VictorJuiz/thesis huggingface dataset:
Germline Polymorphisms Contribute to Somatic Variability in Prostate Cancer
Keywords: Epigenetics
Germline
mpMRI
Prostate cancer

Cancer is the result of the successive accumulation of genomic mutations that confer biological capabilities, including sustained proliferation, resisting cell death and metastasis. Genomic mutations are caused by environmental, genetic and stochastic processes that promote tumour development and progression. These processes vary amongst individuals resulting in tumours with different somatic mutations catalogues, i.e. inter-tumoural heterogeneity. Inter-tumoural heterogeneity can influence diagnosis and treatment response. Understanding the origins of inter-tumoural heterogeneity facilitates personalize medicine.Germline genetics play an important role in cancer initiation and progression. Over 100 cancer predisposition genes and more than 403 predisposition loci have been identified to-date. However, it remains unclear how the germline genome influences the somatic mutational landscape of a tumour. To address this gap, I quantified the effect of the germline on the somatic genomic and epigenomic landscape in localized prostate cancer because prostate cancer is prevalent, heritable and presents with molecular and clinical heterogeneity. I identified 1,178 loci associated with DNA methylation changes in prostate tumour tissue but not non-malignant prostate epithelial tissue, termed tumour methylation quantitative trait loci (tumour meQTLs). Tumour meQTLs influence mRNA and protein abundances and chromatin structure and a subset of tumour meQTLs are predictive of aggressive disease, including an intronic loci within the oncogene AKT1. Next, I identified 62 loci associated with acquisition of somatic driver events, termed driver QTLs (dQTLs). dQTLs can predict risk of developing somatic driver events and may explain observed differences in somatic mutation frequencies across ancestry populations. Altogether, these data suggest the germline genome is a determinant of the somatic epigenomic and genomic landscape of localized prostate cancer, contributing to inter-tumoural heterogeneity. Finally, I illustrate how inter-tumoural heterogeneity can manifest clinically in prostate cancer diagnostic imaging. Specifically, I interrogated the molecular hallmarks of multiparametric magnetic resonance imaging (mpMRI) visibility and identified a confluence of aggressive pathological, molecular and microenvironmental hallmarks enriched in mpMRI visible compared to invisible tumours. These findings provide confidence in the ability of mpMRI to identify aggressive prostate cancer tumours and further motivate the importance of understanding inter-tumoural heterogeneity to improve personalized medicine.
A Monolithic Masterless Fault-tolerant Hybrid Switched-capacitor Dickson Converter for 48-V Multi-phase Automotive Applications
Keywords: automotive
fault tolerant
hybrid switched capacitor
masterless
monolithic
multi-phase system

Self-driving systems require a Fault-Tolerant (FT) power-management system to ensure continuous power delivery to safety processors, while the forthcoming 48-V bus necessitates high and wide power conversion ratios (e.g., 20-V-to-60-V input and 3.3-V output). To tackle these challenges, this work demonstrates a masterless FT multi-phase system with N+1 redundancy as the pre-regulator stage of a two-stage conversion system. Each phase is implemented based on a hybrid switched-capacitor 4-to-1 Dickson converter, which offers the best electrical performance and comparable cost and reliability among all common dc-dc topologies. This work proposes: 1) an independent quasi-fixed-frequency control scheme based on the valley-current on-time control, which enables masterless interleaving, current sharing, and self-balancing of the flying-capacitor voltages, 2) a fast and robust short-circuit and open-circuit fault detection of any power switches or flying capacitors, which only observes the switching-node voltage, and 3) an automotive-grade monolithic closed-loop single-phase FT 4-to-1 hybrid Dickson converter IC with masterless multi-phase operation capability, fabricated in a 0.13-um 90-V silicon-on-insulator bipolar-CMOS-DMOS process. The IC offers above 90 % efficiency at maximum 60-V-to-3.3-V conversion and 3-A load current while provides a peak efficiency of 95.3 % for 20-V-to-3.3-V conversion with 0.8-A load current and 320-kHz effective switching frequency. The performance of the design is evaluated and verified subject to various fault scenarios as well as input-voltage and load transients using discrete and IC prototypes.
The Role of Oxoguanine Glycosylase 1 (OGG1) as a DNA Damage Repair Enzyme and Epigenetic Modifier in Mitigating the Neurodevelopmental Disorders Initiated by Physiological and Ethanol-enhanced Levels of Reactive Oxygen Species
Keywords: 8-oxoguanine (8-oxoG)
DNA damage and repair
Epigenetics
Oxidative stress
Oxoguanine glycosylase 1 (OGG1)
Trichostatin A (TSA)

