VictorJuiz/thesis huggingface dataset:
Genetic Characterization of Two Cases of Non-syndromic Inherited Retinal Disease

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of disorders that lead to progressive photoreceptor degeneration. Next Generation Sequencing of IRD gene panels are now commonly used for clinical genetic testing and current diagnostic yield is around 66%. For two cases of non-syndromic IRD, with no pathogenic variant identified by panel-based screening, genome sequencing was used to help uncover putative disease-causing variants. For case 1, candidate disease-causing variants were identified and validated for the cytoplasmic dynein-2, heavy chain 1 gene (DYNC2H1). For case 2, a known disease-causing variant was identified and validated in the RP GTPase regulator (RPGR) gene. Both these variants were also seen in other undiagnosed, unrelated cases. In this thesis I discuss the discovery and validation approaches, describe validation strategies which can be applied to other unsolved cases of IRD, and highlight the power of collaboration when exploring the pathogenicity of putative disease-causing variants.

Keywords: blindness
Inherited Retinal Disease
photoreceptor
primary cilia
Retinitis Pigmentosa
Advisor: Heon, Elise
Simple and Choice Reaction Time in Patients with Moderate and Severe Traumatic Brain Injury: A Longitudinal Examination of Change During the First Year of Injury

Moderate-to-severe traumatic brain injury (m-s TBI) can result in reduced speed of information processing and elevated reaction time intra-individual variability (RT-IIV). However, our understanding of longitudinal change during the first year of injury on measures of these processes is limited. This thesis employed a secondary analysis of findings from a simple- and a choice-reaction time (SRT; CRT) task to investigate change from 2- to 5- to 12-months following m-s TBI in (1) mean RT, (2) RT-IIV, and (3) ex-Gaussian parameters. We observed three different patterns of change depending on the outcome measure and/or analytic approach: asymptotic, characterized by significant early change (i.e., 2- to 5-months) and an absence of delayed change (i.e., from 5- to 12-months); ongoing, characterized by significant change from 2- to 5- to 12-months; and delayed, characterized by an absence of significant early change, but significant delayed change from 5- to 12-months. Clinical implications are discussed.

Keywords: Ex-Gaussian analysis
Intra-individual variability
Longitudinal change
Reaction time
Traumatic brain injury
Advisor: Green, Robin EA
Floristic Quality as an Indicator to Inform Natural Areas Management in Lake Simcoe Watershed

Floristic Quality Assessment (FQA) is used to describe the quality of natural areas based on plant species composition. Despite widespread application of FQA in the USA, less research exists in Ontario. To better understand FQA’s monitoring, reporting, and management relevance to southern Ontario I investigated: (1) performance of FQA against a composite disturbance gradient; and, (2) differences in FQA between different vegetation communities and successional stages. My work utilized monitoring data from 422 Vegetation Sampling Protocol plots sampled throughout Lake Simcoe watershed. FQA indices were found to significantly decrease in response to increasing disturbance, outperforming native species richness and percent exotic species as indicators of disturbance. Values of FQA indices differed among vegetation communities and successional stages, indicating comparisons should not be made across natural area classes. I demonstrate FQA as an effective tool for assessing natural cover quality; however, appropriate interpretation and management application require understanding FQA’s properties.

Keywords: Coefficient of Conservatism
Disturbance gradient
Ecological indicators
Ecological integrity
Floristic Quality Assessment
Vegetation
Advisor: Puric-Mladenovic, Danijela
Skeletal Muscle Injury and Repair - A Role for Complement

Skeletal muscle contains a dynamic microenvironment, including a stem cell niche, in which immune pathways, including complement, are activated to promote endogenous repair. The objective of this study was to determine the role of complement in skeletal muscle tissue injury and repair. We hypothesized that complement exacerbated skeletal muscle injury and promoted stem cell mediated repair. This study utilized barium chloride injury in three-dimensional tissue culture and in experiments with complement deficient mice. The results from in vitro experiments show that injured skeletal muscle cells have a processed intracellular source of C3, activate the membrane attack complex (MAC) upon addition of serum, and benefit from complement blockade. The in vivo experiment indicated that complement was required for efficient regeneration and affected the quiescent stem cell population. In summary, these results revealed a new mechanism involved in muscle injury and indicated translation potential for utilizing complement blockers to treat muscle pathology.

