Doctoral Theses (2009 - )

Permanent URI for this collectionhttps://hdl.handle.net/1807/9945

The School of Graduate Studies (SGS) requires doctoral and masters graduands to submit a thesis written as a required element of their degree program in electronic format.

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Development and Characterization of Inductively Coupled Plasma (ICP) Spectrometry for Single-particle Analysis
(2022-11) Guo, Xiaoman; Mostaghimi, Javad; Mechanical and Industrial Engineering
ICP spectrometry, such as ICP-optical emission spectrometry (OES) and -mass spectrometry (MS), is a dominant technique for trace element analysis. Detecting elements at the single-particle/cell level is challenging, requiring improvements in the current ICP-based systems. Common limitations faced by ICP spectrometry originate from the ICP source and the sample introduction system in the first place. Recently, a conical ICP torch has been designed to provide a plasma with higher temperature and less gas and power consumption compared with the conventional Fassel torch. In this thesis, to meet the requirements of single-particle/cell analysis, a sample introduction system has been proposed and the ICP source has been characterized. First, the inherent properties of ICP produced by the conical torch over conventional ones in terms of flow patterns, particle trajectory, velocity, and residence time were characterized both experimentally and numerically. The conical torch was shown to be superior to the conventional torch in several aspects for single-particle applications. Secondly, the analytical performance of the conical torch in axially-viewed ICP-OES was investigated. The conical torch provided better single- and multi-element detection limits and was more resistant against sodium interference than the Fassel torch. In the second approach, to overcome the drawbacks of current sample introduction systems, dielectrophoresis (DEP) effect, used for droplet manipulation, was studied experimentally and numerically. Also, a new heated sample introduction chamber was designed which enables efficient transportation and accelerated desolvation of droplets. Consequently, single-particle and cell analyses were successfully conducted by ICP-OES with the conical torch and the new chamber. Monodisperse SiO2 microparticles and three mammalian cells were detected individually. The new chamber was shown to offer better performance than the conventional spray chamber. The differences in calcium content in the three cell lines were revealed. Finally, drug treatment research was presented by single-cell analysis, for which the impact of Yoda1, which acts as an agonist of the Piezo1 calcium channel, on the MLO-Y4 cells was investigated. The results shown that the treatment of Yoda1 increases calcium concentration in MLO-Y4 cells. These investigations proved that the conical torch and the new chamber are capable of serving the single-particle/cell analysis.
Development of a Novel Assay to Quantify Inflammation for Investigating Mitochondrial Health and White Matter Integrity in Mood Disorders
(2022-11) Zhou, Xinyang Young; Andreazza, Ana C; Pharmacology
Progress in understanding the pathophysiology of mood disorders has been limited because current criteria for psychiatric diagnoses are based on self-reported information or behavioral observation and lack substantial biological validation. As a result, there is a pressing need to identify novel biological targets reflecting underlying pathophysiological processes for the majority of psychiatric disorders. Several psychiatric illnesses exhibit mitochondrial dysfunction, elevated inflammation, and impaired white matter integrity. The NLR family pyrin domain containing 3 (NLRP3) inflammasome is a multiprotein complex which integrates mitochondrial stress and triggers inflammatory responses. This thesis outlines the development of a novel assay to measure NLRP3 inflammasome activation, which is used to explore the intersection of mitochondrial health, NLRP3 inflammasome activation, and white matter integrity in a cohort of 29 adolescent patients with mood disorders and 19 healthy controls, as well as a cohort of 90 diabetic patients, 19 of which had a history of major depressive disorder (MDD). Adolescents with mood disorders showed lower fractional anisotropy of the ventral cingulum bundle than healthy controls, and a significant relationship was demonstrated between mitochondrial electron transport chain gene expression as a predictor of NLRP3 inflammasome gene expression and activation. Furthermore, a predictive relationship exists between circulating cell free mitochondrial DNA and white matter integrity in the anterior thalamic radiation. Exploratory analyses revealed a nuanced distinction in early mood disorder pathophysiology for bipolar patients who exhibit lower levels of mitochondrial gene expression and volume, along with increased sensitivity to NLRP3 inflammasome activation compared to depression patients. Patients with type 2 diabetes mellitus (T2DM) and MDD had a higher proportion of patients in the upper quantiles of NLRP3 inflammasome activation compared to those with T2DM or prediabetes, suggesting an additive effect of T2DM and MDD in mood disorder patients with metabolic disease co-morbidity. Overall, results show meaningful relationships between peripherally measured endpoints of mitochondrial health and NLRP3 inflammasome activation, and centrally measured endpoints of white matter integrity, which may guide specific therapeutic strategy in mood disorders.
