VictorJuiz/thesis huggingface dataset:
High Vitamin Intakes during Pregnancy and Characteristics of Metabolic Syndrome in Wistar Rat Dams and their Offspring

High vitamin (HV), AIN-93G diet with ten-fold the regular amount of vitamins (RV), consumed by pregnant Wistar rats increases characteristics of metabolic syndrome (MetS) in their first litters. Therefore, the effects of the maternal HV-diet on tissue mechanisms regulating insulin resistance in offspring (Part 1) and on characteristics of MetS in the dams and their second litter (L2) offspring (Part 2) were examined. Part 1 (studies 1 and 2) hypothesis was that the maternal HV-diet alters tissue fatty acid (FA) concentrations, expression of peroxisome-proliferator-activated receptors (PPARs) genes, and their regulation of metabolism in the offspring, favoring insulin resistance. Part 2 (studies 3 and 4) hypothesis was that high-vitamin intakes during the first pregnancy increase weight gain, food intake and markers of MetS in both the dams and their litters. In all experiments, dams were fed the RV or HV-diet. In study 4, a high-folic-acid-diet (HFol, RV+10-fold folic acid) was added. In studies 1 and 2, the offspring were weaned to an obesogenic diet. The HV-diet affected tissue FA concentrations (study 1), increased muscle PPAR-ɑ mRNA levels and uncoupled relationships between hepatic PPAR-γ mRNA levels and insulin resistance (study 2) in male offspring. In study 3, dams fed the HV-diet during the first pregnancy were maintained on the RV-diet and then mated again after 12wk. Their litters were fed the RV-diet. The HV-diet increased weight gain and food intake of both dams and L2, and insulin resistance in their offspring. In study 4, both HV and HFol-diets increased post-weaning weight gain, but differed in their effects on biomarkers of food intake regulation. In conclusion, feeding the HV-diet during the first pregnancy increases post-weaning body weight and food intake in Wistar rat dams, uncouples tissue regulation of glucose metabolism and promotes characteristics of MetS in their litters. Folic acid is not the only vitamin involved.

Keywords: multivitamins
pregnancy
fetal programming
folic acid
Advisor: Anderson, G. Harvey
Ma, David W. L.
Isolation and Characterization of Colon Cancer-initiating Cells

Colorectal cancer is the second leading cause of death from cancer (men and women combined) in the U.S. and Canada. The mainstay of treatment remains surgical resection and although new agents are constantly emerging to treat colorectal cancer, to date none of the agents have been successful at curing patients with advanced disease. In recent years there has been an increasing interest in the notion that cancers are organized as a hierarchy with the cancer-initiating cell (C-IC or cancer stem cell) existing at the apex. The C-ICs only represent a subset of the total tumour cells; however, research indicates that they are responsible for both the initiation and maintenance of tumour growth. In the studies presented here, we determined that human colon cancers are organized in a hierarchical manner. Furthermore, we prospectively isolated a subset of colon cancer-initiating cells (CC-ICs) based on the expression of the cell surface marker, CD133. The identification of CC-ICs has led to a number of questions concerning the molecular mechanisms driving these cells. Functionally all C-ICs are characterized by their ability to: i) generate a xenograft that histologically resembles the parent tumour from which it was derived, (ii) be serially transplanted in a xenograft assay thereby demonstrating the ability to self-renew and, (iii) generate daughter cells that possess some proliferative capacity but are unable to maintain the cancer because they lack intrinsic regenerative potential. It is becoming evident that cancer cells evolve as a result of their ability to hijack normal self-renewal pathways, a process that can drive malignant transformation. Studying self-renewal in the context of cancer and C-IC maintenance will lead to a better understanding of the mechanisms driving tumour growth. In this work we demonstrate that the inhibitors of differentiation genes (Id1 and Id3) play a central role in driving self-renewal in the CC-IC subset. Furthermore, we demonstrate that this effect is partially mediated through the cdk-inhibitor, p21cip1/waf1.

