VictorJuiz/thesis huggingface dataset:
Éloge du baron de Charlus. Trésors et vertus de l'inversion ou, la déception salvatrice

This thesis puts forth an encomiastic portrayal of M. de Charlus, admittedly the most complex of Proustian characters, by way of an intimately immanent reading of two particular scenes from In Search of Lost Time, all the while referring to multiple other episodes of the novel. In terms of its methodology, the thesis pushes the limits of the hermeneutic enterprise by consistently intertwining said immanent reading with an openly referential and resolutely interdisciplinary approach to the Proustian text, minutely delving into a genuinely vast array of sources relevant to the paradoxical positioning of M. de Charlus within French modernity and the history of ideas, sources pertaining not only to literary history and criticism, but also to history, philology, the history of art, architectural studies, sociology, theological writings and queer studies. In terms of its conceptual scope, the thesis situates the development of the argumentation within a framework which, by making use of philosophical and literary sources, both medieval and modern, which include Thomas Aquinas, Roland Barthes and Judith Butler, allows for a re-evaluation of the concept of deception whose privileged manifestation is, as the introduction of the dissertation demonstrates, the polysemantic notion of inversion - spectacularly embodied in all its acceptations by M. de Charlus, who thus acquires, as it is demonstrated in the conclusion, an exemplary and paradigmatic importance for the Narrator's long protracted literary enterprise and for what Barthes refers to as the epistemological surplus value and the "plus-à-jouir de l'écriture".

Advisor: Motsch, Andreas
Glucose-responsive Implantable Polymeric Microdevices for “Smart” Insulin Therapy of Diabetes

Diabetes mellitus is a chronic illness manifested by improper blood glucose management, affecting over 350 million worldwide. As a result, all type 1 patients and roughly 20% of type 2 patients require exogenous insulin therapy to survive. Typically, daily multiple injections are taken to maintain normal glucose levels in response glucose spikes from meals. However, patient compliance and dosing accuracy can fluctuate with variation in meals, exercise, glucose metabolism or stress, leading to poor clinical outcomes. A `smart', closed-loop insulin delivery system providing on-demand release kinetics responding to circulating glucose levels would be a boon for diabetes patients, replacing constant self monitoring and insulin. This thesis focuses on the development of a novel, `smart' insulin microdevice that can provide on-demand insulin release in response to blood glucose levels. In the early stage, the feasibility of integrating a composite membrane with pH-responsive nanoparticles embedded in ethylcellulose membrane to provide pH-responsive in vitro release was examined and confirmed using a model drug, vitamin B12. In the second microdevice, glucose oxidase for generating pH signals from glucose oxidation, catalase and manganese dioxide nanoparticles, as peroxide scavengers, were used in a bioinorganic, albumin-based membrane cross-linked with a polydimethylsiloxane (PDMS) grid-microdevice system. This prototype device demonstrated insulin release in response to glucose levels in vitro and regulating plasma glucose in type 1 diabetic rats when implanted intraperitoneally. Advancement allowing for subcutaneous implantation and improved biocompatibility was achieved with surface modification of PDMS microdevices grafted with activated 20 kDa polyethylene glycol (PEG) chains, dramatically reducing immune response and local inflammation. When implanted subcutaneously in diabetic rats, glucose-responsive insulin delivery microdevices showed short and long-term efficacy up to an 18 day period. Finally, to improve insulin stability within microdevice reservoirs, an in situ gelling zinc-insulin formulation was designed. High concentration insulin gel complexed with zinc provided physical and chemical stability against thermal denaturation over a 30 day period. Long-term stability of the zinc-insulin gel formulation shows potential for sustained release application, providing low-level, basal insulin release. These combined technologies present significant progress towards the goal of an `artificial pancreas' to combat diabetes through `smart' insulin therapy.