Keywords: Complement
Injury
Regeneration
Skeletal Muscle
Advisor: Licht, Christoph
Using Machine Learning to Detect Software Vulnerabilities

Although automatically finding software vulnerabilities is an important problem, existing code analysis tools are not effective enough at finding vulnerabilities. Lightweight static analysis tools are imprecise, while expensive symbolic execution strategies do not scale. Dynamic analysis techniques such as fuzzing can only verify the executed path in programs, and it is impractical to explore all paths in the program using dynamic analysis. As a result, we propose machine learning to detect software vulnerabilities: this approach is more precise than lightweight static analysis, but less expensive than symbolic execution. We evaluate two machine learning strategies: coarse-grained statistical model and fine-grained raw feature representation. The statistical model requires less data but does not capture all relationships in code. The raw feature representation learns subtle relationships in programs and does not require manual feature engineering, but needs more training samples to work well.

Advisor: Lie, David
Kawasaki Disease Related Coronary Artery Aneurysms: Structural and Hemodynamic Factors associated with Thrombosis, Stenosis and Failure to Achieve Dimensional Normalization

Coronary artery (CA) aneurysms are potential sequelae of Kawasaki Disease (KD) that may require long-term follow-up and medical management. Current KD clinical guidelines calibrate treatments based on risk stratification criteria that consider patients’ maximum and current CA aneurysm dimensions. Despite these criteria, patient outcomes at the highest risk-strata are variable, and multiple management strategies may be considered. This study evaluates structural and hemodynamic features of CA aneurysms for associations with thrombosis, stenosis and failure to achieve dimensional normalization using epidemiological data and computational fluid dynamic simulations. Findings suggest greater risk for negative outcomes in CA aneurysms of the right main and left anterior descending coronary arteries; of saccular shape, larger cross-sectional area and lower wall-shear stress; with branches involving the left main bifurcation, multiple CA aneurysms and higher recirculation times. Current risk stratification criteria may benefit from considering these features secondarily to CA aneurysm z-scores.

Advisor: McCrindle, Brian W
Characterizing Genomic Duplication in Autism Spectrum Disorder

Duplication, the gain of additional copies of genomic material relative to its ancestral diploid state is yet to achieve full appreciation for its role in human traits and disease. Challenges include accurately genotyping, annotating, and characterizing the properties of duplications, and resolving duplication mechanisms. Whole genome sequencing, in principle, should enable accurate detection of duplications in a single experiment. This thesis makes use of the technology to catalogue disease relevant duplications in the genomes of 2,739 individuals with Autism Spectrum Disorder (ASD) who enrolled in the Autism Speaks MSSNG Project. Fine-mapping the breakpoint junctions of 259 ASD-relevant duplications identified 34 (13.1%) variants with complex genomic structures as well as tandem (193/259, 74.5%) and NAHR-mediated (6/259, 2.3%) duplications. As whole genome sequencing-based studies expand in scale and reach, a continued focus on generating high-quality, standardized duplication data will be prerequisite to addressing their associated biological mechanisms.

Keywords: Autism
CNV
ddPCR
duplication
Advisor: Scherer, Stephen W
Human Embryonic Stem Cell-derived Cardiomyocytes with Ischemia Resistant Gap Junctions

Ischemic heart disease remains the number one killer worldwide, and no therapies are aimed at restoring lost muscle within patients’ hearts. Human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) demonstrate engraftment and mediate beneficial effects on left ventricular contractile function in rodent and non-human primate models. Unfortunately, ventricular arrhythmias in large animal models post-transplantation prevent their clinical application. Loss of connexin-43 (Cx43) gap junctions (GJs) is hypothesized to contribute to hPSC-CM induced arrhythmias. Phosphomimetic mutations at casein kinase 1 (CK1) targeted residues that mimic the phosphorylated state of Cx43 reduced ischemia induced GJ remodeling and susceptibility to inducible arrhythmias in mice. hESC-CMs heterozygous for these CK1 mutations displayed ischemia resistant Cx43 GJs by immunofluorescence but were not protected from ischemia induced reentrant arrhythmias. Discovery of a frameshift mutation and a heterozygous genotype motivated production of homozygous CK1 hESC clones that merits further investigation as a potential solution to hPSC-CM graft-related arrhythmias.

