VictorJuiz/thesis huggingface dataset:
The Effects of Disc1 on Neurodevelopment in the Mouse

Over the past decade, a combination of genetic, biological and imaging approaches have identified Disrupted-in-Schizophrenia-1 (DISC1) as a strong susceptibility gene for psychiatric illnesses including schizophrenia, bipolar disorder and major depression. DISC1 regulates various neurodevelopmental processes including neurogenesis, neuronal migration, neurite outgrowth, spine development and neurotransmitter signaling. Human post-mortem brain studies in schizophrenia have revealed some consistent neuropathological findings such as abnormal neuron morphology, reduced spine density, aberrant cytoarchitecture and interneuron deficits in the dorsolateral prefrontal cortex and hippocampus. However, the etiology and development of these histological abnormalities remain unclear. Therefore, we investigated brain histology of two independently-derived Disc1 mutant mice with point mutations (Disc1-Q31L and -L100P). Both mutants displayed reductions in cortical neuron density, decreased neurogenesis and altered cortical neuron distribution when compared to wild-type controls. Frontal cortical pyramidal neurons had shorter dendrites and reduced dendritic surface area. Spine density was also reduced on apical dendrites of both frontal cortical and hippocampal pyramidal neurons. In addition, we observed a pronounced defect in tangential migration of interneurons in the embryonic brains of Disc1-L100P mutants when compared to wild-type mice. Adult Disc1-L100P mutants also have selective alterations of calbindin- and parvalbumin-expressing interneurons in the cortex and hippocampus, decreased glutamate decarboxylase 67/parvalbumin co-localization and mis-positioned interneurons across the neocortex. Finally, we investigated the effects of GSK3α inactivation on frontal cortical neuron morphology in Disc1-L100P mutants. Disc1-L100P, GSK3α -/- and 100P/100P;GSK3α double mutants all exhibited significant reductions in dendritic length and surface area while spine density was significantly reduced only in Disc1-L100P and 100P/100P;GSK3α +/- mutants when compared to wild-type mice. Interestingly, spine density was rescued in 100P/100P;GSK3α -/- double mutants and comparable to wild-type mice. Overall, these findings are consistent with the anomalies seen in post-mortem schizophrenia studies and other Disc1 mutant mouse models, providing further evidence that DISC1 participates in neurodevelopment. GSK3 is only one of many pathways modulated by DISC1, so more research is required to fully understand how the network of DISC1-interacting proteins is involved in the pathophysiology of psychiatric disorders. Better understanding of these mechanisms could lead to the development of new treatments.

Keywords: Schizophrenia
DISC1
Advisor: Wong, Albert Hung Choy
Histone Crosstalks involving H3 Phosphorylation and their Role in Transcriptional Regulation

Histone phosphorylation is often a direct outcome of activated intracellular signaling pathways, and functions to translate extracellular signals into appropriate biological outputs such as changes in gene expression. Growth factors and cellular stress trigger rapid and transient expression of immediate-early genes (such as c-fos, c-jun) in mammalian cells, and their induction strongly correlates with a transient phosphorylation of S10 and S28 on histone H3. While many signaling cascades that lead to H3 phosphorylation have been mapped out, mechanistic details of the downstream events and how H3 phosphorylation contributes to transcriptional activation are still poorly defined. To investigate the direct effects of H3 phosphorylation on transcription, we targeted the H3 kinase MSK1 to endogenous c-fos promoter, and found that this is sufficient to activate its expression. Moreover, targeting MSK1 to the tissue-specific -globin gene induces H3S28 phosphorylation and reactivates expression of this polycomb-silenced gene. Mechanistically, H3S28 phosphorylation not only disrupts binding of polycomb repressive complexes, but also induces a methyl-acetylation switch of the adjacent K27 residue. This provides the first indication that H3 phosphorylation is involved in antagonizing polycomb silencing. To further identify post-translational modifications (PTMs) that function together with MSK1-mediated H3 phosphorylation, I developed a novel nucleosome purification approach called Biotinylation-assisted Isolation of CO-modified Nucleosomes (BICON). This technique combines in vivo biotinylation by BirA and H3 phosphorylation by MSK1, allowing enrichment of phosphorylated nucleosomes using streptavidin. I found that MSK1-phosphorylated nucleosomes are hyper-acetylated on H3 and H4, and importantly, I identified a trans-tail crosstalk between H3 phosphorylation and H4 acetylation on K12. This proof-of-principle study demonstrates that BICON can be further adapted to study PTMs and crosstalks associated with other histone-modifying enzymes. Taken together, work described in this thesis shows that histone H3 phosphorylation can initiate additional PTM changes on other residues within the nucleosome, and such crosstalk plays an important role in regulating gene expression.