ʿAzīz-i Nasafī (fl. 7th/13th c.), Hierarchies, and Islamic Cosmopolitanism
(2022-11) Mansouri, Mohammad Amin; Virani, Shafique N.; Religion, Study of
ʿAzīz-i Nasafī (fl. 7th/13th century) was one of the greatest Muslim thinkers and mystics. One of his most-read works, Maqṣad al-aqṣā (The Farthest Aim), testifies to his wide reception. It found readership not just across the Muslim world but also well into Europe. From the east to the west, in the Muslim world and beyond, Nasafī left an undisputable imprint and appealed to generations of thinkers. While Nasafī’s works are generally understudied, those who have attempted to voyage through his works have often reduced him to a popular writer whose accessible style served as a vehicle for transmitting the ideas of Ibn al-ʿArabī (d. 638/1240), the great master of Islamic thought.My dissertation aims to rectify this trend, arguing that Nasafī was a cosmopolitan thinker since he drew on multiple sources and traditions that an average reader may deem remotely related. To demonstrate Nasafī’s cosmopolitanism, the dissertation focuses on the topic of spiritual and cosmological hierarchy, which connects different chapters together. Throughout the dissertation, I place Nasafī’s works in conversation with sources such as those found Shiʿi Ismāʿīlī tradition, ancient Persian mythology, Islamicate occult sciences such as astrology and the science of letters or lettrism, classical Sufism, as well as the writings of his contemporaries like Ibn al-ʿArabī and Saʿd al-Dīn Ḥammuya (d. 650/1260). Nasafī witnessed some of the most catastrophic events, such as the fall of the ʿAbbāsids (656/1258) and the invasions of the Mongols. He saw the fragmentation of the Muslim world, and it was precisely in this environment that he produced his work. I argue that Nasafī aimed to unify the fragmented Muslim world by developing a cosmopolitan intellectual spirit, which allowed him, impressively, to incorporate and reconcile various intellectual strands in his work. He indeed aimed to bring all these fragments of thought into peace (ṣulḥ), and sought to usher the Muslim world into a period of intellectual peace. Nasafī’s cosmopolitan spirit in peacefully living with other intellectual traditions and receiving inspiration from them is at the centre of Nasafī’s intellectual ethos and helps us gain insight into the vibrant and cosmopolitan intellectual climate of post-classical Islam during the Persianate Mongol period.
INTERFACING ARTIFICIAL INTELLIGENCE AND MULTIMODAL BRAIN IMAGING: A NOVEL METHODOLOGY FOR INVESTIGATING TRIGEMINAL NEURALGIA
(2024-11) Latypov, Timur H.; Hodaie, Mojgan; Medical Science
Chronic pain, a critical condition for global health, affects millions and imposes significant economic and social burdens. Despite advancements in neuroimaging, the correlation between central nervous system (CNS) changes and the behavioral and functional consequences of chronic pain remains inadequately understood. This thesis aims to bridge this gap, focusing on Trigeminal Neuralgia (TN), a debilitating form of chronic neuropathic pain. By interfacing artificial intelligence (AI) with magnetic resonance imaging (MRI) and clinical data, this research seeks to unravel the complex CNS changes associated with TN and predict treatment outcomes, enhancing our understanding and management of TN and chronic painin general. In Study 1, machine learning algorithms, combined with gray matter metrics from T1-weighted MR imaging and white matter metrics from Diffusion Tensor Imaging (DTI), were employed to distinguish Classical Trigeminal Neuralgia and Trigeminal Neuropathic Pain from healthy controls. This approach achieved high accuracy, demonstrating the efficacy of AI in derivingimaging signatures of TN pain. Study 2 focused on developing a stratification schema for Classical Trigeminal Neuralgia surgical outcomes using clinical and imaging data processed through machine learning algorithms. This approach allowed us to accurately predict surgical outcomes based on pre-surgical data, suggesting a potential tool for personalized treatment strategies. Study 3 specifically addressed Trigeminal Neuralgia secondary to Multiple Sclerosis (MSTN). By analyzing imaging data from MSTN patients and comparing it with pain-free Multiple Sclerosis subjects, distinct MR imaging signatures of pain were identified, enabling the accurate distinction between the pain-afflicted and pain-free MS cohorts. In summary, this thesis represents a pioneering convergence of neuroimaging and AI in the field of chronic trigeminal pain. Our findings illuminate the intricate CNS abnormalities linked to the experiences of individuals with TN. This research contributes significantly to a more nuanced understanding of chronic pain and its management using TN as a model condition.
Understanding the Perspectives of Black Fathers Engaged in Child Welfare Services: Using the Ecological Framework
(2020-11) Ramjattan, Roxanne; Fang, Dr. Lin; Fallon, Dr. Barbara; Social Work
Black children often reside in fatherless homes and are overrepresented in CWS. International scholars acknowledge the importance of positive father involvement on child outcomes and family functioning as well as recognize fathers’ underrepresentation in child welfare services (CWS). Consequently, it is imperative to encourage positive father engagement among Black fathers in CWS to mitigate the risks associated with child maltreatment and improve the outcomes of Black children and families. Unfortunately, there is a dearth of literature on fathers in CWS, particularly among Black fathers, and a paucity of qualitative research to understand the perspectives of service utilization from these men. The purpose of this dissertation research is to explore the lived experiences of Black fathers in CWS to better understand the barriers to and facilitators of their engagement in these services. Methods This qualitative research study adopted a constructivist grounded theory methodology with requires rigorous data collection and analysis techniques to best understand the unique perspectives of Black fathers engaged in CWS. Eighteen self-identify Black biological fathers from the Greater Toronto Area who received CWS in the last 3 years participated in semi-structured interviews. Results The study revealed that fathers who faced financial hardship, legal involvement, mental health challenges, abandonment, maternal gatekeeping, custody and access disputes, as well as incidents of domestic violence struggled to engage in CWS. At the organizational level, fathers who felt devalued or experienced gender bias, systemic racism, and a poor working relationship with their case workers often contemplated disengagement. With regards to the facilitators of engagement, fathers who felt securely attached to their children, held employment, and had connections with other fathers engaged in CWS were more likely to continue service utilization at the time of the study despite the barriers faced. Furthermore, fathers who felt valued by their caseworkers and who reported gender inclusivity in service delivery were more likely to be resilient and remained engaged. The findings from this research will grant child welfare agencies and affiliated community service partners new knowledge which may aid in the development of effective policies and practices to better engage fathers, especially Black fathers, in services.
