VictorJuiz/thesis huggingface dataset:
The Diabetogenic Effects of Antipsychotic Medications: From Rodents to Humans

A growing body of literature has linked atypical antipsychotics (AAPs) to an increased propensity for weight gain and metabolic disturbances, including type 2 diabetes. While weight gain is a leading risk factor for diabetes, evidence suggests that AAPs may influence glucose homeostasis independently of changes in adiposity. These ‘direct’ drug effects have been consistently supported by animal models, where following even a single dose of certain AAPs immediate effects are observed with noted perturbations on insulin sensitivity, and insulin secretion. However, the mechanisms underlying these effects remain poorly understood. Also, the translational value of the acute dosing rodent model has not been established in humans. As such, we set out to first elucidate mechanisms of these ‘direct’ effects by deconstructing antipsychotic receptor binding profiles using selective antagonists and gold standard clamping techniques to examine effects on glucose metabolism. We also investigated antipsychotic administration directly into the brain in rodents to tease out central vs. peripheral effects on glucose metabolism. Finally, we examined whether the effects of a single dose of olanzapine on glucose metabolism could be replicated in healthy humans, independently of adiposity or the confounding effects of the illness of schizophrenia. Our findings suggest that cholinergic, serotonergic, and dopaminergic pathways may be involved in antipsychotic-induced glucose dysregulation. We also suggest that such effects may be mediated in part through the central nervous system. Our results in humans suggest that acute drug effects may be less pronounced than in rodents, failing to note an effect on insulin sensitivity or secretion, but observing other early perturbations in lipid and glucose metabolism. Taken together, the work here begins to elucidate mechanisms underlying the diabetogenic risk associated with AAPs, findings which have important implications given the widespread use of these drugs, as well as the increased mortality attributable to cardiovascular disease that defines those with schizophrenia.

Keywords: diabetes
antipsychotic medications
Advisor: Remington, Gary
Working Memory Training in College Students with Attention-deficit/Hyperactivity Disorder and Learning Disabilities

Working memory (WM) refers to the information processing system that is responsible for the maintenance plus manipulation of information. WM is necessary for the performance of complex tasks, such as reasoning and comprehension. Until relatively recently, WM capacity was thought to be a fixed trait of the individual. However, research findings on the effects of WM training programs have demonstrated otherwise. Therefore, this dissertation examined the impact of WM training in college students with Attention-Deficit/Hyperactivity Disorder (ADHD) and Learning Disabilities (LD), two neuro-developmental disorders in which WM is impaired. The main objectives of this dissertation were to investigate training gains on the WM training program itself, transfer effects, and 2-month maintenance effects. College students with ADHD/LD, all of whom were registered with student disability services, were randomized to either the WM training program or a wait-list control group. Those who received WM training showed significantly greater improvements in the criterion WM measures (WAIS-IV Digit Span, CANTAB Spatial Span) and self-reported fewer ADHD symptoms and daily cognitive failures, compared to the control group. Analysis of participants who completed the follow-up assessment indicated that the gains in WM were maintained for at least 2 months after training. The dissertation is presented in four chapters. The introduction provides a broad overview of the research on WM, ADHD/LD, and WM training. The second chapter expands upon the methods used in the current study. The third chapter consists of a manuscript that will be submitted for publication. The fourth and final chapter summarizes the findings of the current study and discusses its implications for future research and clinical practice.

Keywords: Working Memory
ADHD
Advisor: Tannock, Rosemary
Lsr2: An H-NS Functional Analog and Global Regulator of Mycobacterium tuberculosis

Mycobacterium tuberculosis (M. tb), the etiological agent of tuberculosis (TB), continues to be one of the leading global health challenges causing ~2 million deaths annually. In the majority of infected individuals, the bacteria establish a latent, asymptomatic infection capable of persisting for decades with 5-10% of infected individuals developing active disease in their lifetime. Currently it is estimated that one-third of the world’s population is latently infected, representing a large reservoir for disease reactivation and subsequent spread. Latent TB infection is a paucibacillary disease in which a small heterogeneous population of bacilli is present in the body. M. tb persisters, which are characterized by reduced or altered metabolic activity and enhanced drug tolerance, are thought to be the major contributor towards latent infection and disease relapse following chemotherapy; however, the molecular mechanisms governing persisters formation remain poorly understood. My thesis concerns the characterization of the highly conserved DNA binding protein Lsr2 of mycobacteria. Previous biochemical study of Lsr2 revealed it exhibits DNA-bridging activity analogous to H-NS, an important nucleoid associated protein found in the proteobacteria. iii Here I show using in vivo complementation assays that Lsr2 is functionally equivalent to H-NS, even though these proteins share no sequence similarity. I also present genetic evidence that Lsr2 is a global regulator of M. tb that acts primarily as a transcriptional repressor. Notably, I found that Lsr2 represses a large cohort of genes induced in M.tb during in vitro models of latency including genes implicated in persister formation. I also present evidence that lsr2 is selectively inactivated during long-term hypoxia, a condition thought to be important for persister formation during latency. Lastly, I tested the lsr2deletion mutant in a mouse model of infection and found it had reduced growth relative to the WT but was still able to persist. Taken together my work implicates Lsr2 as a central regulator of persister formation and opens up exciting future research avenues on latent TB infection.

