VictorJuiz/thesis huggingface dataset:
Neuroimaging of Trigeminal Neuralgia: Application of Population Diffusion Magnetic Resonance Tractography and Machine Learning

Idiopathic (Classic) Trigeminal Neuralgia (TN) is a facial neuropathic pain syndrome characterized by paroxysmal, shock-like pain condition affecting one or more of the three trigeminal nerve (CNV) branches. TN is believed to be associated with nerve-vascular compression in the CNV root-entry-zone, but its pathophysiology is still unclear. Singletensor diffusion tensor neuroimaging (DTI) studies of CNV revealed diffusivity changes in the cistern segment. However, the portion of the nerve within the brainstem remained elusive due to DTI limits. Diffusion imaging of TN is also error-prone due to manual data processing and analysis. This thesis aims to: 1) develop a fully-automated software framework to analyze diffusion tractography to reduce error and increase speed of experiments. 2) to apply the method developed to the analysis of the trigeminal system in a more substantial patient group, and apply state-of-the-art methods to advance the study of TN further. The specific aims are: a) establish the feasibility of multi-tensor tractography of brainstem CNV; b) establish the best way to minimize DWI to T1 co-registration error across multiple subjects; c) Create the software framework to generate and quantify tractography at the group level; d) apply the methodology to the reconstruction and quantification of the trigeminal sensory pathway. Towards these goals, in Study I, we establish the feasibility of applying multi-tensor tractography to delineate the full course of CNV and demonstrate that TN is uniquely identified by disruptions in the cistern/REZ, while MS-TN by disruptions in the brainstem course of the nerve. In Study II, we determine that the best T1-DWI co-registration scalar is the Mean DWI image. In Study III, we present the Selective Automated Group Integrated Tractography (SAGIT) processing pipeline framework. Finally, in Study IV, we deploy end-to-end machine-learning TN classification to automatically discover diffusivity disruptions in the cistern/REZ CNV, the trigeminopontothalamic decussaion, and thalamocortico S1 pathway. In sum, this thesis presents a detailed road-map of the development and application of end-to-end diffusion tractography machine learning classification. The application to TN revealed specific diffusivity changes in trigeminal CN V, pontine, and S1 white matter pathways, and pin-points the locations of the diffusivity disruptions at millimetre level.

Keywords: diffusion imaging
machine learning
neuroimaging
pain
tractography
trigeminal neuralgia
Advisor: Hodaie, Mojgan
A New Framework for Social Collective Epistemology

Epistemic Autonomy is the idea deeply imbedded in the mainstream epistemological tradition that in order to possess knowledge one must possess all the knowledge-requisite goods (KRGs) generating it (e.g. evidence, cognitive abilities). But an increasing number of philosophers claim that a good deal of what we all want to call “knowledge” is knowledge via extended justification (EJK), that is, knowledge for which no individual can possess all KRGs. The most vivid apparent cases are in ‘big science’. For example, some high-energy particle physics collaborations consist of thousands of active researchers (e.g. physicists, engineers, technicians, data analysts, etc.) of various sorts who are spread across the globe. The same can be said of bodies like the Intergovernmental Panel on Climate Change (IPCC). When vast numbers of individuals with diverse expertise produce knowledge-level evidence that, say, Higgs particles exist, who can possess this knowledge? If epistemic autonomy is necessary for possessing knowledge, then individuals cannot possess EJK. It can be possessed only by the groups across which justificatory labour extends (e.g. experimental collaborations, research teams).

