VictorJuiz/thesis huggingface dataset:
A Computational Study of the Role of Neurogenesis in Learning and Memory
Keywords: computational
learning
memory
neurogenesis

Neurogenesis persists throughout life in the dentate gyrus of the mammalian hippocampus. There is a large body of evidence that neurogenesis may impact cognition, particularly concerning learning and memory, though it is unclear what mechanisms underlie these processes. Computational models have established that the addition of neurons degrades existing memories (i.e., produces forgetting). These predictions are supported by empirical observations in rodents, where post-training increases in neurogenesis also promote forgetting of hippocampus-dependent memories. However, in these models that use 10-1,000 neurons to represent the dentate gyrus, forgetting is only observed at new neuron addition rates that greatly exceed adult neurogenesis rates observed in vivo. To address this, we generated an artificial neural network that incorporated more realistic features of the hippocampus – including increased network size, sparse activity, and sparse connectivity and explored how these properties modulate the impact of using biologically relevant rates of neurogenesis in a pattern categorization task. Our model captures several mnemonic phenomena associated with neurogenesis, including forgetting and enhanced reversal learning. These effects were sensitive to changes in increased output connectivity and excitability of new neurons. Crucially, forgetting was observed at lower rates of neurogenesis in larger networks, with the addition of as little as 0.1% of the total DG population sufficient to induce forgetting. We also propose a role for neurogenesis in the generalization of memories using traditional deep learning architectures. At rates of 3% turnover, we found that neurogenesis alone improved generalization on unseen data in two commonly used categorization tasks, the MNIST and CIFAR-10 datasets. Together, we suggest not only that low rates of neurogenesis can have an impact on cognition, but that we can use biologically-inspired and artificial neural networks to investigate the computational functions of neurogenesis that may mirror those occurring in vivo as well.
Evidence to Inform Policy Options for the Elimination of Hepatitis C Virus in First Nations Populations in Ontario
Keywords: First Nations Health
Health Economics
Health Services Research
Hepatitis C
Indigenous Health

In Canada, an estimated 220,000-246,000 people currently live with chronic hepatitis C viral (HCV) infection. To achieve the goals set by the World Health Organization (WHO) strategy to eliminate HCV infection by 2030, a mandate for action in the form of the Blueprint to Inform Hepatitis C Elimination Efforts in Canada was released. The Blueprint outlines what is necessary to achieve HCV elimination in Canada, emphasizing the need to inform specific knowledge gaps and calling on provinces/territories to develop action plans to meet the WHO targets for viral elimination. As a part of Canada’s commitment to the WHO strategy and the Blueprint, Canada has made First Nations-led approaches and First Nations populations a priority focus for national and provincial/territorial HCV strategies. Therefore, the purpose of this thesis is to generate evidence that can inform policy options for HCV elimination efforts in First Nations populations in Ontario. In Ontario, recent negotiations have allowed for partnerships between academic researchers and First Nations organizations to perform First Nations-directed research using administrative health data. In partnership with the Ontario First Nations HIV/AIDS Education Circle (OFNHAEC), we examined the health and economic impacts of HCV on Status First Nations populations in Ontario. The first study explored trends in the epidemiology and testing for HCV among a cohort of Status First Nations individuals across Ontario. The second study estimated the provincial publicly-funded healthcare costs associated with HCV among a cohort of Status First Nations individuals in Ontario. The third study uses the example of HCV screening within the emergency department setting to demonstrate how existing research can be used to perform economic evaluations of novel HCV case-finding approaches. With future work and using the evidence generated from this thesis, a similar approach can be used to evaluate First Nations-specific HCV interventions. Collectively, these studies inform research gaps necessary to reach the WHO goals for viral elimination and serve as reference in beginning to understand the impact of infection among First Nations individuals in Ontario. The data presented by this dissertation provides decision-makers with evidence that can inform the creation of HCV policy, prevention, and treatment efforts.
Effect of Folate Dose and Form during Pregnancy on Early- and Later-life Phenotype of the Wistar Rat Mother and Her Female Offspring
Keywords: 1 carbon metabolism
Folate
Folic acid
in utero programming
Maternal programming
Pregnancy

