VictorJuiz/thesis huggingface dataset:
A General Study of Genetic Association Tests and the Test of Hardy-Weinberg Equilibrium

A great number of statistical methods have been developed to test genetic association between a heritable trait and a genetic marker. However, no single existing method can deal with multiple analytical challenges that include, for example, evaluating multiple (binary and continuous) traits simultaneously, being robust to departure from Hardy-Weinberg equilibrium (HWE), and analyzing correlated data from pedigrees. Further, there is much confusion about the analytical differences and similarities between the different association tests. This thesis work fills in this gap by developing a new analytical framework, which also unifies some of the existing methods for simple yet commonly seen settings. Chapter 1 provides the scientific motivation and genetic background. Chapter 2 focuses on genotype- based approaches, introduces a new ‘reverse’ or retrospective regression model that tests association in related samples with adjustment to Hardy-Weinberg disequilibrium (HWD), and shows the theoretical link between the proposed genotype-based test and the existing ones. Chapters 3 and 4 expand the genotype-based retrospective regression to a robust allele-based (RA) alternative, and generalize the locally most powerful allelic association test to accommodate complex data scenarios. Chapter 5 takes a fresh look at the role of HWD in association analysis, and proposes a RA joint test that leverages the HWD attributed to true association to increase testing power yet remains robust to HWD attributed to genotyping error. Finally, Chapter 6 revisits all the tests introduced in the earlier chapters, and provides additional insights on the analytical connections between the prospective and retrospective regression frameworks, between regression-based and non-parametric methods, and between genotype-based and allele-based association tests.

Keywords: Allele-based
Correlation
Genetic association studies
Hardy-Weinberg equilibrium
Multiple phenotypes
Robustness
Advisor: Sun, Lei
De-Risking PET Radioligand Discovery for Neurodegenerative Diseases

This work sought to characterize novel and existing radioligands, assessing their utility and effectiveness for positron emission tomography (PET) imaging of neurodegeneration. Three proteins were targeted: 1) colony stimulating factor-1 receptor (CSF-1R); 2) glycogen synthase kinase-3 (GSK-3); and 3) transactivation response DNA-binding protein with molecular weight of 43 kDa (TDP-43). Utilizing autoradiography, a putative CSF-1R binding radioligand, [3H]CPPC, did not localize to microglia in the brain tissue of a preclinical model of neuroinflammation and percent displacement did not exceed 50% of signal, requiring use of spleen in screening assays. Selectivity assessment showed numerous binding sites which prevents an interpretation of signal contribution. Using similar methods, two radioligands targeting GSK-3, a kinase implicated in Alzheimer’s disease (AD) pathogenesis, were shown to quantify similar target densities (Bmax) with similar affinity (Kd) in human and rodent post-mortem homogenates. Investigation of human AD brain revealed possible differences in GSK-3 density compared to controls within females. In P301L mice, GSK-3 density in males was elevated compared to control, and a trend was recapitulated by in vivo PET, while females remained unchanged by both methods. GSK-3 PET research could inform the biological role of this critical kinase in pathogenesis of AD. Lastly, autoradiography identified two potential lead structures following evaluation of existing tau PET radioligands in post-mortem amyotrophic lateral sclerosis (ALS) tissues. Colocalization of specific binding with aggregate TDP-43 immunostaining was evaluated for isotopologues of 6 existing tau PET radioligands in varying structural classes. Three radioligands, [3H]MK-6240, [3H]GTP-1, and [3H]JNJ-067, showed no binding in ALS tissues. [3H]CBD-2115 specific binding was elevated but did not correlate to pathology. [3H]Flortaucipir binding was increased in the motor cortex compared to the cerebellum. Immunofluorescent staining with APN-1607 revealed no colocalization with a TDP-43 inclusion but significant binding to -amyloid. Despite revealing both positive and negative results an overarching objective of de-risking radioligands was achieved in each case by providing important information including selectivity, target density, specificity, or affinity. The results presented here are not unexpected due to challenges in developing imaging probes which has led to most putative radioligands failing prior to translation as successful clinical imaging ligands.