Keywords: colon cancer
initating cells
Advisor: Gallinger, Steven
The Role of NKR-P1B:Clr-b Recognition in NK Cell Mediated Immunity To Cytomegalovirus Infection

NK cells are innate lymphocytes that are crucial for host immunity during infections. Discrimination between healthy and infected cells is facilitated through a sum of inhibitory and stimulatory signals. Host cells can modulate the expression of NK ligands in response to infection, transformation, and stress, while viruses can exploit these mechanisms to prevent the killing of the infected cells. This thesis focuses on the interaction between the NK receptor, NKR-P1B, and its ligand, Clr-b. First, we used a reporter cell-based protocol to establish hybridomas producing monoclonal antibodies against a putative viral immunoevasin, RCTL. We express CD3ζ-fusion proteins on the reporter cells, which we then use to immunize and screen hybridoma specificities. Our results demonstrate a rapid, efficient, and high-throughput method of monoclonal antibody screening, and provide the framework for our work on cytomegalovirus evasion of the NKR-P1B:Clr-b system. Next, we show that RCMV infection results in a notable downregulation of rClr-b at the protein and transcript levels. Conversely, RCTL is upregulated during infection, and binds to the same NK-inhibitory receptor as Clr-b, NKR-P1B. In the absence of RCTL, RCMV-mediated Clr-b loss leads to increased NK-killing of infected targets and an NK-dependent reduction of viral titers in vivo. Notably, NKR-P1B is highly polymorphic, and certain rat NKR-P1B alleles have lost binding to the viral RCTL but not to the host Clr-b molecule, suggesting co-evolution between the host and the virus. In the next chapter, we address some of the mechanisms responsible for CMV-mediated Clr-b downregulation, and show that Clr-b downregulation also occurs to mice in response to MCMV infection. Moreover, early gene expression (host or viral) appears to be required for Clr-b downregulation. Interestingly, engagement of any one conventional pattern recognition receptor is insufficient to mimic MCMV-mediated Clr-b downregulation. Similarly, fibroblasts lacking various intermediates for the interferon or inflammasome pathways still downregulate mClr-b, with the exception of the DNA sensor, Zbp-1. Lastly, a recently identified autocatalytic motif conserved in the rat and mouse Clr-b transcripts, the hammerhead ribozyme, appears to be involved in Clr-b regulation. Taken together, our results explore a novel and important role for NKR-P1B:Clr-b interactions in viral immunity.

Keywords: Immunology
Infectious Disease
Advisor: Carlyle, James Robert
Pre-B Cell Colony-enhancing Factor (PBEF) Promotes Neutrophil Inflammatory Function through Enzymatic and Non-enzymatic Mechanisms

Pre-B Cell Colony-Enhancing Factor (PBEF) is a cytokine-like molecule that functions as a nicotinamide phosphoribosyl transferase (Nampt) in a salvage pathway of NAD biosynthesis. PBEF has well-characterized activity as an extracellular inflammatory mediator and has been proposed to signal through the insulin receptor (IR). As neutrophils are key effectors of the innate immune response to infection and injury, we hypothesized that PBEF promotes pro-inflammatory function in neutrophils and that these pro-inflammatory effects may occur through interactions with the neutrophil IR or through PBEF’s enzymatic Nampt activity. Our studies focused on two important facets of neutrophil inflammatory function: their ability to generate reactive oxygen species (ROS) and undergo constitutive apoptosis. We found that, although PBEF does not activate oxidative burst on its own, it primes for ROS generation through the NADPH oxidase. PBEF promotes membrane translocation of cytosolic NADPH oxidase subunits p40phox and p47phox, but not p67phox, induces p40phox phosphorylation and activates Rac. Priming, translocation and phosphorylation are dependent on activation of p38 and ERK mitogen activated protein kinases. PBEF priming of neutrophils occurs independent of its Nampt capacity or of interactions with IR. We next investigated the effects of PBEF on neutrophil constitutive apoptosis. Our lab previously established that extracellular PBEF delays neutrophil apoptosis. Accordingly, we next investigated the mechanism through which this delay was occurring. PBEF-induced delayed apoptosis was enhanced in the presence of Nampt substrates, and NAD alone could delay apoptosis to an extent comparable to PBEF. Delayed apoptosis was blocked by a Nampt inhibitor and was lacking when a mutated PBEF deficient in Nampt activity was utilized. The cell-surface NAD glycohydrolase, CD38, can convert NAD to cyclic ADP-ribose (cADPR). Blocking CD38 activity with a blocking antibody partially reversed the delay of apoptosis induced by PBEF in conjunction with its substrates, and delayed apoptosis could be achieved by addition of the CD38 product cADPR. Finally, we found that delayed apoptosis induced by PBEF did not involve IR. These results indicate that PBEF can prime for enhanced oxidative burst and delay apoptosis in neutrophils, and that these phenomena occur through distinct mechanisms.

