VictorJuiz/thesis huggingface dataset:
Cognitive Phenotype in Pick1 and miR137 Point-mutation Candidate Models for Schizophrenia

With no simple physiological tests available, Schizophrenia can only be diagnosed by its behavioural symptoms. Advances in genetic technology helped to discover hundreds of schizophrenia-associated genes, but most variants contribute just a small amount to risk. New tools to manipulate genes in animals allow for research into the relationship between genes, physiology, and ultimately behaviour. Using animal models to research genes standing atop regulatory networks with multiple links to schizophrenia is a promising avenue for understanding the disorder. Two such genes are the trafficking protein Pick1 and the microRNA miR137. Pick1 has gained interest because of its role in synaptic plasticity by directing transport of glutamate receptors and other important proteins. To examine the role of Pick1 in schizophrenia-related behaviours, mice with an ENU-generated missense mutation in the Pick1 lipid- interacting BAR domain were characterized. Pick1-S262T mice displayed male specific deficits in reversal learning in the Morris water maze (MWM). Adults showed decreased hippocampal synaptic excitability, and deficits in long-term depression (LTD). Underlying these changes were reductions in prefrontal cortex (PFC) expression of glutamate receptor subunits GluR1 and GluR2. This evidence suggests the Pick1-S262T mutation may affect AMPA receptor trafficking leading to disruptions in synaptic plasticity which affect cognitive flexibility. MIR137 has emerged as one of the most robust schizophrenia- associated genes from genome wide association studies. miR137 is implicated in brain development, and human risk variants were shown to have functional relevance. To study the link between miR137 and schizophrenia, a human-like promotor point-mutation near the Mir137 gene (Mir137(A/A)) was introduced into mice using CRISPR/Cas9 technology. Female Mir137 (A/A) mice showed impairments in prepulse inhibition (PPI), working memory measured as spontaneous alternation behaviour, and spatial learning and memory in the MWM. Males displayed improvements in working memory. Mir137(A/A) mice had disruptions in dendritic spine formation and PFC interneuron development which could underlie behavioural deficits. Animal research in disease genetics has focused on major disruptions like complete knockout of genes. These point-mutation mice provide models that more closely reflect human risk variants, revealing how smaller genetic changes can affect disease-relevant processes.

Keywords: miR137
Mouse
Pick1
Schizophrenia
Advisor: Wong, Albert HC
A Black-box Model of Memory Life-span for NAND Flash Devices

The NAND Flash is a solid-state non-volatile memory technology. It performs random access at high speed by its nature with little power. These attributes and a decreasing cost per byte appeal to enterprises seeking cost-effective memories for heavy workloads without equally heavy electricity bills. The NAND Flash manufacturers cut the cost per byte by shrinkingthe size of memory cells and by storing more than one data bit per cell. However, these methods are progressively impacting key resources. The prominent one is Endurance, defined as the maximum bytes writable to a device over its life span. Endurance is related to the memory-cell limit of maximum write and erasure cycles. The culprit for this limit--the end-of-life error ratio of a device, is why State-of-the-art software monitors error ratio to manage cycles consumed off the memory. However, the error ratio is an incomplete description for the remaining cycles. We propose a new metric based on the predicted cycles remaining we call life that provides two advantages. Firstly, it captures the previously ignored rate of change in error ratio. When considering the uncertainty in measurement for the error ratio samples, empirical evidenceindicates the factor yields at least a 20% benefit on Endurance. Secondly, the life metric represents the exact cycle resource, different from the error-ratio metric, which is a piece of partial information. Therefore, it renders future management decisions to make up for earlier suboptimal choices unnecessary, resulting in less overhead. We offer a model to support the new metric with only three parameters compared to the tens of parameters required by the prior art, thus making the scheme suitable for online processing. Experimentally, we achieved a mean accuracy of 3% in predicting the memory life, and we evaluated the benefit of the metric via simulating Endurance management using actual hardware data. With the model alone, we have improved Endurance by 30.8% for the error-ratio-based management. The implication is a new design space where we can exchange the tolerable noise for Endurance. With the proposed life-based metric, we gain an additional 11.6%, proving its edge over the currently best error-ratio metric.

