VictorJuiz/thesis huggingface dataset:
Impact of Maternal Th-17 Associated Inflammatory Disease on the Expression of Placental Transporters

Th-17 cytokines have been associated with the pathogenesis and development of several autoimmune diseases. Th-17- induced inflammation affects the expression and transport capacity of several epithelial and endothelial membrane transporters. Previous research has demonstrated the impact of Th-1-induced inflammation on the expression and function of placental drug transporters. However, little is known about the impact of Th-17 associated diseases on the expression of drug transporters in the placenta.We investigated the impact of autoimmune disease and autoimmune disease related cytokines on the expression of the most abundant drug transporters, PGP, BCRP, OAT4, OATP2B1, and OCT3 in term human placenta. Our results demonstrated that autoimmune-induced Th-17 proinflammatory cytokines dysregulate the mRNA and protein expression of important efflux and uptake transporters in cultured placental explants. Additionally, these cytokines impacted the functionality of OATP2B1 where the accumulation of its substrate was decreased in IL-23 treated JAr choriocarcinoma placental cells. Furthermore, compared to placentas from healthy women, we discovered significant changes in the expression of drug transporters PGP and OCT3 in the placentas of women with autoimmune diseases. Changes in the expression of drug transporters alters the disposition of endogenous and exogenous compounds in the fetus and ultimately may affect fetal development. As clinical implications of these diseases during pregnancy may be significant, more in-depth investigation is warranted.

Keywords: Auto immune disease
Cytokine
Placenta
Pregnancy
Th-17
Transporter
Advisor: Piquette-Miller, Micheline
Containing Meaning: Miniature Pottery on Bronze Age Crete

Often assumed to be ritual votives or toys for children, miniature ceramic vessels in the Bronze Age Aegean have been afforded little thorough study. Their presence at peak sanctuaries, sacred caves, and shrines on Crete has led to their uncritical association with ritual activity, even outside of sacred areas. When miniature pots are found in domestic spaces, they are often dismissed as objects of household ritual or simple toys. Yet miniature vessels, diverse in form and context, are so pervasive in archaeological investigations of Minoan settlements that they merit further comprehensive study. Considered alongside the abundance of small-scale Minoan material culture, including figurines, seals, miniature wall paintings, and models, miniature pottery appears to be one facet of a larger semiotic ideology – one well-versed in the language and power of the miniature. This thesis investigates the use, significance, and meaning of miniature ceramic vessels in settlements on Minoan Crete. By analyzing 504 miniature pots from thirteen sites in central and east Crete, it explores the wide range of miniature types used in the Protopalatial and Neopalatial periods and applies contextual analysis to draw out their meanings. The data is informed by a review of miniature studies over time, particularly in the fields of Aegean and Greek archaeology. Understandings of miniatures outside of the ancient Mediterranean are also examined as particularly useful case studies which bring new perspectives to the phenomenon of scale manipulation. Contextualization and data analysis reveal two distinct categories within the corpus of miniature pots: “micro-miniatures” and “small miniatures.” While micro-miniatures were indeed inherently cultic, small miniatures served a variety of practical functions within the world of Minoan Crete and should not be assumed to relate to ritual. To differentiate between the categories, the relationship between the miniature and its prototype, as well as its semiotic meaning are considered. By applying Peircean understandings of iconicity and indexicality to these two categories, and investigating the cognitive effects of miniaturization and ritual material culture, the use and significance of Bronze Age miniature vessels are further illuminated, in ritual and beyond.

