VictorJuiz/thesis huggingface dataset:
Uncovering a Novel Role for BIRC6 in a Dwarf Mutant Mouse

Baculoviral inhibitor of apoptosis repeat-containing 6 (BIRC6) is a member of the inhibitor of apoptosis protein (IAP) family. The IAP family regulates apoptosis by binding caspase proteins, marking them for degradation and in turn, inhibiting apoptosis. BIRC6 is implicated in additional molecular pathways including autophagy, cell cycle regulation and DNA damage response. However, the role BIRC6 plays in normal development remains unclear. Our lab identified a mouse line with a dwarf-like phenotype in a dominant N-ethyl-N-nitrosourea (ENU) mutagenesis screen. Whole-exome sequencing (WES) identified a point mutation in Birc6 (c.9611G>A) that resulted in a p.R3204Q substitution. The association between Birc6 and dwarfism has not been previously reported; therefore, this work identifies a new model of proportional dwarfism and a novel function for BIRC6. Using CRISPR/Cas9, the Birc6R3204Q/+ dwarf phenotype was confirmed in a new mouse model and the phenotypic basis for short stature was determined to have an endocrine basis.

Keywords: BIRC6
Dwarfism
Inhibitor of apoptosis
Mouse model
Advisor: Justice, Monica J
Investigation of Human Cerebral Organoids as an Enhanced Platform for Developmental Epilepsy Modelling

Approximately 1% of the world population suffers from epilepsy, a neurological disorder characterized by repeated seizures. In vitro models that capture the complexity of the human neuronal system in its early development do not exist. Cerebral organoids, derived from human iPSC lines and human embryonic stem cells, carry the potential to model developmental neurological disorders beyond the capacity of current in vitro models. To date, a detailed electrophysiological analysis of developmental epileptic phenotypes in cerebral organoids has not been performed. Here, cerebral organoids are employed to functionally characterize neonatal seizures in cerebral organoids using traditional electrophysiological methods and engineering analysis methods to reveal features of interest in an induced and genetic model of epilepsy – neonatal hypoxic-ischemic encephalopathy and WWOX-related epileptic encephalopathy, respectively. This work forms the basis of establishing benchmark features for the investigation of specific mechanisms and development of targeted therapies for developmental epileptic encephalopathies in cerebral organoids.

Keywords: cerebral organoids
electrophysiology
neonatal epilepsy
oxygen-glucose deprivation
power spectral density
WWOX-related epileptic encephalopathy
Advisor: Carlen, Peter L.
Perceptions of Professionalism in Dental Students

This thesis explored Canadian dental students’ perceptions of professionalism and the factors associated with these perceptions. Information was collected from undergraduate dental students at the Faculty of Dentistry, University of Toronto (N = 430) using an online survey. Evaluation of professionalism was based on three outcomes: attitudes toward professionalism, moral inclusion and perceived professional roles, which were derived from the American Dental Education Association values of professionalism in dental education and existing measures in the literature. These outcomes were assessed using Likert and visual analog scale questions. Associations with environmental, institutional and student-related factors were investigated using non-parametric tests, chi-square tests and regression analysis. The survey yielded a response rate of 51.4% (n = 221). Results indicate that overall, this sample of dental students had positive perceptions of professionalism, which were negatively impacted when students viewed their future patients as consumers. These findings have implications for professionalism education in dentistry.

Keywords: Dental Students
Dentistry
Education
Social Pschology
Advisor: Quiñonez, Carlos
Relationships between Myeloperoxidase and the Cognitive and Neuroimaging Correlates of Mild Vascular Cognitive Impairment

Mild vascular cognitive impairment (mVCI), the most prevalent form of vascular cognitive impairment, presents with both cognitive impairment and vascular dysfunction, but the underlying disease pathophysiology is not well understood. Building upon the role of the innate immune system in cognitive and vascular disorders, this thesis explores the associations of myeloperoxidase (MPO), a neutrophil specific inflammatory protein marker, with disease markers of mVCI, specifically cognition and neural white matter damage. In n= 27 patients, elevated plasma MPO was related to decreased verbal memory (β= -2.284, p=0.035), after controlling for education and body mass index. Contrarily, elevated MPO was associated with higher periventricular white matter hyperintensity volumes (β= 0.744, p=0.028), before controlling for age and resting systolic blood pressure. The results of this study suggest that MPO may be involved in the pathophysiology of mVCI and may be facilitating its effects on cognition via affecting the neuroimaging correlates of the disease.