High gestational folic acid (FA, synthetic folate) programs long-term metabolic consequences in the offspring. The hypothesis of this research is that the dose and form of folate consumed during pregnancy determines the post-birth and long-term phenotype of Wistar rat mothers and female offspring through effects on central hypothalamic and peripheral energy regulatory mechanisms. Three studies were conducted. In Study 1, pregnant Wistar rat were fed an AIN-93G diet with FA at 0X, 1X (control), 2.5X, 5X, or 10X recommended levels then switched to a control diet during lactation and for 1-week post-weaning when dams were terminated to address early postpartum effects. In Study 23, pregnant dams were fed either 1X- or 5X-FA or equimolar doses of 5-methyltetrahydrofolic acid (MTHF). Mothers and female offspring were maintained on a high-fat (45% lard) diet for 19 weeks. In Study 1, FA below (0X) or above (5X, 10X) recommended intakes delayed the re-set of body weight and metabolism in dams after birth. In Study 2, both 5X doses delayed post-birth maternal weight-loss but 5X-MTHF compared to 5X-FA dams had greater post-weaning weight-gain and food intake. These effects associated with altered expression of energy regulatory genes in the hypothalamus and peripheral hormones. In Study 3, 5X-MTHF compared to 5X-FA diets increased post-weaning weight-gain and food intake in the female offspring and associated with modified central and peripheral mechanisms. Alterations in folate-mediated 1-carbon metabolism were consistently observed. In conclusion, both folate dose and form during pregnancy alter the early- and later-life phenotype of the Wistar rat mother and her female offspring via central hypothalamic and peripheral energy regulatory mechanisms. Further consideration of the amounts and forms of folates added to the food supply and pre-natal supplements is needed.
Mitochondrial Dysfunction in Bipolar Disorder with a Family History of Mitochondrial Disease: From Family Genetics to Patient-derived Induced Pluripotent Stem Cell-based Neuronal Models
Keywords: Bipolar Disorder
Cerebral Organoids
Genetics
Induced Pluripotent Stem Cells
Mitochondria
Psychiatry

Bipolar disorder (BD) is a complex mood disorder with high heterogeneity and unclear pathophysiology. Mitochondrial dysfunction has been repeatedly observed in BD; however, our understanding of mitochondrial dysfunction remains incomplete due to the lack of patient stratification, nuclear and mitochondrial genomics, and patient-derived neuronal models. The objective of this thesis was to investigate mitochondrial genetics and function in BD with or without a family history of mitochondrial disease. To achieve this, we (1) identified two families, each with at least one surviving member with BD and two deceased offspring with mitochondrial disease and BD patients without family history of mitochondrial disease; (2) performed nuclear and mitochondrial genome sequencing to evaluate family genetics and; (3) developed patient-derived induced pluripotent stem cell- (iPSC-) based neuronal models to uncover mitochondrial signatures specific to BD with a family history of mitochondrial disease. Nuclear and mitochondrial genome sequencing uncovered two novel variants in two genes, NUBPL and COMT, shared amongst BD across two unrelated families. While these variants require functional validation, we showed that bi-genomic sequencing could detect novel variants. Next, we generated patient-derived iPSCs and neural progenitor cells (NPCs). Grouping the family cases by the NUBPL and COMT variants, we identified that BD with a family history of mitochondrial disease presented lower maximal respiration in the iPSCs, higher proton leak and lower total ATP levels in NPCs compared to relatives. Furthermore, BD with a family history of mitochondrial disease presented lower glycolytic markers in the iPSCs than BD without a family history of mitochondrial disease. Our study demonstrates the importance of stratifying the heterogeneous BD patients into mitochondrial-based subgroups to unveil unique signatures of mitochondrial dysfunction. While single-cell models like iPSCs and NPCs offer insights into disease pathophysiology, there is a need to develop a disease model that recapitulates the complexity of the human brain. Therefore, we developed cerebral organoids (COs) from iPSCs derived from human peripheral blood mononuclear cells (PBMCs) and demonstrated preserved mitochondrial genetics and function across PBMCs to iPSCs to COs for the first time. These COs may serve as models to further investigate the role of mitochondrial dysfunction in BD.
Urban Neoliberalism and External Partnerships in the City of Toronto's Tower Renewal Program
Keywords: community-based organizations
local governments
neoliberal governance
public policy delivery
public-private partnerships
urban revitalization

