VictorJuiz/thesis huggingface dataset:
Facing Inequity: Social Justice Education in the Training of Pre-service Workers in New York City
Keywords: anti-oppression education
critical social work curriculum
pre-service social workers
racial inequality a
social justice education
social services

This study uses a qualitative approach to construct and examine the impact of a critical social work curriculum delivered to pre-service social workers in New York City, United States. It argues that social justice education principles, specifically critical theories pertaining to race, racial identities and racial formation position social workers-in-training for relational and transformative social work with members of racial, ethnic, religious and sexual minorities, and those living in poverty or without citizenship status. Such relational social work, the study suggests, forces especially self-identified White-social workers to take responsibility for the historical oppression of others and ultimately view the field of social work as a space to foster non-violent and caring relations that do not duplicate and extend injustices faced by racial minorities in the United States. Despite emotional discomfort, White learners who took part in the training also exhibit readiness to engage in critical dialogue about issues of racial inequality and their role in oppressive systems of power. Pre-service social workers identifying as Black or as people of color, appreciate tremendously how the critical social work curriculum opens a space where they can voice out their experiences, and engage White people in facing together the history of racial, gender, ethnic and class inequalities that separate social workers from each other and from those marginalized communities who receive their services. The study discusses the experiential, emotional, and cognitive approaches embedded in the Critical Social Work Curriculum presented here so other educators in the field of social work could use, test and enrich the approach further. The full curriculum is provided in the Appendix. The analysis also documents limitations of the approach, the emotional labor involved in its delivery, as well as the need for institutional and organizational support for social justice education in the training of social workers not just in New York City but across the United States. University programs in social work must commit to critical pedagogies in order to position social workers for delivering services that support others in non-oppressive and meaningful ways.
Elucidating the Role of the Pluripotency Regulator Prdm14 in Cancer Initiation Using Mouse Models of Lymphoblastic Leukemia
Keywords: B-1 cells
Cancer
CBFA2T3
Leukemia
Mouse models
PRDM14

Molecular mechanisms underlying high-risk subtypes of leukemia remain elusive. PR-domain containing 14 (Prdm14) is a potent oncogene implicated in the initiation of many cancers, including leukemia. During development, Prdm14 maintains pluripotency by regulating expression of self-renewal and differentiation genes, and promoting global epigenetic changes. Prdm14 expression is restricted to pluripotent cell types; however, PRDM14 is mis-expressed in numerous human cancers and is associated with poor patient outcomes. To understand the molecular mechanisms driving cancer initiation, I studied mouse models of Prdm14-driven leukemia. I characterized a model of T cell acute lymphoblastic leukemia (T-ALL) expressing FLAG-PRDM14 to show PRDM14 binds to the Notch1 locus prior to acquiring Notch1 activating mutations and leukemia onset. Further, I identified CBFA2T3 as the primary protein interaction partner of PRDM14 in leukemic bone marrow (BM), and demonstrated that Cbfa2t3 is required for PRDM14 to expand progenitor-like cells and initiate T-ALL. The interaction between PRDM14 and CBFA2T3 that occurs in conserved family motifs suggests this complex provides a platform to recruit chromatin modifying enzymes to initiate leukemia. I used CyTOF to deeply profile the phenotype of expanded pre-leukemia progenitor-like cells and demonstrated that Prdm14 can initiate parallel cancer programs in different lymphoid lineages. Single-cell RNA-sequencing revealed that pre-leukemic T cells expressed Notch1 and its target genes, while pre-leukemic B-1-like cells expressed AP-1 proto-oncogenes coupled with mis-regulated DNA damage response and cell cycle genes. B-1 cells are an unconventional, self-renewing type of B cell established in early embryogenesis. To test the capacity of Prdm14-expressing pre-leukemic B-1-like cells to initiate leukemia/lymphoma, cells were isolated and injected into syngeneic host mice, leading to B-1 cell leukemia/lymphoma development. Consistently, I showed that Prdm14 can initiate infiltrative B-1 cell leukemia/lymphoma in a second model where Prdm14 expression is restricted to B-lineage committed progenitors, supporting a novel link between Prdm14 and transformation of B-1 cells. These findings are clinically relevant, as relapsed pediatric B-ALL patient tumours that express PRDM14 have significantly worse outcomes. Collectively, my results provide a mechanism for Prdm14-driven cancer initiation in hematopoietic cells that may inform how Prdm14 initiates cancer in solid tumours and how it could be targeted therapeutically.
Development of Bioanalytical Platforms for the Discovery of Small Molecule-Protein Interactions in Parkinson’s Disease
Keywords: Bioanalytical chemistry
Biosensor
Electrochemistry
Parkinson's disease
Pyrroloquinoline quinone
α-Synuclein