Keywords: Inflammation
Neutrophil
Apoptosis
Oxidative burst
Innate immunity
Nampt
NAD
PBEF
Advisor: Marshall, John
Dissecting the Role of 4-1BB and its Ligand in Enhancing CD8 Effector and Memory T Cell Responses

The Tumor necrosis factor receptor (TNFR) family member 4-1BB and its TNF family ligand, 4-1BBL, are important in modulating multiple stages of the CD8 T cell response. Here I show that during a mild influenza infection, 4-1BBL is completely dispensable for initial T cell responses, viral clearance and mouse survival. In contrast, during severe influenza infection with prolonged viral load, 4-1BB expression is sustained on lung T cells and 4-1BBL is upregulated in the lung compared to mild influenza infection. Under these conditions, 4-1BBL-deficiency results in a decreased CD8 T cell response in the lungs, higher viral load, impaired lung function and increased mortality. These findings suggest that the sustained expression of 4-1BB and its ligand as a function of viral load fine-tunes the CD8 T cell response to a level appropriate for the severity of infection. 4-1BBL is also important for maintaining CD8 memory T cell survival following the clearance of an infection. I found that 4-1BB is selectively expressed on a subset of memory CD8 T cells in the bone marrow. I further showed that the TNFR family member GITR is intrinsically required on CD8 memory T cells for 4-1BB expression in vivo, and that 4-1BB on CD8 T cells interacting with 4-1BBL on a radio-resistant cell in the bone marrow contributes to CD8 memory T cell survival. Immunotherapy with 4-1BB agonists has shown efficacy in eradication of tumors in several mouse models. These effects have been attributed to 4-1BB on multiple cell types. I found that 4-1BB either on transferred T cells or on host T cells was necessary and sufficient for inducing regression of established tumors when anti-4-1BB is combined with adoptive T cell therapy. This thesis highlights the importance of the CD8 T cell intrinsic role of 4-1BB in the immune system.

Keywords: 4-1BB
CD8 T cells
Influenza
Tumor immunotherapy
CD8 memory T cells
Co-stimulation
Advisor: Watts, Tania
Bayes Rules: A Bayesian-Intuit Approach to Legal Evidence

The law too often avoids or misuses statistical evidence. This problem is partially explained by the absence of a shared normative framework for working with such evidence. There is considerable disagreement within the legal community about how statistical evidence relates to legal inquiry. It is proposed that the first step to addressing the problem is to accept Bayesianism as a normative framework that leads to outcomes that largely align with legal intuitions. It is only once this has been accepted that we can proceed to encourage education about common conceptual errors involving statistical evidence as well as techniques to limit their occurrence. Objections to using Bayesianism in the legal context are addressed. It is argued that the objection based on the irrelevance of statistical evidence is fundamentally incoherent in its failure to identify most evidence as statistical. Second, objections to the incompleteness of a Bayesian approach in accounting for non-truth-related values do place legitimate limits on the use of Bayesianism in the law but in no way undermine its normative usefulness. Lastly, many criticisms of the role of Bayesianism in the law rest on misunderstandings of the meaning and manipulation of statistical evidence and are best addressed by presenting statistical evidence in ways that encourage correct understanding. Once it is accepted that, put in its proper place, a Bayesian approach to understanding statistical evidence can align with most fundamental legal intuitions, a less fearful approach to the use of statistical evidence in the law can emerge.