Keywords: cardiovascular disorder
executive function
memory
mild vascular cognitive impairment
myeloperoxidase
white matter hyperintensity
Advisor: Lanctôt, Krista
Synthesis and Characterization of 1,2,4,5-oxadiazaboroles, A Novel Class of Heterocyclic Boron Complex

1,2,4,5-Oxadiazaboroles with tetravalent boron centre have been found to exhibit valuable anti- tumor, anti-fungal and anti-bacterial properties. However, the investigations of such compound has been limited due a lack of general synthetic methods. The traditional approach of this compound is through condensation between pre-synthesized oxime derivatives and boron species. The lack of versatile techniques to directly assemble the 1,2,4,5-oxadiazaborole complexes hinders the development of such complexes in various fields of chemistry. In this research project, a novel three-component condensation of N-hydroxylamines, nitriles and diphenyl borinic anhydrides is investigated. This methodology is shown to be amenable to various substrates and has been successfully used to synthesize 14 examples of 1,2,4,5-oxadiazaborole complexes in moderate to high yields. Limitations of this methodology are also discussed. The structures of two 1,2,4,5- oxadiazaboroles are studied in detail using X-ray crystallography and computational modeling.

Advisor: Taylor, Mark MST
Scheduling for Massive Random Access

Consider a massive random access scenario in which a small set of k active users out of a large number of n potential users need to be scheduled in b≥k slots. What is the minimum common feedback to the users needed to ensure that scheduling is collision-free? Instead of a naive scheme of listing the indices of the k active users in the order in which they should transmit, at a cost of klog(n) bits, this paper shows that for the case of b=k, the rate of the minimum fixed-length common feedback code scales only as klog(e) bits, plus an additive term that scales in n as Θ(loglog(n)) for fixed k. If a variable-length code can be used, assuming uniform activity among the users, the minimum average common feedback rate still requires klog(e) bits, but the dependence on n can be reduced to O(1). When b>k, the number of feedback bits needed for collision-free scheduling can be significantly further reduced. Moreover, a similar scaling on the minimum feedback rate is derived for the case of scheduling m users per slot, when k≤mb. The problem of constructing a minimum collision-free feedback scheduling code is connected to that of constructing a perfect hashing family, which allows practical feedback scheduling codes to be constructed from perfect hashing algorithms

Advisor: Yu, Wei
Development and Pharmacokinetic Evaluation of a Self-nanoemulsifying Drug Delivery System for the Oral Delivery of Cannabidiol

Cannabidiol (CBD) is a non-psychoactive cannabinoid with a notable safety profile. An oral formulation of CBD (Epidiolex®) has been approved by the FDA, and there is some evidence to suggest that CBD may alleviate symptoms of certain chronic diseases. CBD is a lipophilic compound with low oral bioavailability that undergoes significant first-pass metabolism. These characteristics limit the clinical potential of oral CBD therapies. One strategy to overcome these challenges is to develop self-nanoemulsifying drug delivery systems (SNEDDS). Here, CBD-SNEDDS were developed and optimized through in vitro assays. Two lead formulations were administered in healthy Sprague-Dawley rats via oral gavage (20 mg/kg CBD), and pharmacokinetic parameters of CBD were compared against a medium chain triglyceride oil formulation of CBD (MCT-CBD), as well as a sesame oil-based formulation similar in composition to Epidiolex (SO-CBD). The CBD-SNEDDS improved the systemic exposure to CBD compared to MCT-CBD; however, no improvement was found compared to SO-CBD.

