VictorJuiz/thesis huggingface dataset:
Characterizing Genomic Duplication in Autism Spectrum Disorder
Keywords: Autism
CNV
ddPCR
duplication

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.
Human Embryonic Stem Cell-derived Cardiomyocytes with Ischemia Resistant Gap Junctions
Keywords: Casein kinase 1
Connexin-43
CRISPR/Cas9
gap junctions
human pluripotent stem cells
regenerative medicine

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.
Photocontrol of the Z-domain with Azobenzene Crosslinkers
Keywords: Affibody
Azobenzene
Helix 3
IAC
Z-domain

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.
Computational Fluid Dynamics Modelling of Dissolving Tank Hydrodynamics
Keywords: CFD
Dissolving Tank
Hydrodynamics
Mixing

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.
Performance of Nanocrystalline Coatings Under Combined Impact and Fatigue Loads
Keywords: Aerospace
Fatigue
Impact
Materials
Nanocrystalline
Structures

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.
Legacies of Liberalism and Faith-based Institutions: Woodgreen Community Services and Gentrification in Riverdale
Keywords: gentrification
non-profits
Riverdale
Toronto

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.
Application and Comparison of FPI, SLFM, and FPV Chemistry Tabulation to the Prediction of Soot Formation in Laminar Diffusion Flames at Elevated Pressures
Keywords: Chemistry Tabulation
FPI
FPV
Laminar Flames
SLFM
Soot

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.
p38 Mitogen-activated Protein Kinase Inhibition in Castration-Resistant Prostate Cancer
Keywords: Androgen receptor
Castration-resistant prostate cancer
Hsp27
Hypoxia
Oncology
p38 MAPK

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.
Dye Release from Crosslinked Hyaluronic Acid Nanoparticles
Keywords: Counterion Condensation
Drug Release
Hyaluronic Acid
Polymer Collapse
Polymer 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.
Transferability of Inexpensive Air Quality Monitoring Sensors
Keywords: Air Quality
Sensors
Transferability

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.
Phased Array Ultrasonic Testing of Corrosive Resistant Alloy Girth Weld of Cladded Pipes using the Total Focusing Method
Keywords: Corrosive Resistant Alloy
Nondestructive Testing
Phased Array
Total Focusing Method
Ultrasonic Imaging
Weld Inspection

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.
Supporting English Language Learners in Secondary School Mathematics
Keywords: Assessment
English Language Learners
Grade 9 and 10
Mathematics
Meeting Individual Needs
Professional Development

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.
Unsettling White Settler Subjectivity in Social Justice Education: Towards a Pedagogy of Risk
Keywords: Education
Philosophy
Race
Settler Colonialism
Social Justice Education
Subjectivity

This thesis explores the co-constitutive connections between colonial violence and white settler subjectivity in order to highlight the responsibilities that white settlers have in addressing the death, disappearance, and usurpation of Indigenous land and/or life. The three chapters are guided by the assertion that the “issue” at the heart of Indigenous-Settler relations in Canada is not simply settler ignorance or a lack of empathy but access to land and resources. Operating from this perspective, the thesis proposes that white settler subjects are not simply implicated in settler colonialism but also created by it. As such, the thesis rejects a rationalist approach to improving intersubjective relations through “knowing the other” and instead proposes a political and/or educational approach that invites learners to, in a sense, risk themselves and their power by unsettling their psycho-affective investment in the settler colonial project and white settler subjectivity itself.
FPGA Logic Block Architectures for Efficient Deep Learning Inference
Keywords: deep learning
deep neural networks
field-programmable gate arrays
inference
logic blocks
low-precision

Reducing the precision of deep neural networks can yield large efficiency gains with little or no accuracy degradation compared to single-precision floating-point representation. A wide range of precisions fall on the pareto-optimal curve of hardware efficiency vs. accuracy with no single precision dominating, making the variable precision capabilities of field-programmable gate arrays (FPGAs) very valuable. This thesis proposes six FPGA logic block architectures that improve the area efficiency of multiplications and additions implemented in the soft fabric. Increasing the look-up table fracturability and adding two adders to the adaptive logic module leads to a 1.5x area reduction for machine learning (ML) kernels and increases their speed, while simultaneously reducing the area of general applications by 6%. On the other hand, adding a 9-bit shadow multiplier to logic blocks reduces ML kernels' area by 2.4x and critical path delay by 1.4x, but increases the area of general applications by 15%.
Late Interventions in SNX Rats Reveal a Disconnect between GFR and Proteinuria
Keywords: ACE inhibitor
Chronic Kidney Disease
Glomerular Filtration Rate
Proteinuria
SIRT1
Subtotal nephrectomy

Many animal studies investigate therapies in the prevention setting and report proteinuria as the primary efficacy outcome, while the late intervention setting is more representative of human therapy and glomerular filtration rate (GFR) is more important than proteinuria. In this study, we used the subtotal nephrectomy (SNX) model, one of the few models that exhibits progressive GFR decline along with proteinuria, hypertension, glomerulosclerosis and tubulointerstitial fibrosis. To allow for development of kidney disease, we intervened six weeks after surgery with therapies known to be effective in the prevention setting. Both ACE inhibition (enalapril) and SIRT1 activation (SRT3025) reduced proteinuria, but only ACE inhibition reduced structural damage and neither improved GFR contrary to their effects in the prevention setting. These results demonstrate the difference in therapeutic efficacy in prevention versus late intervention, and show that in the SNX model, GFR, proteinuria, and structural damage are not inextricably linked.
The ATCUN Motif as a Paramagnetic Beacon in Fragment-based Drug Discovery
Keywords: adenosine 2A receptor
ATCUN motif
electron paramagnetic resonance
fragment-based drug discovery
G-protein coupled receptor