In 2008, the City of Toronto ('the City') adopted Tower Renewal as a municipal policy and program with the stated objective of helping to revitalize Toronto's postwar high-rise apartment buildings and surrounding neighbourhoods. These apartments were built in the post-World War II period and are predominantly privately owned. This dissertation examines the external partnerships that are being employed by the City for Tower Renewal policy development in municipal offices, and implementation in privately-owned postwar apartment buildings. These external partnerships involve planning professionals from private sector firms, non-profit sector organizations, community-based organizations, and private postwar apartment owners. The overarching argument presented in this dissertation is that Tower Renewal demonstrates the complexities and challenges of local public policy development and delivery in the governance context of urban neoliberalism. Neoliberalism is reflected in four main ways in Tower Renewal that include: (1) discourse and practice of fiscal austerity in municipal offices; (2) popularity of partnership-based policy mechanisms; (3) offloading public policy responsibilities to non-governmental actors; and, (4) the constraints and opportunities that diverse urban actors are confronted with in this new era of partnership-based governance, and within urban neoliberalism more broadly. Although external partnerships have been essential for Tower Renewal policy development and delivery since 2008, my research reveals that the participation of external actors is presently unsustainable and ineffective due to the lack of adequate public-sector financial support and incentives. Theoretically, Tower Renewal also challenges the notion of urban actors as simply passive victims of neoliberalism. Throughout this dissertation, documented are instances where diverse urban actors are strategically engaging in neoliberal policy partnerships with some success in incrementally implementing their progressive agendas. It is through establishing multi-sector policy partnerships, which strive towards more socially and environmentally progressive ends, that these urban actors are challenging neoliberalism from within. In the concluding chapter, I suggest ways to better support the involvement of non-profit and private sector actors in Tower Renewal’s external partnerships. I also recommend an alternative, more traditional approach, to the City’s current emphasis on neoliberal policy partnerships.
A Study of the Influence of Global University Rankings on Institutional Strategies, Decision-Making, and Policy Choice: The Case of Four Canadian Research Universities
Keywords: accountability
Canada
global competitiveness
higher education
international university rankings
organizational theory

Since 2003, global rankings have continued to impact higher education at both the systemic and institutional levels. Emerging in an unprecedented period of intensified global economic competition in which the competitive advantage of individual countries runs on knowledge and innovation, these novel rankings have risen rapidly to the forefront of higher education policies in many countries, leading governments to institute new jurisdictional priorities for universities. In implementing rankings, universities have adopted practices and processes that sometimes have had deleterious effects for both sound educational administration and accountability (Hazelkorn, 2011). This multiple-case study examined how the senior leaders of four Canadian research universities formulate responses to their institutions standing in global university rankings.Theoretically, the topic was intellectualized through the lens of two organizational theory perspectives: institutional theory and resource dependence theory. This integrated approach led the researcher to theorize that due to the intensification of reputational advantage mediated by rankings, the four institutions under analysis would change practices, processes, and administrative structures to improve and/or sustain their positions in global rankings. Empirically, the study used a multi-method approach. Thus, data were derived from three qualitative research strategies: (i) document analysis, (ii) 15 semi-structured interviews with senior administrators of participating universities, (iii) website analysis. This provided triangulation and allowed cross-validation of findings. Data analysis revealed three primary areas wherein rankings exert direct influence: rankings-related capacity, international collaborations, and branding. Rankings additionally influence other interrelated areas: legitimacy seeking, strategic positioning, and internal accountability. Additionally, while the analytical framework has shown to have explanatory power, the study found that the leading drivers of these behaviours are isomorphism and resource dependence, with mimetic isomorphism in pursuit of legitimacy trumping rational considerations of resources. Moreover, interviews showed that the source of such nonrational conduct stems from assumptions which predispose senior administrators to overstate the importance of adopting procedures oriented to rankings. The study identifies implications of these sorts of institutional behaviours for the administrative cost of university education and diversity. Implications for policy and practice are also presented that audiences, such as higher education leaders, university administrators, and future researchers may find useful.
Development of Copper-catalyzed Processes towards the Synthesis of Tetrahydroquinolines, Benzoxazinones and Fused Triazoles
Keywords: Borylation
Catalysis
Copper
CuAAC
Heterocycle
Synthesis

The Lautens group has a long-standing interest in the application of transition metal catalyzed reactions in developing strategies towards synthesizing biologically relevant heterocycles. This thesis focuses on the development of various copper-catalyzed transformations that enable the efficient syntheses of tetrahydroquinoline, benzoxazinone, and fused trisubstitued triazole heterocycles. Chapter 1 describes a process to synthesize borylated tetrahydroquinoline scaffolds using a copper-catalyzed borylation of Michael acceptors in tandem with a Mannich-type cyclization. The use of Michael acceptors as π-systems in copper-catalyzed borylation reactions is well known, however their application to generate heterocycles in domino processes remains largely underdeveloped. This strategy is feasible with a broad range of Michael acceptors, and can be leveraged to generate versatile borylated tetrahydroquinoline scaffolds bearing three contiguous stereocenters in a diastereo- and enantioselective fashion. Chapter 2 details the development of a multi-step strategy enabling the synthesis of benzoxazinone scaffolds. The developed method relies on an initial selective copper-catalyzed borylation across an α,β-unsaturated ester or amide, subsequent C−B bond oxidation to generate the reactive alcohol intermediate, and a cyclization to generate the desired heterocyclic product. The application of chiral ligands in this strategy was also demonstrated, generating the benzoxazinone moiety in an enantioselective fashion. Chapter 3 focuses on the utilization of the copper-catalyzed azide alkyne cycloaddition reaction in the synthesis of trisubstituted 1,2,3-triazoles. The mechanism of the copper-catalyzed azide alkyne cycloaddition involves the generation for a nucleophilic copper-triazolide intermediate. Typically, this intermediate undergoes protodemetallation to generate 1,4-disubstituted 1,2,3-triazole compounds. However, the tethering of carbamoyl chloride functional group enables an intramolecular cyclization generating novel, fully-substituted, fused 5-acyl 1,2,3-triazoles.
Program Domains of Trauma-Informed Practice Associated with Client Perception of Care and Staff Perceived Organizational Support: A Study of Women’s Substance Use Programs Utilizing Qualitative Comparative Analysis
Keywords: Client Perception
Culture
Organizational Capability
Staff Experience
Trauma-informed