Keywords: Casein kinase 1
Connexin-43
CRISPR/Cas9
gap junctions
human pluripotent stem cells
regenerative medicine
Advisor: Laflamme, Michael
Histamine is the Macrophage-derived Factor that Plays a Crucial Role in Promoting Axon Regeneration of Retinal Explants

The role of macrophages in promoting axon regeneration in the injured mammalian CNS is still strongly debated. While there have been past studies that reported regenerative effects induced by inflammation following injuries to the lens or the optic nerve, there are still several gaps in our understanding of the underlying mechanisms behind achieving that successful axon regeneration. With the use of three different primary cell lines, we show that histamine is the active macrophage-derived factor that is responsible for neurite growth-promoting effects observed in the retinal explant cultures. We also report that histamine is mediating these effects by binding to the H1 receptors found on the astroglial cells. Furthermore, our findings indicate that histamine is influencing the exosome secretion from astroglial cells in eliciting these effects. Therefore, our results address the role of macrophages and show the mechanism whereby they are promoting the axon regrowth at the CNS injury site.

Advisor: Monnier, Philippe
Photocontrol of the Z-domain with Azobenzene Crosslinkers

The Z-domain is an engineered variant of the B domain of Staphylococcus aureus protein A, a bacterial protein that binds to mammalian Immunoglobin G (IgG). The Z-domain folds into a three alpha helix bundle. Helix 1 and 2 make up the binding interface to IgG, however previous research has shown that perturbations to helix 3 can also significantly impact binding to IgG. The relationship between the third helix and binding offers a means for photocontrol, using the azobenzene photoswitch. Initial studies of the crosslinked Z-domain prompted point mutations to be made on helix 3 to destabilize the helical bundle. CD and NMR spectroscopy were used to characterize structural perturbations of the third helix, mediated by photoisomerization of the azobenzene moiety. Competitive ELISA were used to assess the binding at different photostationary states of the crosslinked Z-domain mutants to IgG. Through these assays, we have demonstrated photocontrol of the structure and function of the L45S Z-domain through an azobenzene crosslinker.

Keywords: Affibody
Azobenzene
Helix 3
IAC
Z-domain
Advisor: Woolley, George A
Computational Fluid Dynamics Modelling of Dissolving Tank Hydrodynamics

The recovery boiler dissolving tank that is part of the kraft process for pulp and paper production often suffers from calcite and pirssonite scaling. The scales can lead to costly early maintenance, lost production, and safety concerns. Previous work identified that smelt concentration fluctuations could contribute to scaling. In this work, Computational Fluid Dynamics was used to analyze the hydrodynamics within various dissolving tank configurations and to use the information to determine a tank design and an optimum agitation rate that minimizes concentration fluctuations. The key findings are: (i) flow patterns are asymmetric even when the tank configuration is symmetric; (ii) positioning impellers away from the outlet reduces concentration fluctuations; (iii) there is a diminishing rate of return of concentration homogeneity with increasing agitation rate.

Keywords: CFD
Dissolving Tank
Hydrodynamics
Mixing
Advisor: Tran, Honghi
Bussmann, Markus
Performance of Nanocrystalline Coatings Under Combined Impact and Fatigue Loads

Nanocrystalline materials oer many advantages for use in aerospace structures due to their small grain size resulting in an increase in strength, toughness and hardness. Due to their high strength-to-weight ratio, nanocrystalline nickel-cobalt and pure cobalt coatings are under consideration for use in aircraft turbine engine fan blades. As fatigue performance is a critical component of the the design of aircraft structures, this thesis work investigates the combined effect of projectile impact up to 25 joules and fatigue loads on a nanocrystalline nickel-cobalt coating with an aluminum substrate. The experiments show coating stress is the strongest predictor of fatigue life, and impact energy is not strongly correlated with the fatigue failure. In addition, stress concentrations inherent in the test specimen geometry and the quality of electrodeposited coatings can have detrimental effects on the fatigue life. These factors must be carefully considered in applications of nanocrystalline coatings where they experience fatigue loads.

