VictorJuiz/thesis huggingface dataset:
Metabolomic Profiling of Visceral Adiposity in Adolescents and Middle-aged Adults

I studied associations between visceral fat (VF) and the circulating metabolome in a two-generational cohort of 938 adolescents and 507 middle-aged parents from the Saguenay Youth Study. Metabolomic measures (n=228) were quantified from fasting serum samples by nuclear magnetic resonance and VF was measured by magnetic resonance imaging. Linear regression models were fitted between VF and each metabolic measure. In both generations, VF was associated with higher levels of triacylglycerol-rich lipoprotein particles and lipids, fatty acids, and inflammation independently of BMI and SF. In adolescents only, BMI-adjusted VF was further associated with higher cholesterol-rich lipoprotein particles, and in adults only, BMI- and SF-adjusted VF was associated with aberrations of glucose-related metabolites and amino acids. These results indicate that VF independently of BMI or SF is linked to multiple metabolomic aberrations that are risk factors of cardiovascular disease and type 2 diabetes, and that some of them are life-stage specific.

Keywords: Adolescents
Circulating metabolome
Lipoprotein metabolism
Metabolomics
Obesity
Visceral fat
Advisor: Pausova, Zdenka
Intermittent Fasting Modulates Breast Cancer Microenvironment and Pathogenesis

Obesity is a known risk factor for breast cancer. As white adipose tissue (WAT) constitutes a major component of the breast tissue microenvironment, obesity driven WAT inflammation and fibrosis (fibro-inflammation) is tightly associated with breast cancer pathogenesis. Intermittent fasting (IF) is an effective dietary intervention that can improve whole-body metabolism and combat obesity. As previous studies have shown IF to decrease WAT inflammation, we postulate that IF may modulate breast cancer pathogenesis. My current study investigates the impact of fasting on mammary tumor development with an emphasis on microenvironmental alterations. Experiments in orthotopic breast cancer and spontaneous mammary tumor developing mouse models showcase that IF delays tumor progression. Tumor stromal analysis demonstrates that fasting treatment can regulate tumor immune cell phenotypes to exhibit anti-tumor activity. Taken together, our study provides novel insight on fasting as an intervention for adipose-rich breast cancer development and progression through the modulation of tumor microenvironment.

Keywords: Breast Cancer
Intermittent Fasting
Tumor Microenvironment
Advisor: Sung, Hoon-Ki HKS
Letters to a Refusing State: Abyssal Stories of Postcolonial Militarism in Pakistan

This dissertation works to unsettle the territorial supremacy of the postcolonial Pakistan state. Through an intertextual reading of Pakistani-American artist and printmaker Zarina Hashmi (1937- 2020) and the Pashtun Tahafuz Movement (PTM), I offer an alternative account to the ongoing militarization of the Pakistani state that has continued to dispossess and administer pre-mature human death to the most marginal living today in Pakistan. More broadly, I place the Pakistani context within a transnational feminist framework thinking about the modern conditions of structural human conquest emerging from the period of 1492 as a critical ongoing structure of the present.

Keywords: Afghanistan
Art History
Pakistan
Pashtun
Terror
United States
Advisor: Farish, Matthew
Using Zebrafish to Study Multi-Exon Skipping as a Potential Therapy for Nemaline Myopathy

Nemaline Myopathy (NM) is one of the most common forms of congenital myopathy. There are currently no therapies. Mutations in the gene nebulin (NEB) accounts for at least 50% of all cases of NM. The majority of nebulin consists of repetitive domains called super repeats. A potential therapeutic strategy for NEB related NM is to delete the super repeats that harbor pathogenic mutations to express a truncated but functional protein. In order to test this strategy, I successfully generated a stable Super Repeat-knock Out zebrafish line (nebySRKO△4Ex/11bp-/-). This line showed no structural or functional phenotypes in the muscle. In contrast, neb△4Ex/5bp-/-, a model which I made with an incomplete super repeat deletion, showed the absence of striated expression of nebulin, Z-disk thickening, and impaired muscle performance, thus recapitulating NM muscle phenotypes. In all, these data provide strong evidence supporting CRISPR-mediated multi-exon skipping as a therapeutic approach for NM.

