VictorJuiz/thesis huggingface dataset:
The Role of Uric Acid in Renal and Cardiovascular Function in Patients with Uncomplicated Type 1 Diabetes Mellitus

Patients with type 1 diabetes (T1D) have a 30% lifetime risk of developing diabetic nephropathy (DN) despite the use of current available therapies. It is of paramount importance to identify agents that protect patients with T1D from the initiation and progression of DN. Unfortunately, recent renal protection trials in patients with T1D have either failed, demonstrated harm or reported effects that are far below expectations based on data from experimental models. Accumulating evidence suggests that plasma uric acid (PUA) is associated with multiple key pathways involved in the pathogenesis of diabetic complications, including metabolic, cardiovascular and renal abnormalities. Our work is focused on elucidating the pathophysiologic role of PUA in renal and cardiovascular function in patients with T1D. We showed that PUA levels are surprisingly lower in adolescents and young adults with T1D compared to healthy controls (HC) due to glycosuria, which stimulates increased PUA excretion, likely through the GLUT9 isoform 2 transporter. Despite having lower PUA levels, adolescents and young adults with exhibit a negative correlation between PUA and glomerular filtration rate (GFR), possibly due to increased afferent renal arteriolar resistance and reduced renal perfusion. In the context of previous experimental work, our observation suggests that PUA may mediate afferent renal arteriolar disease, causing ischemia to the renal microcirculation, thereby potentiating renal injury. Although not observed in T1D adolescents, the association of higher PUA levels with higher blood pressure emerged in the young adults with T1D. In our final set of experiments, lowering PUA with febuxostat (FBX) for 8 weeks had a modest blood pressure lowering effect in young adults with T1D. FBX enhanced the renal filtration fraction response to clamped hyperglycemia through an increase in efferent renal arteriolar resistance without impacting the RAAS, suggesting that PUA may augment other vasoconstrictor or vasodilatory mechanisms leading to an augmented renal hemodynamic response to hyperglycemia. Longitudinal outcome trials are required to determine whether our physiologic findings impact renal or cardiovascular outcomes in response to PUA lowering therapies in patients with T1D.

Keywords: Cardiovascular Function
Renal Function
Type 1 Diabetes
Uric Acid
Advisor: Cherney, David Z.I.
Dorian, Paul
Ancestral and Spiritual Naming of Children among the Jopadhola Lwo of Eastern Uganda

This study brings Indigenous understandings to the anti-colonial resistance by the Jopadhola Lwo people of Eastern Uganda. The Jopadhola Lwo people link with ancestors in the naming ceremonies for their children. For the study, I employed Indigenous methodology to understand how a minority people resist assimilation. I interviewed elders in Dhopadhola Lwo. The Indigenous methodology is the Padhola elders’ agency for educating the researcher. The study objectives investigated: the Indigenous naming practices and how these are understood in contemporary contexts; the Indigenous practices and the possibilities for decolonization; the understanding of the interface of society, culture, and Nature, the nexus of body, mind, and soul, and the spirit from naming ceremonies of Padhola; and the implications for transforming schooling in African and Euro-American contexts. The research findings revealed: 1. Name variations of Padhola with ongoing ceremonies for Apipili and Yao Rut. 2. Resistance to foreign names as Njawala or twigs. 3. Sacred monotheist Indigenous religion thrives with Kuunu shrines. 4. Ancestors reveal children’s names in dreams. 5. Indigenous education resists Christianity. 6. The Jopadhola elders are not worth their salt if they do not resist foreign influence and advocate for a return to traditional education.