Keywords: Aerospace
Fatigue
Impact
Materials
Nanocrystalline
Structures
Advisor: Steeves, Craig
Legacies of Liberalism and Faith-based Institutions: Woodgreen Community Services and Gentrification in Riverdale

This thesis aims to bring literature on gentrification and the social economy in conversation in order to examine the role of non-profit housing providers in navigating gentrification within their neighbourhoods. Much of the literature on the role of non-profits and community organizations in responding to gentrification focuses on what De Verteuil (2015) calls the ‘post-welfare city’. Through building on the framework of ‘neoliberal communitarianism’ (DeFilippis, 2004), this thesis takes a historical and place-based analysis to demonstrate the ways in which non-profits’ synergy with processes of gentrification should be understood beyond the temporal scope of neoliberal co-optation under the shadow state (Wolch, 1990). This thesis contributes this argument to the literature on non-profit actors and gentrification in Toronto through examining the case study of Woodgreen Community Services and their redevelopment of the Edwin hotel in the Riverdale community.

Keywords: gentrification
non-profits
Riverdale
Toronto
Advisor: Buckley, Michelle
Application and Comparison of FPI, SLFM, and FPV Chemistry Tabulation to the Prediction of Soot Formation in Laminar Diffusion Flames at Elevated Pressures

Numerical methods to predict soot formation often rely on the use of large detailed chemical mechanisms that can make the numerical simulations very computationally expensive. This study aims to address this issue by employing several chemistry tabulation methods and assessing their capabilities when applied to the prediction of soot in laminar coflow diffusion flames. The tabulation methods considered herein include: the flame-prolongation of intrinsic low dimensional manifold (FPI) method, the steady laminar flamelet method (SLFM), and the flamelet/progress variable (FPV) method. Various techniques for coupling the tabulation methods to soot models are investigated. Flames involving pure methane, and methane/ethanol fuel mixtures are evaluated at both 1 and 4 atm, and a Jet-A surrogate fuelled flame is tested at 1 atm. The tabulation methods are compared to results obtained using the full detailed chemical mechanisms and to experimental results. The relative strengths and weaknesses of the various tabulation methods are discussed.

Keywords: Chemistry Tabulation
FPI
FPV
Laminar Flames
SLFM
Soot
Advisor: Groth, Clinton P.T.
Gottlieb, James J.
p38 Mitogen-activated Protein Kinase Inhibition in Castration-Resistant Prostate Cancer

Aberrant androgen receptor (AR) signaling is the major driver of castration-resistant prostate cancer (CRPC). Tumor hypoxia increases AR signaling and is associated with treatment resistance in prostate cancer. Heat shock protein 27 (Hsp27) is a molecular chaperone that facilitates AR nuclear translocation via p38 MAP kinase (MAPK) in castrate-sensitive prostate cancer cell lines. We evaluated p38 MAPK/Hsp27 mediated AR signaling under hypoxia in CRPC. Our results demonstrate that CRPC utilizes p38 MAPK/Hsp27 signaling for AR activity under normoxia and hypoxia. p38 MAPK inhibition decreased AR binding to androgen response elements and expression of AR target genes under normoxia and hypoxia in a cell line representative of CRPC. Additionally, pharmacological inhibition and siRNA knockdown of p38 MAPK decreased cell proliferation and survival in vitro, and prolonged survival in vivo. These results suggest the utility of further investigations of p38 MAPK inhibition as a therapeutic strategy to disrupt AR signaling in CPRC.

