VictorJuiz/thesis huggingface dataset:
Cultural Influences on Help-seeking, Treatment and Support for Mental Health Problems - A Comparative Study using a Gender Perspective
Keywords: Mental Health
Culture
Gender
Help-Seeking
Treatment
Support
Sri Lankan Tamil
Visible Minority
Ethno-cultural
Newcomer
Immigrant
Refugee
Depression
Health
Service Provider
Community

This qualitative research used the Long Interview method to study cultural and gender influences on mental health, health beliefs, health behaviour, help-seeking and treatment expectations for mental health problems in newcomers to Canada who are members of an ethnocultural, visible minority population - the Sri Lankan Tamils. The study employed a comparative design and analyzed data from interviews with Tamil men (N=8) and Tamil women (N=8) who self-identified as having been diagnosed with depression, and service providers (N=8) who provide frontline mental health and related services to the Sri Lankan Tamil community. The objectives were to a) understand cultural and gender factors inherent in the Sri Lankan Tamil community; b) investigate how these cultural and gender factors impact mental health and influence the trajectory of help-seeking and treatment for depression in the Sri Lankan Tamil community; c) explore the intersection of culture and gender as it relates to health behaviour; and d) explore service providers’ perceptions of the influence of culture and gender in relation to help-seeking for mental health problems and the application of this understanding to service delivery. The study found that the respondents equated social function with health and that this concept informed help-seeking and treatment expectations. Socially appropriate functioning was seen as an indicator of health, and this differed by gender. Gender-differentiated social stressors contributed to depression. Women played a role as enablers of care, both for family members and acquaintances. Men were more resistant to help-seeking and tended to disengage from care. There was a distinct preference for service providers who understood the culture and spoke Tamil. Religious groups served a social support function. Family physicians and Tamil service providers in the social service sectors were identified as key players in the pathways to care. Service providers did not appear to understand the community’s holistic view of health; however, they did use their knowledge of the community to make adaptations to practice. Recommendations that result from these findings include health promotion and prevention strategies beyond the traditional health care system, targeted culture and gender-informed interventions, and the need for multisectoral collaborations.
Structural Basis for Enzyme Promiscuity and Specificty - Insights from Human Cytosolic sulfotransferase (SULT) and Sirtuin (SIRT) Families
Keywords: cytosolic sulfotransferases
sirtuins

Understanding the structural basis of specificity and promiscuity of paralogous enzymes is important for deciphering molecular mechanisms and is a necessary step towards designing enzyme-specific modulators. The main objective of this thesis is to provide structural insights that relate protein local sequences to their observed binding and activity profiles through the study of two human protein families – cytosolic sulfotransferases (SULTs) and sirtuins (SIRTs). This was achieved by comparing the family-wide ligand binding fingerprints of these two enzyme families with the structural details of their corresponding enzyme-ligand co-crystal structures. The hSULT enzyme family was profiled against a focused library through binding and activity assays. This suggested a number of novel compounds that bind to the less well-characterized SULT members (SULT1C3 and SULT4A1), and revealed additional broad-spectrum hSULT inhibitors. Based on the profiling data, three enzyme/co-factor/ligand complex structures were solved using X-ray crystallography. The structure of SULT1C2•PAP(3'-phosphoadenosine 5'-phosphate)•pentacholorphenol(PCP) provided a rationale for a novel SULTs inhibition mechanism that depends on substrate acidity. The SULT1B1•PAP•resveratrol structure suggested that the hydrogen-bonding coordination of the 5-OH group on resveratrol is the structural determinant for the observed substrate preference towards resveratrol. SULT2A1•PAP•lithocholic acid(LCA) ternary complex structure confirms that the specificity of SULT2A1 for lithocholic acid derives from its high hydrophobicity in the substrate binding pocket. The same approach was used to interrogate the interaction of the sirtuins with their peptide substrates. The binding and enzymatic assays for human sirtuins have suggested that SIRT1 and SIRT2 are generally less discriminate against substrates while class IV sirtuins - SIRT6 and SIRT7 might be highly specific enzymes. Three different biochemical and kinetic assays showed that SIRT6-dependent histone deacetylation is about 1,000 times slower than for other highly active sirtuins. To understand the molecular basis for the specificity and low activity of SIRT6, I determined the first set of crystal structures for SIRT6 in complex with ADPr (ADP ribose) and the non-hydrolyzable analog of OAADPr (2’-O-acetyl-ADP ribose) – NAADPr (2’-N-acetyl-ADP ribose). The structures revealed human SIRT6 has unique structural features including a splayed zinc-binding domain, lacks a helix bundle and the conserved, highly flexible, NAD(+)-binding loop, which contribute to its observed biochemical behavior.
Fabricating Fidelity: Nation-building, International Law, and the Greek-Turkish Population Exchange
Keywords: nation-building
international law
population exchange
Greece
Turkey
Near East
minority protection
mandates system
humanitarian intervention
nationalism