Keywords: Tuberculosis
Genetics
Advisor: Liu, Jun
Serotonin 5-HT Receptor Currents in the Healthy Rodent Prefrontal Cortex and in a Model of Affective Disorders

Affective disorders represent one of the greatest global burdens of disease. Work in patients with affective disorders demonstrates that serotonin (5-HT) signaling within the prefrontal cortex, particularly at the level of the 5-HT receptors, plays an integral role in both the pathology and treatment of these diseases. Surprisingly, the characterization of the prefrontal 5-HT receptors under both healthy and pathological conditions remains incomplete. The technique of whole cell electrophysiological recording provides an unparalleled tool for investigating the functional effects of these 5-HT receptors on neurons in acute prefrontal cortical slices. The objectives of my thesis were to delve deeper into the 5-HT receptor subtypes that modulate the prefrontal cortex in the healthy control rodents and to examine how this modulation was disrupted in a rodent model of affective disorders. In work from healthy control rodents, I examined two prefrontal 5-HT receptor-mediated currents. I show for the first time the presence of the 5-HT1A receptor during the early postnatal period, a critical developmental window during which this receptor programs adult anxiety behaviors. In adulthood, I characterized an inhibitory current mediated by the 5-ht5A receptor; findings that will permit the classification of this receptor within the 5-HT receptor family. Collectively, this investigation of functional early 5-HT1A receptors and adult 5-ht5A receptors offers a novel conceptual framework for understanding 5-HT receptor modulation of the healthy prefrontal cortex. To model vulnerability to affective disorder in the rodent, I used the early stress of maternal separation. In early stress rodents, I observed a marked increase in 5-HT1A receptor currents during the early postnatal period, the critical time window for the programming of anxiety. By comparison, in adulthood I found that rodents exposed to early stress displayed increased 5-HT2A receptor currents. These findings provide novel insight into the developmental and long-lasting pathology underlying early stress, indicating that the early prefrontal 5-HT1A receptor and adult prefrontal 5-HT2A receptors as a potential therapeutic target in treatment of affective disorders At a fundamental level, the findings provided herein offer critical insight into the cellular mechanisms underlying affective disorders, one of the most debilitating and costly diseases worldwide.

Keywords: Serotonin
Electrophysiology
Prefrontal cortex
5-HT
Anxiety
Depression
Maternal Separation
Stress
pyramidal neuron
acute slice
psychiatric disorders
development
early life stress
whole-cell
Advisor: Lambe, Evelyn K.
Between the Idea and the Reality: An Intersectional Anlaysis of the Challenges of Teaching Health Advocacy as a Means to Achieve Social Responsibility in Medicine

Canada, like other countries around the world, has health inequities. The literature on social accountability and responsibility urges medical schools to be grounded in the needs of communities to address health inequities. The Canadian professional and regulatory bodies promote the CanMEDS Competencies of which one, the Health Advocate Competency, speaks of addressing community issues. Yet medical schools face challenges actualizing social responsibility and teaching the Health Advocate Competency. Therefore it is important to understand how the teaching of health advocacy and social responsibility is incorporated into the undergraduate curricula of self-defined socially responsible medical schools in Canada. In this study, mixed methods were used beginning with a semi-structured questionnaire administered to undergraduate Course Directors at two medical schools in Canada with a response rate of 74% (n=60). This was followed by a series of open-ended interviews with eleven equity leaders to bring their perspective into the data collection and establish knowledge about frontline intersectional equity work. The major theoretical lens encircling this work was intersectionality which examines historical oppression and how the intersection of gender, race, and class compound health inequities. Questionnaire results made it clear that biomedical ideology and the CanMEDS Medical Expert Competency were privileged in the undergraduate curriculum at the expense of other knowledge such as health advocacy and social responsibility. The objective biomedical discourse ignores or marginalizes important social influences on health which are highlighted by using an intersectional lens. The semi-structured interviews provided rich data about working in an intersectional equity framework highlighting the impact of the intersections of race, gender, class and other identities on health inequities. These interviews also demonstrate the importance of health advocacy in improving health care outcomes and addressing social responsibility. Incorporating intersectionality into previously accepted assessment tools for physicians adds an important dimension to the health care encounter. Explicitly embedding social responsibility and health advocacy in the medical school mission and curriculum is essential to their acceptance. A series of supporting recommendations are offered.

