VictorJuiz/thesis huggingface dataset:
Pustaka Pūjā: A Study of Sūtra Worship in Mahāyāna Buddhism

This study deals with the questions of why Mahāyāna texts advocate book worship, what forms of worship they advocate, and what their worship was like historically and in the present day. In answering these questions, it first employs a textual study of Mahāyāna Buddhist, non-Mahāyāna Buddhist, and Brahmanical textual references to book worship or the agency of speech. Secondly, it engages with contemporary Newar Buddhist texts and practices related to Buddhist book wor-ship in the Kathmandu Valley of Nepal. The methodological approach of this study is based in the fields of the study of orality, paratexts, materiality, and book history. Going beyond the bounds of the disciplinary silos of Buddhist studies and South Asian studies, it shows how a trans-sectarian understanding of agency and orality is necessary to explain trends in the development of Buddhist and Brahmanical manuscript culture and worship. On that basis, this study suggests that while South Asian religions view divine speech as imbued with ritual agency, Mahāyāna Buddhist book worship used the same logic with the physical book in advocating their worship. Furthermore, while not renouncing orality, Mahāyāna Buddhist literature hardwired self-referential prescriptions for their worship within the body of their texts to promote themselves in physical form in a way that freed it from reliance upon the system of oral transmission upon which the non-Mahāyāna nikāya and āgama literature relied. Tracing the form of that worship throughout the first millennium, this thesis shows how it became increasingly tantricised, resulting in the incorporation of the Mahāyāna sūtras within maṇḍalas. A continuity of ancient forms of book worship and recitation, as well as a continually evolving and adapting tradition, is explored in the case of Newar Buddhist book worship and recitation in the Kathmandu Valley of Nepal, revealing the continued effects of the agency of these books as texts, objects, and deities.

Keywords: Books
Buddhism
Mahayana
Nepal
Newar
Paratexts
Advisor: Emmrich, Christoph A
Molecular, Cellular and Circuit Mechanisms that Underlie a Two-pore Potassium Channel’s Regulation of Membrane Potential, Synaptic Activity and Locomotion

Two-pore potassium channels (K2Ps) establish the resting membrane potential (RMP) and regulate membrane excitability. Little is known about the physiological roles of K2Ps in the context of intact neural circuits and behaviors.I have identified and functionally characterized a C. elegans K2P, TWK-40. First, through molecular genetic studies, I discovered that the functional increase and decrease of TWK-40 activity drastically alter motor activities and motor patterns through a pair of descending premotor interneurons, AVA. Second, AVA is commonly thought to mainly govern only the backward motor state, antagonizing the forward state. But through the cell and genetic ablation, optogenetics, and calcium imaging, I discovered that AVA is not only critical for backward movement but also promotes forward movement by maintaining an unusually depolarized, ~ -22mV RMP through at least one K2P, TWK-40, and sodium leak channels. Third, I address circuit mechanisms through which AVA regulates the forward state. I discovered that both classic neurotransmitter and neuropeptide signaling from AVA contribute to its promotion of forward movement. In addition, AVB, another pair of premotor interneurons, is a necessary mediator of AVA’s role in the forward circuit. Lastly, AVA’s regulation of the forward state may involve other circuit components, such as the AS motor neurons. These findings offer new physiological insight into how K2Ps regulate RMP and synaptic activity. They shed light on how a professedly simple circuit drives complex motor behaviors.