Keywords: Aegean Bronze Age
miniatures
Minoan Crete
pottery
scale reduction
Advisor: Knappett, Carl
The Regulation of TAZ Expression by Chemical and Mechanical Fibrogenic Stimuli

Fibrosis contributes to 45% of all deaths in the developed world. It is a pathological form of tissue regeneration that features excessive connective tissue build-up, resulting in organ dysfunction and failure. Actin-controlled Myocardin related transcription factor (MRTF) and the Hippo pathway/cytoskeleton-regulated Transcriptional coactivator with PDZ-binding motif (TAZ) are two transcriptional co-activators that play key roles in fibrotic reprogramming. Previous work in the Kapus lab has demonstrated that MRTF and TAZ exhibit crosstalk regulating fibrotic gene expression. However, previous studies concentrated on nuclear translocation of TAZ as the key mechanism of its regulation, with few studies examining the signaling pathways and corresponding transcription factors controlling TAZ at the transcriptional level. This is a central question since increased TAZ expression is a major feature of many fibrotic diseases. This thesis aims to address this knowledge gap. Findings presented show that both chemical/soluble (TGFβ1) and mechanical (stretch) fibrogenic stimuli promote MRTF-dependent induction of TAZ transcription and thereby increase TAZ protein levels. TGFβ1 induces TAZ expression by increasing TAZ transcription (not stability) via smad3-independent, p38/MK2-dependent phosphorylation and activation of MRFT, which acts through the cis-element CArG box in the TAZ promoter. Importantly, TGFβ does not induce the expression of the TAZ paralog, YAP, defining a unique pathway for the regulation of TAZ. In addition to this novel translocation-independent mechanism, MRTF is regulated by actin polymerization-provoked translocation. This raises the intriguing possibility that Rho GTPases, key regulators of the actin cytoskeleton and important mechanotransducers, also control TAZ expression. Indeed, active Rho GTPases (RhoA, Rac1, Cdc42) and mechanical stimulation (cyclic stretch) induce MRTF-dependent TAZ promoter activation and TAZ expression. Since TGFβ also activates heat shock factor-1 (HSF1), a transcription factor with both pro- and anti-fibrotic effects, and the TAZ promoter contains HSF1-binding cis-elements (HSE), we tested if HSF1 regulates TAZ transcription. Interestingly, HSF1 suppresses MRTF-induced TAZ promoter activation. Taken together, these results define new mechanisms in the regulation of TAZ transcription/expression. MRTF, activated through distinct mechanisms by soluble (TGFβ) and mechanical (stretch) fibrogenic stimuli is a central mediator of this process, while HSF1 might act as an antifibrotic factor by counteracting the effect of MRTF on TAZ expression.

Keywords: Fibrosis
HSF1
Mechanobiology
MRTF
TAZ
TGFbeta
Advisor: Kapus, Andras
Simmons, Craig A
Evolution of Metazoan Oxygen Sensing

Molecular oxygen is required for human life and most animals are obligate aerobes. In animals, oxygen tension is monitored at the cellular level by the PHD-pVHL-HIFα axis. This oxygen-sensing pathway first evolved in the ancestor to all parahoxozoa, which includes placozoans, cnidarians, and bilaterians. This essential signaling pathway grew in complexity over evolutionary time, particularly in the vertebrate lineage, with humans encoding three HIFα paralogs (including HIF1α and HIF2α), three PHD paralogs, and two pVHL isoforms. Under normoxic conditions, PHD enzymes catalyze the hydroxylation of the HIF transcription factor, which results in its association with pVHL, the substrate-conferring component of an E3 ubiquitin ligase, and its subsequent degradation via the proteasome. Under hypoxic conditions, HIF avoids degradation and activates pathways necessary for cell survival under low oxygen conditions like erythropoiesis, angiogenesis, and glycolysis. Conversely, the normoxic stabilization of HIFα due to mutation in PHD-pVHL-HIFα axis proteins underlies numerous diseases. In Chapter 2, I demonstrate that HIF2α mutations associated with neuroendocrine tumours lead to a greater ‘dose’ of HIF2α than mutations associated with polycythemia, a noncancerous condition defined by an increase in hematocrit. In Chapter 3, I show that a conserved substitution in HIF2α results in a decreased affinity for pVHL when compared to HIF1α, which may play a role in the functional divergence of the two paralogs. In Chapter 4, I reveal that a frequently observed ‘PTM’ of pVHL is an artefact that results from the covalent modification of pVHL by a AEBSF, a commonly-used protease inhibitor. Combined, the work in this thesis further builds on our fundamental understanding of the evolution of oxygen-sensing proteins and their role in human disease.

