VictorJuiz/thesis huggingface dataset:
Peroxisome Proliferator-activated Receptor-γ (PPARγ) Agonists: Potential Novel Treatment for HIV-1 Associated Brain Inflammation

Despite the use of combinational antiretroviral therapy (cART) for the treatment of HIV-1 infection, cognitive impairments remain prevalent due to persistent viral replication and associated inflammation in the brain. Cellular targets in the brain include microglia and astrocytes which in response to infection release inflammatory markers and viral proteins. Peroxisome Proliferator Activated Receptor-gamma (PPARγ) is a ligand-activated transcription factor that plays a role in glucose and lipid homeostasis. Compelling evidence also suggests that PPARγ agonists can exert anti-inflammatory properties in animal models of neurological disorders. With no treatment currently available for HIV-1 associated neurocognitive disorders (HAND), it is critical to identify compounds that can permeate across the blood-brain barrier (BBB) and exert anti-inflammatory effects. The aim of this doctoral thesis was: i) to investigate the efficacy of PPARγ agonists, rosiglitazone and pioglitazone in reversing brain inflammation in vitro in primary cultures of mixed glial cells exposed to HIV-1ADA glycoprotein 120 (gp120) and in vivo in an intracerebroventricular (ICV) HIV-1ADA gp120 administered rat model, ii) to examine the efficacy of PPARγ agonists, rosiglitazone and pioglitazone in reversing brain inflammation in vitro in primary cultures of mixed glial cells exposed to EcoHIV and in vivo in an intracranial (IC) EcoHIV administered mouse model and iii) to assess the therapeutic potential of the selective PPARγ modulator (SPPARγM), INT131 in EcoHIV infection, and characterize its pharmacokinetic profile. We demonstrated that gp120 can induce an inflammatory response and decrease expression of glutamate transporter-1 (GLT-1) in vitro and in vivo. We then showed that these inflammatory responses could be partially or completely reversed with PPARγ agonists, rosiglitazone or pioglitazone treatment. Next, we successfully implemented a rodent model of HIV-1 associated brain inflammation using a chimeric virus, EcoHIV. Infection with EcoHIV in vitro and/or in vivo, resulted in a potent upregulation of several inflammatory genes that could be partially or completely reversed by rosiglitazone, pioglitazone or INT131. Finally, we characterized in mice the pharmacokinetic profile of INT131 systemically and in the brain. Overall, our data demonstrated that PPARγ agonists could serve as a promising novel therapeutic approach for treatment/prevention of HIV-1 associated brain inflammation.

Advisor: Omeragic, Amila
On Global Solutions of the Parabolic Anderson Model and Directed Polymers in Random Environment

This thesis studies global solutions to the semidiscrete stochastic heat equation and the associated Cauchy problem known as Parabolic Anderson Model. Via a Feynman-Kac formula, it is linked with the analysis of directed polymers in random environment, and this thesis establishes a number of results for the corresponding partition function. We consider a continuous-time simple symmetric random walk on the integer lattice ℤd in dimension d ≥ 3, subject to a random potential given by two-sided Wiener processes. In the high-temperature regime, we prove the existence of the L2- and almost sure limit of the partition function as time t → ± ∞. We show that the L2-convergence rate is at least polynomial and that the limiting partition function is positive almost surely. Furthermore, we show that this limiting partition function defines a global stationary solution to the semidiscrete stochastic heat equation which is unique up to a rescaling, and which in some sense attracts solutions to the Parabolic Anderson Model for any subexponentially growing initial data. One of the primary tools in the proof of this uniqueness and attraction result is a factorization formula for the point-to-point partition function, which is related to the ones obtained by Sinai (1995) and Kifer (1997) for other polymer models, but valid not only on the diffusive scale but up to any sub-ballistic scale. This factorization formula allows us to obtain a uniqueness result for physical invariant probability measures of a certain skew product that can be naturally associated with the semidiscrete stochastic heat equation, which in turns gives uniqueness of global stationary solutions.