Parkinson’s disease is a type of progressive neurodegenerative disease that affects the neuromotor function of the brain. The current theory suggests that its pathologies are connected with α-synuclein (α-syn) aggregation. Monomeric α-syn can cluster to form oligomers. Leading to the formation of β-sheet rich fibrils and the eventual Lewy body inclusion. The presence of biometals such as Cu(II) can drastically enhance the speed of α-syn aggregation as well as induce higher reactive oxygen species (ROS) formation. Plant extracts such as pyrroloquinoline quinone (PQQ) have been shown to contain an anti-fibrillation effect. As such it is critical to examine the rescue effect of PQQ against Cu(II) induced α-syn toxicity. In Chapter 1, a detailed discussion between α-syn in PD pathologies, biometal implications, and plant-based PD therapeutic molecules is presented. This is accompanied by a review of fundamentals of electrochemistry to highlight the advantage of electrochemical sensors. This is followed by a summary of the current available electrochemical platform that studied biometal and neurodegenerative disease-related proteins (Chapter 2). Then, the antioxidative and rescue effect of PQQ against Cu(II) α-syn was studied. Based on circular dichroism and ROS detection assay results PQQ was effective at preventing Cu(II) induced α-syn aggregation (Chapter 3). We found, binding events between α-syn and metal or small molecules occur at the primary structure. Thus, a novel sensor platform was developed to study the α-syn-Cu(II) interaction variance caused by point-mutation on the α-syn sequence (Chapter 4). This result was in agreement with our isothermal titration calorimetry, (ITC) and x-ray photoelectron spectroscopy (XPS). Furthermore, this novel platform was able to be incorporated into a flow-injection system and demonstrate the binding between α-syn and PQQ occurs at the lysine residue (Chapter 5). Finally, in Chapter 6, a ferrocene-modified α-syn peptide fragment was employed to observe Cu(II) induced early misfolding events. Cu(II) was shown to cause α-syn conformation change and PQQ was able to revert the effect. Overall, this thesis proved the feasibility of using peptide fragments as a new approach to designing biosensors. With further development, this system will become a keystone tool in the search for the cure in PD.
Emotion-related Processes in Children: Links to Aggression and Prosociality
Keywords: Aggression
Childhood
Emotion recognition
Physiological regulation
Prosociality
Respiratory sinus arrhythmia

