VictorJuiz/thesis huggingface dataset:
Mechanisms and Consequences of White Adipose Tissue Remodeling and Aging in Response to Thermal Injury
Keywords: Adipose
Beige fat
Browning
Burns
Metabolism
Trauma

Severe burns remain a leading cause of death and disability worldwide. While burn care has improved over the past 50 years, morbidity and mortality rates remain high due to the difficulty of precisely identifying and pharmacologically correcting the biological mediators that contribute to the significant metabolic derangements that occur after injury. It is now recognized that severe burns invoke a specific response, termed white adipose tissue (WAT) browning, that leads to a substantially increased hypermetabolic stress response associated with poor outcomes in adult patients. Interestingly, emerging evidence suggests that burn patients ≥60 years of age fail to initiate this response. Therefore, we investigated the mechanisms and consequences of WAT remodelling and aging in response to thermal injury. First, we delineated how WAT browning contributes to morbidity and mortality in adult burn patients and what regulates this process. We discover that, while burn-induced browning constitutes an adaptive mechanism to alleviate a strong redox pressure generated by increased lactate fluxes, prolonged and hyperactivation of this response leads to a lipotoxic environment, thereby driving hepatic steatosis and dysfunction. Thus, we subsequently tested the hypothesis that inhibition of post-burn browning by therapeutically targeting IL-6, an upstream regulator, is beneficial in terms of improving systemic hypermetabolism and organ function in vivo. Finally, we studied how aging affects hypermetabolism and outcomes after injury. Here, we show that aging impairs the activation of post-burn browning, leading to hypometabolism and significantly worse survival. Importantly, we propose therapeutically targeting aging with metformin can improve outcomes in older burn patients and mice by rescuing WAT browning. Together, our findings indicate that a tightly controlled response of the adipose is central for survival after a burn injury and that activation of browning in either extreme (too much vs. too little) can be detrimental. As such, further research is required to enable more nuanced monitoring of this browning response in burns during aging so that we can better identify the ideal activation levels of this remarkable process. This knowledge will be critical for developing new therapies that take the age of a burn patient into account to ultimately optimize care and recovery.
3D Microgels to Quantify Tumor Dynamics for Identifying Therapeutic Targets
Keywords: 3D in vitro tumor model
cancer regrowth
drug screening
image-based analysis
patient-derived organoids
tumor microenvironment

Cancer remains a global problem and still lacks effective therapeutic strategies that can achieve total tumor response. Despite ongoing efforts to identify novel drug targets and treatment strategies, the attrition rate of the current cancer drug discovery pipeline remains the highest of any disease area. This high failure rate can be attributed in part to three realistic cancer features that impact patient drug response and that are not well captured by current preclinical models for drug discovery: 3D tumor architecture, tumor heterogeneity, and the dynamic nature of tumor progression. This thesis aims to identify novel therapeutic vulnerabilities for two dynamic cancer phenomena, cancer invasion and cancer regrowth, by including these cancer features using tissue engineering tools, cancer patient-derived samples, and imaging informatics, that when combined, improve disease biology representation and enable access to novel mechanistic and phenotypic insights. Both approaches leverage the tissue engineered GLAnCE (Gels for Live Analysis of Compartmentalized Environments) platform, which generates thin, uniform, layers of micro-molded gels, termed 3D microgels, that enable high-throughput, high-content imaging of patient-derived samples in a single system. To investigate cancer invasion dynamics, we used GLAnCE to model the tumor-stroma invasive margin, where the interaction between cancer cells and the cancer-associated fibroblast (CAF) population perpetuates a pro-invasive tumor cell phenotype that drives the initial stages of cancer dissemination. Using this approach, we identify a novel epigenetic CAF target that can be used to inhibit the pro-invasive tumor phenotype observed in our model. We also investigate cancer regrowth after treatment dynamics. To do this we initially scaled-up GLAnCE to a 96-well plate format (96-GLAnCE) to improve throughput and enhanced our image-based analysis workflow. Then using 96-GLAnCE, we reveal unexpected dose-dependent variations in regrowth response, and assess the different regrowth phenotypes within and between patient-derived organoids that could have targetable potential. This thesis showcases the power of leveraging complex in vitro tumor models in conjunction with real-time, high-content imaging to explore the contribution of tumor heterogeneity on dynamic tumor biology. More broadly, this approach promises a new path for discovering new therapeutic targets with clinical translatability and greater potential for curative treatment.
Borrower Information Environment and Institutional Lending
Keywords: Bundling
Cov-Lite
Information Asymmetry Between Institutional Lenders and Bank Lenders
Institutional Loan Facilities
Market Flexing
Within-Package Differential Contract Design