Keywords: Directed Polymers in Random Environment
Probability
Random Dynamical Systems
Stochastic Heat Equation
Stochastic PDEs
Advisor: Khanin, Konstantin M
Faithful Listening: On Sound, Survival, and Becoming in Muslim Toronto

In this dissertation, I follow the trajectories of several contiguous, heterodox Muslim groups in the city of Toronto, and unravel the ways in which they use sound and listening to at once cultivate personal, inward-looking spiritual practices, and a more outward-feeling sense of belonging to a variegated local network of Muslim spaces and institutions, and to the city-at-large in which they reside. In the vast majority of these spaces, conversations about faith, service, justice, advocacy, local politics, global current events, and everyday life are woven into the discursive and affective fabric at hand. Across this faith-based network, fricative, disjunctive encounters are common, but do not rule out the possibility of profound moments of camaraderie and understanding across difference; such is the nature of the ummah—that is, a theoretical or imagined global community that encompasses all Muslims. I listened alongside a handful of groups affiliated with a Sufi halqa (prayer circle) located in the former municipality Scarborough (now a part of the Greater Toronto Area), including a meshk (hymn rehearsal) group and a prayer group called Masjid al-Wali that operates as a place of worship for LGBT2SIQ+ Muslims. These groups’ spiritual journeys were often, but not always, concerned with the internal and inward. Or, in terms derived from the Qur’an and Sunnah, which my interlocutors often use as guidebooks of sorts, the individuals that I encountered during fieldwork were attuned to al-batin (the inner or hidden dimension of reality). Thus, I put forward a batini ethnography—an ethnography of (shared) inner experiences. Importantly, this dissertation homes in on the roles that sounding and listening play in this realm of interiority. I discuss the ways in which the careful cultivation of modes of “faithful listening” is made possible through the development of safe-feeling spaces. In such domains of refuge, my interlocutors are able to move more freely along the maqamat (stations or stages) of being a student of Sufism, passing through difficult times—both personal and political—with hope (raja’), expansiveness (bast), contentment (qana’a), and even humour, but also, at times, with sadness (huzn), and contraction (qabd).

Keywords: canada
ethnomusicology
muslim
phenomenology
practice
sound
Advisor: Pilzer, Joshua D
Hemmasi, Farzaneh
Essays in Macroeconomic Growth

The innovation of new technologies is fundamental for driving aggregate economic growth. The spread (or lack of) of these technologies across countries helps explain growth in developing countries and why large productivity gaps persist. My thesis studies the contribution of technological progress and diffusion for explaining cross-country productivity gaps and aggregate growth. The first chapter studies how the diffusion of new technologies affects growth. I develop a model of endogenous growth, in which firms decide how to invest in the adoption of a new technology and innovation. Knowledge embodied in products is more complementary to future innovations using the same technology. Consequently, as firms adopt the new technology it becomes harder to innovate with the old technology. I calibrate to empirical evidence using patent data on the diffusion of information-communication technology (ICT). Diffusion is driven by adoption early on (about 1/3) and innovation later (about 2/3). Despite large firm-level gains from adoption, aggregate growth falls by 15% over the transition because firms scale back innovation. The second chapter studies how institutional distortions prolong the adoption of new technologies in developing countries. I build a model in which firms choose technology and resource inputs given their underlying productivity and exposure to the institutional environment. I calibrate to US data on the distribution of employment and adoption pattern of new technologies. Increasing distortions to be consistent with low-income countries increases the adoption lag of new technologies by 19 years (43% of the data) and decreases productivity by 65%. The third chapter (with Faisal Ibrahim, Gaelan MacKenzie and Swapnika Rachapalli) studies the role of knowledge embodied within traded products for diffusion. We use patent data to construct a measure of embodied technology. Using this measure, we find that increases in high-knowledge traded goods are associated with higher productivity and R\ growth. To quantify the importance of this channel, we develop an endogenous growth model with trade and knowledge links. We find that a large fraction of long-run growth is attributable to spillovers with developing countries benefiting relatively more.