Keywords: Epistemic Autonomy
Epistemic Extendedness
Group Epistemology
Group Knowledge
Meta-Epistemology
Social Epistemology
Advisor: Thompson, Paul
Rad5 Recruitment and Function in the Saccharomyces cerevisiae Replication Stress Response

DNA replication stress poses a significant threat to the genome integrity of actively dividing cells and is observed in many pathological human disorders. Replication stress is caused by endogenous or exogenous events that slow or block the DNA replication machinery. All cells have an evolutionarily conserved DNA replication stress response that slows down cell division until DNA replication is complete and DNA can be segregated. The Post-Replication Repair (PRR) pathway allows tolerance of chemical- and UV-induced DNA lesions in both an error-free and an error-prone manner. In classical PRR, PCNA monoubiquitination recruits translesion synthesis (TLS) DNA polymerases that can replicate through lesions in a mutagenic manner. Polyubiquitination of PCNA by the ubiquitin ligase Rad5 initiates error-free PRR, using the sister chromatid as a template for DNA synthesis in lieu of the lesion-containing strand. I find that Rad5 forms nuclear foci after exposure to types of replication stress where DNA base lesions are likely absent. In this study I characterize how Rad5 is recruited to nuclear foci and how Rad5 functions in lesion-less replication stress. Using a genome-wide high-throughput screen I identified 23 genes that are required for robust Rad5 recruitment to nuclear foci. I revealed that the HSP40 chaperone Ydj1 in conjunction with the HSP70s Ssa1 and Ssb1 promote Rad5 relocalization and replication stress resistance. To characterize Rad5 function in lesion-less replication stress I monitored the genome-wide association of Rad5 using ChIP-seq and found it binds to sites near stressed DNA replication forks. In addition to template switching activity at stressed replication forks, Rad5 also recruits TLS polymerases to repair ssDNA gaps, preventing mitotic defects and chromosome breaks. My data indicates that Rad5 is the central effector of PRR at stressed replication forks, where it promotes template switching and mutagenic repair of undamaged ssDNA that arises during physiological and exogenous replication stress.

Keywords: DNA replication
Replication stress
Advisor: Brown, Grant W
Functional Connectivity Within the Dynamic Pain Connectome Underlying Inter-Subject Differences in Acute and Chronic Pain

Pain is an individual experience. Given an identical noxious stimulus, some individuals perceive a high level of pain, whereas others perceive minimal pain. Even when a similar level of pain is experienced, individuals’ response to its perception varies. Some people focus on the pain at the detriment of other tasks-at-hand, whereas other people focus on the task-at-hand as a distraction from pain. These differences across people likely reflect differences in their brain circuitry, specifically in and between networks which are involved with pain processing and coping. Clinically, the degree of abnormality across these networks may underlie the level of pain experienced by chronic pain patients. Thus, this thesis investigated how functional communication between brain networks involved with pain processing and coping, as assessed by static and dynamic measures of resting-state functional connectivity, are related to inter-individual differences in pain perception and coping in healthy individuals and in patients with chronic pain. We found that healthy individuals who had greater central sensitization, had an imbalance towards stronger functional connectivity within their ascending nociceptive compared to descending pain-modulatory pathway. In response to a similar level of pain delivered during the performance of a cognitive task, we also found in healthy individuals that those who have more flexible communication between their salience and executive control networks are better able to prioritize cognitive task-performance in the face of pain. Lastly, the use of a machine learning approach with chronic pain patients revealed that more dynamic engagement of executive control networks was related to milder pain, whereas greater engagement of limbic networks was related to greater pain. Across these connections, patients who had greater pain were more dissimilar compared to healthy individuals. Thus, this thesis provides insight into the differences in dynamics in brain communication that underlie inter-subject differences in acute and chronic pain.

Keywords: Chronic Pain
Dynamic Functional Connectivity
Functional Connectivity
Individual Differences
Machine Learning
Neuroimaging
Advisor: Davis, Karen D
Assessing the Exotic: Authority, Reason, and Experience in the Construction of Medieval Natural Knowledge

