VictorJuiz/thesis huggingface dataset:
Focused Ultrasound-Induced Blood-Spinal Cord Barrier Opening: Methods for Clinical Translation

Drug delivery to the central nervous system poses a unique challenge because the blood-brain and blood-spinal cord barriers limit the passage of therapeutics from the vasculature. In preclinical and clinical studies, microbubble-mediated focused ultrasound has resulted in enhanced permeability of the blood-brain barrier to therapeutics, in a manner that is non-invasive, targeted, reproducible and transient. To monitor safety, spectral content of acoustic emissions from cavitating microbubbles can be analyzed to predict and control for bioeffects.While feasibility of this method has been demonstrated in the spinal cord, challenges related to complex vertebral anatomy pose a hurdle to clinical translation. Long focal zones at clinically-relevant frequencies, and reflective boundary conditions imposed by vertebrae, promote the formation of standing waves in the spinal canal, compromising treatment safety and effectiveness. This thesis aimed to demonstrate that a uniform and controlled focus could be achieved within the vertebral canal, for safe and efficient blood-spinal cord barrier opening, through the use of (1) a dual-aperture approach for depth-of-field reduction, and (2) modulated excitation strategies for standing wave mitigation. Initial in silico and ex vivo studies indicated that a dual-aperture approach and a novel pulse scheme comprised of short (2-cycle) bursts with randomized phase shifts reduce the focal depth-of-field (~85% at 0.5 MHz) and mitigate the formation of standing waves. Subsequent ex vivo studies focused on the development of a novel method of acoustic emissions analysis which included short-time analysis; pulse inversion, which resulted in a 2-fold enhancement of trans-vertebral detection of microbubble emissions; and a maximum projection over the sonication. In vivo, emissions at the second- and sub-harmonic frequencies were correlated with successful blood-spinal cord barrier opening and tissue damage, respectively. Finally, a porcine model of successful blood-spinal cord barrier opening through the intact spine was presented. In this thesis, the aim of achieving a controlled and uniform focus within the spinal canal for blood-spinal cord barrier opening was realized, representing a fundamental stepping-stone towards the clinical translation of this technique. In the long term, there is the potential for therapeutic delivery for spinal cord diseases and disorders through a non-invasive and targeted treatment approach.

Keywords: Blood-spinal cord barrier
Drug delivery
Focused ultrasound
Pulse design
Spine
Standing waves
Advisor: O'Reilly, Meaghan A
“It Kind of Made Me Think: Is This the Real Me? Is This Really Who I Am?” A Mixed Methods Investigation of Teacher Learning and Teacher Development in CELTA Courses

Every year, tens of thousands of English language teachers worldwide graduate from the University of Cambridge Certificate in Teaching English to Speaker of Other Languages (CELTA). Despite the significant impact this pre-service certificate exerts in the English language teaching (ELT) profession, research on Language Teacher Education (LTE) has traditionally relied on studies conducted in academic-based programs at higher education institutions. This mixed methods research investigates what it means for student teachers to learn how to teach and develop as English language teachers in CELTA courses. It also investigates the nature of such learning and development, and the ways in which student teachers learn how to teach and develop as teachers in CELTA. A three-phased “enhanced” exploratory sequential mixed methods research design was employed. In Phase 1, data from semi-structured interviews, course documents, classroom observations, field notes, diaries and a WhatsApp group chat were collected at 2 CELTA programs: one in the US, where the researcher co-taught the course, and the other in Canada. Findings showed that student teachers learned teaching knowledge and skills and that, through this learning, they interacted with teacher educators, peers and ESL students, interactions which influenced and were influenced by their emotions and teacher identity. In Phase 2, these findings were used to develop the teacher learning and development (TLD) Scale. Data collected from CELTA graduates and student teachers (N = 880) from 78 countries were analyzed and a novel TLD construct was identified. In Phase 3, mixed methods synthesis occurred, and findings revealed how, by self-regulating and being regulated by teacher educators and peers through the use of course activities, artifacts and concepts, student teachers internalized teaching knowledge and developed pedagogical content knowledge. Findings also showed how student teachers developed as individuals and teachers by resolving the dialectical contradictions that constituted the moving force for their teacher development as well as the forms of their teacher development. The importance of perezhivanie (commonly translated as “lived experience”) as a lens to explain teacher development in LTE is discussed, and the concepts of teaching knowledge as praxis (TKP) and teacher’s teaching knowledge as praxis (TTKP) are proposed.