Institutional (i.e., non-bank) lenders have become major funding providers in the leveraged loan market. Certain loan facilities — institutional facilities — are designed to primarily attract funding from institutional lenders. This dissertation studies the role of borrower information environment and the related information asymmetry problem in institutional lending. Although institutional lenders are the primary funding providers for institutional facilities, they still mostly rely on bank lenders for loan origination. Such market practice embodies less access to borrower private information for institutional lenders, resulting in their information disadvantage compared to bank lenders. In Chapter 1, I find that institutional facilities are more likely to be issued along with a bank facility (thus forming a loan package) when institutional lenders are at a greater information disadvantage. Further, within the same loan package, contractual terms for institutional versus bank facilities can differ. I show that when institutional lenders are at a greater information disadvantage, (1) the spread premium for institutional facilities relative to their bundled bank facilities is larger, and (2) institutional lenders are less willing to delegate their control rights to bank lenders through a covenant-lite arrangement when they have a stronger bargaining power. Taken together, Chapter 1 documents a connection between the “packaged” design of institutional loan deals and the information asymmetry between institutional and bank lenders. Chapter 2 examines the role of accounting quality in the price discovery of institutional loan facilities during syndication. Loan spreads and original-issuance discounts (together forming effective spreads) are first proposed by the lead arranger, and can be subsequently adjusted up or down based on the demand from institutional lenders. In Chapter 2, I show that lower accounting quality is associated with a higher (lower) likelihood that an institutional facility’s effective spread will experience an upward (downward) adjustment during syndication, and associated with a longer time to break into secondary-market trading. I also find that lower accounting quality is related to greater underpricing of the loan as compared to its first secondary-market-trading price. Taken together, Chapter 2 shows that accounting quality affects the efficiency and effectiveness of the price discovery of institutional facilities in the primary market.
A Comparative Analysis of Quebec and Ontario: How each province approached elementary provincial numeracy curricula and corresponding Faculty of Education accredited Teacher Education programs during the period of 2003-2018
Keywords: Comparative Analysis
Elementary Provincial Numeracy Curricula
Faculty of Education
Ontario
Quebec
Teacher Education

The issue of declining student achievement in elementary mathematics can be correlated to the implementation of the curricula reforms that began in the 1990s. The NCTM standards guiding the reforms called for significant change in teachers’ instructional pedagogy and approach (NCTM 1989, 2000). The Ontario government was increasingly concerned about the downward trend on provincial and international mathematical assessments as “results over the 2003 to 2018 period show a steady decline in Canada’s math scores” (Allison & Geloso, 2021, p.5). Quebec is the only province in Canada that has not experienced decline on national and international elementary mathematics assessments; instead, it continues to maintain its status as one of the highest performing jurisdictions in the world (Brochu et al., 2013).This exploratory descriptive and mixed methods research study aimed to understand, from a comparative analysis of Ontario and Quebec, how each province approached the organization and structure of the elementary mathematics curriculum, and how Faculty of Education programs approached teacher training within this changed context. I undertook a quantitative and qualitative analysis of both provincial curricula utilizing the ‘Model of Numeracy in the Twenty-first Century’ (Goos et al., 2011) for coding through four dimensions: context, mathematical knowledge, tools, and dispositions. This process was followed by a case study that included one Faculty of Education from each province. For this study, I conducted interviews with six key informants (three faculty and or administrators from each university) to examine how faculties responded to the large-scale changes and described the theoretical findings of the curricula analysis. These interviews provided valuable insight into the vastly different training structures each Faculty of Education had for certifying teachers. The study findings highlight four key themes that emerged: (a) differences in Ontario and Quebec student achievement in the area of number sense and numeration; (b) differences in curricula structure (size and complexity); (c) statistical differences by province in the dimensions of context and mathematical knowledge; and (d) differences in the incorporation of problem solving, mathematical tools, theoretical underpinnings and the use of supplementary resources. The findings include implications for theory, policy and practice.
The Role of White Adipose Tissue Remodeling in Mediating Burn-Induced Hypermetabolism
Keywords: Adipose Tissue
Burn Injury
Hypermetabolism