Site-specific Human CFTR Gene Integration through CRISPR/Cas9-mediated Targeting
(2020-11) Zhou, Zhichang; Hu, Jim; Laboratory Medicine and Pathobiology
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene coding for cystic fibrosis transmembrane conductance regulator (CFTR). It leads to multiple organ dysfunctions, where lung disease is the major cause of morbidity and mortality. Gene therapy for CF lung disease is still challenged with achieving sustained and sufficient therapeutic transgene expression. The advancement of site-specific endonuclease, CRISPR/Cas9, sheds light on permanent CFTR gene correction. We proposed a novel strategy that can precisely integrate therapeutic human CFTR (hCFTR) gene into genomic safe harbor through Cas9-induced homology directed repair (HDR), via an all-in-one helper-dependent adenoviral (HD-Ad) vector delivery. This strategy can target CFTR mutations regardless of mutation types. We have demonstrated a 10% integration efficiency in porcine CFTR-/- cells. The integrated hCFTR gene is sustainably and functionally expressed in cells. By co-delivering another HD-Ad vector to express HDR factor, Exo1 or CtIP, transgene integration efficiency is further enhanced by an average of 2-fold. We have also proven that the airway basal stem cells can be targeted by our hCFTR gene editing system in vitro. Moreover, functional hCFTR is expressed in primary CFTR-/- porcine airway epithelial cells. Overall, this study demonstrates that our HD-Ad vector-based hCFTR gene targeting system has the potential to be adapted for treating CF lung disease.
Point of Vulnerability or Window of Opportunity? Toward a New View of Women’s Sexual Debut
(2022-11) Peragine, Diana E.; VanderLaan, Doug P; Psychology
Research and guidance on the transition to intercourse has focused more on its timing than on its quality, and on avoiding sexual health risk more than fostering healthy sex. Yet, gender differences in the quality of first intercourse are among the largest in sexuality research, with women recalling less pleasurable and satisfying “sexual debuts” than men. Drawing on experiential and ecological theories of sexuality, the current research examines the origins and impact of this “enjoyment gap,” challenging widely held views about women’s sexual debuts. First, that women’s less rewarding sexual debuts are a product of gender differences in sexuality rather than a precursor to them. Second, that the quality of women’s sexual debuts is neither a pressing nor promising target for sexual health interventions. Third, that the healthiest sexual debut for girls is no sexual debut. To test these assumptions, I revisited the gender gap in sexual desire, the enjoyment gap at sexual debut, and the meaning of sexual debut in three cross-sectional retrospective studies. Study 1 replicated gender differences in sexual desire; however, it found they were contingent on experience and measurement method. When dyadic and solitary desires were parsed, findings supported an experiential gap rather than a gender gap in sexual desire, with women’s diverging from men’s only when enjoyment was lacking at sexual debut. Study 2 replicated gender differences in enjoyment at this event; however, it found they were restricted to heterosexual debuts. When actor gender and partner gender were disentangled, findings suggested a gender gap in enjoyment at solitary sexual debut, but a partner gender gap at dyadic sexual debut—and one driven by inequitable circumstances when women debuted with men. Consequently, Study 3 revisited the meaning of sexual debut, finding that an earlier sexual debut may confer more benefits than risks to sexual health when experiences that are less gendered than first intercourse, and more enjoyable for women, are considered. Collectively, findings suggest that sexual debut is not just a point of vulnerability for women, but a window of opportunity for learning to have healthy sex—and one at which equal opportunity is often lacking.
Healthcare Workers and Decision-Makers’ Understanding of Liberty, Harm, and the Harm Principle in the Case of Tuberculosis in Persons with Severe and Persistent Mental Illnesses
(2012) Silva, Diego ; Upshur, Ross; Dalla Lana School of Public Health
Background: The harm principle, which generally states that individuals are free to act so long as they do not harm other non-consenting persons, is commonly invoked to help determine the boundaries between an individual’s liberty and the public good in public health and mental health. The case of tuberculosis (TB) in persons with severe and persistent mental illnesses (SPMI) provides the opportunity to evaluate the application of the harm principle in a real-world context. TB in persons with SPMI is an ideal case study because (a) the treatment of TB and SPMI are two examples where liberty restrictions are often justified by appealing to the harm principle and (b) the goal of arresting the spread of TB (e.g. through isolation) may conflict with the goals of mental health (e.g. reducing social isolation). However, it is unknown how healthcare workers in public health and mental health understand the notion of liberty and harm, and moreover, whether their views resonate with philosophical literature. Methods: A mixed methods study that includes interviews and an online survey with healthcare workers and decision-makers in public health units and mental health centres in Toronto, Canada. Twenty interviews were conducted and analyzed via thematic analysis. An online survey, where items were generated by reference to philosophical interpretations of the harm principle (including JS Mill, Joel Feinberg, Joseph Raz, and Immaunel Kant), was distributed and analyzed via factor analysis and t-tests. The response rate was 41.5% (n=91). Results: Six themes emerged from the interviews, including accounting for the context surrounding liberty restrictions and the importance of supporting persons who have their liberty restricted for the greater public good. The survey findings suggest statistically significant difference between TB workers and mental health workers regarding the importance of directly observed therapy (DOT) and conceptions of risk. Conclusion: The findings provide an understanding of how notions of liberty and harm are understood by public health and mental health workers. The participants demonstrated nuanced moral reasoning that can enrich and provide real-world context to the existing ethics literature on the topic of the harm principle and liberty restrictions.