Keywords: Growth
Innovation
Institutions
Productivity
R
Technology
Advisor: Restuccia, Diego
Boron-based Lewis Acids: Towards Intramolecular Frustrated Lewis Pairs and Enantioselective Catalysis

A rapid development of metal-free, main group compounds for small molecule activation and as hydrogenation catalysts was triggered after the disclosure of H2 activation by sterically hindered Lewis acids and bases over a decade ago. The combination of a Lewis acid and base with unquenched reactivity was later coined as a “frustrated Lewis pair” (FLP). In this research, boron-based Lewis acids were studied for their application as catalysts in FLP chemistry, with an emphasis on exploring the production of chiral FLPs and intramolecular FLPs. In the exploration towards enantioselective catalysis, 3,5-bicyclic aryl piperidines were synthetically modified to produce B/N FLPs and were shown to activate dihydrogen, demonstrating the potential for expanding chiral FLP templates beyond the typical chiral ligands used in transition metal complexes. Chiral borenium cations were generated from different families of carbene-borane adducts, in which their chirality resides on either the carbene or the borane. Catalytic studies found that they were able to effect imine reduction without epimerisation of the resulting chiral amine, and the reactivity and enantioselectivity of these cations were found to be inversely proportional to steric demands. In the exploration towards a cationic intramolecular FLP, a borenium cation with a pendant phosphine was synthesized through hydroboration of a phosphinoalkene with an isolable B-H borenium cation, and its FLP reactivity was investigated. Finally, initial efforts towards the production of a bisborane-carbene as a tri-functionalized FLP were documented.

Advisor: Stephan, Douglas W
Investigation and Management of Coronary Artery Disease Among Patients with Heart Failure in Ontario

Background: The investigation and management of heart failure (HF) requires extensive use of healthcare resources in Ontario, Canada. Methods: Four cohort studies using administrative databases were conducted to describe the epidemiology of HF; to assess the use of cardiac imaging and coronary revascularization; and to determine the significance of non-obstructive coronary artery disease on clinical outcomes. Results: The incidence rate of HF decreased 32% from 380 new cases (95% CI, 376-384) per 100,000 individuals in 2002 to 256 (95% CI, 254-259) per 100,000 in 2016 (P

Keywords: coronary artery bypass
coronary artery disease
diagnostic imaging
heart failure
percutaneous coronary intervention
Advisor: Lee, Douglas S
N-cadherin Regulation of Vascular Smooth Muscle Cells; the Role of DDR1 and Rho GTPases

N-cadherin mediates cell-cell contacts in vascular smooth muscle cells (VSMCs) and regulates VSMC behaviours. Discoidin domain receptor 1 (DDR1) is a collagen binding receptor also implicated in these processes. Previous studies showed that both N-cadherin and DDR1 are upregulated after vascular injury, but it is not known whether the two molecules are associated. The ability to establish proper N-cadherin junctions is important in regulating VSMC behaviour. In my studies, I found that N-cadherin could associate with DDR1, and that this association was increased during VSMC migration and wound closure. I found that N-cadherin was reduced in lipid rafts and mislocalized from cell-cell junctions in the absence of DDR1. Disruption of lipid rafts by cholesterol oxidase or methyl-β-cyclodextrin removed N-cadherin from lipid rafts of DDR1+/+ VSMCs and disrupted N-cadherin contacts, and these effects were reversed by cholesterol rescue that restored lipid rafts. Knockdown of DDR1 by siRNA resulted in mislocalized N-cadherin contacts from cell junctions, and transfection of DDR1-/- VSMCs with full-length DDR1 rescued the formation of N-cadherin junctions. The mislocalization of N-cadherin contacts in DDR1-/- VSMCs was also accompanied by disruption of the actin cytoskeleton. N-cadherin contacts in VSMCs undergo constant remodeling, especially during disease processes. Calcium switch to disrupt and restore contacts did not affect N-cadherin triton solubility in DDR1+/+ and DDR1-/- VSMCs or the association between N-cadherin and DDR1. While collagen stimulation of DDR1 increased the association between N-cadherin and DDR1 in cells with mature, well-established cell contacts, it did not affect N-cadherin localization, its triton solubility, or the association between N-cadherin and DDR1 during contact disruption, restoration, and wound closure. Rho GTPases are master regulators of the cytoskeleton and can mediate cytoskeletal processes downstream of cell-cell contacts. Using calcium switch and plating on either IgG or N-cadherin-Fc coated surfaces, active Rho GTPase pull-down assays showed a consistent decrease in Cdc42 and RhoA activity after N-cadherin contact establishment in DDR1+/+ SMCs. Overall, these data reveal that N-cadherin cell-cell contacts in VSMCs can be regulated through interaction with DDR1 and localization in lipid rafts, and that the establishment of N-cadherin contacts can suppress Rho GTPase activity.