Keywords: Animals
Evolution
HIF
Hypoxia
VHL
Advisor: Ohh, Michael
Chromosome 16q is a Locus for Tumor Suppression in Breast Cancer

The most frequent genomic alteration in breast cancer (BC) involves hemizygous loss of chromosome 16q (16q). This event occurs in up to 65% of cases. Interestingly, 16q includes two genes with recurrent mutations in BC: CDH1 and CBFB. CDH1 loss-of-function is one of the two most frequently identified focal mutations in lobular BC, along with gain-of-function mutations in PIK3CA. Here I report that homozygous deletion of mouse Cdh1 coupled with expression of activated Pik3ca induces lobular tumors. Based on transcriptional profiling and mass cytometry, these tumors showed immune suppression and exhaustion. This new model for immune-related invasive lobular carcinoma (IR-ILC) can be used as a platform to develop combination therapeutic regiments to improve outcomes for patients. Next, I tested for mammary tumor suppressor activity of Cbfb. To this end, I generated mice with homozygous deletion of Cbfb deletion together with a gain-of-function mutation in Pik3ca. As with Cdh1, homozygous loss of Cbfb dramatically increased the rate of mammary tumor formation. In most breast tumors with focal mutations in CDH1 or CBFB, the second allele is lost through homozygous deletion of 16q. Indeed, I refined both tumor models by crossing focal Cdh1 or Cbfb mutant alleles to mice with activated Pik3ca and to a novel mouse with loxP sites flanking a region of mouse chromosome 8 that is syntenic to 16q. The resulting mice developed mammary tumors that were histologically related to tumors in models for focal deletion of either tumor suppressor, thereby establishing a platform for discovery of therapeutics to treat 16q hemizygous BC. Interestingly, Cdh1 and Cbfb both showed haploinsufficient tumor suppressor activity when combined with activated Pik3ca suggesting that hemizygous loss of either gene may be at least partially responsible for section of 16q loss in BC. Finally, as 16q loss is so common, I tested for tumor formation in mice with mammary specific deletion of this region in the absence of other predisposing events. Remarkably, hemizygous loss of 16q-syntenic sequences was enough to initiate mammary tumor development. Thus, chromosome 16q is a locus for tumor suppression in BC.

Keywords: Breast cancer
CbfB
Chromosome 16q
E-cadherin
Mouse models
PI3K
Advisor: Egan, Sean E
Compensation in a Changing International Legal Order

As is well known, there remain legal and practical obstacles to access to justice for individuals in international law. In the case of mass harms, however, this dissertation demonstrates a new legal sensibility that amounts to an emerging law of international compensation (ELIC), where legal sensibility refers to a characteristic combination of ideas, forms, practices and procedures. ELIC combines an expectation that individuals should have a direct remedy for mass harm caused by a violation of international law, innovation using a mix of familiar procedural frames, the opening of new access points, and a willingness to stretch established international legal principles. Armed conflicts, investment disputes and environmental disasters are just a few of the horrendous scenarios in which violations of international law harm large numbers of individuals. ELIC thus provides extraordinary opportunities for redress at the international level.Existing mass compensation research tends to identify the heyday of international claims as prior to World War II, to explore post-war compensation mechanisms as legally unrelated to one another and to concentrate on the procedural technicalities of each scheme. In contrast, the notion of a common legal sensibility unites diverse international legal contexts. At the same time, as with the idea of Global Administrative Law, which ELIC resembles methodologically, it is predictive rather than formally binding as a substantive right or principle of access to justice would be, and, relatedly, comprehends a broader and more normatively ambiguous range of developments. The dissertation derives ELIC bottom-up from three international law case studies ranging widely from humanitarian to criminal to investment law. It does so by applying to each case a set of analytical and critical questions developed from the history it offers of claims in international law and corresponding history of domestic collective litigation. In keeping with its overall approach, the dissertation offers a more contextual history of international claims than is usually found and identifies four successive compensation models: a collateral private claims model, arbitration- diplomatic model, reparations model and institutional-transitional model. Its history of domestic collective litigation is similarly contextual and includes alternatives to US-style class actions in other legal systems.