Keywords: Bayesian Model
Black Box
Endurance
Raw Bit Error Ratio
Solid State Drive
Wear Leveling
Advisor: Zhu, Jianwen
Masani, Kei
Making Kin / Unmaking the Colony: Indigenous Refusal in the Era of Colonial Child Removal

The Canadian Truth and Reconciliation Commission’s primary “call to action” is to reduce the number of Indigenous children in out-of-home care in this country. Yet, Indigenous children continue to be apprehended into the child welfare system at rates three times higher than at the peak of the Indian Residential School period (1831-1996). Though there is increasing research on the negative impacts of child removal on Indigenous children, families, and communities there is less research that records and analyzes existing community-based and institutional strategies that prevent, resist, or refuse child welfare interventions broadly and child removal specifically. In partnership with Indigenous caregivers on Vancouver Island, and using a combination of ethnographic and participatory action research methodologies, my dissertation aims to answer one key question: In the context of ongoing and disproportionate colonial child removal, how do Indigenous peoples make and maintain kin? This dissertation foregrounds Indigenous scholarship on refusal, resistance, and resurgence, as well as anthropological analyses of kinship and relationality to answer this question, demonstrating how Indigenous communities reconstitute ancestral care roles, resist colonial extraction, build relational solidarities, and affirm their self-determination despite ongoing colonial interference into the realm of the family. By focusing on Indigenous peoples’ resistance and resilience within the system, this research talks back to a problematic narrative of Indigenous victimhood, illuminating the creative and strategic ways Indigenous caregivers and providers sustain kin both within and on the margins of the settler state.

Keywords: decolonization
Indigenous child welfare
Indigenous kinship
Indigenous peoples in Canada
Indigenous resistance
settler colonialism
Advisor: McElhinny, Bonnie
Bamford, Sandra
Fake Goods and Counterfeit Time: Nigerian Entrepreneurs in a Time of China Rising

China’s exponential economic growth and increasing political influence over the past three decades, described as a time of “China rising,” has created new planetary pulls for ordinary Nigerians looking to get ahead. As such, Nigerian entrepreneurs have flocked to market cities such as Guangzhou and Yiwu, hoping to capitalize on a sought-after speed of development compared to the relatively stagnant Nigerian economy. Migration to China offers Nigerians an opportunity to “catch up” or even “jump ahead” in the teleology of development time. In China, Nigerian entrepreneurs export a range of goods, including low-cost household products, copies of African print fabrics, and counterfeit cosmetic brands. However, I argue that the ubiquity of the counterfeit extends beyond people’s claims about fake and copy “Made in China” goods and instead includes other aspects of life in China. The counterfeit, analyzed through its everyday usage, is better captured by its sensorial and semantic denotations of not quite rather than any strict legal and regulatory definitions. Based on 14 months of fieldwork in Yiwu, China, this thesis shows how China is both desirable and suspicious for Nigerian entrepreneurs as a genuine alternative to a Euro-American model of development. Ambivalence arises when their experiences of time spent, invested, and accumulated in China does not quite match their expectations. This thesis shows how the contradictions of lived time – between experience and expectation – occur because ideas of development encompass more than just economics and politics; they also comprise of materiality, language, culture, bureaucracy, and sociality. These contradictions foreground a specific historical conjuncture of temporalities: the speed of China rising, an African postcolonial time of development as not yet fully materialized, and enduring Euro-American hegemonic ideas about progress. Drawing on Nigerian entrepreneurial life in China, this thesis illuminates a distinct experience of African migrant time at this historical juncture, which I call counterfeit time. Counterfeit time gestures to is one’s indeterminant position in China and the ambiguity of whether one is “getting ahead” or “falling behind.” Hence, China rising is regarded as a near rapprochement that culminates as a pace of development rather than cultivates a place of development.