Keywords: circuits
K2P
locomotion
premotor interneurons
TWK-40
Advisor: Zhen, Mei
Liquid Guanxi: Chinese Social Networks in an Age of Digitalization

The enabling and constraining properties of guanxi networking culture, its networking mechanisms, and network-level consequences in personal networks in modern China has been extensively studied in a large and growing literature since Fei Xiaotong’s celebrated From the Soil. Although guanxi continues to be the glue that lubricates transactions in China’s economic, labor market, military, political, scientific, and school systems in China, researchers of guanxi have overlooked the rise of social networking sites (SNSs) in everyday networking in China, which is now home to the largest and fastest population of SNS users worldwide and nearly universal adoption in everyday networking. This dissertation empirically investigates how the widespread uptake of SNSs is transforming the cultural and psychological principles of interpersonal networking in guanxi, Chinese networks. This dissertation argues that the digitalization of interactions on SNSs is rendering guanxi networks in China more liquid and theorizes the expressions of this liquidity across three networking mechanisms (tie-creation, tie-maintenance, and tie-activation) and two networking conditions (proximity and information openness) in guanxi. This dissertation consists of seven standalone papers that examine each of these facets. This dissertation theorizes the liquefying transformations to guanxi culture as refractions of a changing Chinese modernity based in the arrangements of a new social space emerging within SNSs: a digital agora, where public and private spheres come together in an intermediary space that marshals within the individual a compulsion and ability to be communal without abrogating the comforts of the private; a synergy essential to social survival in China. Among the first systematic studies to examine how SNSs fundamentally transform the ways that people in China think about and carry out their networking on an everyday level, this dissertation contributes to the study of guanxi, social networks, and Chinese modernity in general by articulating a sociological account of the changing nature of Chinese social relations in an age of digitalization.

Keywords: China
digitalization
social networks
Advisor: Liu, Sida SL
Grigoryeva, Angelina AG
Cell-Cell Adhesion Dynamics and Cortical Tensions in Embryonic Tissue Structure and Mechanics

The mechanics and dynamics of cell-cell adhesions are fundamental to morphogenesis, the shaping of tissues during development. Modern biophysical approaches model adhesion between cells with surface tensions that arise from cortical actomyosin contractility and adhesion molecule binding, similar to the adhesion of a water droplet to a surface. Collections of adherent cells form tissues, which are modeled as space-filling foams, where each constituent bubble is a cell with a tension along each cell-cell boundary. These tissues are permeated by interstitial networks (“gaps”) and during development can stretch, bend, and flow, resulting in cell rearrangements and changes in interstitial network structure. How cell-level cortical tensions contribute to the structure of gaps and the dynamics of tissues is still unclear. To further our understanding, I investigated how the preexisting surface tension model of cell-cell adhesion can explain the presence of gaps within tissues and if this model quantitatively predicts the behavior of newly forming cell-cell contacts. Through computational analysis in the first part of this work I found that the structure of gaps depends on the ratio of tension at cell-cell contacts relative to cell-gap interfaces, which was supported by accompanying experimental work done by Barua et al. (2017). In the second part of this work, I combined experimental, mathematical, and computational approaches to show that cortical tension from the actomyosin cortex alone is insufficient to explain the dynamic behavior of cell-cell adhesions, which can rapidly grow to a Ca2+-independent low adhesion state before more slowly proceeding in a logistic-like fashion to their Ca2+-dependent high adhesion state. To accommodate these empirical findings, I further develop our surface tension model to show that a combination of adhesion energy, cytoskeletal elasticity, and cytoskeleton network turnover can explain the observed adhesion dynamics. Therefore, cytoskeletal mechanics and dynamics are essential factors regulating cortical tensions, the relative values of which determine gap structure and contact growth, and thus tissue structure and dynamics.

Keywords: cell-cell adhesion
cortical tension
cytoskeleton
interstitial networks
modeling
Xenopus laevis
Advisor: Winklbauer, Rudolf
Bruce, Ashley E. E.
Development of CDK4/6 Inhibitor Resistant ER-positive HER2-negative Breast Cancer Cell Lines to Elucidate Novel Mechanisms of Resistance