Keywords: access to justice
compensation
human rights
Advisor: Knop, Karen C
Reactivity Modulation of Novel Poly-fluorinated Benzenesulfonamide Warheads and Therapeutic Application

This thesis details the progress made toward the development of novel chemical electrophiles based upon a poly-fluorinated benzenesulfonamide (PolyFBS). With an aim of utilizing the PFBS for therapeutic application, we focused on tailoring the reactivity of the PFBS to prevent any undesirable engagement with off-targets and improve the metabolic stability. We demonstrated that by introducing a heteroatom at an ortho-position to the sulfonamide, we can systematically control the reactivity of PolyFBS. This technique was translated to Batabulin, a known PolyFBS-containing clinical candidate with poor clinical efficacy, with an aim of improving the metabolic stability and rejuvenating the unsuccessful clinical candidate. The modified Batabulin analogues showed improved pharmacokinetic profile while maintaining the covalent target engagement in both in vitro and in vivo setting. Novel warhead-containing compounds outperformed the Batabulin in mouse models of acute myeloid leukemia, suggesting that this molecular approach could be widely applied to existing covalentcompounds to modulate their efficacy and pharmacokinetic properties. To measure the reactivity of a large library of PolyFBS compounds, working via a unique SNAr mechanism, involving the release of fluoride ions, a novel high-throughput assay was developed. A fluorogenic chemosensor was employed and shown to reliably detect the generation of fluoride ions with excellent sensitivity. Among the PolyFBS-containing compounds characterized in this assay, a novel covalent UBA5 pathway inhibitor was shown to covalently modify UBA5 at cysteine residue 185 and was further demonstrated to show impressive pharmacokinetic stability. Further evaluation of the inhibitor in an acute myeloid leukemia mouse model demonstrated on-target inhibition of UBA5 pathway and modest tumour growth retardation with negligible demonstrated toxicity.

Advisor: Gunning, Patrick
Dubai Detours: Being Muslim after the Islamic Revival and Arab Spring

This dissertation is an ethnography of Muslim believing, becoming, and belonging set in Dubai, amidst the aftermath of the Islamic Revival and Arab Spring. In this study, I explore how middle-class, migrant Muslim women grapple with Islamic theologies and ethical practices in everyday lives marked by the contingencies of living and laboring in Dubai as noncitizens. Compelled to accommodate changing economic markets, geopolitical alliances, and official stances on Islam in a place where noncitizens can never settle permanently, women develop ways of being Muslim which complicate earlier scholarly accounts of piety and subjectivity. I analyze how, as women cultivate their beliefs in God, destiny, and the afterlife, they falter and flourish through their attempts to be pious. I witness how they debate their role and responsibility in who they are, trying to shape themselves in different ways, sometimes becoming what they never anticipated. Throughout, I find, they form communities of belonging that spring from (and challenge) their existence as transient residents, connections that draw new constellations of commonality and selfhood. This believing, becoming, and belonging takes place in a context where the public, and often political, character of piety which thrived during the Islamic Revival (1970s onward) is undermined by state projects dedicated to depoliticizing Islam and society. Fashioned in response to the political uncertainties generated by the Arab Spring (2010-11) and one financial crisis after the next, these government policies shape the sites in which Dubai’s Muslims learn, work, live, and leisure. Intended as detours which help the UAE avert the strife other states experienced recently, these state-led agendas—which promote an ethos of individualism, self-help, tolerance, and positivity— configure the subjectivities and pieties of migrant Muslims in distinctive ways. For my interlocutors, being in Dubai also entails other kinds of detours— a move from a former self to someone radically new, or an extended diversion in a longer migratory journey. Analyzing these divergent detours, and the marks they leave on places and people, this dissertation offers a portrait of a global city, the UAE’s middle-class migrant experience, and the manifold forms Muslim piety takes after the Islamic Revival.