Keywords: Africa-China
migration and mobility
Nigerian entrepreneurs
Yiwu
China
Advisor: Gaswani, Girish
Lambek, Michael
Elucidating the Interactions Between Circadian L-cell Secretion, the Gut Microbiome, and Intestinal Homeostasis

Circadian rhythms, which are endogenous biological rhythms with a period of approximately 24-hours evolved, due to pre-defined environmental cues, most notably the light-dark cycle. Interestingly, the intestinal epithelium, immune cells and microbiome, all follow a circadian rhythm largely entrained by nutrient intake. Specifically, the enteroendocrine L-cell through the distinct functions of its secretory products, glucagon-like peptide-1 and -2 (GLP-1 and GLP-2), plays an important role in maintaining the overall intestinal environment. The gut microbiome has been extensively linked to L-cell secretion and maintenance of the intestinal environment. Although circadian L-cell secretion has been recently demonstrated, whether this rhythm is entrained by the microbiome as well as its role in the intestine are largely undescribed. Therefore, I hypothesized that the intestinal microbiome and L-cell circadian clock are determinants of L-cell secretion and intestinal homeostasis in mice. Use of diet- and antibiotic-induced microbial depletion (AIMD), as well as germ-free (GF) mice with and without fecal transplantation established the gut microbiome as an essential regulator of time-dependent L-cell secretion. Furthermore, analysis of intestinal structure, mucosal gene expression, and immune composition at the onset of the feeding and fasting periods identified rhythms which were dependent on the presence of an intact microbiome. Moreover, use of L-cell Arntl (core clock gene) knockout mice established the L-cell clock as an important regulator of time-dependent L-cell secretion, intestinal structure, immune composition, and the microbiome. Finally, murine (m) GLUTag L-cells with siRNA-mediated knockdown of Arntl exhibited impaired L-cell secretion as well as downregulation of key pathways involved in vesicular transport, immunity, and epithelial cell integrity processes. In combination, these studies provide novel insight into the interactions between circadian L-cell secretion, the gut microbiome, and intestinal homeostasis. Given that circadian disruption has been extensively linked to intestinal disease, the studies presented herein may aid in the development of therapeutic strategies targeting increasing L-cell secretion to improve intestinal health.

Advisor: Brubaker, Patricia L
Preparation of Lipid-coated NaLnF4 Nanoparticles for High-sensitivity Mass Cytometry Applications

High-sensitivity single-cell bioassays can provide detection, quantification and mapping of low-abundance cellular markers, a key step towards early disease detection. Mass cytometry is a multiparametric single-cell analysis technique in which cellular markers are labelled with heavy metal atoms (mass tags) and then are detected by inductively coupled plasma time-of-flight mass spectrometry. Commercially available reagents are typically metal-chelating polymers (MCPs) conjugated to antibodies (Abs). These MCP-based reagents contain ~150 metal ions/Ab and can detect cellular markers present in >10^4 copies/cell. However, detection of lower abundance markers (<10^4 copies/cell) remains challenging, as the signal in mass cytometry is proportional to the number of ions generated per mass tag. To increase the number of atoms/mass tag, we propose to use nanoparticles (NPs) due to their high ion density. To be used as mass tags, NPs must have a narrow size distribution, and their surface must be modified to impart colloidal stability in phosphate buffers, minimal nonspecific interactions, and active targeting of biomolecules. Here, the preparation of lipid-coated lanthanide (Ln) NPs for use as mass tags in suspension mass cytometry (SMC) and Imaging Mass Cytometry™ (IMC™) is demonstrated. First, reproducible conditions to synthesize 30-40 nm LnNPs with a narrow size distribution were determined (CV <5%). The LnNPs were then transferred to an aqueous buffer using a biphasic citrate exchange. The citrate-LnNPs were coated with a lipid formulation consisting of egg sphingomyelin, 1,2-dioleoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-3-trimethylammonium-propane, cholesterol-PEG600, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[biotinyl(polyethylene glycol)-2000] to encapsulate the LnNPs with a lipid bilayer. Analysis of the lipid-coated LnNPs using liquid chromatography-tandem mass spectrometry revealed that the coating composition was significantly different than the formulation. The resulting lipid-coated LnNPs exhibited colloidal stability in PBS by dynamic light scattering, and targeted binding with minimal non-specific binding of the LnNPs to a model system consisting of streptavidin-coated polystyrene microbeads were demonstrated by SMC and IMC™. Notably, it was found that the lipid composition influences their above performance. These results show that lipid-coated LnNPs can be used as mass cytometry reagents, and establishes the importance of quantifying the composition of lipid coatings. This dissertation provides the foundation for effective design of lipid-coated LnNPs for high-sensitivity mass cytometry bioassays.