Keywords: diabetes
glucose-responsive
insulin
microdevice
nanotechnology
Advisor: Wu, Xiao Yu
Quantitative Carrier Transport in Quantum Dot Photovoltaic Solar Cells from Novel Photocarrier Radiometry and Lock-in Carrierography

Colloidal quantum dots (CQDs) are promising candidates for fabricating large-scale, low-cost, flexible, and lightweight photovoltaic solar cells. However, their power conversion efficiency is still insufficient for commercial applications, partly and significantly, due to the not-well-understood carrier transport mechanisms and the lack of effective characterization techniques. Addressing these issues, carrier transport kinetics in CQD systems were studied to develop high-frequency dynamic testing and/or large-area quantitative imaging techniques: photocarrier radiometry (PCR), and homodyne (HoLIC) and heterodyne (HeLIC) lock-in carrierographies. Based on the discrete carrier hopping transport in CQDs, various carrier drift-diffusion current-voltage (J-V) analytical models and new concepts including the imbalanced carrier mobilities, reversed Schottky barrier, and double-diode model were developed to quantitatively interpret carrier transport and J-V characteristics in CQD solar cells. The further quantitative study of carrier mobility, CQD bandgap energy, phonon-assisted carrier transport, and open-circuit voltage deficit revealed CQD solar cell efficiency optimization strategies. Applying these energy transport mechanisms, for the first time, an analytical PCR signal generation model for CQD systems was developed from a novel trap-state-mediated carrier hopping transport theory. Therefore, multiple carrier transport parameters including carrier hopping lifetime, diffusivity, and diffusion length were extracted to investigate carrier transport dependencies on temperature, quantum dot size, surface-passivation ligands, and carrier hopping activation energies. As an imaging extension of PCR, using a heterodyne method to overcome the limitations of camera frame rate and exposure time of even the state-of-the-art InGaAs cameras, the first camera-based HeLIC theoretical model for ultrahigh-frequency (up to 270 kHz) imaging of CQD solar cells was achieved. Therefore, quantitative imaging of carrier lifetime, diffusivity, and diffusion and drift lengths of CQD solar cells was accomplished to explore the influences of carrier transport and contact/CQD interface on CQD solar cells. Also, low-frequency HoLIC large-area imaging evaluated the sample homogeneity and quality, reflecting preliminary carrier lifetime distribution. The combination of the novel carrier discrete hopping transport mechanism, J-V models, PCR, and the lock-in carrierography techniques (HoLIC and HeLIC) shows great potential for quantitative carrier transport study of CQD solar cells and for fast, all-optical, contactless, large-area, and nondestructive characterization of commercial photovoltaic materials and devices.

Keywords: Carrier transport
Colloidal quantum dot
Current-voltage characteristic
Large-area imaging
Non-destructive testing
Solar cell
Advisor: Mandelis, Andreas
Practising Ideology: Chinese Immigrant Mothers' Learning in Canadian Immigration Settlement Organizations

This research examines how Chinese immigrant mothers’ learning has been socially organized in a Canadian immigration settlement organization (ISO) and how mothering as an ideology shapes immigrant mothers’ learning practice. Drawing on a feminist and anti-racist theoretical framework and a critical ethnography, this dissertation problematizes motherhood learning through exploring the ideology of mothering, unpacking the ruling relations behind the learning practice, and examining immigrant mothers’ standpoint. I argue that immigrant mothers’ everyday experience of learning, mothering and settlement, which are socially organized by the state and its agencies, are not only a cultural nexus of transnational encounters, but also social relations with race, gender and class inequalities. The findings of this dissertation were generated from three parts. First, I revisit the meaning of motherhood. I challenge the ideology of mothering, which is based on Westernized and neoliberalized ideas of “intensive mothering” (Vandenbeld Giles, 2014). I unpack the ruling relations behind Chinese immigrant mothers’ learning and find out how the ruling idea of mothering shapes Chinese immigrant mothers’ learning, settlement, mothering and everyday practice. Second, I examine the social organization of motherhood learning in Canadian immigration settlement organizations. Through critical ethnographical research at MOSAIC, a Vancouver-based immigration settlement organization, I detail how hierarchical actors including the state, program organizers, social workers, and different individuals co-participate in the making of “immigrant mothers.” I provide an account of how Canadian immigration settlement organizations play a role mediating the state’s policy and immigrants’ actual settlement practice to ensure immigrant mothers’ learning is associated with the state’s neoliberal immigration policy. Finally, I investigate Chinese immigrant mothers’ experience as standpoints to understand motherhood learning as an ideological practice. I show that the discursive and material practice of Chinese immigrant mothers’ learning contains unequal social relations, hierarchically structured by race, gender, and class differences. This dissertation contributes to the understanding of migration and motherhood in the field of adult education, women’s and gender studies, anthropology and comparative and international education. The implications for immigration policy and settlement service involve a reframing of Canadian immigration policy and suggestions on the transformative practice in local immigration settlement organizations.