Mechanisms underlying neurodevelopmental disorders such as Autism Spectrum Disorders (ASD) and Fetal Alcohol Spectrum Disorders (FASD) may involve reactive oxygen species (ROS)-initiated DNA damage, measured as 8-oxoguanine (8-oxoG), and epigenetic modifications of histone proteins and DNA that regulate gene expression. 8-OxoG is repaired by oxoguanine glycosylase 1 (OGG1), and recently, 8-oxoG and/or OGG1 have been identified as epigenetic markers contributing to increased or decreased gene expression. This thesis explores the role of 8-oxoG and/or OGG1 in epigenetic modifications and neurodevelopmental abnormalities in Ogg1 knockout mice. The following results demonstrate that OGG1 alters both epigenetic marks and brain function: (A) Compared to wild-type controls, untreated Ogg1 knockout mice exhibit enhanced gene- and sex-dependent DNA damage (strand breaks) and decreased epigenetic methylation marks, increased cerebellar calbindin levels (reflecting Purkinje cell count), reduced hippocampal postsynaptic function and disorders of brain function reflected in behavioural tests for repetitive behaviour, anxiety and fear, object recognition and spatial memory, motor coordination and startle response. These results indicate that OGG1 plays an important role in normal brain development, possibly via both its DNA repair activity and its role as an epigenetic modifier, suggesting that OGG1 deficiencies potentially contribute to developmental disorders like autism. (B) In utero exposure to a single low dose of ethanol (EtOH) can alter epigenetic marks and gene expression in fetal brains, along with postnatal behaviour, in an OGG1-dependent manner. Specifically, OGG1 may play a role in estrogen receptor-mediated gene regulation that is further altered by in utero EtOH exposure, possibly contributing to sex-dependent behavioural differences observed in OGG1-deficient progeny. (C) Furthermore, postnatal administration of the histone deacetylase inhibitor trichostatin A (TSA) to progeny exposed in utero to EtOH variably reversed or enhanced the behavioural disorders caused by EtOH, which were OGG1- and sex-dependent, suggesting that both EtOH and TSA may alter behaviour via an epigenetic mechanism involving OGG1. Overall, these results suggest that OGG1 plays an important role in fetal brain development, and protects against physiological and EtOH-enhanced ROS levels. OGG1 deficiencies may constitute a risk factor for neurodevelopmental disorders such as ASD and FASD.
A New Religious Language for a Secular Age: Canadian Poetry of the Long 1960s and Secularism in Canada
Keywords: Canadian Poetry
Postsecular Studies
Religion and Literature
Secularism