Sacred Trauma: Religion, Trauma Transmission, and the Attribution of Meaning in the Age of Totalitarianism
(2019-11) Sochaczewski, Janina; Hewitt, Marsha; Religion, Study of
This thesis explores the relationship between religion, cultural trauma, and the psychodynamics of human evil and suffering. Its principal contribution is the development of an explanatory model of trauma transmission whereby religion constitutes an important “carrier” of trauma across generations, even in instances where it may also serve as a protective factor. It does so primarily by exploring how the language, thought, and traumas of totalitarianism become encoded in myths, cultural practices, religious rituals, and shared histories. This study begins by examining contemporary definitions of trauma, as well as the modes and mechanisms of trauma transmission proposed in scholarly literature. Chapter One describes the challenges that arise in defining, identifying, and working with traumatic material. Chapter Two critically engages with postwar Polish history and intellectual thought (1945-1989) in order to illustrate how the complex interaction between religion and collective trauma may result in generational conflict, enduring internal division, and an inability to mourn. In Chapter Three, I argue that the concepts of “trauma” and “evil” take on a overlapping meaning in the context of twentieth-century totalitarianism. The integration of discussions around “trauma” and “evil” allows for exploration of the centrality of interpersonal relations in the transmission of trauma and the problems associated with conferring a “sacred” status to trauma narratives and myths, discussed in Chapter Four. Chapter Five critiques attempts to confine the understanding of trauma to the affective sphere of the individual, which minimize the ways in which experiences of trauma are often rooted in interpersonal evil and systemic injustice. The final chapter examines the possibility, necessity, and ethical implications of reconciliation and forgiveness following mass trauma.
Tailoring PA6 Properties with In-Situ Generated Nanofibrils
(2024-11) Mahmud, Mayesha Binte; Park, Chul B.; Lee, Patrick C.; Mechanical and Industrial Engineering
This thesis investigates the enhancement of polyamide 6 (PA6) properties through the incorporation of in-situ generated nanofibrils, focusing on mechanical performance, flame retardancy, and hydrophobicity. The research is divided into three main sections, each addressing a distinct challenge associated with PA6-based composites and proposing innovative solutions using in-situ nanofibrillation techniques.The first section explores the improvement of impact performance in PA6 composites by integrating polyphenylene sulfide (PPS) nanofibrils. The resulting composites exhibit an 85% increase in impact strength compared to neat PA6 without sacrificing its tensile properties. This enhancement is attributed to the formation of transcrystalline structures and smaller crystal sizes within the fibril network, which contribute to improved stress distribution and overall mechanical properties. The second section focuses on developing flame-retardant PA6 composites by incorporating a combination of PPS nanofibrils and ammonium sulfamate (AS). The resulting composite, containing 15 wt% PPS and 1 wt% AS, achieves a UL 94-V0 rating and a limiting oxygen index (LOI) of 33.8%. Rheological, micro-combustion calorimetry and char residue analyses indicate that the entangled PPS fibril network effectively suppresses flame propagation and dripping, leading to a 17% reduction in peak heat release rate (PHRR). This synergistic effect between PPS and AS demonstrates a promising approach to enhancing the flame-retardant performance of PA6 composites. The final section presents a unique method for fabricating hydrophobic PA6-based nonwoven mats. By utilizing a ternary blend system of polypropylene (PP), PA6, and polyvinylidene fluoride (PVDF) with in-situ fibrillation, the study achieves a micro-nano hierarchical structure that significantly enhances hydrophobicity. The optimized mats exhibit an impressive oil-water separation efficiency of up to 97.4%, demonstrating their potential for applications in industries requiring water repellency and efficient oil-water separation. Overall, this research provides comprehensive insights into the material design and enhancement of PA6 composites, addressing specific performance challenges such as impact resistance, flame retardancy, and hydrophobicity. The findings contribute to a deeper understanding of process-structure-property relationships in advanced composite materials, offering practical solutions for broadening the application scope of PA6 in engineering and environmental sectors.