Keywords: Anticolonial Education
Anticolonialism
Decolonization
Indigenous African Knowledge
Indigenous Education
Social Justice
Advisor: Dei, George J.S.
Convexity and Cohomology of the Based Loop Group

Let K be a compact, connected, simply connected Lie group and define ΩK to be the loops on K. Let ΩalgK be those loops which are the restriction of algebraic maps Cx → Kc. Herein we establish two distinct but related results. In the first, we demonstrate the module structure for various generalized abelian equivariant cohomology theories as applied to equivariantly stratified spaces. This result is applied to the algebraic based loop group for the cases of equivariant singular cohomology, K-theory, and complex cobordism cohomology. Subsequently, we examine the image of the based loop group under the non-abelian moment map. We show that both the Kirwan and Duistermaat convexity theorems hold in this infinite dimensional setting.

Keywords: based loop group
convexity
moment map
symplectic geometry
Advisor: Jeffrey, Lisa
A Robust Hierarchical Control Structure for Virtual Power Plants

This dissertation discusses the principles of operation and control requirements of Virtual Power Plants (VPPs). Based on the identied characteristics and performance requirements of VPPs, this dissertation then proposes a robust hierarchical control structure to operate a microgrid in the VPP and islanded modes and to provide a smooth transition between these two modes. Various sources of uncertainties and disturbances aecting dynamics of a microgrid with multiple distributed energy resource (DER) units in both the VPP and islanded modes of operation are identied and classied as local and interconnection uncertainties and exogenous disturbances. An integral quadratic constraint framework is introduced to mathematically represent these perturbations. Based on the obtained uncertain system model, a necessary and sucient condition is proposed to nd robust, decentralized, output-feedback, reference-tracking, local controllers (LCs) for DER units which (i ) guarantee the robust stability of the overall microgrid, and (ii ) ensure disturbance rejection. Rank constrained linear matrix inequalities (LMIs) are further derived to systematically design these LCs. This decentralized structure of LCs constitutes the primary level of the proposed hierarchical control structure. At the secondary level, a robust H1, multivariable, LMI-based, PI control strategy augmented with static, multivariable, LMI-based anti-windup compensator is proposed and designed to operate a microgrid in the VPP mode. The proposed control strategy (i ) guarantees the stability of the overall, closed-loop, unconstrained microgrid while achieving a pre-determined disturbance attenuation level, and (ii ) guarantees the stability of the constrained microgrid while demonstrating graceful performance degradation during controller windup. Furthermore, to operate a microgrid in the islanded mode, a decentralized, droopaugmented, robust voltage control structure is introduced that is composed of: (1) a P- and a Q-V droop-based power sharing controller, (2) the proposed robust LCs, and (3) an open-loop frequency controller. This dissertation adopts frequency-domain and digital time-domain simulation tools, i.e., MATLAB and PSCAD/EMTDC platforms, respectively, to evaluate the attributes and performance of the proposed hierarchical control structure.

Keywords: Hierarchical Control Structure
Linear Matrix Inequality
Microgrids
Robust Control
Virtual Power Plants
Advisor: Iravani, Reza
Yazdani, Amirnaser
From Toronto First Duty Vision to Policy Reality: Scaling Up, Watering Down in the Provincial Implementation of Full-day Kindergarten at the Bruce/WoodGreen Demonstration Site

Ontario’s Full-day Kindergarten (FDK) evolved in part out of Toronto First Duty (TFD), a demonstration project and feasibility study of integrated early childhood programs delivered through a partnership spanning different auspices. TFD used a model in which kindergarten, child care and other services provided an integrated program. This study tracks the evolution of the FDK program using a case study of Bruce Public School. Through a partnership with WoodGreen Community Services this site became part of TFD and evolved into the internationally known Bruce/WoodGreen Early Learning Centre (BWELC). At full implementation, BWELC provided a full-day, play-based, high quality program for 4-year-old and 5-year-old children, delivered by an integrated staff team, with wrap-around, comprehensive child care. It became the seed for the “scaling up” of Ontario’s FDK program. In more recent years, changes to the staffing and program delivery models with the roll-out of FDK have impacted the early learning experience in a way that might be considered “watering down.” This study aims to tell the story of what occurred at BWELC and why it happened, focusing on the cornerstones of quality and staff integration, moving from initial vision to current reality. Building on the research of the TFD project, the current study continued to employ a case study approach and mixed methods, combining both qualitative and quantitative forms of inquiry. Data were collected using the Early Childhood Environment Rating Scale–Revised, the Toronto Operating Criteria, the Indicators of Change tool, a parent/guardian survey and key informant interviews. The study approach involved three intersecting conceptual frameworks: Theory of change, integration/integrated services, and leadership. A concurrent triangulation approach was used to examine convergence among the data sources. The findings point to reductions in integration and leadership as Bruce Public School adopted the scaled-up system of FDK and to the effects of these key challenges on quality. The study contributes to our understanding of elements that need to be in place to provide high quality early learning environments and provides suggestions for further systems change to address the shortfalls in Ontario’s current FDK program and to continue the transformation into an effective system.