Emotion-related processes are considered important for how children respond to social situations. This dissertation focuses on two key emotion-related processes: emotion recognition and physiological regulation. The goal of this dissertation is to gain a better understanding of when, how, and in what contexts these processes relate to children’s socio-emotional development. Studies 1 and 2 assess emotion recognition and physiological regulation to further understand how they individually relate to children’s socio-emotional development. Study 1 focuses on relations between physiological regulation—measured via resting respiratory sinus arrhythmia (RSA)—and prosociality in children. Specifically, this study addresses whether a “Goldilocks” (i.e., curvilinear) model more appropriately matches how physiological regulation is related to prosociality in children, as opposed to a linear relation. Study 2 focuses on how negative emotion (NE) recognition is linked to aggression, as opposed to externalizing problems more generally, in children within and across time. Emotion recognition and physiological regulation are closely anatomically and theoretically related, thus study 3 assesses their potential independent and interacting contributions to overt aggression. The findings suggest that NE recognition is important for understanding overt aggression, as opposed to non-aggressive externalizing problems, in early and middle childhood. Further, NE recognition subcomponents (insensitivity and misspecifications) were differentially related to distinct forms (reactive and proactive) of children’s overt aggression within and across time. Many of these relations were buffered in children with higher resting RSA. Lastly, moderate resting RSA was associated with increased prosociality in middle, but not early, childhood. Together, these findings suggest that (1) poor NE recognition is linked to increased overt aggression in children, (2) lower resting RSA is related to difficulties with prosociality and aggression, especially when combined with other emotion processing challenges (i.e., poor NE recognition), (3) relations differed based on whether relations were assessed concurrently versus longitudinally, and (4) some relations depended on the developmental period of the child. This research suggests that the importance of emotion recognition and physiological regulation depends on the age of the child and the time span assessed. Additionally, these processes interact with one another and may differentially affect prosociality versus aggression in children.
E3 Ubiquitin Ligase Cbl-b deficient T cells resist Treg cell-mediated suppression and enhance anti-tumor immunity
Keywords: Cancer immunology
Immuno-oncology
Immunotherapy
Regulatory T cell
T cell

Regulatory T cells are one of the integral components of the adaptive immune system that contribute to the regulation of anti-tumor T cell responses. However, studies have suggested that alterations in T cell signaling networks can result in T cells that are resistant to the suppressive effects of Treg cells. Here, we specifically investigated the role of E3 ubiquitin ligase Cbl-b in establishing T cell resistance to Treg cell-mediated suppression. First, we found that the absence of Cbl-b, a negative regulator of multiple TCR signaling pathways, rendered CD8+ T cells impartial to Treg cell-mediated suppression. Transcriptomic analyses suggest that pathways associated with cellular proliferation and cytokine production likely contribute to the observed phenotype. In particular, hyper-secretion of IFN-γ by Cbl-b deficient CD8+ T cells served as a novel mechanism which selectively renders CD8+ T cells less sensitive to suppression by Treg cells. We recapitulated our findings in a syngeneic murine model by first confirming that adoptively transferred tumor specific CD8+ T cells are susceptible to regulation by Treg cells. Unlike the wildtype counterpart, Cbl-b deficient CD8+ T cells were resistant to the suppressive effects of Treg cells in the tumor, and the therapeutic benefit of Cbl-b deficiency was abrogated upon IFN-γ blockade. Next we examined the effect of Cbl-b deficiency in CD4+ T cell compartment. Ablation of Cbl-b rendered CD4+ T cells impartial to Treg suppression by regulating cytokine networks leading to improved anti-tumor immunity despite the presence of Treg cells in the tumor. Specifically, Cbl-b deficient CD4+ T cells hyper-produced IL-2 and together with IL-2Rα upregulation served as an essential mechanism to escape suppression by Treg cells. In summary, our data highlight the role of Cbl-b deficiency and subsequent hyper-secretion of cytokines as a key mechanism which renders T cells resistant to Treg cell-mediated suppression. Such a strategy could be potentially incorporated in adoptive T cell therapy to generate robust effector T cell responses and anti-tumor immunity.
Computational Tools for Patient-specific Surgical Planning of Tetralogy of Fallot Repair
Keywords: Computational fluid dynamics
Tetralogy of Fallot
Virtual surgery