Keywords: Legal Evidence
Bayesianism
Reasoning Fallacies
Intuitive Reasoning
Advisor: Heath, Joseph
Ripstein, Arthur
Making Crime TV: Producing Fictional Representations of Crime for Canadian Television

Criminologists and sociolegal scholars have become increasingly interested in studying media representations of crime in popular culture. They have studied representations using content analyses, often examining their “accuracy” against academic research. Alternatively, these scholars have also studied media effects. In contrast to these studies, I focus on the television production process of making entertaining, dramatic representations of crime. In doing so, I empirically address the following research question: how do TV writers know about crime, and how do they transform that knowledge into fictional representations? I answer this question using a triangulation of methods to gather data – specifically, ethnography, archival research, and interviews with writers and producers – and through the juxtaposition of several case studies. My case studies include the following Canadian crime television programs: 1) the police drama 'The Bridge,' 2) an original Canadian drama about insurance fraud, 'Cra$h and Burn,' and 3) crime docudramas, such as 'F2: Forensic Factor' and 'Exhibit A: Secrets of Forensic Science.' Taking cues from Bruno Latour’s actor-network theory, I focus on the site-specific, concrete, dynamic processes through which each television production makes fiction. I conceive of the writers’ room as a laboratory that creates representations through collaborative action and trial and error. This research demonstrates that, during the production process, representations of crime are unstable, constantly in flux as various creative and legal entities compel their revision. Legal entities, such as Errors and Omissions insurance and broadcasters’ Standards and Practices, regulate the content and form of representations of crime prior to their airing. My findings also reveal the contingency of (commercial) success, the heterogeneity of people who make up television production staff, and the piecemeal state of knowledge that circulates between producers, network executives and writers.

Keywords: representations of crime
cultural criminology
actor network theory
television production studies
Advisor: Valverde, Mariana
Component Modeling and Three-phase Power-flow Analysis for Active Distribution Systems

This thesis presents a novel, fast, and accurate 3 steady-state power-flow analysis (PFA) tool for the real-time operation of the active distribution systems, also known as the active distribution networks (ADN), in the grid-tied and islanded operating modes. Three-phase power-flow models of loads, transformers, and multi-phase power lines and laterals are provided. This thesis also presents novel steady-state, fundamental-frequency, power-flow models of voltage-sourced converter (VSC)-based distributed energy resource (DER) units. The proposed models address a wide array of DER units, i.e., (i) variable-speed wind-driven doubly-fed asynchronous generator-based and (ii) single/three-phase VSC-coupled DER units. In addition, a computationally-efficient technique is proposed and implemented to impose the operating constraints of the VSC and the host DER unit within the context of the developed PFA tool. Novel closed forms for updating the corresponding VSC power and voltage reference set-points are proposed to guarantee that the power-flow solution fully complies with the VSC constraints. All the proposed DER models represent (i) the salient VSC control strategies and objectives under balanced and unbalanced power-flow scenarios and (ii) all the operating limits and constraints of the VSC and its host DER unit. Also, the slack bus concept is revisited, associated with the PFA, where a 3 distributed slack bus (DSB) model is proposed for the PFA and operation of islanded ADNs. Distributing the real and reactive slack power among several DER units is essential to provide a realistic power-flow approach for ADNs in the absence of the utility bus. The proposed DSB model is integrated with the developed 3 PFA tool to form a complete ADN PFA package. The new PFA tool, including the proposed DER and DSB models, is tested using several benchmark networks of different sizes, topologies, and parameters. Many case studies, encompassing a wide spectrum of DER control specifications and operating modes, are conducted to demonstrate (i) the numerical accuracy of the proposed models of the DER units and their operating constraints, (ii) the effectiveness of the proposed DSB model for the islanded ADN PFA, and (iii) the computational efficiency of the integrated PFA software tool irrespective of the network topology and parameters.