G-protein coupled receptors (GPCRs) constitute a large family of 7-transmembrane domain proteins that transduce extracellular signals to a cell’s interior. Approximately 35% of all FDA-approved drugs target a disproportionally small part of this family. As our understanding of these receptors continues to evolve, developments in drug discovery focus on facilitating the identification of novel orthosteric and allosteric druggable sites. In this work, an attempt was made to employ fragment-based drug discovery (FBDD) for the adenosine 2A receptor (A2AR), expressed in P. pastoris, via electron paramagnetic resonance (EPR). This technique uses unpaired electrons to provide information on conformation, local topology, and dynamics. In this study, spin labeled A2AR ligands were synthesized, in order to observe ligand binding to A2AR and develop a competition assay to observe drug binding. To enhance the magnitude of EPR spectral changes, an amino-terminal copper and nickel binding (ATCUN) motif was installed at the N-terminus of A2AR.
A CFD Study of the Effects of Rings on Flow and Temperature in Lime Kilns
Keywords: CFD
Lime Kilns
Pulp and Paper
Ringing

Rotary lime kilns, used in the kraft chemical recovery process to convert lime mud into lime, suffer from the formation of ring-shaped deposits called rings. Prior research has led to better understanding of ring growth, although it is still not fully understood, since the process is concealed within the kiln. For this reason, a steady state, 2D axisymmetric lime kiln, ring, and virtual bed heat sink model has been developed in this work, and was validated by predicting the shell temperature of a real kiln with good accuracy. Various ring configurations were then simulated in a typical lime kiln in order to study their effects on flow and temperature. The results show that ring-related jets and recirculation zones form in the gas, temperature deviations occur upstream and downstream of the rings, and, recarbonation, causing ring hardening, occurs over a wide range of ring thickness for both front-end and mid-kiln rings.
Policy-aware Model Learning for Policy Gradient Methods
Keywords: Decision-aware
Maximum Likelihood
MDP
Policy-aware
Policy-gradient
Reinforcement Learning

This thesis studies the problem of learning a model in Model-Based Reinforcement Learning (MBRL). We consider model classes that do not contain a perfect model of the underlying environment, and suggest that model learning should be closely related to how the model will be used. We examine how the planning module of an MBRL algorithm uses the model, and propose that the model learning module should incorporate the way the planner is going to use the model. This is in contrast to conventional model learning approaches that learn a predictive model of the environment without explicitly considering the interaction of the model and the planner. We focus on policy gradient planning algorithms and derive new loss functions for model learning which we call Policy-Aware Model Learning (PAML). We theoretically analyze a generic model-based policy gradient algorithm and empirically evaluate our proposed method on some benchmark problems.
A Study of the Role of Organic Acids in Monel Tube Corrosion in Nuclear Industry Steam Generators
Keywords: Corrosion
Dealloying
Electrochemistry
Monel
Nuclear
Organic acids

Monel 400 tubes in OPG’s Pickering Unit 4 steam generators were found to have undergone dealloying. S, Pb and Cl were not found by Analytical Transmission Electron Microscopy and were hence not causal. Since carbon and associated oxygen were detected near metal-oxide interfaces, the degradation is suspected to be from the build-up of organic acids, due to thermal decomposition of morpholine (added for secondary side cooling water chemistry control). In this thesis, dealloying of Monel was studied in the presence of organic acids and sulfate. Most of the work was done at or near the Cu equilibrium potential, with Cu2+ in solution. Electrochemical tests were conducted on Monel samples in acetic acid, sulfate and formic acid. Cross-sectional SEM-EDX studies showed dealloying and intergranular attack on Monel. It was found that formic acid was the most aggressive, followed by sulfate and acetic acid.
Influence of Chrna5 on Habenulopeduncular Neurotransmission
Keywords: alpha 5 nicotinic receptor subunit
Chrna5
habenula
interpeduncular nucleus
nicotinic receptors

The habenulopeduncular pathway is known to modulate aversion behaviours, which are tightly associated with Chrna5 gene expression. Chrna5 encodes the α5 nicotinic receptor subunit, which is highly expressed in the interpeduncular nucleus but remains pharmacologically intractable. Here we investigate the impact of this subunit using wild-type and Chrna5-deleted mice. We optogenetically activated the habenulopeduncular pathway; thought to co-release acetylcholine and glutamate, to probe the electrophysiological role of α5 in interpeduncular neurons in acute brain slice. Optogenetic stimulation of this pathway yielded heterogenous responses in wild-type and Chrna5 deleted mice. Unexpectedly, the absence of the Chrna5 gene led to stronger light-evoked glutamatergic and GABAergic neurotransmission. These light-evoked glutamatergic responses were acutely attenuated by nicotinic antagonists in Chrna5 deleted mice. Intriguingly, our optogenetic experiments did not evoke a distinct cholinergic current in either genotype. This work provides insight into the action of Chrna5 on habenulopeduncular circuitry and raises new mechanistic questions.