Surgical repair of the congenital heart defect Tetralogy of Fallot (TOF) involves a series of steps to remove right ventricular outflow tract (RVOT) and pulmonary artery (PA) obstruction. However, there is a large degree of geometric variability among TOF anatomies, and the most suitable repair strategy for a given patient is unknown preoperatively. The goal of this thesis is to further our understanding of the relationships between geometry and hemodynamics in the TOF patient population, as well as the patient-specific factors that may influence the choice of surgical repair strategy, using computational methods including computational fluid dynamics (CFD) simulations and virtual surgery techniques. Four studies make up this thesis: the first study presents a methodology to evaluate geometric parameters of the RVOT and PAs and applies this methodology to 11 postoperative TOF patients. Results showed significant variability within the dataset. The second study conducts a morphometric and statistical shape analysis of 16 postoperative TOF patients, as well as computational fluid dynamics (CFD) simulations on the patient-specific geometries. Results demonstrated a negative relationship between cumulative and maximum torsion and the energy efficiency of the geometry, highlighting the importance of avoiding the introduction of torsion during surgical repair. The third study virtually induces a range of stenoses on three TOF geometries to investigate the sensitivity of the efficiency of different anatomies to geometric modification. Results found differences in the peak efficiency across the patients, motivating the pursuit of patient-specific surgical repair strategies. Finally, the fourth study applies virtual surgery techniques to a preoperative TOF anatomy, to explore the effect of different surgical repair strategies on postoperative hemodynamics and efficiency. Results revealed significant differences in the postoperative pressure gradients and energy efficiency for the range of repair strategies, and enabled selection of the optimal repair technique for the patient. Overall, this thesis underscores the utility and benefit of computational tools for patient-specific, surgical planning of TOF repair. Including computational tools in this process has the potential to enable identification of the patient’s optimal surgical repair strategy preoperatively, reducing guesswork in the operating room and improving long-term outcomes for this patient population.
The Virus in the Garrison: Contagious Disease in Canadian Fiction
Keywords: Canadian literature
Health Humanities
Medicine in Literature

This dissertation analyzes Canadian representations of contagious disease in novels written after the emergence of HIV/AIDS. Ultimately, I argue that contagion in literature registers distinctive fears about the fluid and changeable nature of Canadian communities in an increasingly globalized world. Most existing scholarship on contagious disease in fiction considers contagion on a global or transnational scale, often in deference to the ease with which viruses cross borders. In contrast, my project contends that purely transnational considerations of disease risk flattening key differences in how national communities—particularly the imagined national communities present in literature—shape contagious diseases both physically and metaphorically. In a Canadian context, literary engagements with contagious disease are situated in a discursively unique environment informed by legacies of colonialism, globalization, and fraught national identity. This research stands as one of the first inquiries into the representation of contagious disease in contemporary Canadian fiction.Each of the chapters attends to one of three narrative motifs common in how Canadian authors deploy contagious disease in their fiction: contact, apocalypse, and mutation. Crucially, the texts under consideration all pair representations of contagious disease as metaphor with an awareness of contagious disease as embodied reality, a connection that speaks to the intersections of imagined community with lived experience. The first chapter, which considers Lee Maracle’s Ravensong duology, attends both to traumatic colonial contact and to the conditions necessary for more equitable forms of engagement. In the apocalypse chapter, I examine how Emily St. John Mandel’s Station Eleven and Nick Cutter’s The Troop engage with the fraught process of confronting precarity. In the final chapter, which centers on mutation, I argue that Margaret Atwood’s MaddAddam trilogy deconstructs the generic conventions of plague narrative in the service of a commentary on the limitations of narrative in disease contexts. Taken together, these texts chart deep anxieties about the outcomes of confronting the porous boundaries of imagined community on both metaphorical and embodied levels. This dissertation concludes by re- engaging the key claims made in the body of this project in light of the COVID-19 pandemic, finding evidence of further narrative shifts in representations of contagion.
An Organ-on-a-chip Platform for Cardiac Fibrotic Disease Modeling and Pre-clinical Drug Evaluation
Keywords: Cardiac fibrosis
Disease modeling
Organ-on-a-chip
Tissue engineering