Keywords: CRISPR-Cas9
Muscle
Nebulin
Nemaline Myopathy
Zebrafish
Advisor: Dowling , James
Fecal Microbiota Transplant From Healthy Lean Donors To Individuals with Obesity: Effect On Insulin Resistance, Metabolic Parameters, Appetite And Metabolites

The intestinal microbiome and its metabolites may contribute to obesity, insulin resistance (IR) and type 2 diabetes (T2D). The aim was to assess in this patient population, the impact of fecal microbiota transplant (FMT) from healthy lean donors, on IR and other metabolic parameters as well as appetite and metabolites. A 3-months double-blinded randomized controlled trial was performed. Due to COVID-19 delays, only the allogenic arm was analyzed without identifying participants. Results show that FMT did not improve IR but reduced total cholesterol and low-density lipoprotein. Parameters related to hunger, fullness, prospective consumption and craving for sweet and salty food pointed toward a reduction in appetite with reduction in ghrelin at 3-months post-FMTs. FMT also increased fecal indolepropionic acid while decreasing isovalerate and isobutyrate levels, possibly affecting metabolism. Comparing the allogenic to the autologous arm is needed to confirm these results.

Keywords: Appetite
Fecal microbiota transplant
Insulin resistance
Intestinal microbiome
Obesity
Advisor: Allard, Johane P
Central Amygdala-associated Behavioural Phenotypes in a Gain-of-function Voltage-gated Sodium Channel NaV1.5 Mouse Model

Tetrodotoxin-resistant (TTXr) voltage-gated sodium channels (VGSCs) have different electrophysiological properties than TTX-sensitive VGSCs. NaV1.5 is a TTXr VGSC mainly responsible for mediating cardiac action potentials, however it has also been reported in the brain. Interestingly, male patients are disproportionately affected by NaV1.5-related cardiovascular disorders. Via immunofluorescence imaging, we found that NaV1.5 is highly enriched in the central amygdala (where the channel is colocalized with the markers, protein kinase C delta and corticotropin-releasing hormone), as well as the bed nucleus of the stria terminalis. To study the role of NaV1.5 in the brain, we used a mouse model with the gain-of-function mutation, SCN5A R222Q. Mutant mice exhibited amygdala-associated behavioural phenotypes such as hyperactivity, as well as decreased fear memory to tone-conditioned stimulus in the male mutants. Results of this study suggest a role of NaV1.5 in regulating central nervous system function, which has not been previously described.

Keywords: behaviour
brain
central amygdala
fear
Nav1.5
sodium channel
Advisor: Wang, Lu-Yang
Exploring Selective EGFR Inhibition Through Targeted Covalent-based Drugs

The epidermal growth factor receptor (EGFR) is a transmembrane protein that belongs to the ErbB family of receptor tyrosine kinases with biological roles including cell proliferation and apoptosis. Overexpression of EGFR is associated with human malignancies, such as breast cancer, glioblastoma, and non-small cell lung cancer (NSCLC). EGFR activating/acquired resistance mutations have been characterized as oncogenic drivers for NSCLC. Current small molecule therapies, while effective, are plagued by off-target effects and resistance mechanisms. For instance, although the small molecule, afatinib, targets EGFR and was developed to overcome the frequent T790M mutation in NSCLC patients, dosing regimens were beyond treatment ranges with multiple off-targets. As such, this project serves to improve the selectivity profile of afatinib through the use of poly-fluorinated benzene sulfonamides as a new class of exquisitely selective covalent warheads. The reactivity of modified afatinib and corresponding derivatives will be further evaluated via a novel high-throughput fluoride sensor assay.

Keywords: Afatinib
EGFR
Fluoride sensor
PFBS
Targeted covalent inhibitors
Warhead
Advisor: Gunning, Patrick
Unveiling the Mental Health Impacts of Gendered Islamophobic Violence on Canadian Muslim Women

This study examines the challenge of negative mental health outcomes for Canadian Muslim women as a result of gendered Islamophobic violence. This research draws data from semi-structured interviews with service providers working on the frontlines of therapy and counselling with Canadian Muslim women. With the application of intersectionality, psychoanalysis, and a community trauma framework, this study finds a myriad of ways in which Canadian Muslim women routinely face Islamophobic discrimination based on their intersectional identities which in turn creates a host of negative mental health outcomes, all characterized by internal struggle rather outward aggression. Responses to discrimination include affected women channelling their own agency and spirituality, as well as seeking community support. Multiple limitations to care from service providers and the broader mental healthcare system also emerge. This study finds that gendered Islamophobic violence is implicated in white nationalism/terror and that a community trauma informed approach is recommended for healing.