Keywords: adult education
critical ethnography
ideology
Immigrant mothers
immigration settlement organization
race
gender and class relations
Advisor: Mojab, Shahrzad
Pre-clinical analysis of fluvastatin as a metastasis-prevention agent in breast cancer

Fluvastatin is a member of the statin family of drugs, widely prescribed to lower serum cholesterol. Accumulating evidence from epidemiological, pre-clinical, and clinical studies indicate that statins have pleiotropic anti-cancer activities. Previous work have suggested a mechanistic model where depletion of farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP), and consequently inhibition of prenylation of RAS family members, underlies statin-induced cancer cell death. However, several lines of evidence suggest that this model is incomplete, yet alternative mechanisms have not been described. The purpose of this thesis is to (i) elucidate the molecular mechanism of fluvastatin sensitivity in breast cancer cells, and (ii) identify the point of therapeutic intervention in which fluvastatin treatment will provide clinical benefit in breast cancer patients. We first demonstrate that fluvastatin-induced cell death can be uncoupled from inhibition of protein prenylation, in breast cancer cells that have undergone epithelial-mesenchymal transition (EMT). In these cells, the mechanism of fluvastatin sensitivity is an increased dependency on the biosynthesis of dolichol, required for co-translational protein N-glycosylation. Fluvastatin treatment impairs the expression of tri- and tetra-antennary Î˛1,6-branched complex type N-glycans associated with breast cancer cell EMT and metastasis. These results, along with supporting evidence from epidemiological studies, provided rationale to examine the efficacy of fluvastatin as a metastasis-prevention agent in breast cancer. Using a mouse model of post-surgical metastatic breast cancer that fully recapitulates the intravasation and dissemination process, we show that fluvastatin treatment in the adjuvant setting significantly delays breast cancer metastasis, reduces metastatic burden, and improves overall survival. Overall, this research provides novel insight into the mechanism of the anti-cancer effects of fluvastatin, and demonstrates efficacy of fluvastatin use in the adjuvant therapeutic setting to prevent breast cancer metastasis.

Advisor: Penn, Linda Z
Pan-Cancer Study of INPP4B Reveals its Unexpected Oncogene-Like Role and Prognostic Significance

The work presented in this thesis demonstrates and explores the unexpected oncogenic role of a previously known tumor suppressor inositol polyphosphate-4-phosphatase, type-II (INPP4B). Specifically, INPP4B-high AML was found to be associated with poor response to therapy, and shorter overall- and event-free survival. Multivariate analysis revealed that INPP4B expression status improves oneâ s ability to predict patient outcome when added to current prognostic models. Furthermore, INPP4B-high identifies a poor risk patient subgroup in the cytogenetically normal patient subpopulation. In vitro overexpression of INPP4B in AML cell lines revealed that INPP4B contributes to a more aggressive AML disease by enhancing colony forming potential, increasing proliferation, and increasing drug resistance. In addition to being the first in identifying INPP4Bâ s prognostic significance in AML, this thesis is amongst the first studies to uncover the unexpected oncogenic function of this previously known tumor suppressor. Next, to identify transcriptional regulators of INPP4B in AML, and characterize the pan-cancer prognostic significance of INPP4B expression status, I developed subgroup identifier (SubID), a non-median dichotomization tool for heterogeneous populations. Using SubID, I identified significant co-expression between INPP4B and the transcription factor EVI1. In vitro validation revealed EVI1 knockdown in EVI1-high AML cell lines is associated with a significant decrease INPP4B levels. Furthermore, chromatin immunoprecipiation demonstrated EVI1 binding to the INPP4B transcription start site region. Next, in my pan-cancer analysis with SubID, I identified that INPP4B expression may be associated with patient survival in 13 different cancer types. Following stringent multiple testing and permutation corrections, I observed that INPP4B-low expression status was associated with shorter survival in kidney clear cell, liver hepatocellular, and bladder urothelial carcinomas. Conversely, INPP4B-low status was associated with longer survival in pancreatic adenocarcinoma. The unexpected oncogene-like prognostic significance of INPP4B in pancreatic adenocarcinoma was cross-validated in two additional independent pancreatic cancer datasets. Overall, the work presented in this thesis provides evidence that INPP4B expression status is associated with patient outcome in both a tumor-suppressive and oncogenic manner depending on the context. In vitro work demonstrates that overexpression of INPP4B in AML contributes to traits associated with a more aggressive disease in a causative rather than associative manner.