Background: Trauma-informed practice (TIP) is a strength-based service delivery approach that acknowledges the widespread prevalence and impact of trauma in the lives of both the people seeking services as well as amongst its’ workforce (Harris Fallot, 2001; SAMHSA, 2014). As programs and organizations implement a TIP approach to service delivery, examining the degree to which an organization is able to integrate TIP principles into their practices and operations and how it relates to client and staff perception of care can be helpful for program evaluation. Purpose Objectives: Guided by a Knowledge Based View (KBV) of the firm (Grant, 1997; 2002; 1991) and Resource Based Theory (RBT) (Barney, 1991), this study sought to examine combinations of program domains and the degree to which they are trauma-informed that are associated with client perception of care and staff perceived organizational support. Methods: A case study design involving nine women’s substance use agencies across the province of Ontario, Canada was employed to study TIP organizational capability in six program domains. To facilitate the study of combinations of organizational capability domains that are associated with the outcomes, Qualitative Comparative Analysis (QCA) was used as the main analytic approach. Findings: QCA results indicate, that the degree to which program domains are trauma-informed may not be related to staff perceived organizational support and client perception of care outcomes as anticipated. It is possible that organizational capability in TIP has more distal and perhaps little connection to the outcomes as measured by the SPOS and OPOC. Conclusions: Although the CCTIC has utility to inform program planning and implementation for trauma-informed services, it may be challenged as a tool to evaluate the extent to which program domains are associated with client perception of care and staff perceived support. Future studies should look at replicating the CCTIC as a more refined and calibrated measure of TIP that can be readily used to evaluate TIP as it relates to provider and client experiences of care to inform policy and program evaluation.
Essays on Child Mental Health: Estimating Diagnostic Errors, Latent Risk, and Long-term Trajectories
Keywords: Child Health
Diagnostic Error
Health Economics
Machine Learning
Mental Health

Understanding diagnostic decision-making for child mental illness is the central focus of my dissertation research. I combine multiple quasi-experimental methods and machine learning tools with novel individual-level tax and survey data linkages to explore these issues. Over three papers, I address several sources of diagnostic and treatment errors in child mental illness, stemming from school and home environments. In the first paper, I study how a child's school starting age generates over-diagnosis of ADHD in young-for-grade and male students and missed diagnoses in relatively older students, especially females. Importantly, I demonstrate that teacher special education training mitigates these age-based assessment errors. The second paper investigates multiple sources of under-and over-utilization of mental health care by combining a machine learning-derived mental health risk prediction with multiple exogenous changes in diagnosis and treatment likelihood. These changes include the effect of school starting age on diagnosis and the role of Quebec's pharmaceutical insurance plan expansion on treatment uptake. I identify that over-diagnosis may be driven by over-weighting externalized behaviours, which are more common in males. At the same time, I additionally find that removing out-of-pocket costs increases treatment rates, specifically for high-risk children. The final paper expands upon this work to understand the long-term trajectories of children with mental health issues and heterogeneous treatment effects at the population level. I find that measured gaps in educational attainment, social assistance receipt and income due to child mental illness persist well into adulthood. I find evidence that diagnosis and treatment worsen human capital outcomes like educational attainment and unemployment for low-risk individuals. Nevertheless, treatment can help close mental health-related socioeconomic inequalities, but only for very high-risk children. Together these papers outline the growing issue of mental illness in childhood and its long-term implications. They highlight the potential for diagnostic mistakes or misallocation of care and the role of new data-driven tools to alleviate some of these medical errors. In my concluding chapter, I highlight some of the strengths and limitations of machine learning tools for improving mental illness detection and treatment going forward and point towards critical work required to make these tools useful for clinical practice.