Keywords: CELTA/TESOL/TESL/TEFL
Language Teacher Education
Mixed Methods
Perezhivanie
Sociocultural Theory
Teacher Learning and Development
Advisor: Gagne, Antoinette
Oil-sector Strategies of States in the Global South: Comparing State Involvement in the Oil Sectors in Brazil, China and Mexico

Oil-producing states in the Global South adopt different strategies to influence and control their oil sectors. Why does an oil-producing state choose one approach over others? Why does a state change its approach? This dissertation argues that a government’s ideological orientation and a country’s oil balance combine in different ways to generate an oil-sector strategy that is either closed, mixed or open. While the variable of orientation represents the degree to which the government wants to intervene in the economy, the variable of oil balance constrains, facilitates or moderates a government’s preferred oil-sector strategy, depending on the interaction effects that occur from the specific aligning of these independent variables.This research presents four key findings. First, the strategy that immediately follows oil-sector nationalization sets the parameters for politically acceptable oil-related policies going forward. This original strategy often has lasting effects. Second, these constraints allow for change to occur but often limit the extent of that change. Third, a radical change in a government’s orientation or oil balance opens space for major change to an oil-sector strategy. Fourth, the new strategy that comes after this critical juncture sets new parameters for oil policy. This argument emerged inductively from intensive study of ‘big’ Global South oil-producing countries of Brazil, China and Mexico, which included elite interviews as well as studying relevant works in political science, especially historical institutionalism, constructivism and certain theories of public policy. The methods of process-tracing and comparative historical analysis helped uncover the causal variables of government orientation and oil balance, and to identify the processes and logic that ultimately produced this mid-range theoretical argument about oil strategies. The need to identify causes and systematize explanations for a state’s choice of oil-sector strategy stems from the fact that an oil industry is often the most capital-intensive, largest tax contributor and employer in an oil-producing country of the Global South with far-reaching impacts on governance and policy, as well as on political institutions and economic development.

Keywords: China
Global South
National oil companies
Oil
Policy
Strategy
Advisor: Breznitz, Dan
Structural and Functional Elucidation of PRDM Proteins

Epigenetic signalling dictates the dynamic patterns of gene expression that are required for life. In humans, epigenetic lysine methylation is produced by chromatin-bound transcription factors that contain a SET (Su(var)3-9-E(z)-Trx-homology) domain or a Rossmann-fold domain. The PRDM (PRDI-BF1-RIZ homology domain containing) proteins are identified by an N-terminal PR/SET domain that shares the canonical SET domain fold, but with just 20-30% amino acid sequence identity. Humans possess 19 PRDM-coding genes with roles in cellular proliferation and differentiation, and dysregulated PRDM gene expression is often associated with diseases. I hypothesize that only a subgroup of PRDM proteins are active lysine methyltransferases and pursue the objective of this thesis to expand the fields of PRDM biology by revealing novel insights regarding the enzymatic and non-enzymatic properties of PRDM proteins. To address this objective, I characterized MRK-740, which is the first and only chemical probe of a PRDM protein. Here I examined the mechanism of inhibition of MRK-740 for its target PRDM9, using biophysical and structural biology techniques. I characterized specificity of MRK-740 within the PRDM family and uncovered the mechanism of inhibition. Remarkably, a structural survey of all chemical probes targeting protein methyltransferases indicated that MRK-740 functions by a previously unobserved mechanism of inhibition. Next, I examined how PRDM proteins regulate epigenetic signaling through a mechanism that is independent of intrinsic methyltransferase activity. Here I examined the PRDM paralogs, PRDM3 (also known as MECOM or MDS1-EVI1) and PRDM16 (also known as MEL1), which may lack intrinsic methyltransferase activity and identified how they directly interact with the Nucleosome Remodeling Deacetylase (NuRD) complex. Finally, I examined 13 of the 19 human PR/SET domains for their ability to bind a chemical analog of the enzyme cofactor, to identify proteins with enzymatic potential. I used nuclear magnetic resonance spectroscopy to detect binding of fluorinated S-adenosyl-L-homocysteine and identified several previously uncharacterized PR/SET domains that likely bind the cofactor. Taken together, these findings provide the impetus, tools and insights for further research into the roles of PRDM proteins in health and disease.

Keywords: chemical probe
epigenetics
inhibitor
methyltransferases
protein structure
protein-protein interaction
Advisor: Arrowsmith, Cheryl H
Three Ways to Get Your Way: Strategize, Gerrymander, Party

