VictorJuiz/thesis huggingface dataset:
Investigating the Role of Host Genetic Factors and the Microbiome on Microsporidia Infection in C. elegans.

Microsporidia are a group of poorly understood, obligate intracellular eukaryotic pathogens with highly reduced genomes. They are currently a major threat to the agricultural industry and cases of fatal human infections are prevalent in immunocompromised individuals. The Nematocida parisii- Caenorhabditis elegans host pathogen model has recently been established and has provided great insight into N. parisii infection biology, but the host factors critical for infectionremain poorly defined. To overcome this, we performed a forward genetic screen to isolate C. elegans mutants displaying improved fitness during N. parisii infection. I identified a host secreted protein, AAIM-1 used by N. parisii to ensure spores are oriented properly in the intestinal lumen, resulting in successful invasion. AAIM-1 plays an antibacterial role in C. elegans, protecting against the gram-negative bacterial pathogen Pseudomonas aeruginosa. Thus N. parisii utilizes a host antibacterial protein to promote its own invasion. I also screened the C. elegans microbiome “CeMbio” collection of bacteria to investigate its impact on N. parisii infection. C. scopthalmum JUb44 and S. multivorum BIGb0170 impact nematode physiology by modulating feeding behaviour, resulting in increased pharyngeal pumping and thus increased levels of N. parisii invasion. However, within 24 hours N. parisii growth is compromised. Interestingly, linoleic acid supplementation in S. multivorum BIGb0170 can restore N. parisii growth indicating its importance. I also investigated the potential for bacterial secondary products to impact dormant spores. The incubation of N. parisii spores in either Pseudomonas lurida MYb11 or Pseudomonas mendocina MSPm1 conditioned media resulted in decreased infectivity through spore destruction. In P. lurida MYb11 this was a result of the cyclic lipopeptides Massetolide E and F. Excitingly, fractionation of P. mendocina MSPm1 supernatant has revealed that two independent molecules have anti-microsporidia activity. We also demonstrate that Pseudomonas secretomes frequently contain anti-microsporidia compounds that target dormant spores. Collectively, this work identifies a host protein and dietary metabolite important for N. parisii infection. The identification of anti-microsporidia compounds represents a new and exciting avenue to identify novel therapeutic strategies by mining naturally produced bacterial products.

Keywords: C. elegans
Host Pathogen relationships
infection
invasion
Microbiome
Microsporidia
Advisor: Reinke, Aaron W
Evaluating PET Imaging Biomarkers in Chronic Traumatic Encephalopathy

This work aims to characterize novel and existing radioligands to assess their utility for positron emission tomography (PET) imaging of chronic traumatic encephalopathy (CTE). Two pathological mechanisms were targeted: 1) neuroinflammation and 2) tau protein aggregates. Neuroinflammatory PET biomarkers were evaluated in Chapter 2 in CTE post-mortem tissues compared to controls and no significance in target density (Bmax) of the 18 kDa translocator protein (TSPO) or monoamine oxidase-B (MAO-B) was determined. Further validation of TSPO as a PET imaging biomarker in CTE was performed in a young cohort (19-29 year-olds). The activated microglial marker, CD68, and TSPO cell density was significantly higher in the calcarine cortex compared to the dorsolateral frontal cortex (DLFC), in individuals with repetitive head impacts (RHIs), regardless of CTE pathology. There was no significant difference found in TPSO density or in the percentage of CD68+ cells co-expressing TPSO in CTE or RHI groups. Upon evaluation of five tau-PET radiotracers in CTE in Chapter 3, a Bmax and affinity (Kd) for CTE-tau was determined with [3H]flortaucipir and off-target binding to MAO-A with this radiotracer was identified. [3H]MK-6240, [3H]PI-2620 and [3H]APN-1607 bound in late-stage CTE cases with mixed Alzheimer’s disease (AD) pathology and [3H]APN-1607 demonstrated off-target binding to amyloid-b. In a case study of a cognitively impaired former National Football League player, [18F]MK-6240 PET imaging was performed, and radiotracer binding was observed in regions that generally show CTE-related tau pathology at autopsy. Evaluation of PI-2620 derivatives toward the identification of a radioligand suitable for imaging tau beyond AD was performed. Radiotracer development including autoradiography and in vivo PET imaging was performed in Chapter 4 to image other neurodegenerative targets, namely metabotropic glutamate receptor subtype 5 (mGluR5) with [18F]FPEB and glycogen synthase kinase-3 (GSK-3) in which [18F]OCM-50 was identified as a potent, selective GSK-3 targeting radiotracer displaying good brain uptake, quick washout and retention in non-human primate. Kinetic modelling of this radiotracer has now been performed and first-in-human studies are planned. This thesis has contributed to understanding the underlying pathological mechanisms associated with head injuries with PET imaging towards the goal of imaging CTE in life.