Major burns represent one of the most severe forms of trauma due to the magnitude and persistence of an amalgamation of symptoms, including systemic inflammation, glucose and insulin signaling dysregulation and whole-body catabolism, together inducing a hypermetabolic response. Remarkably, hypermetabolism can persist for years after the initial injury, even after full wound closure. Given its pervasiveness, and based on strong correlations between hypermetabolic symptoms and the increased risk of sepsis, multi-organ failure, and death, discovering novel interventions geared towards mitigating hypermetabolism is a top priority to improve patient outcomes. One potential avenue is to target adipose tissue. It is now well-appreciated that adipose tissue is not simply a quiescent lipid storage vessel. Rather, it is profoundly adaptable and possess a wide array of functions that govern systemic metabolism. Moreover, adipose tissue has been implicated as the driving force mediating a diverse spectrum of metabolic pathologies. Thus, we hypothesized that adipose tissue is a central regulator of burn-induced hypermetabolism, and that by reducing its metabolic activity, this may alleviate poor outcomes. We first demonstrated, in both severe burn patients and mouse models of thermal injury, that white adipose tissue (WAT) remodeling, including increased lipolysis, mitochondrial biogenesis, and browning (i.e. the phenotypic switch of adipocytes towards an energy expending state), is initiated by multiple factors, such as adrenergic stimulation and systemic inflammation, and persists long-term. Moreover, this was associated with severe metabolic derangements, such as increased energy expenditure, inflammation and tissue-specific dysfunction. Given this correlative evidence, we next aimed to provide direct support that WAT drives hypermetabolism. Indeed, we showed that WAT can independently induce a systemic dysfunctional state when burn adipose is transplanted into healthy recipients. Remarkably, the dysfunctional phenotype was restored when healthy fat was transplanted into a burn model. This suggests that WAT can independently elicit or improve the hypermetabolic response. Finally, we uncovered a novel mechanism of intra-adipose remodeling, which coordinates an immune-adipocyte crosstalk facilitated by nicotinic acetylcholine receptor signaling. Collectively, this thesis clearly identifies WAT as a dominant mediator of the long-term hypermetabolic response to burns. Thus, future therapeutic interventions should be designed to target adipose metabolism.
Anatomical and Functional Characterization of the Larval Zebrafish Periaqueductal Gray Through the Development of Experimental Tools
Keywords: penka
Periaqueductal gray
rln3a
zebrafish