DEVELOPMENT OF RUBBERY NANOFIBRIL FOR TOUGHENING ENHANCEMENT OF STYRENE-ACRYLONITRILE (SAN) AND POLYLACTIC ACID (PLA)
(2024-11) Monfared, Ali Reza; Park, Chul; Lee, Patrick; Mechanical and Industrial Engineering
This thesis introduces innovative toughening techniques for brittle polymers such as styrene-acrylonitrile (SAN) and polylactic acid (PLA), aimed at enhancing mechanical properties while emphasizing environmental sustainability. A novel in situ fibrillation method was utilized for SAN, integrating thermoplastic polyurethane (TPU) nanofibers within the matrix through silane grafting onto TPU, forming nanofibrils sized 90 to 360 nm, followed by post-crosslinking. This technique significantly enhances tensile toughness by up to 350% with just 1 wt% nanofibril TPU, thereby reducing the reliance on higher rubber contents and preserving SAN's stiffness.Nanofibril TPU proves to be an efficient toughening agent, outperforming traditional agents like butadiene rubber (BR). Introducing 0.6 wt% nanofibril TPU alongside 20 wt% BR amplifies tensile toughness and elongation at break by 239% and 218%, respectively, compared to 20 wt% BR alone. Against pure SAN, these increases reach 1040% and 1220%, respectively. The thesis also explores innovative toughening strategies for PLA to reduce dependence on petroleum-based polymers. Two crosslinking methods are investigated: silane/moisture crosslinking and a tailored diisocyanate method that optimally balances chain extension and crosslinking. The latter method notably increases PLA's tensile toughness to 30-60 MPa and impact strength to 60-140 J/m, facilitating a brittle-to-ductile transition with only 3 wt% nanofibril TPU, while maintaining PLA’s high modulus, crystallinity, and transparency. Additionally, this research explores the synergistic effects of TPU nanofibrils and cellulose nanocrystals (CNC) on PLA composites. Incorporating just 3 wt% TPU and 0.3 wt% CNC substantially enhances PLA's mechanical properties, crystallization kinetics, and barrier capabilities, while maintaining transparency. Isothermal crystallization studies show CNC's efficacy in accelerating PLA crystallization, reducing crystallization half-time to less than a minute at 100°C and significantly lowering oxygen transmission rates. This formulation yields composites with remarkable improvements in tensile strain—up to 3,900 times that of neat PLA—while maintaining tensile strength and Young’s modulus. Overall, this research underscores the potential of TPU and CNC to significantly enhance the performance of PLA composites, offering a viable and sustainable alternative to conventional plastics. The advanced techniques developed in this thesis are poised to broaden the application horizons of bioplastics to high-value uses, promoting sustainable manufacturing practices.
Fluid-Structure Interaction Modelling of High-Frequency Wall Vibrations in Intracranial Aneurysms
(2024-11) Bruneau, David Andrew; Steinman, David A; Mechanical and Industrial Engineering
An intracranial aneurysm is an abnormal outpouching of a blood vessel inside the skull, present in over 3% ofpeople. While aneurysm rupture is deadly, many do not rupture, and therefore there is a clinical need for predictors of growth or rupture for unruptured aneurysms discovered incidentally. Since the, 1960s, intracranial aneurysms have been known to produce sounds due to underlying vibrations, however, the mechanism driving the vibrations has been debated, with proposed mechanisms ranging from self-excitation by stable pulsatile flow, to vibration caused by laminar vortex-shedding or turbulent-like flow. This thesis uses recent advances in fluid-structure interaction (FSI) modelling to simulate aneurysm vibrations and reveal the underlying mechanics. Under a slowly increasing, steady inflow, we induced flow phenotypes ranging from stable flow, to harmonic vortex shedding, to turbulent-like flow, in two aneurysm geometries. Both vortex-shedding and turbulent-like flows induced vibrations at specific narrow-band frequencies (100 – 500 Hz) that corresponded with structural mode shapes. We then incorporated pulsatile flow and found that stable pulsatile flow did not induce vibrations, while underlying flow instabilities transmitted through the wall as broad-band, random vibrations (consistent with previously-described bruits), and the sac also exhibited distinct narrow-band vibrations at specific structural modes, which extended into diastole (consistent with previous clinical recordings of musical murmurs). Finally, we showed how aneurysm vibrations could be estimated by un-coupled computational fluid dynamics (CFD) and modal analysis. The modal frequencies observed in aneurysm FSI were predicted accurately by modal analysis, while CFD reasonably predicted the underlying flow instability. Furthermore, the bruit vibration amplitude could be estimated by a linear relationship with the amplitude of flow instability, while the amplitude of the first mode was estimated by a squared relationship with the amplitude of flow instability, combined with the concentration of flow instability at the modal frequency. Our results provide a plausible explanation for distinct intracranial aneurysm sounds, and a pathway towards estimating the likelihood of an individual aneurysm vibrating. Our enriched understanding of the deformation patterns and amplitudes of vibrating aneurysms can inform future mechanobiological experiments to quantify the role of vibrations in aneurysm growth and remodelling.
Investigating the Relationship Between Chromatin Architecture and Cis-Regulation in the Sox2 and Lefty Loci
(2024-11) Taylor, Tiegh; Mitchell, Jennifer A; Cell and Systems Biology
Gene expression relies on a complex interplay between regulatory elements dispersed across the genome, and chromatin structure guiding functional interactions. Precise spatiotemporal regulation of organism development and tissue patterning involves enhancer-gene interactions, yet mechanisms directing enhancers to their target genes are poorly understood. Enhancers influence gene expression by recruiting transcription factors and establishing long-range contacts with target genes. This targeting process involves an interplay between transcriptional regulatory complexes which are functionally directed or segregated by the action of architectural proteins such as CTCF and Cohesin. In my thesis, I investigate the regulatory interplay among chromatin architecture, genomic distance, and enhancer activity using CRISPR-Cas9 mediated genomic deletions on two model loci. I used the Sox2 loci as a model to study the relationship between enhancer activity and its contact with a target gene. Sox2 is regulated by a cluster of enhancer elements which are located at a distance downstream from it; I systematically removed clusters of transcription factor bound regions to identify that the chromatin topology within this locus is decoupled from the activity of the enhancer and distributed across almost 40 kilobases of chromatin. Within the Lefty locus, the Lefty1 and Lefty2 genes are paralogs which directly interact with one another, but I have identified that they are regulated by separate enhancer elements. Systematic removal of elements between these two genes revealed that the regulatory elements driving gene expression within this locus are insulated from one another in a distributed manner by the genomic distance between the genes, even though they reside close together in the 3D nuclear space. Finally, to better assess the relationship between chromatin distance, architecture, and enhancer activity, I have used the Sox2 locus to develop a high-throughput assay to screen putative regulatory elements for their activity over a moderate genomic distance from the Sox2 gene. Using this system I have identified requirements within synthetically created enhancer sequences for their activity at a distance. Taken together my thesis has identified that enhancers are differentially affected by the chromatin landscape surrounding them, highlighting that there are yet unknown sequence determinants of enhancer-gene targeting encoded within the genome.