Keywords: Canada
Islamophobia
mental health
Muslim
Muslim women
racism
Advisor: Zine, Jasmin
Screening Anti-inflammatory Properties of Histone Deacetylase (HDAC) Inhibitors for Psoriatic Disease

Collectively known as the psoriatic disease, psoriasis and psoriatic arthritis (PsA) are immune-mediated inflammatory diseases in which patients have cutaneous and musculoskeletal inflammation. Despite current treatments, there remain unmet therapeutic needs in both psoriasis and PsA. In this thesis, I describe the screening of a new class of isoform-selective HDAC inhibitors in keratinocytes and macrophages as a potential anti-inflammatory treatment for psoriatic disease. Based on cytotoxic and anti-inflammatory evaluations, I identified 11 isoform-selective HDAC inhibitors that may exert anti-inflammatory effects by suppressing TNF-stimulated IP-10 secretion in HaCaT cells without inflicting cellular toxicity. Overall, my findings present the first study demonstrating the potential efficacy of isoform-selective HDAC inhibitors as anti-inflammatory agents in keratinocytes. Their use as anti-inflammatory agents in other psoriatic disease models warrants further investigation.

Keywords: Drug discovery
Drug screening
Histone deacetylase
Psoriasis
Psoriatic arthritis
Rheumatology
Advisor: Chandran, Vinod VC
Gunning, Patrick PG
Characterization of Sex Differences in the AAV-A53T Alpha-Synuclein Rat Model of Parkinson's Disease

Parkinson’s Disease (PD) shows greater prevalence and earlier disease onset in men than women. The male to female ratio is approximately 1.6:1 and the age of onset of PD is 2 years later in women. Sexual dimorphism have also been shown in animal models of PD. Previous studies have shown reduced dopaminergic neuronal loss and motor dysfunctions in female rodents compared to males. However, most studies using PD animal models do not include sex as a factor. This thesis investigates sex differences in an adeno-associated viral vector (AAV) model that mediates the overexpression of alpha-synuclein in male and female rats. We found that both sexes showed significant degeneration of nigral dopaminergic neurons using immunofluorescence microscopy and standard stereology. Male rats had higher α-synuclein expression six weeks after AAV infection, while females displayed worse behavioural deficits after three weeks. In vitro data showed no sex differences in AAV-A53T expression in primary neurons. These findings suggest that understanding these sex-specific differences is important for optimizing PD treatments for men and women.

Advisor: Kalia, Suneil SK
Association between Hypotension in the Intensive Care Unit and Impaired Cognition after Cardiac Surgery

Impaired cognition after surgery is poorly understood. The literature is limited by short-term and basic cognitive assessments. This thesis assesses longer-term cognitive outcomes with a battery, with the purpose of better characterizing cognitive changes beyond expected surgical recovery. A nested prospective observational cohort study within the CODEX trial, the first section of this thesis examines the association of factors with Impaired Cognition 3 months after cardiac surgery, specifically postoperative hypotension. The logistic regression model also includes age, sex, diabetes, stroke, and pre-existing Borderline Cognition. Due to the COVID-19 pandemic, the sample size to date is less than intended, but the study continues. The second section of this thesis includes two systematic review and meta-analysis projects examining the efficacy of dexmedetomidine in reducing cognitive dysfunction after cardiac and noncardiac surgery. The cardiac review found that dexmedetomidine reduced incidence of cognitive dysfunction after surgery, while the noncardiac review found a nonsignificant trend.

Keywords: cardiac surgery
dexmedetomidine
hypotension
post-operative cognitive dysfunction
post-operative neurocognitive disorder
Advisor: Choi, Stephen
SCAR/WAVE and Arp2/3 Complexes Associate with a Supra-cellular Actomyosin Cable in Response to Myosin and a Cytohesin Arf-GEF

Recently, expansive Arp2/3 actin networks and contractile actomyosin networks, once viewed as being antagonistic assemblies within the cell, were found to closely interact. Molecular mechanisms responsible for coordinating the networks remain unclear. I show that the Arp2/3 complex and its activator, the SCAR/WAVE complex, are enriched at cell-cell junctions of an actomyosin cable at the leading edge (LE) of epidermal sheets during Drosophila dorsal closure (DC). Myosin activity, known to promote the localization of the cytohesin Arf-GEF Steppke, is both necessary and sufficient for these accumulations of the SCAR/WAVE complex. Strikingly, I find that Steppke is also required for the enrichment of the SCAR/WAVE complex. Partial SCAR loss results in LE shape irregularities. Along with genetic interaction data between Step, SCAR and Arp3, this indicates a role for the SCAR/WAVE and Arp2/3 complexes during DC in promoting actin network growth that may be important for actomyosin cable function.