Advisor: Vasdev, Neil
Evaluating the Therapeutic Potential of Angiotensin-converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Drosophila Alzheimer's Disease Models

Alzheimer’s disease (AD) is a degenerative disorder that causes progressive memory and cognitive decline. Recently, studies have reported that inhibitors of the mammalian renin angiotensin system (RAS) result in a significant reduction in the incidence and progression of AD by unknown mechanisms. Here, I used a genetic and pharmacological approach to evaluate the beneficial effects of Angiotensin Converting Enzyme-inhibitors (ACE-Is) and Angiotensin Receptor Blockers (ARBs) in Drosophila expressing AD-related transgenes. Importantly, while ACE orthologs have been identified in Drosophila, other RAS components are not conserved. I show that captopril, an ACE-I, and losartan, an ARB, can suppress brain cell death in flies expressing a mutant human C99 transgene. Captopril also significantly rescues memory defects in these flies. Similarly, both drugs reduce cell death in Drosophila expressing human Ab42 and losartan significantly rescues memory deficits. However, neither drug affects production, accumulation or clearance of C99 and Ab42. Moreover, neither drug rescued brain cell death in Drosophila expressing human Tau suggesting that RAS inhibitors specifically target the amyloid pathway. Of note, I also observed reduced cell death and a complete rescue of memory deficits when I crossed a null mutation in Drosophila Acer into each transgenic line demonstrating that the target of captopril in Drosophila is ACER. In addition, I also found that knockdown of an ACER interactor, CG2233, in flies expressing human Ab42 recapitulated the beneficial effects by Acer null mutationand captopril, suggesting an ACER-CG2233 pathway underlying the captopril-driven beneficial effects. Altogether, these studies demonstrate that captopril and losartan are able to modulate AD related phenotypes in the absence of the canonical RAS pathway and suggest that both drugs have additional targets that can be identified in Drosophila.

Keywords: Alzheimer's Disease
amyloid
Drosophila
memory
presenilin
renin angiotensin system
Advisor: Boulianne, Gabrielle GB
Bioretention Systems for Stormwater Management: Assessment, Performance and Changes Over Time

Bioretention systems function to mimic natural hydrology, by retaining stormwater runoff from routine rain events and returning it to infiltration and evapotranspiration, instead of runoff. This thesis consists of four studies which answer these research questions: How do we assess performance, and how does bioretention performance change over time? A systematic scoping review of 320 studies found that bioretention performance is defined in terms of hydrologic controls, while investigations into mechanisms of contaminant transport and fate are overlooked. Bioretention field research has been primarily conducted by a small number of institutions (26 institutions were responsible for 50% of the research) located mainly in high income countries, and primarily on new systems for a short period of time. Following the definition of performance, a field survey of mature systems (>3 years operation) was conducted on bioretention cells across Ontario, Canada. Saturated hydraulic conductivity (KSat) (a measure of hydrologic performance) was above minimum guidelines for all sites, and KSat improved for 6 of 9 sites. Soil-water interaction properties, such as plant available water and wilting point, more closely resembled loam soils than sandy soils, which may be due to the development of a soil structure over time. A more in-depth analysis of bioretention performance was conducted using a bioretention cell located in Vaughan, Ontario. The hydrologic and water quality performance was compared over two monitoring periods: new (immediately post-construction) and mature (4-5 years post-construction). The hydrologic performance was maintained in the mature system (median volume reductions of 100%) and mature effluent water quality was improved compared to the new condition for some parameters (e.g., dissolved solids, nitrogen species). A complete water balance of the system was performed using inflow, outflow and evapotranspiration data (via a weighing lysimeter). The water balance was further broken down by event size, where the event size was determined by rainfall frequency analysis. Recharge was the largest component of the water balance overall (86 % of inflow), and evapotranspiration was the next largest water balance component (7 % of inflow overall). Evapotranspiration was a significant component of inflow (21 %) when considering small events with a 50% chance of occurrence.