Voting is perhaps the most basic aspect of a well functioning society. How one aggregates the preferences of the members of a group into a single decision has been a fundamental issue to human society for millennia. Today many countries use voting at all levels of their society. It can be used to pick political leaders at various levels of government. Members of admission and hiring committees use it to decide which candidates advance to subsequent rounds. Even mundane tasks like deciding what a group should have for dinner often come down to a vote. How one aggregates, or even elicits, the often conflicting preferences of the members of society is thus critical to how that society functions. Thus it should be clear who designs these preference aggregation procedures can greatly influence the direction of society. Furthermore, how the members of society decide to interact with the procedures can cause far reaching and often unintended outcomes.In this work we will examine voting, and its impacts on society, through the view of both the members of society who have their preferences aggregated and the actors who decide how they are aggregated. What sets this work aside from political science and instead places it in the computer science community is the application of analysis and techniques commonly found in artificial intelligence works. Indeed this work, while written to be broadly approachable and readable for any one possessing a basic understanding of mathematics, is still a work that is intended for the artificial intelligence researcher. Finally we mention this thesis is a broad look at various topics in voting, and while we go into some depth on each individual topic we stress that entire research careers could be devoted to their individual study. This thesis merely scratches the surface of each of these potential directions.

Keywords: AI
Computational social choice
Computer Science
Elections
Gerrymandering
Voting
Advisor: Borodin, Allan
Shah, Nisarg
The Contentious Politics of Mega Oil Sands Pipeline Projects

While the vast majority of oil pipeline projects in Canada have been successfully built, several mega oil sands pipelines within and passing through Canada have been cancelled or significantly delayed. In recent years, oil sands pipelines have received intense scrutiny from a variety of actors. While there has been significant contestation in response to a wave of pipeline proposals, scholars have not yet understood the linkages between social movements and the outcomes of pipeline projects. I identify the causal influence of social movement campaigns, what I call campaign coalitions, against new mega oil sands pipelines. Considering the power and momentum of the oil and gas industry in the early-2000s, this movement’s success in frustrating pipeline development has been truly remarkable. I first use qualitative comparative analysis (QCA) to understand combinations of causal conditions that co-occur across cases of proposed new oil pipelines and pipeline expansions. The findings from the QCA lead me to focus on campaign coalitions, which involve sustained cooperation and communication between resisting groups. I then use in-depth case studies of contested proposed mega oil sands pipeline proposals—the Northern Gateway Pipelines and Trans Mountain Expansion Project—to understand the strategies the anti-pipeline coalitions employed to influence project outcomes and the conditions that produced the project outcomes. I argue that campaign coalitions strongly shaped the project outcomes in both cases. In the NGP case, the alignment of the political and legal opportunities, with the 2015 election and a federal court of appeal ruling, resulted in the project’s cancellation. In the TMEP case, sustained opposition, in combination with a powerful new political ally with the 2017 provincial election in British Columbia created multiple, mutually reinforcing risks that made the project unviable for Kinder Morgan. In understanding the influence of campaign coalitions, I contribute to public policy and social movement scholarship in three ways. First, I refine our understanding of the processes and conditions that facilitate campaign coalition formation. Second, I identify important linkages between the processes of coalition building and mechanisms of influence. Third, I identify how coalition strategies and conditions interact to influence pipeline outcomes.

Keywords: comparative politics
contentious politics
energy politics
environmental politics
political economy
public policy
Advisor: Neville, Kathryn J.
Bernstein, Steven F.
Nests - A Relational Exploration of Children's and Parents' Active and Embodied Habitus: Illustrations of Child-centered and Decentered Socialization

Socialization, generally understood as the civilizing project done by adults to children as passive recipients, is reframed in this arts-based dissertation as an active, participative, and interdependent relational dynamic. Parents and children from 25 families collaboratively explored ideas of “what makes a kid a kid” and the influence of children’s social actions alongside the researcher using comics and narrative research techniques. Drawing on Bourdieu’s concept of habitus as a mode of socialization, this project addresses a conceptual gap regarding the ways that habitus is constituted and integrated – going beyond notions of “acquired during early childhood” by processes of “osmosis” (Bourdieu, 1988; Wacquant, 2016). Leaning on James (2013) and Mayall (2002, 2015), ideas of child-centered socialization, relational negotiations, and habitus as a malleable ongoing process are explored.Combining narrative and visual research techniques, comics research methods (Barry, 2015, 2019; Flowers, 2017a, 2017b) were used for data generation and creative analysis. Processes of relational, emergent, and embodied listening (Davies, 2014; Flowers, 2017a, 2017b; Lenz Taguchi, 2010) were employed in analyses of the effects of children’s doing. Research was conducted in the family home, and took that context into particular consideration. The project explored the ways that children’s social actions contribute to i) their own socialization; ii) to the socialization of their parents; and iii) are a part of the socializing processes of decentered relational networks involving people, materials, contexts, concepts and environments, specifically looking at the family home context. This research proposes that habitus is constituted and integrated through doing particular practices – such as childhood or parenthood practices – in embodied, reflexive, and non-rational ways.