Keywords: bioavailability
cannabidiol
lipophilic drug
oral drug delivery
self-nanoemulsifying drug delivery systems
Advisor: Allen, Christine
ID1 Expression in Glioblastoma Cells Correlates with One-carbon Mediated Purine Synthesis

Glioblastoma is the most common primary brain tumour in adults. Inhibitor of DNA-binding-1 (ID1) is a transcriptional regulatory protein and a regulator of tumourigenesis in glioblastoma. While ID1 was shown to regulate metabolism in other cancer types, the role of ID1 in metabolic reprogramming of glioblastoma is not clear. In this thesis, we identify a correlation between ID1 expression and 1-C-mediated de novo purine synthesis in glioblastoma, and present data in support of a hypothesizes that this metabolic phenotype underlies proliferative capacity and TMZ-resistance of ID1-high glioblastoma cells. The expression of one-carbon (1-C) metabolism and purine synthesis enzymes are significantly reduced with ID1 knockout. Exogenous purine supplementation restores proliferation in ID1-deficient cells. Treatment of temozolomide-resistant glioblastoma cells (U251-TR) with AICAR sensitizes these cells to chemotherapy. Our data suggest that the metabolic phenotype observed in ID1-high treatment-resistant glioma cells is a potential therapeutic target for this cell population.

Keywords: Cancer Metabolism
Glioblastoma
ID1
One-Carbon metabolism
Purine synthesis
Advisor: Das, Sunit
Identification of Novel Radiosensitizers in Small Cell Lung Cancer

Small cell lung cancer (SCLC) is a lethal malignancy, marked by early metastasis into extensive-stage (ES)-SCLC. There is a critical need for improved treatments. After chemotherapy, consolidative thoracic radiotherapy improves patient survival; however, high tumor relapse in intra- and extrathoracic regions remains a challenge. One promising strategy to enhance local tumor control is the addition of radiosensitizers that also possess single agent efficacy to address extrathoracic disease. We performed a targeted CRISPR knockout screen with ionizing radiation (IR) and found several druggable, radiosensitizing candidates. HDAC3 was one top candidate identified, which we validated using genetic and pharmacological approaches. HDAC3 was found to be an essential cancer gene in which its functional loss reduced cell proliferation and, in combination with IR, effectively radiosensitizes SCLC. Our work identifies HDAC3 as a single and combination therapy target, and lays the ground for pursuing other radiosensitizing candidates with clinical translation potential for SCLC patients.

Keywords: CRISPR screen
Epigenetics
HDAC3
Radiation
Radiosensitizers
small cell lung cancer
Advisor: Lok, Benjamin H
Robust Identification of Gene Fusions from RNA Sequencing Data and Their Potential as Biomarkers of Drug Response

Gene fusions occur in solid tumors and hematological malignancies, formed as the result of somatic genomic rearrangements. Gene fusions have been shown to be associated with drug response and can therefore be seen as robust, clinically relevant biomarkers. New fusions can be detected through the use of bioinformatic tools, namely fusion detection algorithms, for which over 30 different tools have been published. However, fusion calling algorithms are error-prone, slow, and call numerous false positives. I show that by using RNA-seq data from biological replicate cell lines, the accuracy of fusion predictions can increase, thereby increasing the reliability of the fusion candidates for use in large-scale gene fusion-drug interaction experiments. I also identify strong drug response in the FO393400.1/NOL4L fusion, showing the potential for novel gene fusions as predictive biomarkers of drug response.

Advisor: Haibe-Kains, Benjamin
Approaches to Integrate Mental Health Services in Primary Care: A Scoping Review of System-level Barriers and Enablers to Implementation

Despite the growing prevalence of mental illness, the integration of mental health services in primary care has been a persistent challenge in Canada. Successful integration has the potential to reduce stigma, improve treatment of comorbidities, and enhance access to care. This scoping review investigated system-level barriers and enablers to implementing collaborative care models to integrate mental health services in primary care. MEDLINE, EMBASE, and PsycINFO were systematically searched in May 2020 resulting in the inclusion of 64 articles. The Consolidated Framework for Implementation Research was utilized to code and analyze implementation barriers and enablers. The main themes that emerged from the findings included: funding and reimbursement; health practitioner workforce and training; relationships with organizations and communities; and policy implementation. Results may inform the scaling up of existing promising local initiatives and pilot projects that integrate mental health services into primary care.