Keywords: Acute Myeloid Leukemia
Cancer
EVI1
INPP4B
Oncogene
Pan-Cancer
Advisor: Minden, Mark
N-3 Polyunsaturated Fatty Acids and Neuroinflammation in Alzheimer's Disease

Neuroinflammation may factor in the etiology of Alzheimer’s Disease (AD). n-3 polyunsaturated fatty acids (PUFA) and their bioactive lipid mediator derivatives have inflammation-modulating properties. Epidemiological and animal data suggests n-3 PUFA may be protective in AD, but whether this protection is conferred by modulating neuroinflammation is unknown. To determine how integral neuroinflammation is to AD pathology, a systematic review was conducted of studies comparing microglial markers in post-mortem human brain samples from patients with AD and controls. The analysis of 114 studies presented in Chapter 2 showed that markers of microglial activation are elevated in AD, suggesting that neuroinflammation is an important feature of the disease. A series of experiments were conducted to examine the effects of n-3 PUFA on neuroinflammation in an AD model. Fat-1 transgenic mice, animals that endogenously synthesize n-3 PUFA, and their wildtype littermates were fed either a n-3 PUFA deprived safflower oil diet, or a fish oil diet containing n-3 PUFA. In Chapter 3, we examined the time-course of neuroinflammation and its resolution following intracerebroventricular infusion of amyloid-β 1-40. Wildtype mice fed the n-3 PUFA-deprived diet exhibited a greater increase in microglia proliferation, more neuronal death, and alterations in microglia morphology consistent with activation, with no changes in the time-course of resolution. In Chapter 4, we show that fish oil-fed mice have a greater astrocyte activation response to amyloid-β than either the safflower-fed or fat-1 animals. Using a microarray in Chapter 5, we found that safflower oil-fed mice exhibited greater enrichment of gene categories associated with inflammation than fish oil-fed mice, independent of changes in levels of lipid mediators. Together, the data in this thesis show that neuroinflammation is a common pathological feature of AD that is modulated by brain n-3 PUFA. This does not seem to require detectable changes in bioactive lipid mediators.

Keywords: Alzheimer's Disease
Docosahexaenoic acid
Fish Oil
Microglia
n-3 polyunsaturated fatty acids
Neuroinflammation
Advisor: Bazinet, Richard P
Novel Metabolic Dependencies in Cancer and Moyamoya Disease