Keywords: Change
Full-day kindergarten
Integration
Leadership
Quality
Advisor: Pelletier, Janette
Structural and Vascular Changes Following Laser for Diabetic Macular Edema

Diabetic Retinopathy (DR) and Diabetic Macular Edema (DME) represent ocular complications of diabetes and DME is the leading cause of severe vision loss. This work investigated morphology, function, and circulation in patients with newly diagnosed DME in order to elucidate fundamental steps of the pathogenesis of DME development and resolution following laser treatment. Using the Canon Laser Blood Flowmeter, we investigated parameters of retinal blood flow (RBF) (diameter, velocity, and blood flow) in patients with newly diagnosed DME and compared with a control (non - diabetic) group. We assessed RBF parameters in patients with DME undergoing focal/grid laser photocoagulation. Using Spectral â Domain Optical Coherence Tomography (SD-OCT), we investigated and compared values of choroidal thickness (ChT) using enhanced depth imaging (EDI) and regular imaging (RI) acquisition approaches. Also, using SD-OCT, we examined morphological retinal changes induced by focal / grid laser photocoagulation. The correlation analysis revealed moderate agreement between EDI and RI at the temporal and nasal areas and poor agreement in the central choroidal area. There was a tendency for ChT values to be higher using RI approach than EDI. There was a trend for retinal blood velocity to be higher in patients with DME compared to controls but this difference was not significant. We demonstrated that there was no significant change in RBF parameters following the three, seven and thirty days post focal / grid laser photocoagulation. These results are the first to show simultaneous measurements of RBF parameters in patients with DME following laser and provided initial values for sample size calculation for the future studies. We found a significant reduction of total retinal volume and retinal thickness in the section of most edema between the 3 and 30 days of follow-up. The evaluation of histological retinal details revealed restoration of the external limiting membrane/photoreceptor complex which suggests mechanisms of retinal healing and reorganization. Future studies are needed to further elucidate the evidence in support of these theories on structural and vascular development of DME and post laser treatment.

Keywords: blood flow
diabetes
diabetic macular edema
laser photocoagulation
Advisor: Hudson, Christopher
Balanced Presentations of the Trivial Group and 4-dimensional Geometry

We construct a sequence of balanced presentations of the trivial group with two generators and two relators with the following property: The minimal number of relations required to demonstrate that a generator represents the trivial element grows faster than the tower of exponentials of any fixed height of the length of the finite presentation. We prove that 1) There exist infinitely many non-trivial codimension one "thick" knots in R5; 2) For each closed four-dimensional smooth manifold M and for each sufficiently small positive ε the set of isometry classes of Riemannian metrics with volume equal to 1 and injectivity radius greater than ε is disconnected; and 3) For each closed four-dimensional PL-manifold M and any m there exist arbitrarily large values of N such that some two triangulations of M with < N simplices cannot be connected by any sequence of < expm( N) bistellar transformations, where expm( N) = exp(exp(...exp(N))) (m times). We construct families of trivial 2-knots Ki in R4 such that the maximal complexity of 2-knots in any isotopy connecting Ki with the standard unknot grows faster than a tower of exponentials of any fixed height of the complexity of Ki. Here we can either construct Ki as smooth embeddings and measure their complexity as the ropelength (a.k.a the crumpledness) or construct PL-knots Ki, consider isotopies through PL knots, and measure the complexity of a PL-knot as the minimal number of at 2-simplices in its triangulation. For any m we produce an exponential number of balanced presentations of the trivial group with four generators and four relations of length N such that the minimal number of Andrews-Curtis transformations needed to connect any two of the presentations is at least expmi(N).