This dissertation examines the work of Canadian poets of the long 1960s who conceptualize their poetry as a new form of religious language for a secular age. I argue that these poets both imagine that certain forms of religion are no longer available in modernity and resist a secular conception of the world. They therefore create poetic languages that blur the boundaries between the religious and the secular. In pursuing this argument, I aim to complicate the longstanding account of secularization as the decline of religion in modernity. Scholars such as Charles Taylor and Talal Asad have challenged this narrative in light of its failure to account for important features of the modern West, such as the rise of religious fundamentalism. As these and other scholars demonstrate, secularity can be more accurately understood as involving the creation of new discourses and practices that reshape the ways in which religion is understood and experienced. Bringing this approach to bear on the poets I study, I read their poetry in the context of the long 1960s as a key period for the emergence of the secular imaginary in Canada. Chapter One examines Dennis Lee’s nationalist response to the secular imaginary: namely, his claim that poetry can maintain a balance between the material and the spiritual that he deems essential to national development. Chapter Two demonstrates that bpNichol registers debates about divine inspiration as he develops a poetics that is open to the sacred but that refuses to confine it within language. Chapter Three explores Leonard Cohen’s foregrounding of a Jewish perspective on secularity that informs his efforts to translate religious experiences into languages that will resonate in secular Canada. Chapter Four argues that Gwendolyn MacEwen critiques alternative spirituality as she frames her poetry as a journey to her inner depths that paradoxically gives her access to a universal reality. Moving beyond the narrative of religious decline, I show that these poets were responding to changing constructions of the religious and the secular in Canadian society as they framed their poetry as a new form of religious expression for a secular age.
Sympathy and Authority in Seventeenth-century Poetry and Philosophy
Keywords: Authority
Embodiment
Subjectivity
Sympathy

When historians of the Renaissance talk about sympathy, they tend to focus on its “occult” associations. This project asks how such an occult concept could have become a key term for the rationalist discourse of eighteenth-century moral and political philosophy. The usual story is that sympathy reemerges in sixteenth- and seventeenth-century natural philosophy as a way to explain mysterious phenomena like magnetism or electricity. Then gradually it migrates inward and becomes a psychological principle that governs human social and political relations. The assumption is that modern science leaves no room for mystical explanations of natural phenomena, and so sympathy loses its cosmic significance and becomes strictly emotional. Through readings of John Milton’s epic Paradise Lost, Katherine Philips’s friendship poetry, work by the Cambridge Platonists including Anne Conway, and commentaries by three prominent Scottish Calvinist divines, I offer two counterclaims. First, sympathy was always-already a psychological concept, even if it also bore associations with metaphysics, magic, and religion. The notion that sympathy just changes into a moral concept is too simple. Second, sympathy becomes a pillar of eighteenth-century moral philosophy precisely because it was understood to be both an internal and an external law of attraction. When moral philosophers like Shaftesbury, Hutcheson, Smith, or Hume try to explain what ultimately binds free citizens together, they all invoke sympathy as a way to describe a type of political association that would be governed less by the state’s external laws and dictates than by the subject’s deepest, most natural desire to be connected with others. Sympathy’s odd status in sixteenth- and seventeenth-century natural philosophy as both an external force and a personal feeling made it the ideal foundation for a new form of political authority whose laws, as Rousseau said, would not be “graven on tablets of marble and brass, but on the hearts of citizens.” Defined both as a feeling in the bosom of nature that draws all things to their proper place, and as an impulse rooted in personal human desires, “sympathy” suggests that creatures are determined by the order of things, while allowing room for human freedom and creativity.
Solid Dispersions in Medium-Insoluble Hydrogels for Enhancing the Solubility and Bioavailability of Poorly Soluble Drugs
Keywords: Amorphous Solid Dispersions
Enabling Formulations
In vivo Evaluation
Kinetic Solubility
Non-sink Dissolution
Supersaturation