It is becoming increasingly clear that deregulation of the cellular environment has crucial roles in disease pathogenesis. The tumour microenvironment, which includes the surrounding vasculature, stromal and/or immune cells, can influence the availability of nutrients, oxygen and extracellular signaling factors. Secondary environmental influences, such as diet or infection, also are required for the progression of certain genetic risk alleles, such as stroke. In this doctoral thesis, I present three independent projects related to the effects of the cellular environment on disease outcomes. First, I identified a critical role for protein-tyrosine phosphatase 1B (PTP1B) in a novel pathway required for the survival of HER2+ breast cancer cells in hypoxia. In this pathway, PTP1B, via RNF213, most likely increase intracellular vitamin C, Îą-ketoglutarate-dependent dioxygenase(s) activity and non-mitochondrial oxygen consumption. Suppression of PTP1B enhanced non-mitochondrial oxygen consumption, tumour hypoxia and hypoxic cell death. In a collaborative effort, I also partially characterized the biochemical properties of the RNF213 RING domain, and found that the moyamoya disease-associated single nucleotide polymorphism (SNP), RNF213R4810K, is loss-of-function mutant with impaired E3-ligase activity and acts as a dominant-negative allele to globally decrease ubiquitylation, similar to the effects of RNF213 knockdown. Therefore, the lack of observable moyamoya phenotypes in Rnf213 knockout and predisposing allele knock-in mice suggests that secondary genetic and/or environmental influences are required for disease progression and outcome. Third, I assessed the biochemical effects of lung adenocarcinoma (LAC)-associated PIK3C3 mutations and the role of such mutations and Pik3c3 hemi- and homozygous deletion on KrasG12D- and BrafV600E-mediated lung tumourigenesis in mice. LAC-associated PIK3C3 mutants have decreased lipid kinase activity and/or impair its ability to form functional complexes, attenuate autophagy, and cooperate with RAS pathway drivers to enhance transformation. Heterozygous LAC-associated Pik3c3 mutation or deletion in KrasG12D-expressing lung epithelial cells alters the proportion of activated tumour-associated macrophages to accelerate tumourigenesis. Finally, I discuss some remaining questions and provide potential insight of these findings to disease pathogenesis. Taken together, my studies provide additional examples of the importance of the tumour microenvironment and/or secondary environmental influences for the progression and/or maintenance of cancers and diseases.

Keywords: Autophagy
Cancer
Hypoxia
Metabolism
Moyamoya Disease
Advisor: Neel, Benjamin G
Targeting the Angiopoietin-Tie2 pathway to inhibit early-stage cancer metastasis

Antiangiogenic cancer treatments seek to inhibit tumor growth by blocking the sprouting development of critical tumor blood vessels. All of the antiangiogenic drugs clinically approved thus far mainly target the vascular endothelial growth factor (VEGF) pathway â most effectively in advanced metastatic disease settings. In contrast, VEGF pathway inhibitors as postsurgical adjuvant therapies have been disappointing in randomized Phase III trials involving early (resectable) cancers. In recent years, newer investigational antiangiogenic drugs have been designed to inhibit the Angiopoietin-Tie2 pathway. Acting through endothelial Tie2 receptors, the Angiopoietin-1 (Ang1) ligand is a constitutively expressed gatekeeper of blood vessel integrity and endothelial quiescence, while Angiopoietin-2 (Ang2) is a dynamically expressed pro-angiogenic and pro-inflammatory destabilizer of endothelial cells. Upregulated Ang2 often prognosticates poor prognosis in cancer patients. While the field has largely focused on developing Ang2 blockers to inhibit angiogenic tumor blood vessels, we hypothesized that Ang2 blockers may have greater therapeutic potential when used to stabilize or reinforce normal blood vessels in the host to inhibit tumor cell extravasation and metastatic spread to distant organs. In clinical trials, Ang2 blockers have shown limited efficacy thus far as antiangiogenic drugs in advanced metastatic disease settings. The work done for this thesis evaluated Ang2 blockers in multiple immunocompromised as well as immunocompetent mouse models of postoperative minimally residual and/or micrometastatic disease. The preclinical data presented here suggest that selective Ang2 blockers may have greater utility in these postsurgical treatment settings, especially in combination with VEGF pathway inhibitors. This thesis also tested a related hypothesis â that Ang1 supplementation therapy may also be a viable strategy for stabilizing host blood vessels to inhibit metastatic dissemination. The preclinical data presented here suggest that short-term perioperative Ang1 supplementation may improve the efficacy of adjuvant chemotherapy, with or without concurrent anti-VEGF therapy.

Keywords: Angiopoietin
antiangiogenic
cancer
metastasis
Tie2
VEGF
Advisor: Kerbel, Robert S.