Keywords: Lanthanide Nanoparticles
Lipid-Coating
Mass Cytometry
Nanoparticle Characterization
Nanoparticles
Advisor: Winnik, Mitchell A
A Study of Differentiation within the Ontario College Sector and the Impact of Geography

In 1965 Ontario Education Minister, William G. Davis, introduced a new sector of Ontario post-secondary institutions, Colleges of Applied Arts and Technology. A primary purpose of this sector was to create access to education, particularly for those who were not accessing university. Additional primary characteristics of colleges were that they were to be comprehensive institutions offering a variety of primarily occupationally focused programs, and that they were to respond to local education and training needs. Over five decades later, although colleges have evolved in numerous ways, this study demonstrates that these key characteristics are still present. In 2012 the Ministry of Training, Colleges and Universities (MTCU) indicated it would be pursuing a policy direction of differentiation to, in part, create a more efficient post-secondary system in Ontario. This study explores potential impacts of differentiation policy on the traditional mandate of colleges as institutions designed to promote local student access and to respond to local community needs, and the potential impact on Ontario students and communities. Using theoretical frameworks of institutional diversity and differentiation, social policy theory and the capability approach, this study examines the levels and dimensions of existing diversity and differentiation in the Ontario post-secondary system. It draws on three data sources to undertake this study: document analysis of strategic mandate agreements; geographic attendance data for college and university students in Ontario; and interviews with institutional leaders and senior policy actors. The study’s findings confirm that college students in rural and remote communities tend to attend colleges that are located close to them. Students in the Toronto area demonstrate higher mobility between colleges located in Toronto but overall also display a tendency to attend regionally close institutions. University students also demonstrate in-region attendance patterns within the Toronto area but rural and remote university students overall are more mobile across the province. Through qualitative interviews and document analysis, this study also finds that rural and remote colleges still, five decades after their inception, demonstrate very high community connectedness and characteristics of strong regional responsiveness.

Keywords: Differentiation
Advisor: Wheelahan, Leesa
Connected Yet Disconnected: New Public Management and Labour Expropriation within Public Employment Services Work

This study examines public employment services in Ontario from the standpoint of those who deliver the services. There is a paucity of empirical research in this particular field of public service delivery, specifically Canadian based research that focuses on the work of the employment specialists who are client-facing workers. The thesis distinctly applies Marxist Labour Process Theory and Foucauldian Governmentality to explicate the work experiences of employment specialists in Ontario’s current iteration of public employment services, Employment Ontario (EO), while taking into consideration the transitions of the EO labour process. In researching public employment services in advanced neoliberal capitalist countries, such as Canada, New Public Management (NPM) is likely unavoidable and is a focal point in this analysis. The thesis presents NPM as a systemic outgrowth of neoliberal governance and as a mechanism by which the government seeks to control-manage vulnerable people and public resources through the imposition of for-profit-businesslike practices in public service administration and delivery. With EO, NPM governance stretches to not-for-profit (NFP) work, and stimulates a drift from NFP social economy values. The current EO service delivery network predominantly consists of publicly-funded NFP organizations. This research takes a distinct focus in how it applies a unique analytic framework while it simultaneously seeks to fill a gap in public employment services and NFP research. Using qualitative interview data from thirty-two research participants, this thesis analyzes the work, identity, and behaviours of NFPs and their EO employment specialists, as well as the current outgoing and incoming funding structures of EO. It highlights the intended and unintended consequences of operationalizing public employment services through market-based policies and practices. The thesis concludes by providing a discussion on pathways to extend this study and alternative policies and practices that challenge the current businesslike approach to the administration and delivery of public employment services in Canada.

