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Longitudinal Sex Differences in Brain and Cognitive Function in Older Adults: Multivariate Analyses of Alzheimer’s Disease Risk Factors and Mild Cognitive Impairment
Get PDFLate-onset Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects millions of older adults worldwide. Although characterized by cognitive impairments that disrupt daily functioning, these clinical symptoms typically emerge after years of underlying neuropathological changes. The delayed onset of clinical symptoms suggests a critical window for early intervention, prompting a research focus on the earlier stages of the disease. This has led to the conceptualization of AD as a spectrum, encompassing a continuum from healthy cognitive aging to formal AD diagnosis. Therefore, lots of research has focused on the earlier stages of this spectrum, investigating cross-sectional brain and cognitive differences between healthy individuals and those with AD-related pathology. However, results across studies reveal substantial variability, highlighting the need for longitudinal research to capture and understand these diverse trajectories more effectively. Several well-established non-modifiable risk factors for AD—such as female biological sex, the presence of the apolipoprotein E ε4 allele (APOE4), and a positive family history of the disease (+FH)—warrant further investigation to elucidate their roles in disease development as well. This dissertation addresses this gap by analyzing longitudinal sex differences in brain and cognitive measures across different stages of the AD spectrum using a robust multivariate statistical technique. Study 1 examines changes in episodic memory-related brain function over two years in +FH healthy older adults, comparing males and females and APOE4 status. Study 2 extends this analysis over five years, exploring sex differences in brain structure and their association with cognitive performance and APOE4 status. Study 3 investigates subcortical brain volume changes and cognitive trajectories between the sexes over six years in individuals with prodromal AD (mild cognitive impairment) compared to cognitively healthy counterparts. Overall, across all three studies, longitudinal sex differences in brain structure, function, and cognition were identified. Females showed better memory performance but experienced greater language-based declines at more advanced stages of the AD spectrum, whereas males exhibited more pronounced medial temporal lobe changes regardless of diagnostic status. This dissertation underscores the importance of integrating biological sex in AD spectrum research, offering novel insights to inform future research and advance understanding of disease development.Ph.D
ANTI-INFLAMMATORY PROPERTIES OF GLP-1 RECEPTOR AGONISTS AND OTHER ANCILLARY BENEFITS FROM A PHARMACOLOGICAL PERSPECTIVE.
Get PDFIncretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), exert a wide range of beneficial effects beyond glycemic control, largely mediated by their anti-inflammatory properties. Chronic low-grade inflammation is a common pathological mechanism underlying metabolic, cardiovascular, hepatic, and neurodegenerative diseases. GLP-1RAs reduce systemic and tissue-specific inflammation through both direct and indirect mechanisms, including inhibition of NF-kB signaling, reduction of proinflammatory cytokines, and modulation of immune cell activity, such as that of macrophages and microglia. In type 2 diabetes and obesity, GLP-1RAs improve insulin sensitivity and endothelial function by attenuating inflammation. In metabolic dysfunction-associated steatotic liver disease, GLP-1RAs reduce hepatic steatosis and fibrosis by modulating inflammation in hepatocytes and Kupffer cells. In cardiovascular disease, they mitigate atherosclerosis progression and improve vascular health. GLP-1RAs also exert direct nephroprotective effects by reducing renal inflammation, oxidative stress, and glomerular hyperfiltration in both diabetic and non-diabetic models. GLP-RAs have been also associated with the preservation of cognitive and motor function. Preclinical studies suggest that these neuroprotective effects may involve the attenuation of neuroinflammation and reduced aggregation of pathological proteins. Overall, these pleiotropic actions position incretin-based therapies as promising tools for the management of complex chronic diseases with an inflammatory component.The presentation of the authors' names and (or) special characters in the title of the pdf file of the accepted manuscript may differ slightly from what is displayed on the item page. The information in the pdf file of the accepted manuscript reflects the original submission by the author