Keywords: Arp2/3
Dorsal closure
Drosophila
SCAR/WAVE
Steppke
Supracellular cable
Advisor: Harris, Tony
Biased or Motivated? Starting Point Biases May Erroneously Capture Motivated Attentional Dynamics

Computational models of choice have shown success at formalizing and testing specific mechanisms underlying choice processes. In the domain of altruistic choice, models such as the drift diffusion model (DDM) have been used to study whether prosociality is a dual process, with automatic, rapid generosity biases and an effortful deliberative process. However, current debates on generosity biases have not reached consensus on the mechanism(s) involved-- from automatic response tendencies to motivated changes in attention-- or whether such biases are generous or selfish. I hypothesized that prosocial choice involves a directed, early attentional bias, and that models which did not account for this prioritization mechanism may erroneously attribute these effects to other parameters, particularly starting point biases. This thesis work identifies how underlying mechanisms of generosity biases could be obscured or mimicked by ill-suited parameters. I discuss the implications and limitations of using a relatively simple DDM to study attentional influences.

Keywords: altruistic choice
drift diffusion model
generosity bias
Advisor: Hutcherson, Cendri A
Immunotherapeutic Approaches to Diffuse Intrinsic Pontine Gliomas

Diffuse intrinsic pontine glioma (DIPG) is a lethal brain tumour for which there are no effective therapies. Recently, immunotherapy has emerged as a promising therapeutic option for solid brain tumours, but its implementation requires an in-depth understanding of the immune landscape and the identification of protein targets. To date, the immune landscape of DIPG has been poorly defined with controversies around cell identities and activation states and various protein targets have been identified however with limited efficacy. Our analysis of RNA sequencing data from 42 tumour bulk revealed increased immune cell abundance and pathways involving regulation of immune cells in tumour samples when compared to normal brain. Complemented by single cell RNA sequencing, our analysis reveals increased immune activity within the tumour core and the invading margin of DIPG tumours. There is limited infiltration of T cells, but high infiltration of tumour associated macrophages (TAMs) specifically bone-marrow derived macrophages and resident microglia in the primary and disseminated locations of the tumour. Using marker discovery algorithms to define TAM specific signatures, we inferred TAM states and found activation states distributed along a scale of M1 (“pro-inflammatory”) to M2 (“oncogenic”) macrophage states. Our results further add to the growing body of evidence that TAMs do not cleanly fit into the dichotomous M1/M2 classification of activation. Our results suggest immune cells in DIPG are lacking inflammation signatures and are promoting an immune suppressed microenvironment thus elucidating a target for therapy. Finally, we identify a cancer-testis antigen that is upregulated in DIPGs and can be exploited as an adoptive T cell immunotherapeutic target.

Keywords: brain tumour
cancer
diffuse intrinsic pontine glioma
immunotherapy
single cell RNA sequencing
tumour associated macrophages
Advisor: Rutka, James T
Hawkins, Cynthia E
Social Support and Living Arrangements of Older Adults with Hip Fracture

Hip fractures are traumatic, life-changing events affecting older adults. Social support mayinfluence health outcomes, however, less is known about its relationship with outcomes in older adults with hip fracture. A retrospective cohort study was carried out to examine the association between functional social support and living arrangements of older adults with hip fracture. The study cohort included 139 older adults. Persons with more emotional support, or frequency of interaction one week pre-fracture, had higher odds of being discharged home (OR 6.80, 95% CI 1.08, 22.31, P

Keywords: aging in place
hip fracture
older adult
social support
Advisor: McGilton, Katherine
Influence of Parenting Cognitions on Child Mental Health and Educational Experiences at Home During COVID-19

Suboptimal parenting characterized by low self-efficacy and perceived impact, is associated with poor child mental health and academic outcomes, especially for at-risk families. This study capitalized on a longitudinal design conducted prior to and after the COVID-19 pandemic to test how prior parenting quality and environmental risk factors predict mental health and educational challenges faced by children during the pandemic. Pre-pandemic parenting and environmental risk data are available for a sample of 252 low-income mother-child dyads in Toronto, Canada. Mothers with higher educational attainment felt less efficacious in their maternal role prior to COVID-19. Mothers who had higher perceived parental impact prior to COVID-19 reported that their children faced higher levels of educational challenges during the pandemic. Pre-pandemic parental self-efficacy reduced children’s conduct problems and increased their prosocial behaviour. Parents with specific profiles of parenting cognitions may need additional supports to help their children cope during the pandemic.