Treatment with CDK4/6 inhibitors (CDK4/6i) in combination with hormone therapy is now the standard of care for patients with advanced or metastatic ER-positive/HER2-negative (ER+/HER2-) breast cancer. However, many patients experience disease progression due to intrinsic or acquired resistance. Predictive biomarkers to identify patients most likely to respond to initial therapy as well as therapeutic targets to overcome or delay onset of resistance, are needed to improve patient outcomes. To achieve these outcomes will require a better understanding of the molecular mechanisms responsible for CDK4/6i sensitivity and resistance. In this study, I established in-vitro models of acquired resistance to two CDK4/6i, palbociclib and abemaciclib, using MCF7 and T47D cell lines. Genomic, transcriptomic, and proteomic analyses were performed in parental cells and resistant derivatives. Strikingly, acquired resistance across all models was associated with an upregulated interferon (IFN) response as well as loss of ER/PR expression and signaling. Importantly, expression of an IFN-based gene signature (IFN-sig) derived from these models was also upregulated in early-stage breast tumours intrinsically resistant to CDK4/6i as well as to endocrine therapy, and thus warrants further clinical evaluation as a novel predictive biomarker. While additional signaling pathways altered in resistant cell lines included cyclin D-CDK4/6-RB, EGFR/HER, and AKT/mTORC1, therapeutic targeting of these pathways could not re-sensitize all models to CDK4/6 inhibition. However, EGFR/HER or AKT/mTOR inhibitors in combination with CDK4/6i synergistically reduced cell viability in parental cell lines, representing potential treatment strategies to delay onset of resistance. In summary, I have developed and characterized CDK4/6i resistant ER+/HER2- breast cancer cell lines and demonstrated that mechanisms of resistance are diverse. Importantly, I have identified the IFN-sig as a potential novel predictive biomarker of CDK4/6i response, and potential treatment strategies to overcome or prevent the development of resistance, for further evaluation.

Advisor: Bartlett, John
Spears, Melanie
Sequencing Protein Interaction Dynamics at Proteome Scale

Protein interactions link genotypes to phenotypes. Although phenotypes are known to depend on environmental context, the response of protein interactions to environmental change has not yet been explored at the scale of proteome. Here, I engineered and validated the fluorescence Barcode Fusion Genetics Yeast-Two Hybrid (fBFG-Y2H) technology, which enables multi-environment proteome-scale interaction measurements via recombinatorial barcode sequencing. I demonstrate two proteome-scale applications of fBFG-Y2H: First, I describe the use of fBFG-Y2H to generate the first binary protein interaction map connecting SARS-CoV-2 and human proteins. The identified human protein targets are enriched for interactors of proteins in severe COVID-19-associated loci, suggesting mechanistic connections involving vesicle trafficking and TNF-signaling. Second, I describe the application of fBFG-Y2H to generate an interaction map amongst ~30 million yeast protein pairs under baseline, DNA damage, carbon starvation, and oxidative stress environments, yielding the first proteome-scale atlas of dynamic protein interactions for any organism. Integrating the dynamic interactome map with transcriptome and phosphoproteome measurements in matching conditions reveals both local mechanisms underlying individual pathways and global patterns of cellular response to changing environments. Finally, I provide proof-of-principle results for a messenger BFG-Y2H (mBFG-Y2H) technology, which counts transcripts bearing recombinatorial barcode loci and has the potential to capture global protein interaction dynamics at an unprecedented 10-minute resolution.

Keywords: Barcode Fusion Genetics
interactome
protein-protein interaction
recombinatorial multiplexing
sequencing
Yeast Two-Hybrid
Advisor: Roth, Frederick P
Critical Period, High-acuity Illness, Inequitable Access: Understanding Outcomes following Postpartum Psychiatric Emergency Visits, and the Role of Social Determinants of Health