Formulating poorly water-soluble drugs into Amorphous Solid Dispersions (ASDs) based on medium-insoluble hydrogels is an emerging approach showing promise for tackling solubility related oral bioavailability problems. However, critical parameters important to the design of these ASDs have not been fully elucidated. Thus, the first part of the present study examines design factors for ASDs based on Poly(2-Hydroxyethyl methacrylate) (PHEMA) hydrogel beads. Here, it is shown that one can obtain a more sustained supersaturation either through increasing the particle size of medium-insoluble hydrogels to reduce the rate of supersaturation generation or by lowering the total dose under non-sink dissolution conditions. The results of the second part demonstrate that the interplay of particle size, total dose and the swelling capacity is an essential aspect to be considered when tailoring the supersaturation generation from these ASDs. Generally, the higher the swelling capacity of the medium-insoluble carrier, the faster the rate of supersaturation generation, and the shorter the sustained supersaturation due to associated drug precipitation. Furthermore, a large drug partitioning effect between the polymer carrier and dissolution medium has been found to limit the extent of drug supersaturation buildup from these ASDs. The subsequent third part of the study highlights the benefit of defining the Sink Index (SI) as when one simply changes the volume of the dissolution medium or its scale; the resulting kinetic solubility profiles can still remain similar as long as SI is kept constant. It also reveals the difficulty in predicting in vivo performance due to the impact of changing the media buffer composition on the kinetic solubility profiles of amorphous pharmaceuticals. The results of the fourth and the last part of the study serve as a proof of concept exercise for the combined effects of supersaturation rate and dose approach in rats. Here, the head-to-head in vivo comparison of ASDs in water-insoluble and soluble carriers coupled with the Physiologically based Biopharmaceutics Modeling using GastroPlus® demonstrates that these test carriers can provide similar oral absorption enhancement. Further optimization of ASDs in water-insoluble carriers is still required before they can be employed as alternative strategies for bioavailability enhancement.
Dúngal: A Study of his Life and Works
Keywords: Carolingian
Dungal
Early Medieval
Intellectual History
Latin
Palaeography

This study provides the first comprehensive treatment of the life and works of Dúngal, cleric and scholar active on the European continent during the ninth century. This dissertation has two main aims. First, it seeks to clarify what we can know about Dúngal based on an examination of the texts and manuscripts. It establishes a corpus of texts that can be attributed to Dúngal, and reassesses the palaeographic evidence of the manuscripts associated with him. Second, this dissertation provides a study of Dúngal in order to investigate broader questions about Carolingian intellectual history in the ninth century: what texts were they reading, what questions were they asking, or how were manuscripts being constructed, used, and reused? In sum, it examines Dúngal in order to contribute to our understanding of Carolingian intellectual culture in the ninth century.
DNA Secondary Structures and Cytogenetic Fragility of the C9orf72 (GGGGCC)n Repeat Expansion, Associated with ALS/FTD
Keywords: C9orf72-ALS/FTD
cytogenetic fragility
DNA methylation
DNA secondary structures
genome instability
repeat expansion disease

Expansion of the C9orf72 repeat (GGGGCC)n is the most common cause of amyotrophic lateral sclerosis and fronto-temporal dementia. Here I characterize the unusual structures formed by the C9orf72 repeat in vitro, the effect of DNA methylation on these structures, and explore the effects of structure and methylation on protein interactions. With this foundation, we can begin to unravel therapeutic targets for ALS/FTD-targeted treatments that could arrest or even reverse disease progression such as structure-specific compounds that could be used to induce contractions or halt somatic expansion in affected tissues. Furthermore, I show that the C9orf72 expansion is in fact a cytogenetic folate-sensitive chromosomal fragile site (FSFS), similar to the ten cloned FSFS that each have been mapped to (CGG)n expansions, including FRAXA, the cause of fragile X syndrome (FXS) and a plethora of other diseases. Like other FSFS, C9orf72 repeat expansions predispose to chromosome breaks, gaps, elongated under-condensed regions, aberrant CpG methylation, unusual DNA structures, micronuclei, double-strand breaks, sister-chromatid exchanges, and lead to aberrant chromatin packaging. That the C9orf72 expansion is a fragile site now broadens the repeat sequences associated with FSFS, and sheds light on the varied genetic alterations, variable manifestations and multiple modes of pathogeneses that can arise at the C9orf72 locus, as observed with FXS.
Identifying MYC-dependent Vulnerabilities in Breast Cancer
Keywords: Cancer
Modelling
MYC
Oncogene
Synthetic Lethality
Topoisomerase