This dissertation concerns a crucial episode in the international legal history of nation-building: the Greek-Turkish population exchange. Supported by Athens and Ankara, and implemented largely by the League of Nations, the population exchange showcased the new pragmatism of the post-1919 order, an increased willingness to adapt legal doctrine to local conditions. It also exemplified a new mode of non-military nation-building, one initially designed for sovereign but politico-economically weak states on the semi-periphery of the international legal order. The chief aim here, I argue, was not to organize plebiscites, channel self-determination claims, or install protective mechanisms for vulnerable minorities – all familiar features of the Allied Powers’ management of imperial disintegration in central and eastern Europe after the First World War. Nor was the objective to restructure a given economy and society from top to bottom, generating an entirely new legal order in the process; this had often been the case with colonialism in Asia and Africa, and would characterize much of the mandates system throughout the interwar years. Instead, the goal was to deploy a unique mechanism – not entirely in conformity with European practice, but also distinct from non-European governance regimes – to reshape the demographic composition of Greece and Turkey. I substantiate this argument by marshalling a range of material from international law, legal history, and historical sociology. I first examine minority protection’s development into an instrument of intra-European nation-building during the long nineteenth century, showing how population exchange emerged in the Near East in the 1910s as a radical alternative to minority protection. I then provide a close reading of the travaux préparatoires of the 1922-3 Conference of Lausanne, at which a peace settlement formalizing the exchange was concluded. Finally, I analyze the Permanent Court of International Justice’s 1925 opinion in Exchange of Greek and Turkish Populations, examining it from the standpoint of wide-ranging disputes concerning the place of religion and ethnicity in the exchange process. My aim throughout is to show that the Greek-Turkish exchange laid the groundwork for a mechanism of legal nation-building which would later come to be deployed in a variety of different contexts but whose precise status under international law would remain contested.
Hydrological, Biogeochemical and Landscape Controls on Mercury Distribution and Mobility in a Boreal Shield Soil Landscape
Keywords: catchment hydrology
mercury biogeochemistry

Mercury (Hg)-contaminated freshwater fisheries are a global toxicological concern. Previous research suggests that the slow release of Hg in runoff from upland soils may delay the recovery of Hg-contaminated aquatic systems. Four complementary studies were undertaken in a small boreal Shield headwater catchment as part of the Mercury Experiment to Assess Atmospheric Loading in Canada and the U.S. (METAALICUS) to assess the controls on the retention and release of historically-deposited Hg (ambient Hg) and newly-deposited (spike Hg) in the soil landscape. In the first study, hydrometric and GIS-based methods were used to quantify thresholds in terrestrial water storage and their relationship to observed rainfall-runoff response. It was found that event-scale hydrologic response displayed a threshold relationship with antecedent storage in the terminal depression and predictions of event runoff improved when storage excesses from upslope depressions were explicitly routed through the catchment. In the second study, it was shown that the dominant source of ambient Hg to the lake was likely derived from shallow soil-water flowing through the lower, well-humified organic soil horizon. Throughout the catchment, ambient Hg to soil organic carbon (SOC) ratios increased with depth and the experimentally-applied spike Hg was concentrated in the surface litter layer, suggesting that the vertical redistribution of Hg in the soil profile is a function of the rate of decomposition of SOC. In the third study, canopy type was found to be a good predictor of ambient Hg and spike Hg stocks in the lower organic horizon, while drainage conditions were not, suggesting that vertical fluxes of Hg dominate over lateral fluxes in topographically-complex landscapes. Lastly, it was shown that catchment discharge, antecedent depression storage and antecedent precipitation were the best predictors of dissolved organic carbon (DOC), ambient Hg and spike Hg concentrations in catchment runoff. A comparison of DOC, ambient Hg and spike Hg dynamics for two storm events showed that distinct shifts occurred in the concentration-discharge relationship as a result of differences in antecedent moisture conditions. Combined, the results of the four studies demonstrate the need to incorporate hydrological, biogeochemical and landscape controls into predictive models of terrestrial-aquatic Hg export.
Circuit Performance Verification and Optimization in the Presence of Variability
Keywords: Digital Circuit Performance, Process Variations, Computer-Aided Design