Within the year following childbirth, approximately 1 in 100 postpartum individuals visit an emergency department (ED) for a psychiatric reason. Postpartum psychiatric ED visits are an indication of acute need for mental health care, and an opportunity to coordinate services. This thesis aimed to fill gaps in knowledge about the outcomes of postpartum individuals following psychiatric ED visits, and specifically understand how individual and intersecting social determinants of health relate (1) to inpatient hospital admission from the ED, and for discharged individuals, (2) to outpatient physician follow-up within 30 days, and (3) to subsequent psychiatric admission within 365 days. The thesis is comprised of three projects, all of which use Ontario health administrative data to examine a cohort of postpartum individuals with psychiatric ED visits (2008 to 2020). In each project, social determinants were examined independently, then in intersection using three distinct methods. In Project 1, 16.0% of individuals were admitted to hospital from the initial ED visit and, of the examined social determinants of health, only Chinese ethnicity was associated with an increased risk of admission after adjusting for clinical and other factors. Additive interaction to evaluate for synergistic or antagonistic effects between social determinants was non-significant. In Project 2, 44.8% of discharged individuals saw a physician for mental health care in the 30 days following the ED visit, with less follow-up in younger individuals, those in low-income and rural areas, and immigrants. Conditional inference trees used to examine social determinants in intersection identified patterns not evident from traditional regression (e.g., neighbourhoods diversity related to follow-up only among those aged ≤25 years). In Project 3, 9.5% of those discharged had a subsequent psychiatric admission, with a lower likelihood of admission among younger and immigrant individuals. Latent class analysis identified 4 socially distinct subgroups, which had differing risk of admission. Taken together, this thesis identified gaps in both inpatient and outpatient mental health care in a high-acuity postpartum population. Complexity in the relationships between social determinants and health service access underscore the need for intersectionality-informed approaches to improve equitable postpartum mental health service delivery.

Keywords: Emergency department
Health services
Postpartum mental health
Social determinants of health
Advisor: Vigod, Simone N
The Political Development of the Treaty System in Canada

Are Crown-Indigenous treaties instruments of dispossession? Or are they best hope for a just political order in Canada? This question has divided Indigenous and anticolonial advocates and scholars. To adequately respond to it, we need a clearer account of what treaties are. Rather than seeing treaties as Indigenous practices of kin-making, nation-to-nation agreements, or real estate contracts, we need to recognize that the treaty system is a complex, multilayered institution that includes each of these elements. The treaty system combines Indigenous, Imperial, and Settler governance traditions. So understood, the treaty system is a fundamental, intersocietal institution of governance in Canada. It provides the overarching framework through which Indigenous and non-Indigenous peoples contest the terms of their territorial co-existence. It follows that treaties are neither instruments of consent nor dispossession; instead, they are sites of contestation and struggle. This dissertation traces the emergence, consolidation, and development of the treaty system from the early modern period to the present. It focuses on the emergence of the treaty system in the mid-eighteenth century, and its transformation into a system of treaty colonialism in nineteenth century Upper Canada. Throughout, I emphasize the simultaneous operation of three treaty traditions: Indigenous relational, Imperial diplomatic, and Settler contractual. These traditions constrained political agents, but they also provided resources that could be mobilized by diversely situated Indigenous and colonial actors, often in surprising ways. The dissertation concludes by endorsing a multi-pronged strategy of treaty renewal, one that simultaneously emphasizes Indigenous relational visions of treaty while strategically deploying the contractual and diplomatic traditions to combat dispossession. In this way, it contributes to debates about the role of treaties in reconciliation and decolonization. It also intervenes in disciplinary debates by insisting that Indigenous institutions, such as treaties, belong at the center of the emerging field of Canadian Political Development

Keywords: Anishinaabe
Canadian Constitution
Canadian Political Development
Haudenosaunee
Indigenous Politics
Treaties
Advisor: Williams, Melissa S
Integrated Systems for CO2 Capture-and-Upgrade