Keywords: balanced presentations
geometry
group theory
Advisor: Nabutovsky, Alex
Width, Ricci Curvature, and Bisecting Surfaces

In this thesis we studied width-volume inequalities, bisecting surfaces in three spheres, and the planar case of Larry Guth's sponge problem. Our main result is a width-volume inequality for conformally non-negatively Ricci curved manifolds. We obtain several estimates on the size of minimal hypersurfaces in such manifolds. Concerning geometric subdivision and 3-spheres, we give a positive answer to a question of Papasoglu . Regarding the sponge problem, we show that any open bounded Jordan measurable set in the plane of small area admits an expanding embedding in to a strip of unit height. We also prove that a generalization of the planar sponge problem is NP-complete. This thesis is partially based on joint work with Ye. Liokumovich and Z. Zhu.

Keywords: conformal geometry
geometric inqualities
homological filling
quantitative geometry
Ricci curvature
Advisor: Young, Robert
Rotman, Regina
Impact of Climate Change on Winter Road Systems in Ontario's Far North: First Nations' and Climatological Perspectives on the Changing Viability and Longevity of Winter Roads

Climate change is already being experienced in Ontario’s Far North with implications for First Nations communities that are reliant on winter road systems. The first study of this thesis examined how winter road seasons have been affected historically by particular climate conditions by focusing on the timing of opening dates of the James Bay Winter Road (JBWR). This study established a minimum threshold of 380 freezing degree-days (FDDs) below 0°C, a threshold subsequently used to assess the impacts of climate change on winter road systems in the future using climate change projections. The second study explored the current vulnerability of the Fort Albany First Nation community regarding physical, social/cultural, economic impacts associated with changing winter roads and its seasons, as well as river ice regimes. Through the analysis of key informant interviews and winter road user surveys on the changes in winter roads and river ice regimes, the six major themes were identified. As a result, the JBWR has now become a critical seasonal lifeline for not only providing a relatively inexpensive land transport of essential goods and supplies, but also reconnecting coastal remote communities by physical, social, and cultural activities during winter. The third study focused on the viability and longevity of winter road systems in Ontario’s Far North for the next century using recent climate model projections using three Representative Concentration Pathway (RCP) scenarios. Using FDD threshold established in the first study as the main metric, climate conditions are expected to remain favourable in Big Trout Lake and Lansdowne House during winter road construction through the end of 2100. However, climate conditions would possibly be unfavourable for winter road construction at Moosonee, Kapuskasing, and Red Lake by 2041−2070. These studies demonstrate that there is an immediate need to develop adaptation strategies in response to impacts of climate change on winter roads in Ontario’s Far North.

Keywords: Climate Change
Climate modeling
First Nations
Northern Ontario
Winter roads
Advisor: Gough, William A.
Synthesis and Biological Evaluation of Antibacterial Small Molecule Activators of Caseinolytic Protease P and the Synthetic Utility of Metal Carboxylate Salts in Amidation Reactions with Amines