The continued scaling of digital integrated circuits has led to an increasingly larger impact of process, supply voltage, and temperature (PVT) variations. The effect of these variations on logic cell and interconnect delays has introduced challenges to both circuit performance (timing)verification and optimization. In order for us to fully take advantage of the benefits of technology scaling, it is essential that ``variation-aware''techniques for performance verification and optimization be developed and used in modern design flows. In this thesis such techniques for both performance verification and optimization are presented. First, we present a fast method for finding the worst-case slacks over all process and environmental corners. This method uses the standard set of PVT corners available in industry, and provides large runtime gains while maintaining a high degree of accuracy. After that, we propose an efficient block-based parameterized timing analysis technique that can accurately capture circuit delays at every point in the parameter space, by reporting all paths that can become critical. This method employs parameterized static timing analysis (PSTA) variability models, and allows one to easily examine local robustness to parameters in different regions of the parameter space. Next, we introduce an optimization method that alters clock network lines so that a circuit meets its timing constraints at all PVT settings under PSTA variability models. This is formulated as a Linear Program (LP), which is based on a clock skew optimization formulation, and as a result it can be solved efficiently. Finally, we present a method that uses characterized, pre-silicon, PSTA variational timing models to identify speedpaths that can best explain the observed delay measurements during silicon debug. This is a crucial step, required for both ``fixing'' failing paths and for accurate learning from silicon data.
Global Analysis of Gene Expression in the Developing Brain of Gtf2ird1-/- Mice
Keywords: Williams-Beuren syndrome
Gtf2ird1

Williams-Beuren Syndrome (WBS) is an autosomal dominant neurodevelopmental disorder caused by hemizygous deletion of a 1.5 Mb region on chromosome 7q11.23. Symptoms are numerous and include behavioural and cognitive components. One of the deleted genes, GTF2IRD1, a putative transcription factor, has been implicated in the neurological features of WBS by studying patients with atypical deletions of 7q11.23. Gtf2ird1-targeted mice have features consistent with the WBS phenotype, namely reduced innate fear and increased sociability. To identify neural targets of GTF2IRD1, microarray analyses were performed comparing gene expression in whole brains of Gtf2ird1-/- and wildtype (WT) mice at embryonic day 15.5 and at birth. Overall, the changes in gene expression in the mutant mice were not striking, with most falling in the range of 0.3 to 2 fold. qRT-PCR was used to verify the expression levels of candidate genes and examination of verified genes revealed that most were located on chromosome 5, within 50 Mb of Gtf2ird1. Expression of these candidate genes in Gtf2ird1-/- mice was found to be the same as in WT 129S1/SvImJ mice, indicating the differences were the result of flanking chromosomal material from the, 129-derived, R1 ES cells from which the Gtf2ird1-/- mice were generated, and that expression differences were unrelated to Gtf2ird1 dosage. Further analysis found that while many genes showed decreased expression using primers targeting the 3’ UTR, expression of upstream exons was not affected. Transcripts using alternative polyadenylation sites were identified using 3’ RACE, and qRT-PCR showed that expression of different 3’ UTR isoforms can occur in a strain specific manner. Expression analysis of previously identified GTF2IRD1 targets also failed to demonstrate an in vivo effect. In summary, I was unable to find any in vivo neuronal targets of this putative transcription factor, despite its robust expression in the developing rodent brain.
Clonal Analysis of Normal and Malignant Human Hematopoietic Hierarchies
Keywords: hematopoiesis
leukemia