Emerging technologies to capture CO2 from air are projected to be energy-intensive and capital-intensive. They rely on a temperature and/or pressure swing to release CO2 from capture sites, and today this comes at a high energy cost. The ensuing step in CO2 valorization – its upgrade to a valuable chemical or fuel – requires additional energy. This upgrading step suffers from incomplete CO2 utilization (the fraction of input CO2 converted to desired products) limited to ≤50% for C1 production, ≤ 25% for C2 production, the result of carbonate formation in locally alkaline conditions. It leads to a high cost to regenerate/separate (otherwise-lost/unreacted) CO2. In this thesis, I report systems for what is known as reactive capture: the integrated capture and upgrade of CO2 to valuable products. I pursue approaches, based on carbonate and amine capture molecules, that are particularly amenable to processing dilute streams, such as those from the air. I find that – when one looks at total energy including CO2 capture, reduction to CO, and final purification – the best approach reported herein improves the energy efficiency of the overall process. Specifically, the best prior approach costs 44 GJ/tonne of CO, while my system achieves 27 GJ/tonne of CO. One major benefit of reactive capture is that it enables ~ 100% CO2 utilization with no CO2 losses and without unreacted CO2 at the system's outlet. This obviates the need for energy to regenerate CO2 losses and separate unreacted CO2. Because the system has the potential to utilize CO2 captured from the air, it suggests a route to provide cradle-to-gate carbon-negative chemicals/materials. I pursue several strategies herein, each centered around electrochemical conversion of captured carbon, exploring alternatives such as carbonate capture liquid and amine capture liquid. I exploit facile acid/base reactions between protons and carbonate ions for in-situ CO2 generation. In the case of amine-CO2 upgrading, I tune the electrochemical double layer with alkali cations to place the reactants at the catalyst surface – a strategy that enables efficient electron transfer. This work contributes to the advancement of reactive capture, providing benefits in energy efficiency and integration.

Advisor: Sargent, Edward E.H.S.
Development of Mn(III) Porphyrins as Gd-free Contrast Agents for Targeted MR Imaging

Personalized medicine requires precision diagnosis, and a targeted medical imaging method addressing this requirement is highly anticipated. Targeted magnetic resonance imaging (MRI) requires a contrast agent (CA) capable of detecting specific cellular or molecular biomarkers in a sensitive and selective manner. Currently, mainstream MRI CAs are Gd(III)-based, which is limited by low contrast efficiency (r1) and toxicity of free Gd(III) upon metal dissociation. To address these limitations, we are developing a new class of Gd(III)-free CAs based on the biocompatible Mn(III) porphyrin (MnP), which is desirable for their high r1 at high fields, stability against metal dissociation, and versatility for structural modification to achieve functional diversity. In this thesis, the development of MnP-based CAs for targeted MRI is explored. In chapter 2, we studied MnP2, the first MnP-based blood pool agent (BPA) on its binding behavior with its target, human serum albumin (HSA). We unexpectedly discovered a novel sequential binding model, in which MnP2 binds first to a kinetically favorable site, followed by migration to a thermodynamically favorable hydrophobic site (subdomain IB), causing r1 decrease in MnP2, possibly due to limited water accessibility. Based on the crucial findings, in chapter 2, a series of MnPs designed to overcome the water accessibility issue, either by twisting MnP2’s geometry (chapter 3) or incorporating smaller, more polar functional groups (chapter 4) were developed as next-generation BPAs. Amongst them, MnTriCPP especially showed significant r1 increase at high fields upon HSA binding (chapter 4). In chapter 5, MnTriCP-B(OH)2 was developed as a saccharide-targeted CA based on boronic acid-diol interactions, and the binding was found to be pH dependent. In chapter 6, MnTriCP-NTA was designed to target His-tag, a post-translational modification widely utilized in protein purification. Finally, in chapter 7, MnMOB and MnEOB were developed as MRI probes for organic anion transport proteins (OATPs). In vitro and in vivo evaluations show that MnEOB is highly specific and sensitive towards OATP uptake, demonstrating its potential for targeted liver imaging as well as gene reporting. Overall, MnP is a stable, sensitive, and flexible platform for next generation CAs for targeted molecular imaging.

Keywords: Magnetic Resonance Imaging
Manganese
Porphyrins
Advisor: Zhang, Xiao-an