VictorJuiz/thesis huggingface dataset:
Effects of Vitamin D Receptor (VDR), Age and Cholesterol-status on Aβ Peptide Accumulation in the Brain
Keywords: Alzheimers disease
Cholesterol
Neuroscience
Pharmacokinetics
Vitamin D
β-amyloid

Alzheimer’s disease (AD) is associated with accumulation of toxic amyloid-beta peptides, 40 and 42 amino acid lengths (Aβ40 and Aβ42) in brain. Calcitriol, natural ligand of the vitamin D receptor (VDR), activates P-glycoprotein (P-gp) to efflux these toxic peptides out of the brain and lower peripheral cholesterol, events that could be linked to brain cholesterol and Aβ formation via BACE1 from the amyloid precursor protein (APP). We applied an improved and facile enzyme-linked immunosorbent assay (ELISA) to measure the low endogenous Aβ40 and Aβ42 concentrations in mouse and guinea pig brains, with 1 instead of 5 M guanidine HCl (a chaotropic agent and protein denaturant) for homogenization, thereby increasing the sensitivity by 5×. We documented age-dependent (2, 4-8, or >10 months) elevation of mouse brain Aβ, showing that protein expressions of P-gp, neprilysin (Aβ degradation enzyme) and Cyp46a1, which metabolizes brain cholesterol, were reduced and calcitriol treatment partially mitigated the changes via P-gp induction with TNF-α and IL-1β reduction. We also examined age-dependent changes in the guinea pig (GP), a species with similar Aβ homology and cholesterol processing as humans, where Aβ40 and Aβ42 accumulation, P-gp and Lrp1 (for Aβ and cholesterol transport) reduction, and free cholesterol elevation commensurate with aging (9- to 40-weeks). In 8-week-old GPs, calcitriol treatment led to increased Aβ and cholesterol clearance processes due to higher P-gp and Lrp1 protein expression, with elevated neprilysin and Cyp46a1 mRNA levels in brain, and Cyp7a1 protein, Abca1, Abcg5, and Abcg8 mRNA levels in liver. Exploiting our collaborator’s surgical skill and stereotaxic instrument for injections into brain, we defined the biodisposition of hAβ40 after intravenous or intracerebroventricular injection in rats with calcitriol treatment. The exogenously administered hAβ40 was best described by a catenary-mammillary model with one cerebrospinal fluid compartment and a slow exchange within the brain compartments. The composite findings suggest that age, cholesterol status, and vitamin D deficiency are risk factors that can alter Aβ accumulation in brain. Age is a dominant risk factor for Aβ accumulation due to reduced clearance pathways and higher cholesterol levels in brain.
Modelling and Characterisation of the Thermomechanical Behaviour of Thermal Barrier Coatings
Keywords: Coupled numerical modelling
Finite element analysis
Fracture mechanics
Molecular dynamics
Thermal barrier coatings
thermally grown oxide