Keywords: Chronic traumatic encephalopathy
Neuroinflammation
PET Imaging
Tau
Advisor: Vasdev, Neil
Hymn to Aphrodite

Hymn to Aphrodite is an 18-minute self-contained work and the first of four overall sections of a large cantata titled From Sappho’s Lyre. It uses fragments of one of (only two) of Sappho’s major poems surviving in their entirety: “The Hymn to Aphrodite,” both in Greek and English. Conceived as a stage work to be accompanied by dance and spectacle—and though it can be performed as a traditional vocal work with instrumental accompaniment— the composition’s formal design functions as a hybrid, one that lavishly fuses elements of ancient Greek play and theatre with Western ballet and opera. Scored for two solo voices (soprano and mezzo), chamber orchestra, chamber choir, pre-recorded audio, and narrator, Hymn to Aphrodite is based on—and heavily inspired by—The Lesbian Lyre: Reclaiming Sappho for the 21st Century, a groundbreaking book by classicist Jeffrey M. Duban (Clairview Books, 2016). It usesthe author’s translations to portray, interpret, and dramatize the charm and elegance of the originals so magnificently conveyed in the English language while offering the listener a journey that orbits around ever-evolving and constantly shifting sonic and visual realms.

Keywords: Chamber Music
Classics
Electronic Music
Multimedia Composition
New Music
Orchestral Conducting
Advisor: Palej, Norbert
The Motivated Creation and Use of Social Categories

Social categorization is often framed as the antecedent to stereotyping, with perceivers rationally sorting the social world on the basis of perceptually salient categories before applying biased beliefs about those categories. Here, I instead suggest that both the construction and use of social categories are themselves subject to motivational influences. In chapter 2, I present a theory of how motivations derived from structural sources shape the social categories that people form. I argue that motivations to maintain shared schemas and resource distributions influence social attention, such that perceivers will attend to a given dimension (e.g., race or gender) insofar as doing so fits within their motivations. Drawing from classic conceptualizations of social structure as the interplay of schemas and resources, I focus on how the motivations for shared schemas and for material benefits may shape attention to social category dimensions. I outline potential cognitive mechanisms through which these motivations may act, before discussing the implications of the model. In chapter 3, I examine how environmental factors interact with motivations to shape reliance on social categories. Across three experiments, I use a computational model of category learning to discover the structure of the category representations that participants hold, allowing me to distinguish participants who individuate targets from those who rely wholly on group-based representations. I find that individual differences interact with the environmental feedback structure to predict individuation: those higher in racism or lower in social justice orientation form more group-based representations of negative targets only when they are in an environment that ties feedback to approach behaviour. Finally, in chapter 4, I turn to motivated effects on the use of social categories, examining how people navigate motivational tradeoffs when making decisions for themselves, ingroup members, and outgroup members. Across four behavioural studies and one eye-tracking study, I find evidence for stronger self-ingroup than self-outgroup tradeoffs, which manifest in both altered attention to information and altered use of the attended information in decision-making. Overall, this work presents an investigation of motivational influences on category formation and use, suggesting that motivations may shape very early stages of social perception.