Keywords: Smart Grids
Voltage-Sourced Converter
Active Distribution Networks
Three-Phase Power-Flow
Advisor: Iravani, Mohammad Reza
Exploring the Roles of Lysine Deacetylases in Saccharomyces cerevisiae

This work investigates two distinct roles of lysine deacetylases (KDACs) in the budding yeast Saccharomyces cerevisiae. The first part focused on the classical, well characterized role of KDACs as transcriptional regulators and deciphering their role in G1 transcription. I show that two yeast KDACs, Rpd3 and Hos3 are recruited to G1 promoters through their interactions with the negative regulator Whi5 and that these KDACs are necessary for proper Whi5-mediated repression. The second part examines a newly discovered role for KDACs extending their role beyond the chromatin as modifiers of proteins other than the histones. I present here the first systematic approach that comprehensively examines these non-histone targets of KDACs in vivo. I identified 73 non-histone proteins acetylated in vivo involved in diverse cellular processes. Swi4, a component of the G1 transcription factor SBF, was identified in the Rpd3 screen and I show that the interaction between Swi4 and its heterodimeric partner Swi6 was regulated by acetylation. My findings significantly expand the scope of the yeast acetylome and demonstrate the utility of systematic functional genomic screens to explore enzymatic pathways.

Keywords: Cell cycle
Lysine Deacetylase
Functional Genomics
Advisor: Andrews, Brenda
“Governing” the “Girl Effect” through Sport, Gender and Development? Postcolonial Girlhoods, Constellations of Aid and Global Corporate Social Engagement

The “Girl Effect” is becoming a growing global movement that assumes young women are catalysts capable of bringing social and economic change to their families, communities and countries, particularly in the Two-Thirds World. The evolving discourse associated with the Girl Effect movement holds implications for sport, gender and development (SGD) programs. Increasingly, SGD interventions are funded and implemented by transnational corporations (TNCs) as part of the mounting portfolio of global corporate social engagement (GCSE) initiatives in development. Drawing on postcolonial feminist international relations theory, cultural studies of girlhood, sociology of sport and governmentality studies, the purpose of this study was to explore: a) how young women in Eastern Uganda experience SGD programs; and b) how constellations of aid relations among a sport transnational corporation (STNC), international non-governmental organization (INGO), and southern non-governmental organization (SNGO) impacted and influenced the ways that SGD programs are executed, implemented and “taken up” by young women. This study used qualitative methods, including 35 semi-structured in-depth interviews with organizational staff members and young women, participant observation and document analysis in order to investigate how a SGD program in Eastern Uganda that is funded by a STNC and INGO used martial arts to build young women’s self-defence skills to help address gender-based, sexual and domestic violence. Results revealed martial arts programming increased confidence, challenged gender norms, augmented social networks and provided social entrepreneurial opportunities. At the same time, the program also attempted to govern young women’s sexuality and health, but did so while ignoring culturally distinct gender relations. Findings also highlighted the colonial residue and power of aid relations, STNC’s brand authority over SGD programming, the involvement of Western actors in locating “authentic” subaltern stories about social entrepreneurial work in SGD, and how the politics of the “global” sisterhood is enmeshed in saving “distant others” in gender and development work. Overall, this study found that the drive for GCSE, when entangled with neo-liberal globalization, impels actors working in SGD to look to social innovation and entrepreneurship as strategies for survival in an increasingly competitive international development climate.

Keywords: global governance
sociology of sport
postcolonial feminist theory
girlhood studies
corporate social responsibility
international relations
Advisor: MacNeill, Margaret
Kidd, Bruce