Machine Learning Perspectives in Compression, Distributed Computing, and Brain Imaging
(2024-11) Ebrahimi, MohammadReza; Khisti, Ashish; Electrical and Computer Engineering
This thesis explores three critical dimensions in machine learning: modeling, training, and theory. Each dimension, represented by studies in brain imaging, distributed computing, and compression, addresses unique challenges with the goal of advancing machine learning methodologies and applications. First, within the domain of data modeling, we introduce Shared Gaussian Process Factor Analysis (S-GPFA), a novel probabilistic model for analyzing multi-subject fMRI datasets. S-GPFA addresses the challenge of modeling individual variability while uncovering shared temporal dynamics and spatial organization of brain activity. By incorporating Gaussian Process priors and emphasizing the temporal dimension of data, S-GPFA offers a more accurate and interpretable representation of brain activity compared to traditional static methods. The application of S-GPFA to a large fMRI dataset demonstrates its ability to identify group-specific dynamical characteristics and brain regions with meaningful functional variability, providing valuable insights into socioemotional cognitive capacity and potential avenues for studying psychiatric disorders. Second, focusing on the training aspect, we address the problem of straggler mitigation in distributed training of machine learning models. We present two innovative coding schemes, Selective Reattempt Sequential Gradient Coding (SR-SGC) and Multiplexed Sequential Gradient Coding (M-SGC), that leverage coding across both the spatial and temporal dimensions to achieve straggler resilience while reducing computational load. These schemes exploit the temporal diversity of straggler behavior, adapting to varying worker speeds and minimizing delays. Experiments on a large-scale AWS Lambda cluster demonstrate the effectiveness of the proposed schemes in reducing runtime and improving training performance under real-world conditions. Third, from a theoretical perspective, we investigate the foundations of data coupling and compression through the lens of information theory. We introduce the Minimum Entropy Coupling with Bottleneck (MEC-B) framework for lossy compression under logarithmic loss. This framework extends the classical Minimum Entropy Coupling (MEC) by incorporating rate limits, enabling a more controlled and flexible approach to compression. We explore the Entropy-Bounded Information Maximization (EBIM) formulation for compression and propose a novel search algorithm for identifying deterministic mappings with guaranteed performance bounds. Additionally, we characterize the optimal solution in the neighbourhood of deterministic mappings, providing valuable theoretical insights into the problem structure. Through these studies, this thesis contributes to machine learning methodologies and applications across diverse domains, ranging from brain imaging and distributed computing to information theory and data compression.
The Anonymous God: Critical Psychoanalytic Inquiries into Social Domination
(2024-11) Pascoe, Emily Jane; Hewitt, Marsha A.; Religion, Study of
In the early to mid-twentieth century, the leading Critical Theorists of the Frankfurt Institute for Social Research turned to a psychoanalytic study of the authoritarian subject to better understand the rise of fascism. In this dissertation, I focus on Critical Theory’s integration of Freudian psychoanalysis to explain the appeal of dangerous and irrational authorities and modern trends of domination. Throughout this genealogy of anti-authoritarian thought, I pay special interest to the unconscious psychodynamics that characterize reactionary deference to impersonal authorities, that is, modern, techno-bureaucratic authorities that have become so abstract and hyper-reified, they begin to resemble what Max Horkheimer termed an “anonymous god.” The authoritarian experiences themselves as more powerless, impotent, and victimized than anyone else, subjected to an infinitely more powerful entity that hobbles their capacity for self-determination. The anonymous god, as I use it here, refers to a variety of psychological demands and social pressures that come to assume the mystique of ersatz-divinity within the authoritarian imagination. From Critical Theory’s investigation into the patriarchal imago of the fascist super-father to their analysis of the increasingly impersonal regimentation of everyday life, I trace the intellectual history of the authoritarian character and use interpretive inquiry to establish theoretical linkages unrealized in the concept’s development. I explore further the authoritarian’s relationship with the anonymous god, the role of aggression and libidinal attachment in unconscious collusion, and the archaic imago that Critical Theory failed to excavate by limiting their analysis to a critique of the father. I call into question the inevitability of social domination by challenging top-down explanations for submission and command, including claims of supernatural immutability as they are tied to the unseen. In my conclusion, I suggest that the anonymous god operates as an alibi, jettisoning human agency and denying responsibility by appealing to an unalterable social order before which the adherent can only submit.