Keywords: attention
computational modeling
motivation
social categorization
social structure
stereotypes
Advisor: Cunningham, William
Uncertainty in Quantification of Material Use and Embodied Greenhouse Gas Emissions of Single-Family Dwellings

Reducing embodied greenhouse gas (GHG) emissions in the construction of buildings is globally recognized as important for meeting climate targets. However, quantitative understanding of building material use is limited and employing material efficiency strategies to reduce building embodied and global GHG emissions is underutilized. This dissertation advances the understanding of building material intensity (MI) and embodied GHG intensity with specific focus on single-family dwellings (SFD). The thesis examines the uncertainty and variability associated with current and practical approaches to built environment industrial ecology and building regulations, the variation in MI and embodied GHG emissions within and between cities, and the potential for material efficiency strategies to reduce embodied GHG emissions in SFDs. The three central chapters build an evidence-based approach to advance understanding of MI in SFDs and then combine MI with material GHG intensity to investigate embodied GHG emissions. Chapter 3 investigates variations in MI and implications for uncertainty in MI research focusing on buildings within one city (Toronto, Canada). Chapter 4 expands on this and examines differences in MI both within and between places with investigation of buildings in Toronto, Canada, Perth, Australia, and Luzon, Philippines. In Chapter 5, embodied GHG intensity is estimated and examined to determine whether the observed ranges of MI or material GHG intensity drive overall embodied GHG emissions of buildings. Three design and material strategies (light-weight design of structures, more intensive building use, very low GHG material substitution) are evaluated for their potential to reduce embodied GHG emissions of housing construction. Through the study of 80 buildings across three locations, this dissertation identifies important implications of uncertainty and variability within and between locations, determines implications of functional unit selection on interpreting MI, and identifies large contributors and drivers of building material use and embodied GHG emissions. The findings support uncertainty examination in bottom-up MFAs and inform building regulations on the use of functional units when developing benchmarks for building material and embodied GHG estimates. Material intensity and embodied GHG interventions for housing are location and context specific, but regardless of location, constructing smaller houses would reduce overall MI and embodied GHG emissions.

Advisor: Saxe, Shoshanna
MacLean, Heather L.
Digital Health Technology for Chronic Respiratory Disease Management

Background: Digital health technology (DHT) interventions—including mobile applications (apps), wearable devices, and telerehabilitation—have the potential to support chronic respiratory disease management and self-regulation of behaviour. Considerable heterogeneity in the design of digital technologies exists, leading to ambiguity about the most feasible, valid, and effective DHTs for chronic respiratory disease management. Objective: To better understand the feasibility, acceptability, validity, and the effectiveness of various DHT interventions.Methods: To understand the effectiveness of DHTs for chronic respiratory disease management, one systematic review and meta-analysis was conducted assessing the effectiveness of interactive mobile apps and wearables for chronic respiratory disease self-management (Study 1). To understand the acceptability and feasibility of a wearable device intervention designed to reduce sitting time in people with COPD, an observational, cross-sectional study was conducted with 15 participants who wore a fitness tracker providing vibration reminders to break up sitting time for two weeks (Study 2). Finally, in Study 3, the validity of a commercially-available fitness tracker to measure sedentary time in healthy older adults and in people with COPD was assessed through an observational, cross-sectional study in 15 people with COPD and 15 healthy older adults. Both groups simultaneously wore a validated research-grade activity monitor and a commercially available activity monitor for two weeks and measures of agreement between devices were obtained. Results: Study 1 found low-quality evidence suggesting that interactive, digital self-management interventions improve health status and physical activity in people with COPD and may not lead to improvements in health outcomes for people with asthma. Study 2 found that a wearable device sitting time reduction strategy was feasible, safe, and acceptable to participants with COPD. Study 3 showed that a commercially available fitness tracker had moderate agreement with a validated research-grade device, overestimating sitting time in healthy older adults and slightly underestimating it in people with COPD. Conclusion: This thesis provides further insight into the effectiveness, feasibility and acceptability, and the validity of various DHT interventions for chronic respiratory disease management. The findings reveal the need for greater standardization of DHT interventions and more high-quality DHT research trials.