Keywords: health advocacy
social responsibility
intersectionality
medical schools
determinants of health
medical education
Advisor: Magnusson, Jamie Lynn
Robust Network Design and Robustness Factor

This thesis presents a robust design approach for communication networks that includes capacitation and routing strategy design. Robustness is a mandatory property of core networks to respond to perturbations in network parameters for performance stability and reliable service delivery to different customers. Our proposed design approach is applicable to any system that is modelled by a weighted directed graph. To quantify the robustness measure, we borrow and develop different concepts and properties from Markov chain literatures as well as graph theory survivability discussions. We propose a new robustness definition for Markov chains. The new Markov chain robustness definition has different applications in network design. We define robustness as the sensitivity of the mean first passage time between any two states of the Markov chain. This sensitivity is measured based on the variations of the mean first passage times to the perturbations in transition probabilities. We show that this definition of robustness is related to the sensitivity of the betweenness of a node/state in a Markov chain, which is defined as the number of visits by a random walker that wanders around in the Markov chain according to its transition probabilities. It was shown that for an infinite walk, the proportion of number of visits to the total number of hops converges to the stationary probabilities. Therefore, an analogy can be seen between the well-known condition number and the robustness factor in a Markov chain. We also extend the robustness factor definition to network design problems. We show that the robustness factor can be used as a design criterion. The newly defined robustness factor is a function of the network capacitation, routing and external input and output traffic. We also emphasize the importance of the newly discovered graph theoretic metric, called the Kemeny constant, in network design problems. We discuss that a function of the Kemeny constant and robustness factor limits the sensitivity of network performance parameters to the perturbations in the network.

Keywords: Robustness Factor
Advisor: Leon-Garcia, Alberto
Grade 9 Teachers Use of Technology in Linear Relations

The purpose of this study is to examine secondary mathematics teachers’ perceptions about technology integration in teaching the grade 9 Linear Relations Unit and to investigate the impact of these perceptions and teachers’ everyday practices on the development of student tasks, construction of content knowledge, and facilitation of students’ mathematical communication within the context of the Linear Relations Unit in grade 9 mathematics. Case studies were conducted with three mathematics teachers teaching in three urban secondary schools in Ontario. Qualitative data was collected through a series of ongoing classroom observations of the teachers. Additionally, interviews were conducted at the beginning and end of the data collection phase with each teacher. The results from this study suggest that the teachers perceived that the integration of technology in the Linear Relations Unit assisted them to: 1) create interactive and dynamic learning environments which helped make the content meaningful to students; 2) guide their instruction and to closely monitor students’ understanding and track their progress, by providing real time feedback; 3) help struggling students move forward in their learning when they did not master the prerequisite skills required to build upon a new math concept and to help them develop math interpretative and problem solving skills; 4) differentiate instruction and address different learning styles and skills making abstract content more tangible and helping students connect words to images and graphs; 5) teach students to verify and validate their answers and check for their correctness, as well as to avoid relying only on the visual aspect of mathematics; and 6) assist students build mathematical communication skills. Implications of the findings for future research and suggestions to secondary mathematics teachers integrating technology, in the context of the Linear Relations Unit, are also included.

Keywords: linear relations
technology
teachers' perceptions
Advisor: McDougall, Douglas Emerson
Observations of Reactive Nitrogen Oxides: From Ground Level Ozone Production to Biosphere-atmosphere Exchange in Downwind Forest Environments

In urban areas, emissions of nitrogen oxide radicals (NOx ≡ NO + NO2) to the atmosphere from anthropogenic activities such as fossil fuel combustion contribute to poor air quality through the production of ozone and particulate matter. Soils are also a significant global source of NOx, but at downind forest environments the deposition of transported reactive nitrogen can be much more important than local emissions. Data from a government monitoring network in the Toronto area from 2000-2007 was used to explore the impact of long-term trends in NO2 and other ozone precursors on local ozone levels. Non-linear chemistry and the influence of meteorology explained why reductions in precursor levels during this period did not lead to significant improvements in ozone. Data from this network was also used to investigate the ability of a satellite-borne spectrometer to represent spatial patterns of ground-level NO2 in the same region. Selection biases, resulting from the need to discard satellite data on cloudy days, were shown to affect locations differently and were most severe at a receptor site. The sum of all reactive nitrogen oxides including NOx is known as NOy. A custom-built instrument for high precision and time resolution measurements of reactive nitrogen oxides was tested under various lab and field conditions, and used in field work where direct biosphere-atmosphere exchange of NOy was measured by eddy covariance above two comparable North American mixed forests (Haliburton Forest Wildlife Reserve and the University of Michigan Biological Station). While these forests were found to be small net sources of NOx, they were subject to elevated rates of NOy deposition overall, driven by the transport of polluted air from upwind source regions. Wet deposition measurements were used to show that dry deposition contributed a significant fraction of total deposition during the observation periods.