Thermal barrier coatings (TBCs) are adopted in aeroengines to enable higher operating temperatures. Whilst some progress has been made in their development, there remain major challenges to overcome. These challenges include processing defects, development and progression of undesirable thermal residual stresses and interphases. These challenges have motivated the undertaking of this study. Specifically, the main objective of this research is to develop reliable modelling techniques, which are supported experimentally, to assess the effect of defects, thermal residual stresses and interphases upon the structural integrity of TBCs. Four aspects were accordingly examined. In the first, we examined the effect of thermal cycling on the dynamic growth of thermally grown oxide (TGO) and mixed oxides (MOs) using an integrated finite volume (FV) – finite element (FE) model. We were able to accurately predict the growth of TGO and MOs at varied temperatures and show that the presence of undulated interface led to uneven growth of TGO. The second was concerned with the effect of thermal cycling, growth strain and stress relaxation of TGO stresses on the build-up of residual stresses in TBC. This was achieved using a coupled non-linear transient thermomechanical analysis that incorporated a modified FV-FE model. Model results revealed that the combined effect of growth strains and thermal cycling could lead to elastic, shakedown or ratcheting phenomena. The third involved the use of micromechanics and adaptive FE model to investigate the role of inherent microdefects on crack propagation and failure of TBC. This led to determining the effect of shielding and amplification of the stress field on the critical stress intensity factor of interacting microdefects. The fourth was concerned with examining the effect of YSZ/α-Al2O3 interphase upon the thermomechanical behaviour of TBCs using novel hybrid molecular dynamics-finite element simulations. Unlike existing work, our results show that assuming a line interphase between TC and TGO will lead to erroneous estimates of the effective stiffness of YSZ/α-Al2O3 system. In this thesis, we offer newly developed coupled mechanistic models to determine the varied thermomechanical stress states, failure modes and inelastic deformation that will undoubtedly improve our understanding and lead to better coatings.
From Exercise to Physical Literacy Measurement in Individuals with Intellectual Disabilities
Keywords: Adults
Exercise
Health
Intellectual Disability
Physical activity
Physical Literacy

Physical inactivity is prevalent among individuals with intellectual disabilities, which has significant negative health consequences for this population. Increasing physical activity is one strategy for improving health outcomes but to be active, one must have the competence, confidence and knowledge to be active for life; collectively, this has been called physical literacy. Unfortunately, there has been no research exploring how best to measure physical literacy in individuals with intellectual disabilities. The purpose of this dissertation was to investigate how to measure physical literacy in adults with intellectual disabilities. Study one was a systematic review and meta-analysis on the broader physical activity and exercise literature. This study served to identify current trends within the literature. The review found that exercise had the most significant impact on the psychological domain, specifically anxiety and depression (SMD=-3.07). While the review did serve to identify key areas lacking in terms of measurement of movement competencies, its primary purpose was to examine how exercise and physical activity impact the physical and psychological well-being of this population. Study two used Generalizability Theory to evaluate the measurement properties of PLAYable. PLAYable was the first movement assessment designed specifically for individuals with intellectual disabilities. Fourteen raters utilized the tool to score 368 video clips each depicting individuals with various intellectual disabilities performing one of the 23 movement skills included in the assessment. The study found that the variability in scores was primarily due to the participant (facet of measurement) performing the skill. Study three examined the feasibility of using the Physical Literacy for Children Questionnaire to measure perceived physical literacy adults with ID. A total of 12 individuals with intellectual disabilities completed the questionnaire while their parents served as a proxy and completed the PLAYparent questionnaire. Overall, the results illustrated that the Physical Literacy for Children Questionnaire was a feasible measure of perceived physical literacy adults with ID. Overall, the three studies from this dissertation provided vital evidence to support and justify the need to explore physical literacy in adults with intellectual disabilities. In addition, this dissertation presented two promising measures, which researchers could use successfully with this population.
Writing Skills and Students’ Aspirations to Pursue Post-Secondary Educational Opportunities
Keywords: Lawrence Heights
marginalized
Pathways
tutor
volunteer
writing