The overall aim of my thesis is to gain insight into the cellular and molecular basis of the hierarchical organization of the human blood system, and how these normal development processes are subverted into leukemogenesis. To date, the major cellular classes that comprise human blood remain ill defined as rigorous clonal analysis required to define the self-renewal and lineage potential of single cells has not yet been performed. Here, identification CD49f as a novel marker of human HSC led to the ability to transplant single human HSC in NOD-scid IL2Rgc-/- mice. Loss of CD49f and Thy1 uniquely demarcated multi-potent progenitors (MPP) from HSC. The classical model of hematopoiesis posits the segregation of lymphoid and myeloid lineages as the earliest fate decision during lineage restriction from HSC. The validity of this model in the mouse has been questioned; however, little is known about the lineage potential of human progenitors. By clonally mapping the developmental potential of seven progenitor classes from neonatal cord blood and adult bone marrow, human multi-lymphoid progenitors (MLP) were identified as a distinct population of Thy1-/loCD45RA+ cells in the CD34+CD38- stem cell compartment that can give rise to all lymphoid cell types, as well as monocytes, macrophages and dendritic cells. This indicates that these myeloid lineages arise in early lymphoid lineage specification. Thus, as in the mouse, human hematopoiesis does not follow a rigid model of myeloid-lymphoid segregation. While non-genetic mechanisms govern cell-fate commitment and lineage specification, hematopoietic malignancies are often initiated by aberrant gene rearrangements that can subvert normal cellular processes. Full transformation requires the accumulation of multiple genetic lesions. Most tumours exhibit dramatic genetic heterogeneity downstream of the initiating oncogenic event and are composed of pockets of genetically distinct clonal subpopulations. However little is known of how diversity evolves or the impact diversity has on functional properties. Here, using xenografting and DNA copy number alteration (CNA) profiling of human BCR-ABL1 lymphoblastic leukaemia, it was demonstrated that genetic diversity occurs in functionally defined leukaemia-initiating cells (L-IC) and that many diagnostic patient samples contain multiple genetically distinct L-IC subclones. Reconstructing the subclonal genetic ancestry of several samples by CNA profiling demonstrated a branching multi-clonal evolution model of leukaemogenesis, rather than linear succession. For some patient samples, the predominant diagnostic clone repopulated xenografts, while in others it was outcompeted by minor subclones. Reconstitution with the predominant diagnosis clone was associated with more aggressive growth properties in xenografts, deletion of CDKN2A/B, and a trend to poor patient outcome. Our findings link clonal diversity with L-IC function and underscore the importance of developing therapies that eradicate all intratumoural subclones.
Holistic Education: The Flow and Pulse of Learning
Keywords: Holistic Education
Eco-Spirituality
Depth Psychology
Youth
Phenomenology

Situated in the holistic education field, this research explores the mind/body experiences of six youth who remained in a drama group from the time they were children to their late adolescence. In the first phase of this research these participants reflected on their experiences of the imagination, thought and felt sensation as they engaged in meditation and mind/body warm-up exercises during the drama years. The participants applied their understanding of mind/body awareness to a question posed by Vivian Darroch-Lozwoski; what happens when we attend to nature feelingly? Over the course of one year, the youth explored the above question, individually and collectively through dreaming, reveries, the imagination, experiences of energy and as they wandered in nature. The inquiry directly addresses the existential, ontological and epistemological implications of holistic mind/body development and outlines approaches for gentling the mind and body to nature.
Cognitive Abilities Underlying the Bilingual Advantage in Set Shifting
Keywords: bilingualism
theory of mind
executive functioning
working memory

Prior research has demonstrated that bilinguals outperform monolinguals on tasks requiring set shifting – that is, the ability to shift between different ways of thinking about an object or situation. For example, bilingual children have been shown to outperform monolingual controls on false-belief tasks and on the Dimensional Change Card Sort (DCCS) task. The present study aimed (a) to examine whether the bilingual advantage in false-belief and DCCS tasks can be replicated when accounting for languages/cultures and socio-economic status and (b) to determine whether inhibitory control, metarepresentation, and/or working memory underlie the advantage, if any exists. Three language groups (24 English monolingual, 24 French monolingual, and 24 English-French bilingual preschoolers) were tested on the following tasks: false-belief (FB) tasks, the DCCS task, an inhibitory control task (Stroop task), a metarepresentation task (Identity Statements task), a working memory task (Backward Word Span), and receptive language proficiency tests. Socio-economic status was measured through a parental questionnaire containing questions about parental income and education. Results showed that the three language groups were equivalent on socio-economic measures. Despite having significantly lower language proficiency scores, bilinguals’ raw scores on FB and DCCS tasks did not differ from monolinguals’ raw scores. After statistically controlling for language proficiency and age, bilinguals had significantly higher FB scores, but did not differ from monolinguals on DCCS scores. Analyses were then performed to determine whether inhibitory control, metarepresentation, and/or working memory help bilinguals “do more” in FB “with less” language proficiency. Working memory emerged as the likely candidate that compensates for the negative effect of bilingual children’s low language proficiency on FB performance because, after controlling for age and language proficiency, it was the only cognitive ability that fulfilled both criteria: (a) its measure correlated significantly with FB and (b) there was a bilingual advantage over both monolingual groups in the measure. A mediation analysis confirmed that the working memory measure significantly mediates the relation between bilingual status and FB while controlling for age and language proficiency. Both components of the working memory measure – that is, understanding of task instructions and maintenance/manipulation capacity – mediate this relation.