the actor seems to step out of the character and the line between the two identities supposedly becomes thinner. My focus is on the fourth-century BC—hence the choice of fragments—, which I argue is a turning point not only for the evolution of the theatre but also for the mechanisms of blending
MicroRNAs and DNA Damage Response: Modulating stress response during germination in cereals
No full textThe ability of plants to endure environmental challenges during germination is important for guaranteeing optimal crop establishment and productivity. Germination is a developmental stage that is especially vulnerable to stress, resulting in DNA damage and diminished seedling vigour. Plants depend on the DNA damage response (DDR), a system of sensors, transducers, and repair effectors, to preserve genomic integrity. However, the post-transcriptional regulation of DDR is not fully comprehended in cereals, despite their importance for global food security. Understanding the role of microRNAs (miRNAs) in modulating DDR during germination may yield novel insights into stress tolerance mechanisms and guide approaches for crop enhancement. This PhD thesis examined the role of miRNAs in modulating DDR during germination in wheat and rice cereals. Two experimental systems were utilised: (1) wheat seeds exposed to gamma (γ)-radiation, and (2) rice seeds subjected to salinity stress. In both cases, in silico predictions were integrated with expression profiling of potential miRNAs and target DDR genes, together with a phenotypic evaluation of germination behaviour under stress.
In wheat (Triticum aestivum), the findings indicated that DDR-related genes, encompassing sensors (MRE11, NBS1, RAD50), a transducer (ATM), and repair proteins (BRCA1, TDP1, OGG1), along with their putative miRNAs (miR164, miR5086, miR112), were differentially regulated in a time- and genotype-dependent fashion post-irradiation. A significant negative correlation identified for the tae-miR5086–RAD50 pair offers an indirect evidence for miRNA-gene interaction. The function of RAD50, a dual-purpose element of the MRN complex engaged, in detecting and repairing double-strand breaks highlights the significance of miRNA-mediated modulation on DDR,
In rice (Oryza sativa), a bioinformatic selection identified ten DDR genes (MRE11, SOG1, RAD50, NBS1, ATM, ATR, RPA, RBR, RFC, WEE1-like) as potential targets of eight miRNAs (osa-miR414, osa-miR5519, osa-miR818a, osa-miR2879, osa-miR395t, osa-miR2102, osa-miR415, osa-miR2925). Salinity stress was demonstrated to influence rice germination in a dose-dependent way, revealing distinctions between tolerant (IR64, Apollo, Carnaroli, Lomello, Unico, Inpari) and susceptible (Cerere, Rc460) cultivars. Variety-dependent expression patterns of DDR genes and respective miRNAs have been observed, with the osa-miR818a–NBS1 exhibiting a significant negative correlation.
Collectively, these data indicate that miRNAs could act as regulators of DDR during germination under stress in cereals. The identified correlations between miRNAs and DDR genes offer an indirect confirmation of this regulatory function while emphasising the potential use of miRNA–gene pairs as indicators of stress tolerance. The possibility to modify miRNA expression presents options for regulating DDR and improving stress resilience. This understanding may influence crop improvement strategies, such as the generation of tolerant cultivars, promoting future sustainable agriculture.The ability of plants to endure environmental challenges during germination is important for guaranteeing optimal crop establishment and productivity. Germination is a developmental stage that is especially vulnerable to stress, resulting in DNA damage and diminished seedling vigour. Plants depend on the DNA damage response (DDR), a system of sensors, transducers, and repair effectors, to preserve genomic integrity. However, the post-transcriptional regulation of DDR is not fully comprehended in cereals, despite their importance for global food security. Understanding the role of microRNAs (miRNAs) in modulating DDR during germination may yield novel insights into stress tolerance mechanisms and guide approaches for crop enhancement. This PhD thesis examined the role of miRNAs in modulating DDR during germination in wheat and rice cereals. Two experimental systems were utilised: (1) wheat seeds exposed to gamma (γ)-radiation, and (2) rice seeds subjected to salinity stress. In both cases, in silico predictions were integrated with expression profiling of potential miRNAs and target DDR genes, together with a phenotypic evaluation of germination behaviour under stress.
In wheat (Triticum aestivum), the findings indicated that DDR-related genes, encompassing sensors (MRE11, NBS1, RAD50), a transducer (ATM), and repair proteins (BRCA1, TDP1, OGG1), along with their putative miRNAs (miR164, miR5086, miR112), were differentially regulated in a time- and genotype-dependent fashion post-irradiation. A significant negative correlation identified for the tae-miR5086–RAD50 pair offers an indirect evidence for miRNA-gene interaction. The function of RAD50, a dual-purpose element of the MRN complex engaged, in detecting and repairing double-strand breaks highlights the significance of miRNA-mediated modulation on DDR,
In rice (Oryza sativa), a bioinformatic selection identified ten DDR genes (MRE11, SOG1, RAD50, NBS1, ATM, ATR, RPA, RBR, RFC, WEE1-like) as potential targets of eight miRNAs (osa-miR414, osa-miR5519, osa-miR818a, osa-miR2879, osa-miR395t, osa-miR2102, osa-miR415, osa-miR2925). Salinity stress was demonstrated to influence rice germination in a dose-dependent way, revealing distinctions between tolerant (IR64, Apollo, Carnaroli, Lomello, Unico, Inpari) and susceptible (Cerere, Rc460) cultivars. Variety-dependent expression patterns of DDR genes and respective miRNAs have been observed, with the osa-miR818a–NBS1 exhibiting a significant negative correlation.
Collectively, these data indicate that miRNAs could act as regulators of DDR during germination under stress in cereals. The identified correlations between miRNAs and DDR genes offer an indirect confirmation of this regulatory function while emphasising the potential use of miRNA–gene pairs as indicators of stress tolerance. The possibility to modify miRNA expression presents options for regulating DDR and improving stress resilience. This understanding may influence crop improvement strategies, such as the generation of tolerant cultivars, promoting future sustainable agriculture
Universal Design for Education. Prospettive giuridiche per una nuova concezione di educazione interculturale.
No full text