Investigation of sensorimotor neural circuitry has evolved tremendously from traditional experimental approaches that relied on electrophysiological recordings and lesioning. Modern optical technologies allow for in vivo cellular resolution monitoring of activity across thousands of neurons, and selective neuronal inhibition or activation with light. Larval zebrafish are apopular model system to investigate neural circuitry using optical approaches owing to their small vertebrate brain and transparency. They also exhibit a diverse behavioural repertoire at early ages, including prey capture and predator avoidance. In this thesis, I take advantage of the experimental benefits offered by larval zebrafish to investigate the periaqueductal gray (PAG), a midbrain region with a variety of functions including the regulation of active and passive responses to threats. Due to the small size of the larval brain, all neurons within the PAG are accessible for near simultaneous recording of activity, an approach not currently feasible in mammals. To investigate PAG function in zebrafish, I first developed an experimental pipeline that allowed for precise visual stimulation, while recording behaviour and neural activity from whole populations of identified PAG cell-types. The two populations I examined express either the rln3a or penka neuropeptide genes, landmarks used in mammalian PAG studies. I found that the populations are partially overlapping, and reside near the cerebral aqueduct. Fluorescent in situ hybridization revealed that both populations are overwhelming GABAergic. Through calcium imaging, I uncovered that roughly half of rln3a neurons, and a small percentage of penka neurons respond to a threatening looming disk visual stimulus. Rln3a neurons displayed similar activity when presented with other decreasing luminance stimuli, with a return to high luminance abruptly terminating rln3a activity. This indicates these neurons can encode environmental light levels. Combined calcium imaging and behavioural experiments demonstrated that both rln3a and penka neurons have increased activity when fish produce fewer swim bouts after expansion of the looming disk. This suggests a role for these neurons in behavioural suppression during visual threats. This partially contradicts the presumed role for inhibitory neurons within the mammalian PAG, and sets the stage for future studies into the functional evolution of this ancient brain region.
The Role of Programmed Germline Mitophagy in mtDNA Quality Control
Keywords: Drosophila
mitophagy
mtDNA
oogenesis
quality control

Mitochondrial DNA (mtDNA) is subject to high mutation rates and undergoes little recombination, making it susceptible to the accumulation of mutations. To prevent deleterious mutations from being inherited, the female germline has evolved a special, conserved quality control mechanism that has thus far remained poorly understood. Through a large-scale RNAi screen, I uncover a novel programmed germline mitophagy (PGM) that drives mtDNA quality control in the female Drosophila germline. I show that PGM requires the mitophagy receptor BNIP3, mitochondrial fission factors, and members of the Atg1 complex, but not the canonical mitophagy factors Pink1 and Parkin. Surprisingly PGM is not induced by the presence of deleterious mtDNA, but rather is developmentally triggered in germ cells upon entry to meiosis through the inhibition of the Target Of Rapamycin Complex 1 (TORC1). I also identify the translation regulator, Ataxin-2, as required for PGM. Detailed structure-function analysis demonstrated that Ataxin-2 inhibits TORC1 predominantly through its PAM2 domain, suggesting translational activation is required to inhibit TORC1. By coordinating the timing of PGM with meiosis, I reveal that mtDNA quality control, the mechanism that maintains mtDNA integrity across generations, is developmentally and genetically coupled to meiosis, the mechanism that maintains nuclear genomic integrity across generations. The precise role of PGM in mtDNA selection is yet to be fully understood, but could involve turnover of mtDNA or mitochondrially-encoded proteins. This work also identifies numerous new mtDNA quality control factors and reveals a generalizable strategy for mtDNA quality control applicable across species, tissues, and disease states.
Middle Eastern Refugees in Europe: The Polarization of Affect through Digital Remediations of Migration as Crisis
Keywords: 2015 refugee crisis
affect studies
digital hate
humanitarianism
political polarization
trauma studies