Keywords: histone
chromatin
transcription
phosphorylation
acetylation
crosstalk
MSK1
polycomb
Advisor: Cheung, Peter
A Variant of Lehmer's Conjecture in the CM Case

Lehmer's conjecture asserts that τ(p) ≠ 0, where τ is the Ramanujan τ-function. This is equivalent to the assertion that τ( n) ≠ 0 for any n. A related problem is to find the distribution of primes p for which τ(p) ≡ 0 (mod p). These are open problems. However, the variant of estimating the number of integers n for which n and τ( n) do not have a non-trivial common factor is more amenable to study. More generally, let f be a normalized eigenform for the Hecke operators of weight k ≥ 2 and having rational integer Fourier coefficients {a(n)}. It is interesting to study the quantity (n, a(n)). It was proved by S. Gun and V. K. Murty (2009) that for Hecke eigenforms f of weight 2 with CM and integer coefficients a(n)[special characters omitted] for some constant Uf. We extend this result to higher weight forms.

Keywords: a variant of Lehmer's conjecture
cusp forms
Fourier coefficients
Advisor: Murty, V. Kumar
1H NMR-based Metabolomics for Elucidating the Mode of Action of Ccontaminants in the Earthworm Eisenia Fetida after Sub-lethal Exposure

There is a growing need to develop rapid and cost-effective ecotoxicological tools for risk assessment because traditional methods examine endpoints such as mortality, which do not provide any insight into the mode of action (MOA) of the chemical. Research presented within this thesis illustrates the potential of 1H NMR-based metabolomics as a rapid and routine ecotoxicological tool that can elucidate a chemical’s MOA and also aid in the identification of metabolites of exposure. Metabolomics involves measuring the fluctuations in the endogenous metabolites of an organism within a cell, tissue, bio-fluid or whole organism in response to an external stressor. We focused on the model polycyclic aromatic hydrocarbon (PAH) phenanthrene, and the perfluoroalkyl acids (PFAAs) perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), due to their recalcitrant nature and widespread prevalence in soil environments. 1H NMR-based metabolomics analysis of the exposure of Eisenia fetida earthworms to sub-lethal phenanthrene exposure via filter paper contact tests revealed a concentration-dependent two-phased MOA: a linear correlation between the metabolic response and exposure concentration at low concentrations followed by a plateau in the responses at high concentrations. Alanine, glutamate, maltose, cholesterol and phosphatidylcholine emerged as potential indicators of phenanthrene exposure. An increased energy demand and an interruption in the conversion of succinate to fumarate in the Krebs cycle were observed due to phenanthrene exposure. Sub-lethal PFOA and PFOS exposure to E. fetida via contact tests for two days revealed heightened responses with higher PFOA and PFOS concentrations. Leucine, arginine, glutamate, maltose, and ATP were identified as potential indicators of PFOA or PFOS exposure. E. fetida responses were then investigated after exposure for two, seven and fourteen days to an artificial soil that was spiked with sub-lethal PFOS concentrations. An exposure time-dependent operation of two separate MOAs were identified. Both the contact tests and artificial soil exposure studies identified an elevation in fatty acid oxidation, a disruption in energy metabolism and biological membrane structure, and also an interruption of ATP synthesis following PFOA and PFOS exposure. This thesis illustrates the promise of NMR-based metabolomics as a routine tool for ecotoxicological assessment of contaminated sites.