Keywords: Collaborative Care
Health Policy
Implementation Science
Mental Health Services
Primary Care
Advisor: Allin, Sara
Rudoler, David
Impact of Anemia and SGLT-2 Inhibition on Renal Microvascular Oxygen Tension: Evidence for Renal Hypoxia Sensing

Sodium glucose linked transporter 2 (SGLT2) inhibitors have been demonstrated to improve cardiovascular outcomes in patients with type 2 diabetes mellitus; by mechanisms unknown. Probability analyses have estimated that an increase in erythropoiesis may contribute to these positive outcomes. We have utilized translational animal models to investigate the impact of anemia, hyperoxia, and SGLT2 inhibitors in control and diabetic rats, to assess the impact of these treatments on renal microvascular PO2. We have demonstrated that anemia and hyperoxia alter the renal microvascular PO2 proportionally to arterial blood oxygen content. By contrast, rats with diabetes treated with the SGLT2 inhibitor dapagliflozin showed decreased renal microvascular PO2 in the renal outer medullary region, increased renal erythropoietin RNA levels, and possible evidence of enhanced erythropoiesis. This suggests that mild renal tissue hypoxia is responsible for increasing hematocrit with SGLT2 inhibition, providing insight into the potential mechanism by which SGLT2 inhibition improves cardiovascular outcomes.

Keywords: diabetes
erythropoiesis
hemodilution
kidney
oxygen sensing
SGLT2 inhibition
Advisor: Hare, Gregory M. T.
Mazer, C. David
Effect of Intravenous Alcohol on Resting Perfusion: Implications for the use of fMRI in the Study of the Acute Effects of Alcohol

Evidence suggests that alcohol’s vasodilatory properties increase resting cerebral blood perfusion, which has the potential to confound the interpretation of the BOLD signal which depends on cerebral blood flow (CBF) to index neural activity. The dynamics of alcohol’s effects on resting perfusion however are still not well understood. Participants (N=50) completed two sessions in which they received intravenous alcohol infusions calculated to achieve 80mg% BAC or saline in counterbalanced order. Arterial Spin Labeling (ASL) was used to quantify CBF at three time points (0, 40mg%, and 80mg% BAC) finding dose dependent increases in CBF related to alcohol. A subset of participants (N=29) underwent a fourth ASL scan with BAC clamped at 80mg% to investigate acute tolerance to increases in CBF, finding reductions in CBF over time during both saline and alcohol conditions despite constant BAC during the latter. Acute subjective effects were examined as moderators of CBF change, with no significant clusters emerging from these analyses.

Keywords: Alcohol
Arterial Spin Labeling
CBF
fMRI
vasodilation
Advisor: Hendershot, Christian
Computational Fluid Dynamics Modeling of Cell Distributions Towards Targeted Re-endothelialization in the Lung

Complete re-endothelialization of acellular lung scaffolds remains a significant barrier for the clinical application of regenerated lungs. Current methods of delivering endothelial cells have led to insufficient coverage of the pulmonary vasculature. Understanding how reseeding parameters affect cell deposition is necessary to optimize lung re endothelialization. In this thesis, we created a computational fluid dynamics model featuring an inertial particle deposition function to quantify the deposition of cells in mouse lung vasculature for re-endothelialization. Our novel inertial algorithm demonstrated a significant reduction in cell seeding efficiency error compared to two established particle deposition algorithms when validated with experiments. With this newly presented model, cell seeding efficiency and uniformity increased with higher flow rates. Cell seeding efficiency was further improved by utilizing a surrounding parenchymal pressure. Modulating the parenchymal pressure also enabled the targeting of cell deposition locations. This work lays the foundation to computationally optimize lung regeneration towards clinical use.

Keywords: cell seeding
computational fluid dynamics
lung regeneration
re-endothelialization
recellularization
tissue engineering
Advisor: Bazylak, Aimy
Investigating the Response of Neural Precursor Cells to Chondroitin Sulfate Proteoglycan

Spinal cord injury (SCI) is a devastating condition causing lifelong disability for over one million North Americans. While human neural precursor cell transplantation (hNPC) has shown promise in early stages of the injury, the glial scar chondroitin sulfate proteoglycan (CSPG) remains a barrier to neuroregeneration in the chronic stages. Here, we aim to investigate if CSPG inhibits neuroregenerative mechanisms of hNPCs by using RNA-sequencing to explore the transcriptome of hNPCs exposed to CSPG in vitro. Our results show that hNPC global transcriptional activity is repressed and that hNPCs upregulate key genes, LINGO4 and NRTN. Gene ontology analysis reveals that upregulated genes are associated with inhibiting neurogenesis, reducing neuronal differentiation and cell migration while downregulated genes are associated with the immune response. Ultimately, we uncover key genes that could be targeted to overcome the CSPG-mediated inhibition and used to bioengineer improved hNPC therapies for chronic SCI.