This study explores evidence structures in the medieval investigation of nature, particularly the marvelous or exotic nature that exists near the boundaries of natural philosophy. The marvelous, exotic, and unusual are fascinating to both readers and authors, providing windows into the ways in which the evidence structures of reason, authority, and experience were balanced in the assessment, explanation, and presentation of these phenomena. I look at four related works, each engaged with the compilation and presentation of particular information concerning animals and the diversity of the natural world. While these texts are bound together by shared topics and draw from a shared body of ancient and contemporary works, they each speak to different audiences and participate in different genres of literature. I argue that we can see in these works a contextually sensitive approach to the evaluation and presentation of evidence on the part of both the author and the audience. This project also seeks to bridge a gap between the intellectually rigorous medieval texts and works targeted at a wider reading audience that made use of the knowledge base of natural philosophy but were not necessarily produced or consumed within the scholastic context. Albertus Magnus’s De animalibus and Bartholomaeus Anglicus’s De proprietatibus rerum were produced, and expected to be consumed, within the Friars’ studium. While these texts also enjoyed a complex life outside these educational houses, they are marked by the scholastic educational context they were designed within and for. The Pseudo-Albertus experimentum texts Liber de virtutibus herbarum, lapidum, et animalium and De mirabilibus mundi as well as the travel narrative The Book of John Mandeville, on the other hand, may have been produced within an educated context but were consumed by a diverse cross-section of the reading population. By looking at these four texts together I explore the ways epistemic structures shift from the more scholastically inclined to the more popular texts, as well as point to the cross-pollination of medical, legal, and natural philosophical epistemologies in the ways each text shapes its epistemic structures to reflect the needs of its genre and audience.

Keywords: Albertus Magnus
Bartholomaeus Anglicus
Construction of Knowledge
Evidence
John Mandeville
Vernacular natural knowledge
Advisor: Hall, Bert
Evaluating the Application of Photochemical Mass-Independent Fractionation of Mercury (Hg) in Natural Systems

Mercury (Hg) is a toxic and globally distributed contaminant that poses a serious risk to humans, wildlife, and the environment due to its ability to bioaccumulate along the food webs in aquatic ecosystems. The overarching goals for this dissertation are to: (1) evaluate the potential of mass-independent fractionation (MIF) of Hg during photochemical reactions to understand biogeochemical Hg cycling in natural systems; and (2) utilize Hg mass-dependent (MDF) and mass-independent fractionation (MIF) to characterize and trace Hg sources in the environment. In Chapter 2, Hg isotopes link environmental factors to Hg MIF preserved in freshwater lower trophic organisms to quantify MMHg photodegradation in freshwaters and understand how Hg MIF is preserved in natural systems. In Chapter 3, Hg isotopes in pelagic ocean higher trophic biota assess the relative contribution of Hg sources, transformation processes (methylation/photodemethylation), and other factors that may control the Hg isotopic signature of open-ocean fish in different regions and depths of the pelagic ocean. Chapter 4 assess Hg isotopes in atmospheric gaseous Hg(0), particulate Hg (PHg), and snow to understand Hg photochemical processes and sources in the Arctic. This dissertation demonstrates source characterization of atmospheric Hg species from multiple emission sources and better understanding of transformation processes that alter Hg source signatures, and highlights the potential of stable Hg isotopes to contribute to the increasing knowledge of Hg sources and transformation processes in the atmosphere, aqueous ecosystems and cryosphere.

Keywords: aquatic biota
Mercury
Methylmercury
photodegradation
photo-oxidation
Stable mercury isotopes
Advisor: Bergquist, Bridget A
Next-Generation Approaches for Understanding Physical and Genetic Networks

Two approaches for understanding biological systems and gene function at a large scale are the mapping of protein-protein interactions (PPIs) and genetic interactions (GIs). PPIs map the physical connectivity structure of proteins, while GIs map dependence in phenotype when two or more genes are perturbed simultaneously. Current large-scale maps of PPIs and GIs are subject to various limitations, such as being measured in a single environment, and in the case of GI maps, a lack of exploration of complex dependencies beyond double knockouts. Here, I describe the analysis and development of emerging methods in PPIs and GIs to overcome these limitations. Analysis of a dynamic PPI assay (barcoded protein complementation assay; BC-PCA), finds that the majority of complexes (55%) change in abundance between conditions, and reveals a striking relationship between relative complex levels and relative mRNA expression during a diauxic shift from growth in glucose compared to ethanol (explaining an estimated 47% of the observed changes). A new method to analyze arbitrarily complex GIs in multiple environments is developed, and its ability to uncover new phenotypes for ABC transporters is demonstrated. Amongst the complex GIs, a four-knockout phenotype was found which confers unexpected resistance to the antifungal drug fluconazole. These methods and resulting analyzes demonstrate the need for an expansion of the scope of PPI and GI interaction mapping, and motivate their further development towards understanding living systems and gene function at a large scale.