Keywords: bioretention
green infrastructure
green stormwater infrastructure
low impact development
stormwater
Advisor: Drake, Jennifer
Development of an Automated Computational Cell Tracking Tool for High-throughput Screening of Cellular Migration in Exosome-stimulated Wnt-PCP Signaling

Intercellular delivery of WNT ligands across tissues is required for development, regeneration and is also involved in many pathologies. One method of this transport is facilitated by being carried on exosomes, which are small, stable extracellular vesicles. Exosomes released by cancer associated fibroblasts (CAFs) interact with various types of cancer cells to stimulate motility through transport of WNT11 to promote WNT-PCP signaling. This model system presented a unique opportunity to identify new regulators of exosome-based WNT-PCP signaling. However manual measurement of the motility is slow, thus greatly inhibiting our ability to screen large number of candidate regulators. As such, I devised a method to automate the measurement and analysis of cell motility by tracking cells over a time course using live cell imaging. The algorithm I developed was able to accurately and precisely measure the movements of 100s of cells in a multi-well format. Additionally, my approach considers possible track fragmentations to ensure that the majority of tracks encompass the entire time course. I also expanded the algorithm to measure changes in cell morphology and cell death. High-throughput screening of kinase inhibitor tool compounds in a proof-of-concept screen identified various kinases with putative roles in exosome-stimulated motility. One such kinase I chose to focus on was RET, a receptor tyrosine kinase, that is closely linked to migration and morphogenesis in development and is often mutated or overexpressed in cancer. RET loss showed loss of motility in both MDA-MB-231 triple negative breast cancer cells and T24 bladder cancer cells as well as morphological changes that led to increased cell aspect ratios. Furthermore, RET and WNT11 interactions in the embryonic kidney are required to promote branching morphogenesis. I inhibited the release of exosomes in ex vivo E11.5 kidneys through treatment with Manumycin A, which resulted in a reduction in branching. My work describes an efficient, automated method to screen for regulators of WNT-PCP associated cell motility and illustrates a potential role for RET and WNT11 interaction in exosome-stimulated cell migration.

Keywords: Algorithm
Cell tracking/methods
High-throughput screening
Planar cell polarity
WNT
Advisor: Wrana, Jeffrey L
Assessing the Value and Impacts of Vision Care Services for Children in Ontario

BACKGROUND: Refractive errors and amblyopia cause the most vision impairment in children. Early vision testing is crucial to prevent permanent impairment. The uptake of optometry exams amongst children in Ontario is unknown. Limited evidence exists on the accessibility and value of vision care services. This evidence is needed for equitable and cost-effective services to prevent needless vision loss in Ontario. OBJECTIVES: To 1) determine the uptake of comprehensive eye exams and test its associations with socioeconomic status amongst young children in Ontario, 2) synthesize and appraise the literature on economic evaluations of vision screening to detect vision impairment in children, and 3) determine the cost-effectiveness of (a) mandatory comprehensive eye exams by optometrists once between 2 to 5 years of age (CEE); and (b) universal school screening by contracted screeners at age 5 years (USS) compared to (c) usual care (i.e., vision screening as part of well-child visits annually from age 3 to 5 years [WCC(RS)] in Toronto, Ontario. METHODS: A population-based cohort study, systematic review of the literature, and a cost-utility analysis using a probabilistic health-state microsimulation model. RESULTS: Sixty-five percent of children in Ontario had at least one comprehensive eye exam by their 7th birthday, with children in neighborhoods of least material deprivation having a higher odds [adjusted odds ratio (aOR) 1.43; 95%CI 1.36, 1.51] compared to children in most deprived neighborhoods. The review yielded 13 economic evaluation studies, six of high quality with incremental cost-effectiveness ratios (ICER) between C$1,056 to C$151,274/case detected or prevented and between C$9,429 to C$30,254,703/QALY gained. From the societal perspective of the cost-utility analysis, USS was less costly and less effective than WCC(RS), and the ICER was C$500/QALY gained comparing CEE to WCC(RS). There was significant parameter uncertainty in the probabilistic analysis. At a willingness-to pay of C$50,000/QALY gained, USS was cost-effective in 19% of iterations relative to WCC(RS), CEE was cost-effective in 26% of iterations relative to WCC(RS). CONCLUSION: Low socioeconomic status is associated with poor uptake of comprehensive eye exams in Ontario however, USS and CEE are not cost-effective alternatives to usual care screening [WCC(RS)] at a willingness-to-pay of C$50,000/QALY gained.