Keywords: Dubai
God
Islam
Migration
Subjectivity
Women
Advisor: Mittermaier, Amira
Healthcare utilization among adults with a history of homelessness: The distribution and determinants of high-cost use of the healthcare system

People experiencing homelessness face a multitude of health challenges that increase their need for acute health services. While there is not a one-size fits all approach to end the homelessness crisis in Canada and abroad, the healthcare system offers an important point of contact to intervene. This dissertation offers an in-depth view of the distribution and determinants of healthcare use among adults with a history of homelessness to inform the development of tailored housing and support strategies. Survey data from two large cohorts of homeless adults were linked with healthcare records under a single-payer healthcare system. These data represent a cohort of adults with a history of homelessness and a subgroup of homeless adults with a mental illness. Data linkage offers a unique opportunity to combine survey and administrative records to overcome the limitations of using each data source alone. Throughout this dissertation, the findings from three studies are described in detail. The first study offers a complete assessment of health care encounters (hospitalizations, emergency department visits, and physician visits) and applies the Behavioral Model for Vulnerable Populations to identify the predisposing, enabling, and need factors associated with higher use of these health services. The second study uses a novel approach to study healthcare costs within the homeless population by using previously established cut-offs from the general population to classify healthcare users in the top 5%, top 6-10%, top 11-50% and bottom 50% of total cost users. This approach permits comparisons in the distribution and determinants of higher cost use across the cohorts and with the general population. The third study informs the use of often arbitrary frequent user definitions by comparing health care encounters and costs across the commonly applied classifications. This work also advances research on high-cost healthcare use among adults with a history of homelessness in absence of validated cost data by validating a new method of using encounter data to identify high-cost users (top 5%). This dissertation provides insight into the use of health services within the homeless population to inform tailored housing and support strategies for people who use the health system while homeless.

Keywords: emergency services
healthcare costs
homeless persons
hospitalizations
Advisor: Hwang, Stephen W
Land Forms: The Literary Jurisprudence of Indigenous Rights in Canada

This dissertation reads contemporary works of Indigenous literature alongside Supreme Court of Canada decisions that interpret Section 35 of the Constitution Act, 1982. By recognizing "Aboriginal and treaty rights" in Canada's foundational legal document, Section 35 signalled a potentially significant change in relations between Indigenous peoples and the Canadian state. This potential has not been realized because in the legal decisions that have since defined Section 35, the Supreme Court of Canada has refused to recognize Indigenous law. My dissertation examines how Indigenous authored-works of poetry, fiction, and drama by Leanne Betasamosake Simpson, Jordan Abel, Marie Clements, and Shirley Sterling intervene in this refusal through the representation of what I call land forms, other-than-human agents who embody principles of Indigenous law. I develop this concept by building on Indigenous legal scholarship that identifies Indigenous stories as a key source for Indigenous law. I argue that, by representing how land forms are distorted, constrained, or erased by colonial agents, Indigenous authors critique the Supreme Court's reluctance to acknowledge the continuing force of Indigenous legal orders in lands claimed by Canada. By demonstrating how land forms retain agency despite their distortion in Canadian law, these authors model possibilities for Indigenous law otherwise foreclosed in Section 35 jurisprudence. These writers therefore participate in vital debates about Indigenous resurgence and sovereignty currently unfolding in Indigenous studies. I develop this argument through four case studies, each of which pairs a literary text with a legal issue explored in Section 35 jurisprudence. The first chapter reads Simpson's 2013 poem "jiibay or aandizooke" as a critique of the Doctrine of Discovery. The second chapter analyzes representations of temporality in Abel's The Place of Scraps (2013) and R v. Van der Peet (1996). The third chapter examines Indigenous jurisdiction in Delgamuukw v. British Columbia (1997) and Clements' 2003 play Burning Vision. The final chapter tracks shifting legal definitions of Indigenous religious freedom through Sterling's 1992 residential school novel My Name Is Seepeetza. This study contributes to critical conversations in Indigenous literary studies by attending to Indigenous law in literature as a crucial component of Indigenous anticolonial resistance.

Keywords: Canadian law
Indigenous law
Indigenous literatures
Advisor: Kamboureli, Smaro