Keywords: Employment Ontario
Governmentality
Labour Process
New Public Management
Not For Profit
Public Employment Services
Advisor: Sawchuk, Peter H
Hypertranscription in Human Cancer

Cancer is a disease driven by aberrant gene expression leading to uncontrolled cellular proliferation. To date, tens-of-thousands of patient tumors have undergone RNA-sequencing, creating a catalog of the genes and pathways differentially expressed in cancer tissues. Despite these significant advances, a fundamental aspect of gene regulation remains poorly characterized: the overall expression level across all genes. Recent work has demonstrated that certain oncogenes, such as MYC, might drive tumor growth by globally increasing transcription of all active genes, a phenomenon known as hypertranscription. While hypertranscription has been studied in model systems and cell lines, where drugs that dampen global transcription have shown promise against aggressive ‘transcriptionally addicted’ cancers, hypertranscription has never been characterized in human patients. Thus, we do not know hypertranscription’s prevalence across cancer types, its drivers, or its impact on patient outcomes. This gap in knowledge is driven in large part by the absence of appropriate methods to accurately measure global transcription. Nearly all reported gene expression estimates incorrectly assume relatively equal RNA output across samples. In Chapter 2, a novel computational method is developed that allows joint measurement of global and focal gene expression changes in patient tumor RNA-sequencing data. Critically, this method accounts for differences in tumor purity and ploidy, providing a direct fold-change measure in overall cancer-cell transcription. In Chapter 3, this method is applied to 7,494 tumor samples spanning 31 types, revealing that hypertranscription is a hallmark of aggressive cancers, with over 40% of all cancers harboring hypertranscription levels of at least 2-fold. Investigation of single-cell RNA-sequencing data revealed hypertranscriptional clones that dominated transcript production regardless of their size. Exploration of transcription factors revealed that loss of transcriptional suppression may be fundamental to the hypertranscriptional phenotype. In Chapter 4, the clinical implications of hypertranscription are explored. Hypertranscription defined patient subgroups with worse survival across multiple cancers, even within well-established subtypes. Finally, patients with hypertranscribed mutations have improved response to immune checkpoint therapy. Taken together, this work provides fundamental insights into gene dysregulation across human cancers and may prove useful in identifying patients that would benefit from novel therapies.

Advisor: Shlien, Adam
Stellar Halos of Nearby Edge-on Spiral Galaxies with the Dragonfly Telephoto Array

Stellar halos are built up from stars stripped during past merger events, and therefore can inform us about a galaxy's accretion history. However, they are challenging to observe due to their faint and very extended nature. Most of the stellar halos observed around spiral galaxies beyond the Local Group have been biased towards higher mass spirals similar to the Milky Way and M31. In order to increase the number of known stellar halos and to improve representation of lower mass spirals, we have collected deep multi-band observations of a dozen nearby edge-on spiral galaxies with the Dragonfly Telephoto Array. Dragonfly is optimized for imaging extended emission with minimal interference from scattered light and its data reduction pipeline is designed to preserve low surface brightness structures. We have discovered a new extension to the well known massive stellar stream surrounding NGC 5907. After measuring the stellar halo mass fractions for our entire sample, we found a correlation between these fractions and the host galaxy stellar mass. We also carried out a case study of the outer disc of NGC 4565, whose asymmetrical structures may indicate disc growth via accretion. We discuss prospects for further exploitation of our data, current and upcoming developments in the study of stellar halos, and future surveys covering large fractions of the sky that have the potential to be sensitive to low surface brightness structures with the adoption of careful calibration and reduction techniques.

Keywords: Galaxy photometry
Spiral galaxies
Stellar halos
Stellar streams
Advisor: Abraham, Roberto