Keywords: amblyopia
comprehensive eye exams
cost-effectiveness
refractive errors
vision impairment
vision screening
Advisor: Wong, Agnes M.F.
Maurer, Daphne
The Effects of Urbanization on the Ecology and Evolution of Species Interactions

Urbanization alters the environment in profound ways that affects both the ecology and evolution of species and their interactions with one another. My thesis explores how urbanization alters ecological processes in urban populations and communities and investigates how patterns of ecological change feedback to influence the evolution of populations. Throughout my thesis, I use a combination of perspective pieces, literature reviews, and empirical research to identify and test avenues of research in the field of urban evolutionary ecology. In my first chapter, I reviewed the literature and identified key questions that needed to be addressed by the field. I followed up on one of these questions in my second chapter, where I reviewed the literature to identify patterns on non-adaptive evolution in urban populations. In the next two chapters, I measured the effects of urbanization on plant-pollinator and plant-herbivore interactions. My results demonstrated that urbanization alters interactions between Brassica rapa and its pollinators, leading to altered patterns of pollen dispersal and reproductive success in cities. Similarly, my results demonstrated that even small human settlements lead to increased seed predation rates and modified natural selection in Tribulus cistoides. My sixth chapter looked at the effects of urbanization on the mating system and population genetic variation of Impatiens capensis, and found that despite high outcrossing, urban populations were less genetically diverse than rural populations. My last chapter broadens the scope of my research and identifies joint effects latitude and sexual system on resistance to herbivory in Sagittaria latifolia. My thesis identified consistent effects of urbanization on the ecology and evolution of species and their interactions with one another and provides research directives to develop and broaden the scope of the field of urban evolutionary ecology.

Keywords: Plant-herbivore
Plant-pollinator
Species interactions
Urban ecology
Urban evolution
Urbanization
Advisor: Johnson, Marc
Intermaterial Collaboration: The Spatiotemporal Nexus of Nonhuman Agency in Cultural Heritage Knowledge Production

This exploratory research into cultural heritage collections management practice develops a process by which richer knowledge of prospective —and existing—collections can be cultivated while taking the agency of the bodies being considered seriously. Recognizing that interactions require documentation to be useful for knowledge production, perspectives for bolstering non-anthropocentric awareness are presented using the case study of an art collection created and assembled by Indo-Canadian artist P. Mansaram to bring nonhuman agency into the purview of cultural heritage documentation. Influenced by the preceding three decades of material culture theory, especially the theoretical lens of political theorist Jane Bennett (2010) that actively notices nonhuman agency, the dissertation presents multiple methods of reinforcing this awareness in the documentation of objects during the acquisitional process--a moment when contexts and relationships are at their most accessible to collections managers and curators. Recognizing that there is an ahistorical bias to these methods that decontextualizes the interactions from their spatiotemporal contexts, this research puts forward an augmentation of social anthropologist Alfred Gell’s art nexus (1998) to provide a richer method for capturing the agential roles and classifications of interactions in a standardized manner across objects and collections, positioning temporality and spatiality as capable of agential roles. This dissertation demonstrates how knowledge production of collections can be enriched through the application of the nexus to thick narratives developed in the acquisition moment by cultural heritage professionals with the intention of recognizing agency, as well as retroactively to interview and archival materials that were not generated with this purpose in mind. In doing so, it advocates for a fundamental change in how cultural heritage information is managed, building on the calls to evolve existing documentation practices that uphold limitations from rational and standardized contexts toward more relational, unexpected, "crunchy knowledge” (Chapman 2015).