Keywords: computational biology
genetic interactions
genomics
protein-protein interactions
systems biology
Advisor: Roth, Frederick P
Red-shifted Azobenzenes and Photocontrol of Protein Affinity Reagents

Azobenzene derivatives are a class of molecular switches that have found broad use in photocontrol of various biological systems. A key feature of azobenzenes designed to photoswitch in vivo is the wavelength of light that is required for their photoisomerization. To pass through tissue, wavelengths in the red, far-red, or ideally near-infrared region of the spectrum are required. This thesis elucidates the mechanism by which a tetra-ortho-methoxy aminoazobenzene derivative exhibits robust red light switching by forming azonium ions at physiological pH. With the design and characterization of other azobenzenes, it is shown that the photophysical properties of azonium ions can be tuned to achieve water-stable near-infrared photoswitches. Finally, a generalizable approach is proposed for obtaining light controllable bioactive agents by modifying the scaffold of a protein affinity reagent using an azobenzene cross-linker. It is shown that the azobenzene-cross-linked affinity reagent is a modular system where the photoswitch, and the affinity reagent’s target can be independently altered to optimize the system for a particular application.

Advisor: Woolley, Andrew
A Voice in the Wilderness: A Singer's Guide to the Implications of Performance Context in R. Murray Schafer's Wolf Music

This dissertation investigates some of the challenges and opportunities inherent in the performance of Canadian composer R. Murray Schafer’s environmental compositions for female solo voice. Of particular relevance to this project are the vocal selections from Wolf Music (1996), a collection of pieces from Schafer’s Patria: The Epilogue; And Wolf Shall Inherit the Moon (1983- ). This dissertation aims to facilitate and improve performances of these pieces by providing insight and practical advice to their potential singers. Chapter One looks at how Schafer’s artistic goals, his beliefs, and his professional preoccupations all intersect in his environmental music, and in Wolf Music in particular. The second chapter compares Schafer’s vocal music intended for indoor and outdoor performance to reveal context-related changes in both his compositional style and in the aesthetic values of the music. Chapter Three describes the Wolf Music vocal selections in their original And Wolf Shall Inherit the Moon context, revealing the distinctive ethos that this context facilitates, and the remarkable experiences it has made possible for performers. The fourth chapter provides practical solutions for managing some of the potential challenges of performing these pieces. The implications of the previous chapters are thrown into clear focus in Chapter Five, through my performance journals from preparing Ariadne’s Aria in indoor and outdoor contexts in 2016. Throughout the paper I argue that with these compositions, Schafer is attempting to create something more than a beautiful soundscape; rather he seeks to engage the performer in a process of interactive creation with the natural environment, an interaction intended to be transformative.

Keywords: Patria
Schafer
Singing
Space
vocal
Wolf
Advisor: Elliott, Robin
Packman, Jeff
Manufacturing Debt: A History of the Bank Credit Card Infrastructure