Keywords: Cell-cell interaction
DDR1
N-cadherin
Rho GTPases
Vascular smooth muscle cells
Advisor: Bendeck, Michelle
Static, Cyclic Deformation Responses and Related Micromechanisms of Ni-Carbonyl CVD Material of Bimodal Grain Structures – Columnar Grains with Ultrafine Nano-Twins and Ultrafine-grained Matrix

To achieve a synergy of strength and ductility, the current Ni-Carbonyl CVD Material (CVD Ni) is developed by incorporating bimodal microstructures, i.e. large columnar grains containing ultrafine/nano twins embedded in ultrafine/nano-grain matrix. This dissertation systematically studies the effect of this unique microstructure on the mechanical properties in the following aspects: monotonic and cyclic deformation responses, cyclic creep, low cycle fatigue and fatigue cracking behaviors. The employed strategy is to monitor the mechanical responses under designed tests in parallel with the microstructural and surface morphology evolutions so that the associated micro-mechanisms can be identified. Through intensive experimental studies, it is discovered that the stability of the ultrafine/nano twin boundaries, especially the occurrence of detwinning, affects the deformation behaviors. Under monotonic deformation, it is confirmed that strength and ductility can be enhanced simultaneously for CVD Ni. However, massive detwinning is found causing a major drop of the strain hardening rate to the same level of coarse-grained Ni and as the applied strain increases, dislocation cell structures could form. Under cyclic deformation, similar massive detwinning occurs and cause the transition of cyclic hardening to cyclic saturation. In addition, cell structures are found responsible for the additional softening stage observed at higher maximum cyclic stress only. Such microstructural evolutions, i.e. detwinning followed by cell formations observed under all three modes of monotonic deformation with increasing strain, cyclic deformation with increasing maximum cyclic stress and previously annealing with increasing temperature are identified as a consistent energy reduction path for CVD Ni. An energy criterion to predict the softening caused by massive detwinning under cyclic deformation is further established. Meanwhile, under the asymmetrical cyclic loading with positive mean stress, primary, secondary/steady state and tertiary cyclic creep can be well identified and correlated to processes of the cyclic hardening, saturation/moderate softening and severe softening, respectively. Lastly, the low cycle fatigue life of CVD Ni is found to be lower than ultrafine-grained Ni despite its advantageous high ductility due to the early concentrated slip activities on the large twin boundaries near highly detwinned regions leading to premature crack formations.

Advisor: Wang, Zhirui
The Influence of Junior Hockey Participation on Ontario University Male Hockey Players' Identity Development

The over-prioritization of a professional hockey career in junior hockey has impacts on athletes’ academic motivation and identity development. Systematically, junior hockey does not support the traditional path that students take into postsecondary education, leaving many male hockey players viewing their Canadian postsecondary options as a ‘backup plan’ they hope they never have to use (Chard, 2013). The purpose of this study was to identify the influence of junior hockey participation on university expectations, experiences, and motivations. An explanatory mixed-methods approach was followed consisting of two phases of data collection and analysis (Creswell, 2009). The phase one online survey collected responses from Gaston Gayles’ (2005) Student-Athlete Motivation towards Sport and Academic Questionnaire (SAMSAQ), and produced a two-factor modified academic and sport motivation solution. The survey was completed by 113 male hockey players from 12 Ontario universities and indicated that while in university, athletes’ academic motivation is slightly higher than sport motivation, and similar to previous research on university student-athletes, male hockey players experienced a role conflict between their academic and sport roles. In phase two, semi-structured interviews were completed with 14 participants representing 9 institutions across Ontario. A thematic analysis of the data (Braun Clarke, 2013) produced results that pertained to identity development theories and led to the creation of a proposed Professional Hockey Identity Mindset Model. This model provides unique insight into the impact of sport-over-prioritization in high school on identity development and has significance for future research in hockey and athletics more broadly.