Keywords: Ecotoxicology
Environmental Chemistry
Metabolic Profiling
PAHs
PFOA
PFOS
Soil contamination
Earthworms
Advisor: Simpson, Myrna J.
Eager, Lazy, and Other Executions for Predicative Programming

Many programs are executed according to the conventional, eager execution order, for which verification of execution costs is well-understood. However, there are other execution orders in use. One such order in common use is lazy execution or lazy evaluation, which is mostly demand-driven. Laziness supports better decompositions of algorithms, e.g., into modular producers and consumers, which enables compositional reasoning of answer correctness, but then timing correctness is more elusive. This thesis gives a formal method for verifying lazy timing, compositional with respect to program structure; it is an extension of a predicative programming theory. Predicative programming theories are formal methods that unify both specifications and programs as predicates or boolean-typed expressions over memory state and other quantities of interest. Their strengths are mathematical simplicity and support of program development and verification by incremental refinements. Among these theories, Hehner's a Practical Theory of Programming has the further strength of leaving termination and timing open rather than a built-in, and therefore is a flexible substrate for various timing schemes corresponding to various execution strategies. We use this substrate for our method for lazy timing. This thesis also proves soundness of the eager timing scheme in Hehner's work with respect to an eager operational semantics, and our lazy timing scheme with respect to a lazy operational semantics. Thus, if refinements promise an upper time bound, then execution actually stops within that time. Lastly, this thesis outlines a space of more operational semantics. It is possible ground for more execution strategies.

Keywords: software engineering
programming methodology
formal methods
predicative programming
operational semantics
evaluation strategies
lazy evaluation
bound analysis
Advisor: Hehner, Eric C. R.
Characterization of Kallikrein 6 N-glycosylation Patterns and Identification of Sialylated Glycoproteins in Ovarian Cancer

Ovarian cancer is the leading cause of death among all gynecological disorders. Aberrant glycosylation, or more specifically, increased sialylation of proteins has been observed in this malignancy. Several sialyltransferase genes have been shown to be up-regulated at both mRNA and and protein levels in a number of cancers, including that of the ovary. In the present study, we have analyzed the glycosylation patterns of kallikrein 6 in the context of ovarian cancer. We have discovered that the carbohydrate structures found at the single N-glycosylation site of kallikrein 6 derived from ovarian cancer cells found in the ascites fluid of ovarian cancer patients is enriched in sialic acid moieties and has an increased branching pattern when compared to controls. We have also developed a reliable anion-exchange HPLC-based methodology capable of quantifying different glycoform subpopulations of kallikrein 6 in serum and other biological fluids, which was capable of differentiating between samples from ovarian cancer patients and healthy controls. A variety of classic molecular biology and mass spectrometry based techniques were utilized in these experiments. Based on the results of the analysis of kallikrein 6 glycosylation and other literature reports showing upregulated sialylation of proteins in ovarian cancer, we have also identified sialylated glycoproteins from ovarian cancer proximal fluids and conditioned media of ovarian cancer cell lines. Sialylated proteins were enriched utilizing lectin affinity or hydrazide chemistry. In total, 333 sialylated glycoproteins and 579 glycosylation sites were identified. A list of 21 potential candidate ovarian cancer biomarkers was produced from proteins that were identified solely in ovarian cancer proximal fluids, which could form the basis for any future studies.

Keywords: glycosylation
ovarian cancer
Advisor: Diamandis, Eleftherios P.
HIV Vulnerability amongst South Asian Immigrant Women in Toronto