This dissertation reads the contemporary political polarization through an affective network, attending to the various manufactured anti-Muslim, multidirectional traumatic and humanitarian sympathetic responses that have accompanied representations of the migratory “crisis,” and exploring the European reactions toward war refugees fleeing the Middle East over the last decade (2012-2022). I bring both poles—humanitarian gestures and alternately patriotic disavowals of migrants—under scrutiny when thinking how technological advancements in communication utilize visual culture to unveil and influence public opinion on social, economic, cultural, and political issues. The first two chapters discuss fearful and sympathetic approaches in depicting refugees and migrants by scrutinizing echo chambers, social media, online videos, television coverage and film festival circuit. Following theories of Sara Ahmed and Tony D. Sampson in approaching fearful and populistic discourses, I argue that conjoining refugees with crises has become a “stuck” association that amalgamates specific events with those narratives shaping governance decisions and border policies. The 2015 European migrant “crisis” is a prominent illustration of this, as it has since been used to justify economic problems and political shifts. Additionally, the “crisis” came to espouse some of the empathetic humanitarian narratives, criticized by Lilie Chouliaraki and Tijana Stolic, that have circulated since the traumatic events of World War II, but also inspired populistic and nationalistic attitudes reminiscent of those towards terrorism, which have led to the problematic treatment of Middle Eastern and Muslim identities in the aftermath of 9/11. A way to move beyond these polarizing remediations is through the refugees’ own accounts of their trauma, as well as their migratory and war experiences, analyzed in the last chapter of this dissertation. There, affect and trauma as theorized on by Michael Rothberg, emerge as the most suitable theoretical languages for addressing the refugee “crisis” because their micropolitics are able to measure intensities and disappearances of affective sensations in the network. Consequently, the analyses produced here look at different media and their affective capabilities to create polarizing viral and immunologic responses to the migration discourse.
Exploring the Discourse Attributes of Referential Process in Emotion Focused and Cognitive Behavioural Therapies for Depression
Keywords: Cognitive behavioural therapy
Discourse attributes
Emotion focused therapy
Referential process

The referential process (RP) refers to the way one’s nonverbal experiences are translated into verbal forms (Bucci, 1993; Bucci, Maskit, & Murphy, 2015). In the context of psychotherapy, three stages of the RP – activation of emotions, symbolization, and reflection – have been presented as a general framework for understanding change (Bucci, 2013). However, most of the studies on RP has been conducted in the context of psychodynamic treatment and in single case designs. Thus, the current study examined the discourse attributes of RP using session transcripts of 40 clients who underwent 16 sessions of cognitive behavioural therapy (CBT) or emotion focused therapy (EFT) for depression.The Discourse Attributes Analysis Program (DAAP; Maskit, Bucci, & Murphy, 2012), a computerized text analysis program that measures the discourse attributes RP, were applied to 80 session transcripts. Given that some therapists had worked with multiple clients and two sessions belonged to each client, Generalized Estimating Equation (GEE) was used to account for the nested structure of the data. The DAAP measures differed between EFT and CBT in the expected ways based on the theories of change that are rooted in each modality: there were more affect words in the EFT transcripts and more reflection words in the CBT transcripts. Overall, the two modalities did not differ in terms of the major measures of RP applied to clients’ and therapists’ speech. This substantiated Bucci (2013)’s theory that RP is an atheoretical framework for understanding change. The study unveiled novel information about specific in-session therapist processes that contribute to clients’ session ratings, as well as their overall treatment outcome. Therapists whose clients belonged to the good outcome group used more concrete, imagistic, specific, and clear language in the highest client rated sessions Additionally, the more that therapists used this style of language and spent more of the sessions doing so, the greater changes their clients perceived from their sessions. These findings imply that it is important for therapists to effectively connect to their experiences and communicate themselves clearly to their clients. Theoretical, clinical, and measurement implications, limitations, and directions for future research are discussed.
Molecular, Metabolic and Functional CD4 T Cell Paralysis Impedes Tumor Control
Keywords: cancer immunology
CD4 T cells
CTLA4
Tregs

CD4 T cells are central effectors of anti-cancer immunity and immunotherapy, yet the regulation of CD4 tumor-specific T (TTS) cells is unclear. In this study, we demonstrate that CD4 TTS cells are quickly primed and begin to divide following tumor initiation. However, unlike CD8 TTS cells or exhaustion programming, CD4 TTS cell proliferation is rapidly frozen in place by a functional interplay of regulatory T cells and CTLA4. Together these mechanisms paralyze CD4 TTS cell differentiation, redirecting metabolic circuits, and prohibiting their accumulation in the tumor. Paralysis is actively maintained throughout cancer progression and CD4 TTS cells rapidly resume proliferation and functional differentiation when the suppressive constraints are alleviated. Overcoming their paralysis established long-term tumor control, demonstrating the fundamental necessity of rapidly crippling CD4 TTS cells for tumor progression and their potential importance as therapeutic targets.