Stress Tested: Impact of Salinity on Cyanobacteria Surface Chemistry and Mineral Precipitation - Implications for Biotechnological Applications
No full textCyanobacteria play essential roles in global biogeochemical cycles, yet the impact of salinity stress on their surface chemistry and biomineralization potential remains underexplored. This thesis investigates how cyanobacterial membrane remodeling under variable salinity influences ion-binding properties, phosphorus dynamics, and precipitate formation. Three taxonomically and ecologically distinct cyanobacteria, Synechocystis sp. PCC6803, Synechococcus sp. PCC8806, and Spirulina platensis, were acclimated to freshwater, saline, and hypersaline conditions. Using potentiometric titration, FTIR, and XPS, salinity was shown to induce lineage-specific changes in surface charge, lipid saturation, and phosphoryl content, supporting a model where membrane phospholipids act as a phosphorus reservoir. Precipitation experiments revealed that salt-induced lysis alone triggered the formation of amorphous calcium-phosphate and carbonate phases, with the composition of precipitates influenced by pre-acclimation conditions. These findings suggest that lysis-driven biomineralization may represent a previously underrecognized pathway of phosphorus cycling. Finally, bio-addition of photoautotrophic cyanobacteria to ternary cement mortars improved compressive strength and pore structure compared to sporulated heterotrophic additives, highlighting a sustainable application for construction biotechnology. Together, this work integrates microbial stress physiology with geochemical and material outcomes, offering new insights into adaptation mechanisms, mineral formation processes, and environmentally friendly engineering strategies for carbon and nutrient management.Ph.D
Early Detection of Cardiac Disease with a Paper Based Fluorescence Biosensor
Get PDFEarly detection of cardiac heart disease is essential for timely intervention. Cardiac troponin I (cTnI) is a validated biomarker of myocardial injury; however, current diagnostic platforms are often lab-based, time-intensive, and inaccessible at the point of care. This thesis presents the development of a fluorescence-based lateral flow assay (fLFA) for sensitive cTnI detection, combining technical optimization with patient-centered design. A Taguchi orthogonal matrix guided refinement of assay parameters, including conjugate pad composition, stabilizers, surfactants, and membrane type. Fluorescent signal quantification using a Zeiss AxioZoom microscope (Cy5 channel) was enhanced through sugar bridge–mediated release, yielding an LOD of 0.032 ng/mL and LOQ of 0.096 ng/mL with strong reproducibility (CV% 5.34% @ LOQ). Patient surveys and engagement identified needs and barriers, informing recommendations for home and clinical integration. This work demonstrates that an optimized fLFA can deliver clinically relevant sensitivity while addressing end-user adoption, supporting translation toward rapid, accessible cardiac diagnostics.M.A.S
Canada in an Era of Intelligent Machines: How Institutions Condition Knowledge Generation and Innovation in a Learning Economy
Get PDFThis dissertation project develops a human-centered approach to innovation founded on the competence of people and firms. It seeks to establish a link between learning and innovative capacity by examining two industrial sectors crucial to the Canadian economy: accounting professional services and auto parts manufacturing. While the contours of the emerging AI-driven economy remain uncertain, as digitization gains momentum and intersects with the imperative of transitioning to a post-carbon economy, it is clear that economic value is increasingly derived from the contribution of intangibles – software, large scale databases, and intellectual property that embody human knowledge and ingenuity. Results provide evidence to challenge the prevailing innovation policy regime that assumes investments in research and development alone are adequate to ensure the transition to the AI-driven technological paradigm.