Full-waveform seismic tomography using earthquake and ambient noise data: with application to the Alaskan lithosphere
(2024-11) Liu, Tianshi; Liu, Qinya; Earth Sciences
Utilizing seismic waves propagating in the subsurface, seismic tomography is one of the most important methods to image the Earth's interior. Benefiting from the use of numerical simulations as forward operators, full-waveform-based seismic tomography is able to account for the 3-D complex geometries and heterogeneities of the Earth, and image the subsurface with high resolutions and high fidelity. Despite its success in tomographic studies over the past two decades, efforts are still needed to improve the efficiency and accuracy of the full-waveform seismic tomography workflow, and adapt full-waveform seismic tomography to imaging tasks at various scales and of different datasets. This thesis aims to address three key challenges in full-waveform seismic tomography, namely efficient continental-scale seismic wave simulation, joint inversion of ambient noise and earthquake data, and accurate and flexible implementation of wavefield injection for scattering imaging of teleseismic waves. A method is first developed to enable flexible and accurate seismic wave simulations with perfectly matched layers (PML) at continental scales (10-60 degrees), and a series of numerical examples are provided to validate its effectiveness. A workflow is then established to jointly invert ambient noise and local earthquake data, which, in combination with the method developed for continental-scale wave simulations, is applied to imaging the Alaskan lithosphere using recently available seismic datasets in Alaska. The obtained images provide new insights into several key questions regarding the tectonic evolution of Alaska. Finally, a new formulation for the wavefield injection problem is derived as a special case of interface discontinuity problem which not only allows for an accurate and flexible implementation of wavefield injection, but also ties together various published implementations of wavefield injection. Numerical examples demonstrate that the proposed implementation of wavefield injection is useful for modeling interactions between incoming waves and local structures at various scales, and inverting scattered waves based on full-waveform seismic tomography.
microRNA-133a as an Indicator of Disease Progression and Treatment Response in a Mouse Model of X-linked Myotubular Myopathy
(2024-11) Maani, Nika; Dowling, James J; Molecular Genetics
X-linked Myotubular myopathy (XLMTM) is a rare pediatric neuromuscular disease caused by loss-of-function variants in myotubularin (MTM1). XLMTM is associated with severe disabilities and early death and is at present, without effective therapy. As interventional clinical trials for XLMTM gather momentum, the discovery of robust biomarkers that reflect disease severity and therapeutic efficacy is critically required. Using high-throughput and directed approaches, I identified a decrease in miR-133a expression as a marker of XLMTM disease in skeletal muscle and plasma of a mouse model of XLMTM (Mtm1 KO). miR-133a is a muscle-enriched non-coding RNA that is involved in muscle development and has emerged as a treatment-effect biomarker and therapeutic candidate in other neuromuscular disorders. miR-133a is also a demonstrated negative regulator of DNM2, holding significant pathomechanistic and therapeutic implications for XLMTM. I show that miR-133a expression significantly and positively correlates with myofiber size and disease severity in Mtm1 KO mice and is upregulated in response to treatments that rescue XLMTM. Using predictive modelling, I show that miR-133a expression demonstrates a powerful therapeutic response and is a robust classifier for XLMTM with a classification accuracy of 70-90% by linear discriminant analysis in both treated and untreated conditions. Receiver operating characteristic (ROC) curve analysis further demonstrated that miR-133a has high discrimination accuracy for XLMTM (AUC >0.80). Moving beyond correlation to test causation, I show that miR-133a overexpression in Mtm1 KO mice using an AAV9-based construct significantly improves survival, myofiber size, muscle strength and modulates overall body composition in XLMTM. In this work, I identify the first small RNA based non-invasive biomarker for XLMTM that reflects both disease severity and treatment response. I also introduce a novel treatment strategy for XLMTM with excellent potential for clinical translation. This work results in completely new knowledge of disease pathogenesis and sets the stage for future biomarker validation and treatment development for XLMTM at a time of great clinical need.
Child sex trafficking identification and response in Ontario pediatric emergency departments: An intersectional mixed methods study
(2024-11) Balasa, Rebecca; Perez-Brumer, Amaya; Dalla Lana School of Public Health
Background: Children in Ontario are disproportionately recruited into sex trafficking when compared to other Canadian provinces, and many of those affected access hospital emergency departments for related concerns. Yet, emergency department healthcare providers continue to self-report limited ability to identify and respond to child sex trafficking. Attending to this gap, this dissertation explores child sex trafficking identification and response practices in Ontario pediatric emergency departments. Methods: Guided by intersectionality, an exploratory sequential mixed methods study was conducted between March to October 2023. Twelve in-depth interviews were conducted with pediatric emergency department healthcare providers to examine child sex trafficking identification and response strategies currently enacted in Ontario. Interviews were analyzed using a reflexive thematic analytic approach. Subsequently, a three-round modified Delphi method was conducted with a professionally diverse sample of experts to inform consensus-based practices related to child sex trafficking identification and response. Descriptive and Kappa statistics were calculated for closed-ended survey responses. Content analysis was used to analyze write-in responses. Results: Across 12 interviews, healthcare providers reported having predominantly identified child sex trafficking among white, feminine presenting youth. Providers used trauma- and violence-informed principles to guide their intervention practices. Findings informed the modified Delphi method survey, which was completed by 58 experts in the field of child sex trafficking. Across phases, participants acknowledged the disproportionate representation of marginalized groups in known cases of child sex trafficking; however, Delphi method experts endorsed child sex trafficking identification practices that assess for children’s social environments and behaviours rather than solely considering their intersecting sociodemographic characteristics. Experts endorsed providing patient education on safer sexual health practices and engagement with online platforms. Across study phases, participants underscored the need for integrated rather than siloed service provision including referral submissions to in-hospital and community services. Conclusion: Findings underscored the complexity of child sex trafficking across numerous axes of inequality including poverty, misogyny, and racism. These inequalities uniquely intersected for children along the lifecourse, necessitating a network of services extending beyond the emergency department. Integrated and collaborative services are therefore needed across hospital and community organizations to effectively fulfill the complex and diverse needs of children exposed to sex trafficking.