This study highlights potential positive impacts of tutoring writing to marginalized youth at a community service after-school programme. Although many secondary school students possess language fluency and competency, youths from low-income and/or minority cultures may experience unequal access to essential writing instruction in school. Students’ potential for academic advancement depends on the procurement of written language “codes” necessary to familiarize them with the manners, culture and language of power. Writing tutoring responds to the individual learning needs of youth at-risk; tutoring programmes are effective in supporting the advancement of their goals and values and for their integration into society. Interview data from nine students, staff and tutors at Pathways, Lawrence Heights and observations, field notes and journal entries from my position as researcher and volunteer tutor, reveal that the dialogic nature of tutoring facilitates an unconstrained interchange of ideas, which generates knowledge applicable to the students’ particular needs, and fosters a bond between the tutor and tutee unlike the teacher/student relationship experienced in the school context. My investigations explore how one-to-one tutoring for teaching writing skills to youth at-risk might be especially conducive to improving writing effectiveness because the tutor’s non-evaluative and non-autocratic responses are personalized to the contexts, situational needs and nuances of each student. By acknowledging the unequal distribution of writing proficiency among Ontario’s students and the inequities within the system, educators and policymakers may look for occasions in the writing curriculum that address students’ perceptions of themselves as thinkers and learners. With a broadened appreciation for the impact of tutoring programmes and their relevance to students’ pursuit of post-secondary opportunities, collaboration between researchers, schools and their communities, a thoughtfully developed educational agenda that supports our students is possible.
Investigating the Cardiac Immune Response in Viral Myocarditis
Keywords: BATF3
Dendritic cell

Heart failure (HF) is a growing global epidemic affecting people of all demographics. Non-ischemic cardiomyopathies (NICM) accounts for up to 40% of HF patients. Myocarditis, inflammation of the myocardium is the underlying cause of NICM in 9-16% of patients. The most common cause of myocarditis is due to viral infection, known as viral myocarditis. The immune response is critical in mitigating cardiac injury due to viral infection; however, it can also be pathological due to the cytotoxic effects of certain innate and adaptive immune cells. Conventional or classical dendritic cells (cDCs) are important antigen presenting cells linking the innate and adaptive immune response. Type 1 cDCs (cDC1) are critical for initiating an antigen-specific CD8+ T cell response during viral myocarditis. Mice lacking cDC1s have increased cardiac injury and dysfunction following viral myocarditis, indicating their importance in mitigating cardiac injury. The transcription factor (TF) BATF3 is necessary for the development of cDC1s. Batf3-/- mice lack cardiac cDC1s at steady state. However, during viral infection, cDC1s develop in a BATF3-independent pathway. In this thesis we investigate the BATF3-indepdent development of cardiac cDC1s during viral myocarditis. Cardiac cDC1s from Batf3-/- mice are transcriptionally similar to those from wildtype mice at 7dpi by single cell RNA-sequencing. We have shown that the cytokine GM-CSF is essential for the compensatory cDC1 development while IFNγ is partially involved. Interestingly, these compensatory cDC1s are present in the heart after inflammation has resolved and their continued presence is due to tissue-specific changes that support their persistence. We also explore sex differences in young mice (5-weeks of age) in both susceptibility and immune response to viral myocarditis. We show that young male mice have increased mortality and cardiac injury post-infection in comparison to female littermates. Importantly, we found there is a delayed response of type I interferon (IFN-I) by 12 hours in the young males have a compared to females. This thesis increases our knowledge about the BATF3-independent cDC1 development in peripheral tissues, specifically cardiac cDC1s, during both acute and resolved inflammation. More broadly, we also examine sex differences in viral myocarditis identifying IFN-I as a potential therapeutic target in early viral myocarditis.
Development of Orthogonal and Cooperative Catalytic Processes via Dual Metal Catalysis
Keywords: catalysis
palladium
rhodium
transition metal