Keywords: nitrogen oxides
air quality
remote sensing
nitrogen deposition
ground level ozone
land-atmosphere fluxes
Advisor: Murphy, Jennifer
Making Waves without Rocking the Boat: Women&rsquo;s Reinforcement of Gender Status Hierarchies as a Protectant against Discrimination

Research on sex discrimination has found consistent support for the idea that women who violate gender roles by succeeding in male-dominated domains elicit hot forms of discrimination. In particular, evidence suggests that a perceivers' conservatism, which represents a preference against gender change toward greater equality, might motivate this kind of discrimination. Therefore, I hypothesized that perceiver conservatism would predict discrimination against female gender role violators. In two studies, I found evidence that conservatism predicts negative evaluations of targets (Study 1), as well as sabotage (Study 2). In addition, Study 2 revealed that the relationship between conservatism and sabotage was partially mediated by the perceivers' anxiety. However, if the discrimination that conservative perceivers direct at gender role violators is motivated by conservatives' preference against social change toward greater equality, then targets who support gender status hierarchies while they violate gender roles should experience less discrimination from conservative perceivers than those who challenge status hierarchies. Consistent with this reasoning, perceivers' conservatism was negatively related to perceived interpersonal hostility of female gender role violators who expressed support for gender hierarchy. In contrast, perceivers' conservatism was positively related to perceived interpersonal hostility of female gender role violators who expressed opposition to gender hierarchy (Study 1). However, targets' expressions of support for gender hierarchy did not have this effect on the relationship between perceivers' conservatism and perceptions of the target's ineffectuality (Study 1), respect for the target (Study 1), or sabotage of the target (Study 2). Moreover, while supporting status hierarchies reduced perceptions of interpersonal hostility from perceivers high in conservatism, it increased perceptions of hostility from those low in conservatism. Thus, supporting gender hierarchies may appear to help in some contexts, but is associated with significant costs, as well. The implications of these findings for theory and practice are discussed.

Keywords: Social Conservatism
Sex Discrimination
Gender Roles
Advisor: Berdahl, Jennifer
Role of the Cannabinoid System in Modulating the Reinforcing and Relapse Related Properties of Nicotine in Rats

There are several lines of evidence supporting the existence of a pivotal role of the cannabinoid system in mediating the reinforcing effects of nicotine. Characterization of the crosstalk between nicotine addiction and the cannabinoid system may have significant implications for our understanding of the neurobiological mechanisms underlying nicotine dependence. Objectives: The current series of experiments, we investigated the effects of activating CB1 receptors, modulating CB2 receptors as well as elevating levels of the endogenous cannabinoid ligand anandamide on nicotine taking and reinstatement of nicotine seeking behaviour. METHODS: In the first series of experiments, we investigated the effects of pretreatment with the CB receptor agonist WIN 55, 212-2 (0.1-1mg/kg), on nicotine self-administration and on the reinstatement of nicotine seeking behaviour. In the next series of experiments, we used a selective CB1 inverse agonist rimonabant (0.3mg/kg) and CB2 antagonist AM630 (5mg/kg) to delineate wether the effects obsereved with WIN 55, 212-2 are CB1 or CB2 meidated. Moreover, we investigated the effect of selective CB2 receptor activation (AM1241 1-10 mg/kg) and inhibition (AM630 1.25-5 mg/kg) on nicotine self-administration under fixed ratio (FR) and progressive (PR) schedules of reinforcement and on reinstatement of nicotine seeking induced by nicotine associated cues and nicotine priming. Finally, the effects of activation of CB receptors through administration of anandamide reuptake inhibitor VDM11 (1-10 mg/kg) on nicotine self-administration and on reinstatement of nicotine seeking were investigated. RESULTS: WIN 55,212-2 enhanced the break points for nicotine self-administration under a PR schedule of reinforcement, reinstated nicotine seeking behaviour and enhanced cue induced reinstatement of nicotine seeking. Neither activation nor blockade of CB2 receptors affected the responding of the animals for nicotine self-administration under FR or PR schedules of reinforcement or for reinstatement of nicotine seeking induced by nicotine associated cues and priming. Pretreatment with VDM11 dose dependently attenuated the reinstatement of nicotine seeking behaviour induced by nicotine associated cues and priming without affecting stable nicotine self administration. CONCLUSION: CB1 but not CB2 receptors appear to play a pivotal role in modulating the reinforcing effects of nicotine. Inhibition of anandamide reuptake could be a potentially useful tool in modulating relapse to smoking

Keywords: Nicotine
Cannabinoid system
Self-administration
Reinstatement
Advisor: Foll, Bernard Le