Keywords: Androgen receptor
Castration-resistant prostate cancer
Hsp27
Hypoxia
Oncology
p38 MAPK
Advisor: Koritzinsky, Marianne
Dye Release from Crosslinked Hyaluronic Acid Nanoparticles

Polymer-based nanoparticles (NPs) have been explored as potential drug delivery systems for many years. Hyaluronic acid (HA) is a naturally derived and biodegradable anionic polyelectrolyte that serves as an exceptional candidate for such delivery systems due to its compatibility with physiological systems, breakdown into non-toxic products, and its predictable switch from extended to collapsed conformation induced by counterion condensation. The dependence of HA conformation on ionic strength, valence state of the counterion, and pH has been confirmed with kinematic viscosity measurements. Chemical crosslinking via reaction with a water-soluble carbodiimide was optimized to permanently maintain NP structure and create a host for the guest-host delivery system. The release of entrapped dye from the polymer nanoparticles was studied by monitoring diffusion into different valency saline solutions of physiological concentration. Release of associated dye molecules was found to be triggered by ion-exchange with other cations and protected when associated with HA-NPs when compared to free diffusion.

Keywords: Counterion Condensation
Drug Release
Hyaluronic Acid
Polymer Collapse
Polymer Nanoparticles
Advisor: Goh, M. Cynthia
Transferability of Inexpensive Air Quality Monitoring Sensors

Air pollution is the world's largest environmental burden on health, associated with 7 million premature deaths globally each year. Inexpensive air quality monitors are a growing requirement for air quality monitoring systems for public health evaluation. Prototype sensor-based air quality monitoring devices, which measure PM2.5, NO, NO2, O3, and CO, were evaluated against reference grade devices at two different locations to test transferability. CO, NO, and PM2.5 transferred well between measurement sites while NO2 and O3 experienced linear biases from the reference when the location was changed. Mixed calibration using data from both locations improved calibration across the board. NO2 and O3 were improved by combining calibration sets, however they failed to maintain that improvement when deployed at a third testing location. As both NO2 and O3 are key components of the AQHI, these sensors should not be used for urban health evaluations until these transference issues are resolved.

Keywords: Air Quality
Sensors
Transferability
Advisor: Evans, Gregory
Phased Array Ultrasonic Testing of Corrosive Resistant Alloy Girth Weld of Cladded Pipes using the Total Focusing Method

TFM implementation was adapted to support the usage of Transmit Receive Longitudinal (TRL) ultrasonic probes. A new algorithm was developed to correct for ultrasonic wave velocity variations caused by anisotropic material properties of Corrosive Resistant Alloy (CRA). Experimental testing was conducted on an XRD verified Austenitic Stainless-Steel girth weld sample. A cut-section macrographic image of the weld showing grain orientation and distribution was obtained. Ultrasonic wave velocity when pulse passes normal and parallel to weld grains are measured. The challenges in using TRL probes for TFM delay computation, including curved surface and 3D ray-tracing are addressed. A benchmarking sample was manufactured. The adapted TFM implementation was compared with an industrial phased array scanner. Comparison shows improved resolving capabilities and noise reduction with TFM compared with standard phased array. A velocity correction algorithm is proposed, where individual rays from TFM are analyzed and corrected based on the weld grain structure.

Keywords: Corrosive Resistant Alloy
Nondestructive Testing
Phased Array
Total Focusing Method
Ultrasonic Imaging
Weld Inspection
Advisor: Sinclair, Anthony N
Supporting English Language Learners in Secondary School Mathematics

This qualitative case study of five grade nine and ten mathematics educators explores how teachers support English Language Learners in their math classrooms. The findings suggest that teachers getting to know their students and creating a positive community within their classroom form the foundation for supporting English Language Learners and should be a priority in mathematics classrooms. While teachers do not have access to resources they need, they manage with what they have and support students as best they can. A collective effort from the school staff creates a multi-level support system for ELL students and their teachers. Finally, there is a lack of formal professional development around ELL students in the mathematics classroom, but teachers pursue their own learning to improve their methods and strategies for this group. Overall, this study discovered that many of the strategies used for ELL students are, in fact, useful for all students.

Keywords: Assessment
English Language Learners
Grade 9 and 10
Mathematics
Meeting Individual Needs
Professional Development
Advisor: McDougall, Doug