Keywords: Cataloguing
Collections Management
Cultural Heritage
Documentation
Knowledge Production
Nonhuman Agency
Advisor: Krmpotich, Cara
Crafty Impressions: The (New) Visual Culture of Contemporary Fibre Craft

In recent years in the Global North, there has been an extraordinary resurgence of craft. Do-it yourself and domestic fibre-based arts and crafts have proliferated in homes, workshops and online. The pandemic has further extended these developments. Today, craft is practiced for its physical slowness, intrinsic rewards, creative expression and psychological benefits. Craft is also pursued as a form of paid work. This is particularly true for a growing number of middle-class,white women in Canada and the United States. Increasingly, many craft workers are turning to visual and digital mediums, such as photography, video, blogging and social media, in an effort to showcase their work, exchange creative and technical ideas, cultivate communities, and generate business opportunities. Drawing on a mixed-methods approach and focusing on the hand-knitting industry in Canada and the United States, this dissertation explores the ways in which photographs circulated on social media platforms are bound up in the creative and labour practices, subjectivities, bodies, affects and politics of particular craft workers. The research suggests as craft workers use visual and digital media for the purposes of cultivating creativity, income, communities and political solidarity, they are simultaneously caught up in broader techno-capitalist systems of power.These systems can create opportunities and pathways; they can also limit capacity to earn a secure and stable living, encourage the governing and surveillance of creativity, bodies and emotions, and facilitate the marginalization of transformative politics. Highlighting the ways in which the visual and material are not separate but conjoined, the case of the hand-knitting industry demonstrates how images circulated on social media platforms are bound up in networks of power that span across geography and time, and have important human, social, political and economic contexts and consequences. Adding empirical analysis to the ways in which images circulated on social media platforms do not just show things, but do things (Tolia-Kelly and Rose, 2012), this dissertation offers new perspectives on, and contributes to broader conversations about, visual culture, creative labour, platform economies and social justice, providing analysis on the interconnectedness of these systems, and how they relate to life both online and offline.

Keywords: craft
Instagram
knitting
labour
photography
platform economy
Advisor: Leslie, Deborah
The Role of NCX1 in the Pathogenesis of Kawasaki Disease

Kawasaki disease (KD) is an acute multisystem vasculitis that predominantly affects children under the age of five. The pathobiology of KD is characterized by systemic inflammation localizing at the coronary arteries, where inflammatory cells, such as macrophages, infiltrate the arterial wall. The production of pro-inflammatory cytokines through NLRP3 inflammasome activation is thought to be involved in the pathogenesis of KD. Interestingly, many of the SNPs associated with KD susceptibility and CAL formation are in genes involved in calcium mobilization, a trigger of NLRP3 inflammasome activation, including SLC8A1. The protein encoded by SLC8A1, the sodium–calcium exchanger 1 (NCX1), mediates intracellular calcium efflux or extracellular calcium influx in exchange for sodium. In macrophages, canonical NLRP3 inflammasome activation requires two signals: priming and activation. The priming signal can be induced by TLR ligands, resulting in the activation of the NF-kB pathway including the transcriptional upregulation of pro-IL-1B and production of pro-inflammatory cytokines, such as TNF-a. We show that reverse-mode NCX1 activity modulates TLR-induced extracellular calcium influx, phosphorylation of p38 MAPK and NF-kB, upregulation of pro-IL-1B and production of TNF-a in PMA-differentiated THP-1 cells, a model of human macrophages. Additionally, we demonstrate that genes involved in the NLRP3 inflammasome pathway are upregulated in KD patients in the acute phase of disease, in comparison to the convalescent phase. Moreover, NLRP3 inflammasome activation can be induced by ion fluxes including calcium mobilization and mitochondrial dysfunction, resulting in the release of IL-1B and IL-18, and gasdermin D cleavage. We demonstrate that low extracellular sodium concentrations induce the dose-dependent release of IL-1B in primed macrophages. In addition, we show that low extracellular sodium concentration mediates intracellular calcium mobilization through NCX1 and production of mtROS in macrophages. Furthermore, low extracellular sodium concentration mediates the release of IL-1B and IL-18, and gasdermin D cleavage through NLRP3 inflammasome activation and release of IL-1B through mtROS production. Lastly, KD patients with hyponatremia have higher Z-max score in comparison to patients with normal serum sodium concentration. Taken together, these results highlight the role of NCX1 in the pathogenesis of KD.

Advisor: Yeung, Rae SM