A key contribution of this study is to provide an institutional account for automation-driven labour market bifurcation. A theoretical framework combining Historical Institutionalism and Schumpeterian inspired evolutionary economics explains why the dynamic concept of a ‘learning economy’ is superior to the static conception of a knowledge economy to explain the effect of automation on labour markets. Empirical research examines labour market policy related specifically to skills development and continuing education aimed a working age adults popularly conceived as ‘lifelong learning’. Findings reveal that policy choices are the outcome of intrinsic socio-political forces unique to each industrial sector producing workforce development trajectories that are critical to understanding Canada’s lacklustre innovation performance.Ph.D
Studies of Primary Mismatch Repair Deficient Glioma: Insights into Mutagenesis and Oncogenesis
Get PDFHigh-grade gliomas are the most common and lethal type of primary brain tumour in children and adults. Up to 10% of high-grade gliomas in children, adolescents, and young adults have defects in the mismatch repair (MMR) system. Primary mismatch repair deficient (priMMRD) gliomas are characterized by underlying germline MMR deficiency, young age of onset, hypermutation, and resistance to chemoradiation. Owing to their universal hypermutation and microsatellite instability, some priMMRD glioma display susceptibility to immune checkpoint inhibitors (ICI), though responses are variable and the contribution of the MMRD-driven intrinsic mutagenic process to their oncogenesis is poorly understood. To better understand the mechanisms driving priMMRD glioma and their treatment-refractory biology, I curated multiomic (whole exome sequencing, DNA methylation panel, immunohistochemistry, RNA Nanostring), clinical, and treatment data on 162 human priMMRD gliomas through the International Replication Repair Deficiency Consortium (Chapter 2). Three subgroups emerged, defined by the presence or absence of secondary driver mutations in replicative DNA polymerases (POLE/POLD1) or IDH1: priMMRD-1 (MMRD + Polymerase Proofreading Deficient (PPD)), priMMRD-2 (MMRD-only), and priMMRD-3 (MMRD + IDH1). These subgroups arose from different germline MMRD-genotypes, displayed distinct clinical features, and converged on shared glioma drivers through combinations of mutational mechanisms, displaying an inverse correlation between point mutation and copy number alteration. Interestingly, priMMRD glioma subgroups were also associated with differential responses to anti-PD-1 monotherapy, partially explaining variability in treatment responses. While these immune checkpoint inhibitors greatly improved survival of priMMRD gliomas, most tumours eventually progress on anti-PD-1. Therefore, I also collected genetic, clinical, and treatment data for 75 priMMRD glioma which relapsed on anti-PD-1 to understand the factors contributing to treatment failure and efficacy of salvage therapy through a retrospective analysis (Chapter 3). Continued treatment with anti-PD-1 monotherapy and re-irradiation improved overall survival of refractory priMMRD glioma, suggesting potential treatment pathways after relapse. Collectively, these findings provide insight into how intrinsic mutagenesis fueled by replication errors shapes the development, progression, and treatment responses of priMMRD glioma and offer a rational basis for future improvements to therapeutic combinations in these patients.Ph.D
Recognition of Indigenous Peoples' Inherent Jurisdiction in the Act respecting First Nations, Inuit and Métis children, youth and families: A Step Towards the Institutionalization of Canadian Pluralism
Get PDFIt is generally accepted that Canada is a legally plural country where common law, civil law and Indigenous law coexist within a shared social space. However, while common law and civil law are institutionalized and recognized as components of the Canadian legal system, Indigenous traditions do not yet benefit from any similar recognition. The recent adoption and judicial validation of An Act respecting First Nations, Inuit and Métis children, youth and families, which affirms Indigenous peoples’ have a constitutional right of self-government in relation to child and family services, offers elements to reflect on this situation. In this study, I first explain why I believe Canada’s pluralism needs to be institutionalized. I then examine the Act and the subsequent Reference to determine the source, scope and force of the inherent jurisdiction they recognize to Indigenous peoples, and whether it furthers or falls short of this objective.LL.M
How Shall We Measure Participation: Patient Preferences
Get PDFBackground – “Participation” is defined as “involvement in life situations” by the World Health Organization, in their International Classification of Functioning, Disability and Health (ICF). No one yet knows whether a patient-reported or patient-centred approach is preferred for measuring participation.
Hypothesis – Patient-centred questionnaires are preferred to patient-reported.
Methods – Eighty participants, aged 9 to 17, were recruited from the SickKids rheumatology clinic. After completion of three questionnaires participants scored each based on how satisfied they were with how it allowed them to express their participation.
Results – We found no evidence that one questionnaire was preferred over the others. Patient-Centred Participation Questionnaire (PCPQ) scores were normally distributed and did not correlate well with other questionnaire scores. Participant comments showed questionnaire likes and dislikes of participants.