Myocardial fibrosis is a severe global health problem due to its prevalence in all forms of cardiac diseases and direct role in causing heart failure. The discovery of efficient anti-fibrotic compounds has been hampered due to the lack of physiologically relevant models that can faithfully replicate disease-related phenotypes. Herein, we propose the Biowire II platform as a powerful tool for cardiac disease modeling and pre-clinical compound screening. The disease model is constructed to recapitulate contractile, biomechanical, and electrophysiological complexities of fibrotic myocardium. Additionally, we constructed a heteropolar integrated model with fibrotic and healthy cardiac tissues coupled together. The integrated model captures the regional heterogeneity of scar lesion, border zone and adjacent healthy myocardium. Through precision phosphoproteomics analysis, the Biowire disease model provides a comprehensive profile of molecular pathways and targets involved in fibrosis remodeling. To set up an analytical system for the investigation of therapeutic targets and time-dependent biological actions in disease progression, we developed another modified model to recapitulate non-genetic cardiomyopathy. The long-term tissue cultivation and real-time functional readouts enable monitoring of both acute and chronic cardiac responses to Angiotensin II (Ang II), a key mediator in cardiac physiology. Along with mapping of cytokine secretion and proteomic profiles, this model presents an opportunity to quantitatively measure the dynamic pathological changes that could not be otherwise identified in conventional animal and 2D models. A further optimized screening strategy is used to evaluate compounds that target Ang II-induced cardiac remodeling. Through assessing the effects of different compounds, the drug screening data implicated multifaceted cardioprotective effects of relaxin in restoring contractile function and reducing fibrotic remodeling. Overall, this thesis provides an engineered platform where cardiac disease remodeling can be explicitly studied over the pathological process, thereby enabling the investigation of new disease mechanisms and the discovery of potential drug candidates.
Investigating the Therapeutic Potential of Targeting Kallikrein-related Peptidases in Inflammatory Dermatoses
Keywords: Drug Screening
Inflammation
Kallikrein
Netherton Syndrome
Skin
Therapeutics

Kallikrein-related peptidases (KLKs) are a family of 15 serine proteases with various (patho)physiological functions in the human body. KLKs are involved in the homeostasis and establishment of skin barrier integrity in human epidermis. Among the skin KLKs, KLK5 and KLK7 carry out key processes and are highly regulated by endogenous inhibitors. Dysregulated and unconstrained KLK5 and KLK7 activity and expression in the skin is detrimental. This has been observed in several inflammatory skin disorders, with increased KLK proteolytic activity causing inflammation via activation of pro-inflammatory receptors and pathways and breakdown of the essential epidermal barrier. Therapeutics targeted at regulating the disrupted KLK5 and KLK7 in inflammatory skin disorders may enable the restoration of physiological skin KLK activity and provide improved therapeutic benefits over current treatments focused on symptom alleviation. To that end, a drug discovery screening approach was conducted aimed at identifying small molecule inhibitors of KLK5 and KLK7 activity and expression. A screen of a kinase inhibitor library yielded no compounds capable of reducing KLK5 expression in human keratinocytes. A high-throughput screen of five chemical libraries led to the identification of a naturally occurring chemical compound called, Brazilin, which was capable of inhibiting KLK5 proteolytic activity with a Ki of 6.4 μM. In addition, a screen of a kallikrein-targeted library of chemical compounds led to the characterization of a 1,2,4-triazolo[1,5-a]pyrimidine (TP) heterocycle backbone as a KLK7-specific inhibitor. These TP structures display highly favorable characteristics for further drug development. There remains a need to better understand the mechanisms by which KLK5 causes inflammation and barrier disruption in inflammatory skin disorders. This would help to determine possible effects of KLK5 inhibition in human keratinocytes. Here we use MS-based proteomics to gain insight into the molecular events and mechanism that may lead to disease occurrence in those patients with unregulated KLK5 in the epidermis. To address this aim we utilized shotgun label-free quantification (LFQ) mass spectrometry to define the protein signature of the secretome in keratinocytes treated with KLK5. Keratinocytes appear to have a mechanism through which they try to regulate KLK cascade proteolytic activity and KLK5 can downregulate this response.