This thesis focuses on the structural and behavioural factors that placed South Asian immigrant women living with HIV/AIDS in the Greater Toronto Area at risk. Informed by Connell's social theory of gender (1987), this study examined the role of hegemonic masculinity in legitimizing male power and contributing to the HIV risk of these women. By conducting one-on-one interviews with 12 HIV-positive immigrant women, meaningful constructions of the women's narratives and accounts of their experiences relative to HIV were created. This study examined the intersection of power ideologies such as gender, race and class in specific contexts as they generated particular experiences that affected women's risk for HIV. Following a community-based research approach, a collaborative relationship was established with the Alliance for South Asian AIDS Prevention where qualitative methods of analysis and an inductive approach with an iterative process were followed. Factors such as isolation, economic dependence on their husbands, discrimination, racism, investment in psychologically and emotionally abusive relationships, combined with the absence of support from their family of origin exacerbated the women's risk of HIV infection. The strong ties exhibited by most of the women to their religious/ethnic communities helped sustain a gender-based social hierarchy. To facilitate dialogue and social change for South Asian women, gender and culture need to be situated in social and historical contexts. As such, programs should be understood within a larger critical understanding of the social power relations and history of Canadian immigration patterns. Using anti-racist frameworks, initiatives should address violence against women, while tackling interrelated issues (i.e., housing, poverty, etc.). This work draws attention to oppressions through the experiences of a community of women who are rarely given a voice within the context of research on HIV/AIDS. It will be also helpful for Ontario’s HIV prevention strategy and the field of women's sexual health.

Keywords: HIV Risk
South Asian Women
Immigrant Women
Social Theory of Gender
Power Ideologies
Anti-racist Frameworks
Feminist Theories
Narratives
Structural Factors
Women PHAs
Advisor: Mirchandani, Kiran
Architecting the Optics, Energetics and Geometry of Colloidal Quantum Dot Photovoltaics

Solution processed solar cells offer the promise of a low cost solution to global energy concerns. Colloidal quantum dots are one material that can be easily synthesized in and deposited from solution. These nanoparticles also offer the unique ability to select the desired optical and electrical characteristics, all within the same materials system, through small variations in their physical dimensions. These materials, unfortunately, are not without their limitations. To date, films made from colloidal quantum dots exhibit limited mobilities and short minority diffusion lengths. These limitations imply that simple device structures may not be sufficient to make an efficient solar cell. Here we show that through clever manipulation of the geometric and energetic structures, we can utilize the size-tunability of CQDs while masking their poor electrical characteristics. We further outline the physical mechanisms present within these architectures, namely the utilization of a distributed built-in electric field to extract current through drift rather than diffusion. These architectures have consequently exceeded the performance of legacy architectures such as the Schottky cell. Finally, we discuss some of the limiting modes within these architectures and within CQD films in general including the impact of surface traps and polydispersity in CQD populations. Through the development of these novel architectures, the power conversion efficiency of CQD solar cells has increased from ~3.5% to 7.4%; the highest efficiencies yet reported for colloidal quantum dot solar cells.

Keywords: Photovoltaics
Solar Cell
Quantum Dot
Semiconductor
Device Architecture
Advisor: Sargent, Edward H.
Goethe and the Sublime

The dissertation situates the Goethean sublime in an obscured countermovement of resistance to the aestheticization the concept underwent in the 18th century. Before the encounter with the English aesthetic concept of the sublime, the German notion of das Erhabene (the sublime) named not a category of aesthetic experience, but a social affect. In contrast to the Sublime of Edmund Burke's theory, which explicitly excludes melancholy from the sources of the Sublime, das Erhabene is an affect related to the self-overcoming of melancholic subjectivity. As the aestheticized notion of the sublime displaced das Erhabene, Goethe became one of the most radical innovators of the aesthetics of the sublime. But as is demonstrated in chapters on The Sorrows of Young Werther, Elective Affinities, Faust and Wilhelm Meister, he did so with the aim of recovering the displaced meaning of das Erhabene as social affect. Goethe's sublime aims to show at every turn that the so-called "aesthetic experience" of the sublime is really displaced social affect. His treatment of the sublime therefore constitutes a radical critique of the establishment of aesthetics as an independent sphere of inquiry. There is for Goethe no way to understand aesthetic experience independently of its social context. By reconnecting the sublime it to the original social meaning of das Erhabene, Goethe recovers the aesthetics of the sublime as a means of mediating and facilitating the movement of subjectivity from frustrated stasis to divine creativity; i.e., from exclusion to participation in the material creation of reality.