In this thesis, the concept of dual metal catalysis will be explored in different contexts: one-pot orthogonal catalysis where both metal catalysts act sequentially and cooperative tandem catalysis where the two metal catalysts act in a synergistic fashion. In Chapter 1, a rhodium-catalyzed tandem isomerization-allylation of unsymmetrical diallyl carbonates enables the synthesis of α-quaternary allylated aldehydes. Notably, the rhodium catalyst can discriminate between two allyl groups of the unsymmetrical diallyl carbonate via a selective oxidative addition. Reaction progress kinetic analysis (RPKA) of this reaction uncovered second order kinetics with respect to rhodium, suggesting a bimetallic rate-determining step. In Chapter 2, the tandem isomerization-allylation of unsymmetrical carbonates is re-investigated from a dual metal perspective. A novel variant of this catalytic reaction is developed where a Pd(0) catalyst forms the electrophilic π-allyl species and a Rh(I) catalyst mediates the isomerization to form the enolate nucleophile. This dual metal approach was found to be more efficient and enables access to a large variety of α-quaternary allylated ketones. In Chapter 3, a one-pot reaction featuring two orthogonal transition metal-catalyzed asymmetric transformations is disclosed. The one-pot reaction combines a Pd-catalyzed asymmetric allylic alkylation and a Rh-catalyzed Miyaura-Hayashi reaction, converting allyl enol carbonates or allyl β-keto esters into enantioenriched cyclic ketones with two non-contiguous stereocenters. The process is enantio- and diastereodivergent and the major diastereomer is formed in excellent enantiopurity, owing to the Horeau principle.
Transition Metal Hydride Complexes: From Computation to Catalysis and Everything in Between
Keywords: Density functional theory
Hydride
Hydrogenation
N-heterocyclic carbene
Transition metal

Computational methods were used to investigate transition metal hydride complexes both in the ground state and as reactive intermediates. Chapter 2 investigates an interesting phenomenon concerning the reversal of the relative position of the antisymmetric and symmetric vibrational modes of trans-dihydrides of transition metals and main group elements. These findings were used to show the different modes of hydride attack on CO2 by a transition metal and main group porphyrinate trans-dihydride complex. Chapter 3 details both an experimental and computational study on the catalytic transfer hydrogenation of aryl ketones with basic iso-propanol by a ruthenium hydride complex with a protic N-heterocyclic carbene ligand. The bifunctional character of the protic N-heterocyclic carbene moiety was determined to play a crucial role in the mechanism of the inner-sphere hydride transfer to acetophenone in a computational study. Chapter 4 describes the synthesis of an iridium(III) azolato complex through rearrangement of a tethered C8-iodinated theophylline fragment. The rearrangement proceeds through an unusual seven-coordinate cationic iridium(V) hydride intermediate which is supported by computational analysis. Finally, chapter 5 concerns the development of an undergraduate laboratory experiment in which an iron carbonyl complex is synthesized to investigate its catalytic activity in the transfer hydrogenation of acetophenone.
Prescriptive Partnerships: Black Mothers of Disabled Children and Educators in Ontario's Public School System
Keywords: critical race theory
disability studies
education policy
mother
parental engagement
special education

This study draws on key teachings and principles of Critical Race Theory to examine the experiences of seven Black mothers as they perform as agents on behalf of their children who are enrolled in the special education environments in elementary schools across the Greater Toronto Area of Ontario, Canada. This qualitative study uses techniques of constructivism and bricolage as it disrupts normalized, hegemonic approaches to parental engagement. The Black mothers’ voices are foregrounded as they share their experiences of engagement with, and disengagement by, members of the in-school team (including educators and health professionals). Critical policy analysis was employed to analyze two Ontario educational policies: (1) parent engagement and (2) special education.This study presents a multi-layered analysis of seven Black mothers as they fight to access special education services; advocate on behalf of their children to get teacher feedback and classwork samples; and negotiate with educators to ensure their children receive timely access to the Ontario curriculum. Notions of power relations between home and school are explored. Black mothers have significantly less power than educators who are all backed by the powerful master legislation, the Education Act of Ontario. This dissertation reveals that educators’ responses to Black students and their parents will vary based upon educator’s values and attitudes, their levels of professionalism, the local school culture as well as the expectations of the district school board and the Ontario Ministry of Education. This study is unique in that through a brief, selective history of Ontario’s general and special education, it investigates the impact of race and racism on Black mothering and mother-work within the special education environment in public elementary schools. Also, by weaving the experiences and perspectives of the seven Black mothers into the analysis of Ontario’s current educational policies, this dissertation shows further how it stands apart: this unique study looks at the role that race and racism play within the discourse of (and discursive practice inherent to) parental engagement within special education environments in elementary public schools in the Greater Toronto Area (GTA) of Ontario.
Population Dynamics of CRISPR Adaptive Immunity in Communities of Bacteria and Phages: a Window into Another World
Keywords: adaptive immunity
CRISPR
model
simulation