Keywords: Child Mental Health
COVID-19
Parenting
Advisor: Perlman, Michal
Donor-derived Double Negative T cells as a Vehicle for the Off-the-shelf Delivery of Chimeric Antigen Receptor Therapies for B-ALL

Patient-derived anti-CD19 chimeric antigen receptor T-cell (CAR19-T) therapies have revolutionized the treatment of relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL). Due to problems associated with patient-derived immunotherapies, this life-saving treatment is inaccessible to many, leading to the development of donor-derived CAR19-T-cells. However, toxicities can arise when infusing donor T-cells into a patient. CD3+CD4-CD8- double negative T-cells (DNTs) can be expanded from the blood of healthy donors and fulfill the requirements of an off-the-shelf (OtS) cellular therapy. Incorporating CAR19 technology onto DNTs would create a safe and potent OtS cellular therapy against B-ALL. We transduced DNTs with a CAR19 construct and evaluated their efficacy, safety and OtS properties via various in vitro assays and a B-ALL xenograft model. Our results demonstrate the safety and efficacy of CAR19-DNTs against B-ALL, and provide proof of concept for using donor-derived DNTs as a platform for CAR technology to deliver OtS CAR-based cellular therapies.

Keywords: Cancer Immunotherapy
Cellular Therapy
Double Negative T cells
Immunology
Oncology
Advisor: Zhang, Li
SGLT2 Inhibition Induces Kidney Enlargement in Experimental Rats

Sodium-glucose linked transporter 2 inhibitors are a class of antihyperglycemic medication that reduces the risk of chronic kidney disease and acute kidney injury. While several mechanisms have been proposed, none were conclusive in explaining the entire range of effects of this drug class. Having noted the surprise finding of kidney enlargement in SGLT2i-treated animals in an experiment study from our laboratory, this thesis involved a confirmation and further exploration of this phenomenon. Using Ki67 and PCNA Immunohistochemistry, a significant increase in tubular cell proliferation was found 48h following SGLT2 inhibition via dapagliflozin. After 6 weeks of dapagliflozin treatment, proximal straight tubule and distal nephron grew longitudinally by 30-60%, and kidney weights increased by 20%. Furthermore, dapagliflozin had an additive effect to uninephrectomy-induced kidney growth. While the present findings identify a novel form of kidney growth, its relevance to the organ-protective effects of this drug class will require further extensive investigation.

Advisor: Gilbert, Richard
Electrophysiological Studies of Medical Cannabis in Epileptic Mouse Cerebral Cortex

Over 30% of patients with Epilepsy exhibit drug-resistance, elucidating the need for novel anticonvulsant drugs. The cannabis plant has been shown to be beneficial in treating epilepsy. This study examines the efficacy of Cannabidiol (CBD) alone and in combination with Delta-9 Tetrahydrocannabinol (Δ9-THC) on wildtype mouse cortical slices after seizure induction with 4-aminopyridine and explores the role that 5-HT1α receptor plays in CBD’s effects. We observed significant anticonvulsant effects with ≥30 µM CBD addition. 10 µM CBD showed an anticonvulsant trend but these changes were not significant, suggesting that this dose is subtherapeutic. 20:3 CBD:Δ9-THC displayed significant anticonvulsant effects, demonstrating that low dose Δ9-THC potentiates subtherapeutic doses of CBD. Lastly, we observed that blocking a 5-HT1α receptor abolished the effects of 30 µM CBD. Thus, CBD exerts its anticonvulsant effect, at least in part, through the 5-HT1α receptor. These studies lay the groundwork for further testing of cannabinoids as anticonvulsants.

Keywords: 5HT1A Receptor
Cannabidiol
Electrophysiology
Epilepsy
Medical Cannabis
Δ9-THC
Advisor: Carlen, Peter L