MYC is deregulated in the majority of human cancers making it an ideal candidate for therapeutic inhibition. However, targeting MYC directly with small molecule inhibitors is difficult and so alternative approaches are needed. One promising strategy is to identify and exploit non-oncogene addictions (NOA) that arise in MYC-transformed tumours. Targeting NOAs therapeutically can result in synthetic lethality and so we refer to these vulnerabilities as MYC synthetic lethal interactions (MYC-SLIs). Our working assumption is that MYC-SLIs are targetable and are likely to have little to no side-effects in normal tissues. NOAs are usually identified by comparing a wildtype cell line to one expressing a knockout or mutant gene. However, as MYC is essential for growth and rarely mutated, we instead developed an isogenic model that was transformed solely by deregulated MYC, thereby creating a tumour and normal cell pair in which NOAs could be identified. This model is dependent on MYC and can recapitulate human disease at both the pathological and molecular levels in vivo. Using this model, we were able to identify TOP1 as a MYC-SLI. Knockdown of TOP1 in MYC-transformed cells resulted in reduced colony formation when compared to control cells, demonstrating synthetic lethality. Furthermore, knock-down of TOP1 in a MYC-driven xenograft model was sufficient to reduce tumour volume. TOP1 relieves torsional stress in DNA during transcription and prevents R-loop formation. Interestingly, we identified other R-loop regulators as MYC-SLIs, suggesting that MYC imposes an increased burden onto this regulatory system. Finally, we examined the effect of cell-culture context on MYC protein:protein interactions (PPIs) and MYC-SLIs by comparing traditional adherent and mammosphere cultures. We identified unique MYC-PPIs and MYC-SLIs that are only observed in MYC-driven mammosphere culture, including components of epigenetic regulatory complexes. These data suggest that certain vulnerabilities and protein-interactions will only appear in specific contexts. As mammosphere cultures better reflect phenotypes observed in vivo, vulnerabilities identified using these methods may better translate clinically. Together, using a novel MYC-dependent transformation model, I identified novel and targetable MYC-SLIs and highlighted context-dependent changes to MYC-SLIs and MYC-PPIs.
Flowable Approach for the Formation of Biomaterial Sheets
Keywords: aligned collagen
anisotropic biomaterial sheets
biomanufacturing
microfluidics
molecular alignment
roll-to-roll processing

Nature routinely uses a bottom – up approach for the organization of materials arounds us. This unique structural and hierarchical organization spans seven orders of magnitude in length scale: from molecular (~ nm) to organ dimensions (~ cm) is a hallmark of many organs. The variation in the structural organization imparts different functionalities and macroscopic properties such as elasticity, permeability, and optical transparency to tissues. Tissue – engineering routinely uses several promising strategies to engineer tissues that mimic the complex architecture and functionality of native tissues. However, some of their limitations include the inability to recapitulate the hierarchical assembly of materials, tunability of nanoscale properties, lack of scalability, and time – consuming fabrication methods. In this thesis, we have developed two microfluidics – enabled approaches for the scalable formation of fibrillar and polysaccharide – based hierarchical soft materials with precise control over the material composition, geometric and mechanical properties, cellular response, and structural assembly. In the first approach, we adopted a microfluidic strategy for the continuous formation of centimeter – wide, ultrathin collagen sheets. Application of shear via hydrodynamic flow – focusing through a geometric constriction and strain – induced pulling by a rotating mandrel, and the osmotic and evaporation – induced removal of water resulted in anisotropically aligned and compacted sheets with ultimate tensile strengths of 0.5 – 2.5 MPa and elastic moduli of 3 – 36 MPa. We used multi – lamellar collagen sheets to produce tissue – engineered vascular grafts with biomechanical properties similar to native vessels. The collagen sheets were also used as transwell – membranes for drug screening purposes. Human bronchial epithelial cells showed a high trans – epithelial resistance of 1900Ω x cm2. F508del – CFTR cells showed a three – fold increase in chloride conductance when treated with Cystic Fibrosis Trans –Regulator corrector, lumacaftor (VX – 809). The second microfluidic strategy allowed the continuous preparation, and processing of meter – long, roll – to – roll processed biomaterial sheets with control over thickness, morphology, and elastic properties. 3D structures with deterministic and stochastic voids were produced using layer – by – layer folding and stacking techniques. The approaches presented here find application in areas such as tissue engineering, regenerative medicine, drug – screening, and biohybrid devices.