Clara Faisst - The Woman and her Songs
(2024-11) Becqué, Helen; Philcox, Steven; Music
In the realm of lieder compositions, the name “Clara Faisst” evokes, for most, a reaction of puzzlement. This forgotten German composer has slowly been making her way back into the spotlight; while she has yet to experience a Renaissance of performances and recordings, a rather recent re-discovery of her music at the end of the 20th century has given Faisst recognition, and a place among song composers which she deserves. This re-discovery occurred in 1993, when a linen folder, containing autographs, pictures, programmes and more, was saved from a waste pile and sold to the Badische Landesbibliothek. Thus began the start of a slow reconstruction process of Clara Faisst’s life, a process which remains challenging today mainly due to the fact that much of Karlsruhe was destroyed during the Second World War, and along with it, precious documents, letters, and scores. Faisst’s compositional voice was firmly rooted in the Romanticism of the 19th century. She wrote mainly in small-scale genres but with more than 100 Lieder compositions and several chamber music works, Faisst was a highly prolific and well-known composer in Karlsruhe at the turn of the 20th century. Most significantly, it was her song compositions which made her famous outside of Karlsruhe. Part 1 of this dissertation provides a biographical context of Clara Faisst, including an overview of her early life and musical education, her friendships, and her work as a composer and poet. Part 2 introduces the Lieder of Clara Faisst, giving focus to her published opuses. Even in her first works for voice and piano, written during her studies at the Conservatory in Berlin, one sees a remarkable and profound sensitivity to this genre, and a total internalization of all the best impulses of Schubert, Schumann, and Brahms. The published songs have been organized into three categories (songs before WWI, songs during WWI, and songs following WWI), and thus show the growth of Faisst as a composer during these important years.
Narrow-Bandgap Perovskites: Optoelectronic Properties and Applications in All-Perovskite Multi-Junction Photovoltaics
(2024-11) Maxwell, Aidan Thomas; Sargent, Edward; Materials Science and Engineering
Meeting global energy demand while simultaneously reducing carbon emissions will require a significant increase in renewable energy capacity; solar photovoltaics (PV) account for the majority of projected renewable capacity additions worldwide. Lower-cost and more efficient alternatives to conventional Si PV are being explored as a means of reaching PV growth targets. Halide perovskite solar cells (PSCs) have reached and recently even slightly surpassed the efficiencies of conventional semiconducting materials, owing to solution processability, low cost and defect tolerance. Further, perovskite-based multi-junction solar cells promise theoretical efficiencies far greater than that of single-junction solar cells. Unfortunately, since the narrow-bandgap subcells within multi-junction devices necessitate a reduction in bandgap achieved via partial substitution of Pb with Sn, this introduces additional challenges associated with Sn oxidation and defect formation. In this thesis I study the optoelectronic properties of mixed Pb-Sn perovskites, as well as strategies to improve the performance and operating lifetime of all-perovskite multijunction photovoltaics. I begin by studying bulk and interface defects in Pb-Sn perovskites, examining their compositionally-dependent effects on perovskite optoelectronic quality as well as their formation and evolution under various environmental stressors. I find a defect-tolerant compositional space in Pb-Sn perovskites, and lever insights into dynamic defect behavior towards targeted defect passivation. This results in an improvement in single-junction Pb-Sn PSC solar power conversion efficiency (PCE) from 18.4% to 21.6%. Next, I pursue the integration of narrow-bandgap Pb-Sn perovskite active layers in tandem and triple-junction photovoltaics. I present advances in the interlayer structure through procedural optimization, as well as insights into optimal layer thicknesses for subcell current-matching in the 2-terminal configuration using a combination of optical transfer matrix modelling and experimental measurements. The result is record-voltage all-perovskite tandems achieving a certified PCE of 26.3%, as well as record-performance all-perovskite triple-junction solar cells with a PCE of 25.1% (23.9% certified). Finally, I characterize energetic losses at each interface within the narrow-bandgap subcell, developing a surface passivation treatment using long-chain carboxylic acid compounds to specifically target the perovskite/electron transport layer interface. The result is a significant reduction in interface recombination, leading to a PCE of 23.0% for single-junction Pb-Sn PSCs with a record-low open-circuit voltage deficit. This strategy is then applied in all-perovskite tandem solar cells, leading to a record open-circuit voltage of 2.21 V and efficiency of > 27%, surpassing the record performance of conventional Si solar cells (26.8%). By investigating the optoelectronic properties and defect management of narrow-bandgap perovskites, I demonstrate significant improvements in solar PCE of single- and multi-junction perovskite solar cells. These advances represent an important step towards the integration of low cost, high efficiency next generation solar materials in the quest to sustainably meet global energy demands.

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