VictorJuiz/thesis huggingface dataset:
Quantitative Carrier Transport in Quantum Dot Photovoltaic Solar Cells from Novel Photocarrier Radiometry and Lock-in Carrierography
Keywords: Carrier transport
Colloidal quantum dot
Current-voltage characteristic
Large-area imaging
Non-destructive testing
Solar cell

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.
Practising Ideology: Chinese Immigrant Mothers' Learning in Canadian Immigration Settlement Organizations
Keywords: adult education
critical ethnography
ideology
Immigrant mothers
immigration settlement organization
race
gender and class relations

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.
Pan-Cancer Study of INPP4B Reveals its Unexpected Oncogene-Like Role and Prognostic Significance
Keywords: Acute Myeloid Leukemia
Cancer
EVI1
INPP4B
Oncogene
Pan-Cancer

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.
N-3 Polyunsaturated Fatty Acids and Neuroinflammation in Alzheimer's Disease
Keywords: Alzheimer's Disease
Docosahexaenoic acid
Fish Oil
Microglia
n-3 polyunsaturated fatty acids
Neuroinflammation

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.
Novel Metabolic Dependencies in Cancer and Moyamoya Disease
Keywords: Autophagy
Cancer
Hypoxia
Metabolism
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.
Targeting the Angiopoietin-Tie2 pathway to inhibit early-stage cancer metastasis
Keywords: Angiopoietin
antiangiogenic
cancer
metastasis
Tie2
VEGF

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.
Chromatin Regulators of MYC Oncoprotein Activity in Cancer
Keywords: Cancer
Epigenetics
G9a
MYC
SWI/SNF
Transcription

The MYC oncoprotein is a key contributor to the development of virtually all cancer types. MYC is known as a global regulator of transcription that controls diverse physiological and oncogenic functions. Though there are 35 yearsâ worth of research on this protein, mechanistic understanding and therapeutic targeting of MYC are still needed. We hypothesize that chromatin interactors are critical for MYC to achieve transcriptional control and biological outcomes. Our proteomic study of the MYC interactome yielded chromatin complexes and epigenetic regulators. In this thesis, we investigated two MYC-interacting complexes and defined the chromatin landscape of the MYC interactome. We characterized the novel interaction of MYC and the G9a histone methyltransferase and demonstrated their coordinated regulation of genome-wide transcriptional repression. This interaction and their resulting gene expression output support breast cancer growth, which is impaired with G9a inhibition. This study underscores the crucial role of epigenetics and epigenetic regulators in modulating MYC activity; this serves as the basis for a compelling strategy to target oncogenic MYC. We also interrogated the interaction of MYC and the SWI/SNF chromatin remodeling complex, whose many components are inactivated in a multitude of cancer types. We specifically showed the direct interaction of MYC and the INI1 subunit and their antagonistic relationship in regulating transcription and biological functions. Combining our proteomic approach with genome-wide resources, we established the chromatin landscape of the MYC interactome, defining chromatin profiles and target gene networks of known and novel MYC interactors. Collectively, these studies brought new insights to the understanding of MYC through the identification of novel chromatin interactors of MYC, their coordinated roles in regulating transcriptional activation and repression, their contributions to MYC-driven oncogenesis, and their therapeutic potential.
Within-host Diversification of Pseudomonas aeruginosa in the Cystic Fibrosis Airways and its Effects on Antimicrobial Resistance
Keywords: antibiotic resistance
cystic fibrosis
Pseudomonas aeruginosa

The opportunistic bacterial pathogen Pseudomonas aeruginosa causes fatal pulmonary infections in patients with the genetic disease cystic fibrosis (CF). Phenotypic and genetic diversity are prominent features of P. aeruginosa populations adapting to changes in the lung microenvironment during chronic infection. However, little is known about how this diversity impacts factors such as antimicrobial resistance and patient clinical outcome. Here, we characterized diversity within a P. aeruginosa population from a chronically infected CF patient to identify the extent of phenotypic and genetic change over time. Significant heterogeneity was observed in 34 phenotypes tested among 233 sputum cultured P. aeruginosa isolates from a single study patient, making predictions of an isolate’s phenotypic properties by colony morphology alone difficult. Fluctuations in susceptibility profiles for β-lactam antibiotics over a 350 day period coincided with the emergence of three variant alleles of the penicillin binding protein 3 gene (pbpB). Distinct allele-specific susceptibility patterns for different types of β-lactam antibiotics were not associated with other common mechanisms of resistance. Multiple variant alleles of pbpB carrying novel non-synonymous mutations were common among other P. aeruginosa isolated from CF patients with a history of β-lactam treatment. The work described in this thesis demonstrates that P. aeruginosa can behave somewhat unpredictably to antimicrobials in CF infections due to high levels of phenotypic and genetic diversity, and identifies that antibiotic target modification, in the form of penicillin binding protein 3, is a common adaptation among β-lactam exposed P. aeruginosa and may be clinically relevant.
The role of RNF168 in PML-NB recruitment to DNA damage and maintenance of genetic stability under oxia and hypoxia conditions
Keywords: DNA repair
genetic instability
hypoxia
PML
RNF168

The repair of DNA damage, such as DNA double strand breaks (DSBs) is dependent on a choreographed DNA damage response (DDR) to maintain genetic fidelity and to prevent genetic instability. While the roles of the ubiquitin E3 ligase RNF168 in DDR signaling and DNA pathway selection are being elucidated, little is known about the interaction between ubiquitin E3 ligase RNF168 and nuclear components, such as PML, at the DNA double strand breaks (DSBs). In addition, it is not known if RNF168 activity differs under oxic versus hypoxic conditions to alter DNA repair and genetic stability, which is the basis of the oxygen enhancement ratio in radiotherapy. In this thesis, I have shown that PML-NB is actively recruited to DSBs and juxtaposes to open chromatin with residual DDR activity at the DSB and this recruitment is dependent on an ubiquitin-mediated recruitment process (Chapter 2). Using a RNF168 isogenic system (RIDDLE cells), I discovered that PML-NB recruitment to DSB is abolished in the RNF168-deficient RIDDLE cells, leading to increases in chromosomal and centrosomal aberrations de novo and post-IR. These defects can be restored with the complementation of human RNF168. Thus, I show that RNF168-mediated PML-NB recruitment to DSB is critical to the maintenance of genetic stability (Chapter 3). Surprisingly, I discovered that hypoxia did not synergize with RNF168-deficiency to produce greater residual DSBs. This is likely attributed to an OER of 1 at 0.2% O2 and OER of 1.86 at 0% O2 in the RIDDLE cells. As a result, hypoxia only slightly increases chromosomal and centrosomal aberrations (Chapter 4). These findings may have important implications in personalized medicine and molecular targeting of RNF168 loss or mutations in subsets of human tumors. However, I acknowledge that addition work is required to augment my data, since preexisting genetic instability in RIDDLE cells may be a confounding factor in my results. Thus, I proposed an inducible system using CRISPR-Cas9 knockout and knockin technologies to interrogate functional domains that are critical for RNF168 activity and PML-NB recruitment, and suggested improvements to live cell imaging to observe DNA repair events across longer (e.g. 4-24h) periods to corroborate our results (Chapter 5)