Keywords: Academic Motivation
Hockey
Identity Development
Junior Hockey
Student-Athlete
University
Advisor: Kerr, Gretchen
Structural and Functional Characterization of the RING-like Protein RTF2

RING and RING-like domains represent the functional component on the vast majority of E3 ligases. With over 600 known members, the family of RING E3 ligases promote the direct transfer of ubiquitin from an E2 onto a substrate, acting as the key mediators of specificity during the reaction. However, beyond acting as a simple scaffold for E2-binding, many RING and RING-like domains have been found to play a more active role by inducing conformational selectivity in the otherwise flexible E2~ubiquitin conjugate. With their central role in the ubiquitination reaction, it is no surprise that RING and RING-like domains exhibit a wide array of regulatory mechanisms that govern their activity, including the ability to function in different oligomeric states. Specifically, while some function as monomers, many RING and RING-like E3 ligases are dependent on dimerization for their activity. This thesis explores the structure and function of a poorly characterized, evolutionarily conserved RING-like protein RTF2. In the first chapter, I examine the crystal structure of human RTF2 revealing two conserved RING-like domains: an N-terminal U-box-like domain associated with a SP-RING domain in an arrangement I describe as an intra-chain heterodimer. I then move on to describe a role for RTF2 in pre-mRNA splicing and begin to explore its interactome using proximity-dependent biotin identification (BioID). In the third chapter, I identify conserved functional elements on both RING-like domains and demonstrate the importance of these residues for RTF2-dependent splicing, possibly by facilitating E2 recruitment. Together, these results reveal a novel RING-like structural mode and provide a foundation for further work examining the mechanism underlying RTF2 function and its role in pre-mRNA splicing.

Keywords: dimer
E3 ligase
RING domain
splicing
Advisor: Privé, Gilbert G
The Role of the E-protein HEBAlt in T-Cell Development

Developing T-cells require the coordinated function of various transcription factors to promote T-lineage progression, among which is the E-protein HeLa E-box Binding (HEB) factor involved in promoting T-lineage specification and commitment. HEB-deficient mice have altered gene expression, changes in proliferation in the early double-negative (DN) stages, and blocks in T-cell development at the CD8+ Immature Single Positive (ISP8) stage. Although previous studies highlighted the importance of HEB in T-cell development, they failed to distinguish between the HEB isoforms HEBCan (Canonical) and HEBAlt (Alternative) which are produced by different transcription start sites. I set out to identify the functional differences between the HEB factors by investigating specifically the function of HEBAlt in the context of T-cell development. I began by investigating whether the Alt-domain, the defining feature of HEBAlt, is required for HEBAlt transcriptional activity. My findings demonstrated that phosphorylation of a tyrosine (Y)-rich YYY motif is required to activate HEBAlt, and that this phosphorylation may be dependent on Janus kinases, as a result of interleukin-7-receptor signaling within the thymus. Phosphorylation of HEBAlt does not affect subcellular localization and the activity of other E-proteins, however it reduces protein degradation. HEBAlt phosphorylation at the YYY-motif results in greater resistance to Inhibitor of DNA-binding protein-mediated inhibition and comparable transcriptional activity to other E-proteins involved in T-cell development. Phosphorylated HEBAlt also appears to be required for the regulation of a pre-T Cell Receptor- enhancer. In addition, we generated HEBAlt-transgenic and HEBAlt-deficient mice. Our analyses showed that HEBAlt-transgenic mice have reduced proportions of ISP8 cells, opposite to HEB-deficient mice, suggesting HEBAlt may promote developmental progression at the ISP8-to-CD4+CD8+ Double Positive (DP) stages. In vitro T-cell differentiation of HEBAlt-transgenic progenitors have reduced ISP8 cell and greater DP cell proportions, further supporting the role for HEBAlt promoting faster ISP8-to-DP transition. Interestingly, HEBAlt-deficient mice appeared to have no altered proportions in their ISP8 compartments, possibly due to the presence of HEBCan and other E-proteins that may compensate for HEBAlt absence. Overall, our results suggest that HEBAlt function requires phosphorylation at the YYY-motif to be activated, and that HEBAlt may promote the transition of ISP8-to-DP cells in T-cell development.

Keywords: bHLH
E protein
Immunity
T cell
Transcription factor
Tyrosine Phosphorylation
Advisor: Zuniga-Pflucker, Juan Carlos
Anderson, Michele K