Adaptive immunity shapes organisms at all scales of life, from bacteria to humans, allowing organisms to learn from past exposure to pathogens by storing specific immune memories. In humans and other vertebrates, these memories are contained in a diverse pool of specialized cells that express a range of unique immune receptors, while bacteria and archaea store immune memories using the CRISPR-Cas system. Bacteria incorporate small samples of phage DNA, called spacers, into their own genome, using this genetic memory to recognize and destroy future phage infections. Experiments have revealed high spacer diversity on the level of populations, dynamic gain and loss of immunity in bacteria, and phage evolution under pressure from CRISPR targeting, all of which is accessible through DNA sequencing. In both vertebrate and CRISPR adaptive immunity, many biological processes overlap to produce observed outcomes, but by simplifying these complicated systems, phenomenological models have the potential to reveal intuitive patterns. This thesis is about using simple phenomenological models to understand adaptive immunity in bacteria. Starting with basic bacteria and phage interactions with CRISPR immunity, I find remarkable emergent complexity that provides new but simple ways to interpret data. First, I show that stochastic bacteria-phage interactions lead to broad spacer abundance distributions that are stable in time, matching experimental data. Next, I add phage evolution in response to CRISPR targeting. I show that phage mutations and CRISPR immunity drive the emergence of stable genetic diversity and that new phage mutants experience strong positive selection. This model also provides insight into the timescale of immune memories through the summary parameter average immunity which can be calculated from whole-genome sequencing data. Finally, I show that cross-reactivity between spacers and phage genomes leads to fundamentally different regimes of evolution that are analogous to regimes appearing in models of vertebrate adaptive immunity, highlighting shared features in these very different systems. My work is a step forward in the theoretical understanding of both bacterial communities and adaptive immunity in general and illustrates the power of simple models to build intuition about complex phenomena.
Fast Algorithms for $\ell_p$-Regression and Other Problems
Keywords: Optimization
Regression
Theoretical Computer Science

Regression in $\ell_p$-norm is a canonical problem in optimization, machine learning and theoretical computer science which asks for a vector with minimum $\ell_p$-norm in a linear subspace. In this thesis, we give fast, high-accuracy algorithms for $\ell_p$ regression for all $p\geq 2$. Our algorithms are built on novel techniques including {\it iterative refinement for $\ell_p$-norms}, and a fast {\it width-reduced} multiplicative weight update routine among others. Furthermore, via a new {\it inverse maintenance} scheme, we can solve $\ell_p$-regression almost as fast as linear regression for all $p>2$. For graph instances, where the goal is to optimize $\ell_p$-norm objectives (flow or voltages), our algorithms incorporate sparsification routines that preserve such objectives, to obtain {\it near-linear-time} algorithms. As a consequence, we also obtain a fast algorithm for the maximum flow problem in unweighted graphs. A popular approach to fast algorithms for $\ell_p$-regression in practice is via empirical modifications of the {Iteratively Reweighted Least Squares (IRLS)} algorithm since the basic version of IRLS is known to converge only for $p \in (1, 3)$ and diverge even for moderate $p$ (e.g., $p > 3.5$). We give the first IRLS algorithm that provably converges to a high accuracy solution in a few iterations. Our algorithm has shown exemplary practical performance as well beating standard MATLAB CVX implementations by 10-50x. We further extend our techniques to obtain fast algorithms for {\it Quasi-self-concordant (QSC)} functions, which includes $\ell_p$-regression, softmax regression, and logistic regression among others. We show how iterative refinement and width reduction techniques extend and give fast rates of convergence for all QSC functions.