Advisor: Brooks, Dina
Investigating Cortical Plasticity in Movement Disorders using Transcranial Magnetic Stimulation

The human primary motor cortex (M1) plays a key role in motor control, and cortical plasticity is key to its functioning. At the systems level, transcranial magnetic stimulation (TMS) in theta burst (TBS) mode and paired associative stimulation (PAS) provide opportunities to induce LTP and LTD-like effects in the human brain non-invasively. TMS studies have elucidated common themes in the pathophysiology of movement disorders such as aberrant cortical plasticity and interactions between motor cortical circuits in both Parkinson’s disease (PD) and focal hand dystonia (FHD). However, no standardized biomarkers or treatments that employ TMS have been developed for these diseases. This thesis investigated the central effects of treatments such as botulinum toxin (BoNT) injections and deep brain stimulation (DBS) on cortical plasticity in movement disorders using TMS. In 14 FHD patients, we found an abnormal facilitatory response to a depotentiation protocol and similar intracortical circuit activity compared to healthy age-matched controls. In 11 FHD patients, we found impaired depotentiation and intracortical circuits remained consistent throughout the BoNT treatment cycle. In 11 PD patients treated with subthalamic nucleus (STN) DBS, we demonstrated that long-lasting LTP-like plasticity can be induced in less than 5 minutes with a PAS-like protocol that pairs 3 Hz DBS and rTMS at timing-specific interstimulus intervals. Taken together, our findings highlight the relevance of cortical plasticity in the pathophysiology of both PD (a hypokinetic movement disorder known to have deficient plasticity) and FHD (a hyperkinetic movement disorder known to have excessive plasticity). Overall, these studies provide novel insight on the pathophysiology of FHD and PD that will help design future treatment strategies that leverage the modulation of cortical plasticity.

Advisor: Chen, Robert
Co-designing and Evaluating a Workplace Disability Disclosure Decision-aid Tool for Autistic Youth and Young Adults to Enhance Self-determination and Decision-making Skills

Autism is a neurodevelopmental disability that often presents as non-visible in the workplace; thus, autistic people have the choice of whether to disclose their autism at work. This disclosure decision-making process is complex and may be even more so for autistic youth and young adults who are newly entering the workforce. Little is known about their workplace disclosure experiences and no tools exist to support this decision-making process. The objectives of this knowledge translation (KT) grounded doctoral thesis were to: i) explore workplace disclosure needs, experiences, and influencers among autistic young people; ii) co-design, test the usability (ease of use, satisfaction, usefulness), and revise a prototype of an autism disclosure decision-aid tool; and iii) evaluate the revised tool in terms of its: impact on self-determination and decision-making capabilities; usability; feasibility; and acceptability. The first study involved six Zoom focus groups with 23 autistic young adults and findings revealed numerous influencers impacting disclosure needs and experiences; noteworthy factors include the workplace environment, fear of negative disclosure outcomes, and disclosure knowledge and skill gaps. The second study used co-design and patient-oriented research strategies and KT tool development literature to co-design the decision-aid prototype with four autistic collaborators. Usability testing involved four focus group / participatory design Zoom sessions with 19 autistic youth and young adults; findings were positive suggesting the prototype’s usability. Revisions addressed mainly the prototype’s ease of use. The third study used online pre-post surveys with 30 autistic youth and young adults. The tool was deemed usable, feasible, and acceptable; there were significant changes in decision-making capabilities, with impact on self-determination requiring future investigation. This thesis uncovered the disclosure experiences of autistic young people and produced a tangible disclosure decision-aid tool that may support navigation of disclosure processes. Future research should continue exploring autistic young peoples’ disclosure experiences and testing the tool to determine its effectiveness and potential for implementation.