This dissertation provides a history of the bank credit card infrastructure in the United States from 1952 to 2007 and outlines the bank management strategies, tactics, and philosophies that helped to transform the bank credit card into a tool for survival. The dissertation traces the commercial bank management strategies, tactics, and philosophies that guided the development of the bank credit card ‘infrastructure’ and were integral to the manufacturing of debt and a financial system that enabled the widespread distribution of precarious debt. The dissertation argues that the infrastructure that makes up the credit card is simultaneously, one, the technical creation of a payment platform; two, the creation of new ways of managing and planning in banking; and three, represents explicit efforts to alter the legal, social and economic conditions that banks and payment companies operated in. It examines how postwar military inspired corporate strategies guided the design, construction, and growth of the bank credit card associations responsible for the growth and development of the bank credit card ‘infrastructure.’ The dissertation claims that beginning in the mid-1960s, American commercial bankers utilized an ‘environmentality’ approach to management, that is, they used a variety of governance techniques and strategies to understand and deliberately attempt to alter their external environment, or those external elements not under the direct control or ownership of the bank, to ensure the bank credit card’s long-term survival and growth. This systematic or environmental approach to understanding a bank’s milieu provoked bank officers into taking pre-emptive measures to avoid, eliminate, or capitalize on the risks associated with these external variables. By detailing these banking strategies, pre-emptive actions, and their effects, the dissertation claims that the 2007-2008 global financial and economic crisis was not a mistake but rather a consequence of the manufacturing of debt.

Keywords: Banking
Business Environment
Credit Card
Debt
Financial Crisis
Infrastructure
Advisor: Murphy, Michelle
More than just a Fine Drink: Processes of Cultural Translation, Taste Formation and Idealized Consumption in the Wine World

My dissertation, presented as three interrelated studies prepared as standalone articles, uses the cultural practice of wine to examine how ideas, tastes and consumption practices travel and are adopted in new places. Through field observations, interviews and discourse analysis in the established Châteauneuf-du-Pape and the emerging Niagara, I begin by examining how the concept of terroir is expressed and used across a French and a Canadian regional cultural context in Chapter 3. Through a comparative analysis of terroir, a complex French cultural term used to identify and classify artisanal foods and drinks in relation to a specific place, this first study clarifies the factors that drive consistency and change in the translation of a cultural idea like terroir, advancing our understanding of what translates and what must be adapted when a cultural idea travels in a globalized context. In Chapters 4 and 5, I further deepen this questioning by examining how wine consumers and producers in the emerging, non-traditionally wine producing Ontario wine market consider the development of a taste for wine, a cultural good that is often viewed as complex and intimidating. In Chapter 4, I consider how consumers frame their interest in wine to understand how cultural practices and tastes “take”, and become more interesting to cultural consumers. I show that consumers frame their interest in learning about wine in terms of different cognitive, sensory and status pleasures. This chapter builds on emerging research that examines the pleasurable and embodied aspects of cultural practices by investigating how the sensory and cognitive interact to produce engagement with cultural objects and practices like wine appreciation. Chapter 5 examines how wine producers conceptualize the domestic market for their product in a context of emerging wine connoisseurship and nascent wine knowledge. I analyse how producers construct the “good wine consumer” through three key dimensions: 1) spending, 2) tasting, and 3) knowledge. This study contributes to better scholarly understanding of producers’ role in creating conventions of good taste, and of the contours of taste hierarchies in times of shifting cultural standards and cultural democratization trends, alongside continued patterns of distinction.

Keywords: Consumption
Culture
Taste
Wine
Advisor: Johnston, Josée
Drug Monitoring in Breast Milk: Novel Insights on Pharmacokinetics and Infant Exposure Estimates

The health benefits of breastfeeding are numerous and well described. It has been reported that ~70% of women take medication in the postpartum period; however, little is known about drug excretion into breast milk and infant exposure estimates are often unreliable. This gap in knowledge is due to the fact that women are excluded from clinical trials if they are lactating and carrying out a formal pharmacokinetic study is both ethically and practically challenging. The lack of knowledge and uncertainty on drug safety during lactation causes women to discontinue breastfeeding prematurely in order to take a medication or decide not to initiate breastfeeding altogether. While most drugs are considered to be compatible with breastfeeding, inaccurate infant exposure predictions of drugs in breast milk have led to infant adverse events and even fatalities. The overall aims of this thesis were to investigate the safety of three drugs and their use during lactation: methotrexate, escitalopram, and infliximab. Using a combination of newly developed analytical techniques, in silico methods, and animal lactation models, this thesis helps provide an updated framework for studying the safety of drugs during breastfeeding.

Advisor: Ito, Shinya
Colantonio, David