This thesis is presented in two parts and summarizes work carried out in the laboratory of Professor Robert A. Batey at the University of Toronto from September 2009 through March 2016. Part 1 of this thesis covers the synthesis and biological evaluation of two types of small molecules which target bacterial Caseinolytic Protease P (ClpP); these are the cyclic acyldepsipeptide (ADEP) class of antibiotics and related analogues (Chapter 2) and the ACP1 analogues (Chapter 3). Part 2 of this thesis outlines work related to the synthetic utility of metal carboxylate salts in amide bond-forming reactions with amines. Part 1 of this thesis begins with an introductory chapter (Chapter 1) on antibiotics to familiarize the reader with antibiotic classes, bacterial mechanisms of drug resistance as well as strategies for antibacterial drug discovery. Next, Chapter 2 details the total synthesis and biological evaluation of the A54556 ADEP natural products and related analogues. In the course of our investigations on this class of compound, a rapid two-step synthetic approach was developed that utilized a combination of solid-phase peptide chemistry and a novel lanthanide salt-promoted macrolactonization reaction. Importantly, this methodology was used to prepare several structurally diverse analogues. Chapter 3 then describes the synthesis and biological evaluation of ACP1 and related analogues. In contrast to the ADEPs, ACP1 was discovered using a high-throughput screen and several structurally unique analogues were synthesized in an attempt to improve potency and understand the structural features that impart biological activity. Part 2 of this thesis covers amidation reactions from the direct coupling of metal carboxylate salts with amines or ammonium salts in the presence of the coupling reagent HBTU (Chapter 4). A wide variety of carboxylate salts were examined and the methodology was later extended to multistep, one-pot variants using carboxylate salts that were generated in situ.

Keywords: Amidation
Antibacterial
Carboxylate Salts
Depsipeptides
Small Molecules
Synthesis
Advisor: Batey, Robert A
Inhibition of eIF2α Kinases by Viral and Small Molecule Inhibitors

Phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 (eIF2α) on Ser51 is a key event in the eukaryotic stress response pathway. Specifically, this phosphorylation signal potently blocks protein synthesis, which allows cells to conserve energy under stress conditions, to upregulate genes that promote stress remediation, or alternatively, to induce apoptosis should the triggering insult become insurmountable. Phosphorylation of eIF2α is carried out by the eIF2α family kinases comprised of four prototypical members in mammals: the heme-regulated inhibitor kinase (HRI), the RNA-dependent protein kinase (PKR), the PKR-like endoplasmic reticulum kinase (PERK) and the general control nonrepressible 2 kinase (GCN2). Due to the importance of maintaining protein homeostasis under stress conditions, misregulation of eIF2α kinases underlies the pathophysiology of many human diseases including diabetes, neurodegeneration and cancer, and has thus propelled these kinases as attractive targets for pharmacological intervention in the clinical setting. Moreover, since conserved or all together novel eIF2α kinases have also been identified in pathogenic protozoans such as Plasmodium and Toxoplasma, targeting these kinases have also gained traction for the treatment of malaria and related infectious diseases. While much work has been done to elucidate the catalytic switching mechanism of eIF2α kinases as well as the activated state of their catalytic domains, little is known about how eIF2α kinases become inhibited. The work described in this thesis was conducted with the aim of exploring the inhibition of eIF2α kinases by viral or small molecule inhibitors using a combination of structural biology, biochemistry, and cell biology approaches. In chapter 2 a biochemical and biological framework is described detailing how a baculovirus-encoded protein kinase mimic called PK2 inhibits human PKR and insect HRI eIF2α kinases by a novel lobe-swap mechanism of action. In chapter 3, a high-throughput kinase activity screen was performed, which led to the discovery of five small molecule inhibitors of the plasmodium eIF2α kinase PK4. These inhibitors were then validated in vitro and in vivo with respect to both mechanism of action as well as therapeutic potential in malaria. These results have broad implications for understanding catalytic switching and inhibitor design for eIF2α family kinases and their therapeutic application in disease.

Keywords: antimalarial kinase inhibitor
eIF2α kinase
lobe-swap
PK2
PKR
HRI
PK4
viral mimicry
Advisor: Sicheri, Frank