Conclusions – There is a role for the PCPQ because it gives us different information, is mathematically better distributed, and participants like it just as much as traditional tools.M.Sc
Building bio-based carbonyl crosslinkers with carbohydrates and CAZymes
Get PDFWith the intensifying global impacts of the climate crisis, renewable bio-based alternatives to petrochemicals are needed. Crosslinking molecules such as formaldehyde and glutaraldehyde are a class of petrochemicals used in a broad range of applications, from resins to textiles. This research explores the potential to produce bio-based crosslinkers using oxidative enzymes to modify biomass feedstocks. Six enzyme-oxidized carbohydrate crosslinkers were produced using galactose oxidase from Fusarium graminearum (FgrGalOx) and pyranose dehydrogenase from Agaricus bisporus (AbPDH1). Their reactivities were evaluated through differential scanning calorimetry (DSC), gelling experiments, and rheological measurements. Among the crosslinkers, FgrGalOx-oxidized galactose (FgrGalOx-Gal) exhibited the greatest reduction in peak reaction temperature with hexamethylenediamine as measured using DSC, reducing its reaction temperature by 32 °C compared to unmodified galactose. Meanwhile, FgrGalOx-oxidized lactose (FgrGalOx-Lac) demonstrated the strongest gel-forming ability with polyallylamine, forming gels at 5% PAA within 10 min at room temperature. When tested as crosslinkers of the bio-derived polyamine, chitosan, AbPDH1-oxidized xylooligosaccharides (AbPDH1-XOS) showed the best performance, forming gels at 0.7% chitosan and 40 mM crosslinker within 20 min. Notably, AbPDH1-XOS gels exhibited a storage modulus (G') of approximately 3 orders of magnitude higher than unmodified XOS, highlighting the substantial impact of enzymatic oxidation on gel strength. Chemical characterization techniques, including FTIR, XPS, and NMR, confirmed successful enzymatic oxidation and crosslink bond formation. In an effort to identify additional carbohydrate oxidoreductases for crosslinking applications, seven previously uncharacterized Auxiliary Activity family 3 subfamily 2 (AA3_2) enzymes from the Carbohydrate Active Enzyme database (https://www.cazy.org/) were heterologously produced and characterized, deepening our understanding of sequence-functional correlations within the AA3_2 protein family and providing guidance for future studies. Future studies should further investigate gel properties such as self-healing ability, pH stability, controlled degradability, and temperature sensitivity. Optimizing these characteristics will be essential for the development of bio-based crosslinkers and hydrogels in biomedical, food, and agricultural applications.Ph.D
Bridging the Gap: Exploring the Experiences of South Asian Women Immigrant Teachers in Toronto
Get PDFIn this dissertation, I share the voices of South Asian women immigrant school teachers living in Toronto. In this era of global mass migration and the increasing number of women immigrants, I argue that it is important to examine how gender and race affect racialized immigrant women’s working experiences. Historically, racialized immigrant women in Canada have faced various forms of discrimination in the labour market: not only are their previous qualifications and experiences devalued in the job market, but after entering the job market, racial and gender identity remain a concern in their professional lives (Crea-Arsenio et al. 2022; Premji et al. 2014). While scholars have highlighted the common labour market barriers, the struggles of South Asian women when facing these challenges in seeking a specific career do not get enough attention in the academic world. A significant number of South Asian women must engage in precarious jobs that are not consistent with their skills and qualifications. Here, I recruited South Asian immigrant women who hold a teaching certificate in Ontario and are coping with the secondary-education labour market and/or other related jobs in Toronto. Guided by a Critical Race Feminist perspective, I used interpretive inquiry as a research methodology to facilitate participants telling their struggles, challenges, and negotiations of their everyday lives while living in a large urban center like Toronto. My analysis of this research shows that these South Asian groups of women must overcome barriers that are similar to many other non-racialized female professional immigrants - but as racialized female immigrants, they also face more challenges in accessing and coping with their current professions. My findings suggest that policymakers should focus on an adaptable labour-market transition process for these professional groups after migration. This could also be helpful for other racialized groups in general. Promulgation to eliminate systematic barriers through various forms is needed to decrease the substantial existence of teacher diversity gap in Ontario. Therefore, this study extends the available literature by considering voices of racialized immigrant women, thereby addressing some existing gaps in policy framework. Ph.D