Keywords: Goethe, Johann Wolfgang von
the sublime
aesthetics
German Literature
critique
ideology
Benjamin, Walter
German Idealism
Critical Theory
das Erhabene
the beautiful
beauty
aesthetic theory
Critical Theory
Kant, Immanuel
Burke, Edmund
Advisor: Goetschel, Willi
Different Approaches to Care for the Terminally Ill: Barriers and Facilitators to (Best Practice) Service Provision

Despite (national) strategies/frameworks for care at the end of life, many patients do not die at their preferred location or under the form of care desired. This cross-country comparison study analyzed system-level characteristics - such as legislation, regulation and financing - that might influence service delivery in the care for terminally ill adults and their implications for outcomes and costs. Drawing on triangulated data from Canada, England, Germany and the United States of America and taking a 'most similar – most different' perspective, it was hypothesized that system-level factors might impede the broader use of (integrated) models of hospice and palliative care/the system-wide adoption of best practices. An embedded case study examined resource utilization and costs of shared care and its role as a potential best practice avenue. While similar with regard to leading causes of death, patient needs and potential avenues to care, different service models were employed – including hospice and palliative care. Generally offered alongside standard care along the disease continuum and across settings - and featuring common elements like physical, psycho-social and spiritual care - outcomes (e.g., access, utilization) varied. Legislative (e.g., jurisdictional), regulatory (including education and training) and financial issues were identified as barriers, as were public knowledge and perception ('giving up hope') challenges. Advance care planning, dedicated and stable funding, population aging and standards of practice/guidelines to care were seen as facilitators. Successful policy implementation requires concerted action to align system-level characteristics – with each alone being essential but not sufficient. Policies need to be monitored and fine-tuned, with a caveat toward their transferability between jurisdictions. The analysis of the shared-care approach in the rural Niagara-West setting revealed effective and efficient home-based hospice and palliative care – on par with per diem funding for long-term care homes and lower than average alternate level of care and hospital costs in Ontario, and in line with the Medicare Hospice Benefits in the United States of America. The thesis results provide a base for further analyses across jurisdictions and settings and might assist decision makers in the allocation of resources to meet the complex needs of hospice and palliative care populations.

Keywords: barriers and facilitators to care
case studies
end-of-life care
health policy
hospice
palliative care
Canada
England
Germany
United States of America
Advisor: Deber, Raisa Berlin
Social Processes in Canadian Religious Freedom Litigation: Plural Laws, Multicultural Communications, and Civic Belonging

Though there is significant academic interest in the law of religious freedom in Canada, there has been little research into the experiences of participants in religious freedom litigation. Based on a qualitative analysis of participant interviews and legal documents in three decisions of the Supreme Court of Canada, this dissertation explores the social processes at play in that litigation. At issue in the three cases were, respectively, (1) the right of Jewish condominium co-owners to install ritual huts (succoth) on their balconies; (2) the right of a Sikh student to wear a ceremonial dagger (kirpan) in a public high school; and (3) the right of a Hutterite group to be exempted from the photo requirement on driver’s licences for religious reasons. This dissertation adds to the existing academic commentary by looking beyond the judicial decisions and incorporating firsthand accounts of lawyers, litigants, and expert witnesses in these cases. The substantive analysis is divided in three sections. First, the dissertation examines themes of overlapping legal systems in participant narratives. Litigants understood themselves to be subjects of both state and religious laws, and the particular interactions between these legal systems help refine theories of legal pluralism. Second, the work analyzes religious freedom litigation as cross-cultural communication. Specifically, the dissertation employs the normative criteria of respect and self-awareness found in the literature on cross-cultural communication to approach participant narratives and judicial decisions, finding both successes and failures in this regard. Third, the dissertation engages issues of belonging to the Canadian civic community inherent in participant narratives. All litigants told the stories of their litigation as part of their larger immigration and integration narratives, and successful litigants were quick to give positive accounts in this regard. The unsuccessful litigants told more complex stories of integration, complicating the analysis of the impact of a judicial decision on their narratives of civic belonging. Nevertheless, the dissertation argues that the notion of civic belonging ought to be explicitly taken into account by Canadian judgments when dealing with issues of religious freedom.

Keywords: Law
Religion
Religious Freedom
Multiculturalism
Legal Pluralism
Cross-Cultural Communication
Civic Belonging
Qualitative Interviews
Advisor: Shachar, Ayelet