Keywords: childhood
comics research
doing
habitus
interdependent socialization
parenthood
Advisor: Farmer, Diane
Characterizing Retinal Stem Cell Proliferation and Differentiation Potentials

A quiescent population of retinal stem cells (RSCs) in the adult mammalian eye retains the ability to proliferate and generate all retinal cell types when cultured in vitro. Thus, understanding the biological mechanisms that regulate RSC quiescence, proliferation and differentiation could lead to new possibilities for retinal endogenous repair or cell therapy. Previous in vitro experiments in our lab have implicated two proteins, BMP and sFRP2, as potential mediators of RSC quiescence. Herein, I show that antagonism of BMP or sFRP2 proteins in the adult eye can induce the proliferation and expansion of RSCs in vivo and potentiate the effects of exogenous growth factors. Using genetic lineage tracing, I found that RSCs express the gene Msx1. Moreover, in response to BMP/sFRP2 antagonism with growth factor stimulation, photoreceptor degeneration, or all combined, Msx1-lineage cells migrate from the RSC niche into the retina and express markers of mature retinal neurons, including photoreceptors. To identify novel regulators of RSC proliferation, I developed a phenotypic drug screening platform and tested a library of small molecules with well-characterized molecular targets. Screening identified synthetic glucocorticoid (GC) agonists as compounds that increase RSC self-renewal and retinal stem and progenitor cell (RSPC) proliferation. GC agonists did not affect the differentiation profile of RSPCs, suggesting proliferation and differentiation are dissociable processes. In addition, injection of GC agonist, dexamethasone, into the adult mouse eye resulted in proliferation in the RSC niche. Intrinsic and extrinsic signals can influence RSPC fate specification. Here we used a multifunctional antagonist of TGFβ, BMP and Wnt signaling – COCO -- to direct RSC progenitors to produce up to 100% cone photoreceptor progeny. Transcriptome profiling of endogenous cones and RSC-derived cones showed that both cell types are genetically similar and distinct from undifferentiated RSC progenitors. Also, we found COCO is required during the entire differentiation period to specify the cone fate. This suggests the cone fate is the default differentiation program of retinal progenitors, which is instructed via the absence of extrinsic cues. Together, these results provide novel insights into the mechanisms regulating RSC quiescence, proliferation and differentiation in vitro and in vivo.

Keywords: Differentiation
Photoreceptors
Proliferation
Retina
Stem cells
Vision
Advisor: van der Kooy, Derek
Lung Defects Contribute to Respiratory Symptoms in a Mecp2-mutant Mouse Model of Rett Syndrome

Rett syndrome (RTT) is a progressive neuro-metabolic disorder caused by mutations in the X-linked gene, methyl-CpG-binding protein 2 (MECP2). After a period of seemingly normal post-natal development, RTT patients experience a developmental regression, consisting of loss of acquired verbal and motor skills, stereotypic hand movements, respiratory abnormalities, and seizures. Respiratory impairment causes up to 80% of premature patient death; despite this, lung pathology in RTT is understudied and respiratory symptoms are currently attributed to neuronal loss of MECP2. To study the Mecp2-deficient lung, we utilized a Mecp2-mutant mouse model that recapitulates many features of RTT. I found striking lipid metabolism abnormalities in the lungs of Mecp2-mutant mice, including increased cholesterol and triglycerides and decreased phosphatidylcholines. My single cell RNA-sequencing and chromatin immunoprecipitation experiments showed that lipogenesis is increased due to decreased binding of the nuclear repressor coreceptor 1/2 (NCOR1/2) complex in the promoters of its target genes in the absence of MECP2, leading to their upregulation. I also showed that lung AE2 cell-specific depletion of Mecp2 is sufficient to cause lung lipid metabolism abnormalities and respiratory symptoms. In contrast, hindbrain neuron-specific deletion of Mecp2, which removes Mecp2 from the neuronal respiratory control center, imparted a different respiratory phenotype. RNA-sequencing of the Mecp2-deficient lung revealed decreased expression of key extracellular matrix (ECM) genes; consistently, I found alveolar tissue degradation and bronchiolar enlargement in Mecp2-mutant mice. Consistent with these findings, Mecp2-mutant mice have altered pulmonary function. Finally, we treated whole body metabolism in Mecp2-mutant mice using lipid-modulating compounds, including statins and liver X receptor (LXR) agonists; both improved neurological and respiratory symptoms, suggesting clinical utility. Altogether, these findings implicate key functions of Mecp2 in the lung and highlight the importance of studying non-neuronal aspects of RTT. Our findings will aid in developing treatments and clinical recommendations for RTT patients.

Keywords: Lipid metabolism
MECP2
Pulmonary function
Pulmonary surfactant
Rett syndrome
Translational medicine
Advisor: Justice, Monica J