Keywords: chondroitin sulfate proteoglycan
neural stem cells
spinal cord injury
Advisor: Fehlings, Michael G
Teach Me About Your Garden: Indigenous Youth Food Sovereignty in Tkaronto

This project aims to understand the relationship that urban Indigenous young people have with food sovereignty concepts and practices in Tkaronto. Indigenous sovereignty has been discussed at length amongst Indigenous scholars, activists, and thinkers for years. This thesis attends to Indigenous feminist discourses of sovereignty as they relate to experiences of urban Indigenous food growers in asserting self-determination. Engaging the framework of relational reciprocity presented in Robin Wall Kimmerer’s Braiding Sweetgrass, and qualitative interviews with Indigenous food growers across the city, this project seeks to build upon the tradition of Indigenous resistance and support future theorizations towards Indigenous sovereignty.

Keywords: food sovereignty
Indigenous sovereignty
reciprocity
responsibility
Advisor: Tuck, Eve
Brant, Jennifer
Exploring Alternative Methods of Visualizing Patient Data

Patient data visualization can help health care providers gain an overview of their patient’s condition, and assist in decision-making on next steps on management and care. This thesis explores acceptance of, and reactions to five visualizations that can be used to summarize patient data, including a Text Summary, text and frequency-based Word Cloud, a Bar Graph, a Line Graph, and a newly developed Text Graph that combines text with time-based distribution. Results from a qualitative study with medical school students and health care providers show that users can interpret patient health information from all visualizations, and can imagine using these visualizations in their medical practice. Overall, the Text Summary is the most positively received visualization, and the Text Summary and Text Graph are the most useful in extracting patient health information. This thesis provides evidence to support the idea that qualitative patient-generated information can be displayed in ways other than clinical notes.

Keywords: Information visualization
Patient Data visualization
Patient-generated data
Advisor: Chignell, Mark
Fels, Deborah
Coping Mechanisms among Youth and Young Adults with Autism Spectrum Disorder in Competitive Employment

Successful integration into employment is an ongoing issue for individuals with autism spectrum disorder (ASD). A primary barrier to successful employment includes being unable to cope with the social demands of work because people with ASD are more likely to experience higher levels of stress and anxiety. The purpose of this study was to explore how youth and young adults with ASD cope with stress and anxiety in competitive employment. A phenomenological study was conducted involving in-depth interviews with twelve youth and young adults with ASD. Findings revealed three main themes: (1) salient workplace factors, (2) stress and/or anxiety inducers, and (3) coping mechanisms. The findings shed new light on the impact of stress, anxiety and coping on youth and young adults with ASD and have potential to educate employers about the issues that such employees encounter.

Keywords: Anxiety
Autism
Coping
Stress
Work
Advisor: Lindsay, Sally
Annual Biogeochemical Dynamics of a Stormwater Management Pond

Since the 1970’s stormwater ponds (SWPs) have been used to mitigate the risks of flooding and pollution posed by stormwater runoff from paved impervious surfaces. SWPs have been evaluated for their function as a nutrient and sediment sink, but few studies have investigated fine scale spatial and temporal changes in biogeochemical properties. The objective of this study was to analyze N and P dynamics in relation to other water quality indicators in a stormwater pond. Changes in total N and P fractions were examined under different water temperatures, and rain and melt event classes. Vertical gradients of N and P fractions were also compared to water column stability. This thesis shows that a SWP transforms the composition of N and P fractions in water, resulting in higher particulate exports. It also demonstrates that despite a shallow depth, stormwater ponds are capable of producing stratified water columns of variable water chemistry. .

Keywords: Algae
Nitrogen
Phosphorus
Stormwater
Stratification
Urban ponds
Advisor: Duval, Tim P