Keywords: Autism
Co-design
Decision-aid tool
Disability disclosure
Knowledge translation
Youth and young adults
Advisor: Lindsay, Sally
Resource Allocation and Percentile Optimization in Wireless Networks

Coordinated power control and beamforming is essential in improving service in, and enabling new applications for, future generations of wireless networks. However, the associated optimization problems are often mathematically intractable, requiring the use of novel techniques to solve them. This thesis studies resource allocation optimization in two parts. In the first part, we focus on solving classical resource allocation problems by developing novel optimization-theoretic and deep learning techniques to overcome the limitations of conventional resource allocation algorithms. To this end, we first consider sum-rate optimization via power control in a multi-user cellular network. Our key contribution is the development of centralized and distributed deep reinforcement learning algorithms which outperform state-of-the-art optimization techniques while generating solutions orders of magnitude faster and requiring substantially less channel state information exchange between base stations. Next, we consider the classic long-term average proportional fair throughput optimization problem. Contrary to prior works which solve the non-convex and NP-hard proxy weighted sum-rate maximization problem, we prove that the original problem can be recast in convex form and efficiently solved to optimality. In the second part of this thesis, we introduce a novel class of problems called percentile programs in which we seek to optimize a function of a set of variables at a desired percentile. Our primary emphasis lies in developing effective power control and beamforming strategies to improve throughput for cell-edge (i.e., lower-percentile) users in wireless networks. We rigorously establish the computational complexity status of the broader class of percentile throughput optimization problems, and extend the proposed techniques to long-term average utility optimization. Moreover, we showcase that the proposed techniques can be readily extended to optimize all concave nondecreasing utility functions, allowing us to combine percentile and conventional utility functions to construct novel 'hybrid' utility functions.

Advisor: Adve, Raviraj
The Re-Embodiment of Affect in Historical Violin Performance

This dissertation discusses an embodied method of understanding and expressing the musical affects in eighteenth-century performance practice. It argues against the twentieth- and twenty- first-century interpretation of affects as fixed emotions (Bukofzer, Neubauer, Buelow, Weiss, and Taruskin) suggesting that this interpretation based on René Descartes’ work hinders historically informed performers from accessing the depth of physicality required to express affect—particularly for string players in their approach to bow-stroke.The paper brings affect into focus as an historical category, an embodied practice, and a significant aspect of present-day performance practice discourse. To illustrate this, the writings of Aaron Hill (1685-1750), an English actor, are examined. Hill’s treatise emphasizes the bodily gestures and specific muscular movements involved in projecting the affects, which provides an excellent framework for kinaesthetically approaching affect and demonstrates how the affects were more nuanced than Cartesian dualism implies. The second part of the dissertation proposes a pedagogical treatise based on eighteenth-century models, enriched by ethnographic-based interviews with performers, historical research, and video demonstrations based on Richards’ personal practice. This final section of the dissertation uses Hill’s treatise to explore how the physicality of theatrical gesture can be adapted to violin performance to redefine affect from the performer’s perspective.

Keywords: Aaron Hill
affect
baroque
embodiment
historical performance
violin
Advisor: Lockhart, Ellen
The Exit of Nanoparticles from Solid Tumours

The current paradigm of nanoparticle tumour delivery states that after nanoparticles have entered the tumour, collapsed lymphatic vessels impairs their exit and leads to enhanced tumour retention. This paradigm has guided the engineering of nanoparticles for over 35 years but has led nanoparticle designs with minimal therapeutic effect. Here we show that this paradigm is incorrect. We then determined the different vessel pathways that enable nanoparticles to exit the tumour and the dominant exit mechanism. 15nm nanoparticles predominantly exit the tumour via the lymphatics surrounding the tumour, whereas 50nm nanoparticles or larger predominantly exit via the lymphatics within. Nanoparticles that exit the tumour through the lymphatics are returned to the blood system, allowing them to recirculate and interact with the tumour in another pass. These findings were consistent for gold nanoparticles, liposomes, and silica nanoparticles. Our results enable us to define an alternative mechanism of nanoparticle delivery to solid tumours to the enhanced permeability and retention (EPR) effect. We call this mechanism the Active Transport and Retention principle (ATR). This delivery principle provides a framework to engineer nanomedicines for cancer treatment and detection.

Keywords: Cancer
Lymphatics
Nanoparticle
Advisor: Chan, Warren C.W.