VictorJuiz/thesis huggingface dataset:
Working Memory in Oral Contraceptive Users: Does Time of Pill Ingestion and the Catechol-o-methyltransferase Val158Met Single Nucleotide Polymorphism Influence Working Memory?
Keywords: Catechol-o-Methyltransferase
Dopamine
Estrogen
Oral Contraceptives
Pharmacokinetics
Working Memory

The main estrogen produced by the ovaries, 17-beta estradiol (E2), interacts with different DA availabilities due to the COMT Val158Met polymorphism to modulate WM. Whether the commonly used synthetic estrogen, ethinyl estradiol (EE), does the same is unknown. To addressed this question, we investigated WM in OC users. Additionally, we examined if the pharmacokinetics of EE affect WM by testing OC users at a peak EE state 1-2 hours after pill ingestion, and at a low EE state just before pill ingestion. Naturally cycling controls were tested at low and high E2 menstrual cycle phases. Our preliminary results indicate time since pill ingestion does not affect WM performance, but COMT genotype may differentially affect WM in NC and OC women. These data suggest that despite the pharmacokinetics of EE in OC users and the variability of DA breakdown, women on OCs have stable WM throughout the day.
Development of Carbon Tolerant Anodes for Solid Oxide Fuel Cells Fabricated by Solution Precursor Plasma Spraying
Keywords: anode
direct oxidation
ni3sn
plasma spray
SOFC
solid oxide fuel cell

Carbon black (CB) pore former was incorporated into the solution precursor plasma spraying (SPPS) fabrication of Ni-YSZ anodes. Increasing the amount of feedstock CB content led to anodes with higher open porosity, to the detriment of deposition efficiency. Introducing CB to the SPPS of Ni-YSZ did not affect the composition of the deposited coatings. Due to the limited data set from electrochemical tests, no definitive relationship between the feedstock CB content and the polarization processes could be established. A Ni3Sn-YSZ anode was fabricated using an SPPS process. It was determined that the coating was marginally tin rich, yielding a minor Ni3Sn2 phase. A cell containing the Ni3Sn-YSZ anode was operated in dry CH4 at 750℃. The cell was held at a current density of 0.12 A/cm2 for 600 hours and demonstrated remarkable stability. No notable microstructural or compositional changes occurred during the test.
Exploring Deprescribing Opportunities for Community Pharmacists
Keywords: Behaviour Change Wheel
Community Pharmacists
Deprescribing
Qualitative

Background: Deprescribing, the process of stopping medications, can reduce the use of harmful or unnecessary medications, but is challenging for patients and prescribers to implement. We explored Ontario community pharmacists’ involvement with deprescribing and strategies for enhancing this involvement. Methods: We conducted qualitative telephone interviews with 17 Ontario community pharmacists. The Behavior Change Wheel informed the interviews and analysis. Four investigators coded three transcripts independently to develop a codebook. One investigator coded the remainder and generated themes using thematic analysis. Results: Pharmacists’ involvement in deprescribing was affected by: 1) their understanding of deprescribing, 2) their access to patient information, and 3) competing clinical and business/technical demands of their daily activities. Conclusions: Findings support recommendations for optimizing community pharmacists’ involvement in deprescribing by defining their deprescribing role with multi-stakeholder engagement, focusing on specific steps within deprescribing, and expanding pharmacists’ understanding of how to integrate deprescribing into their practices.
Development and Evaluation of a Simulator for Surgical Training in Tracheostomy and Advanced Open Airway Surgery
Keywords: laryngotracheoplasty
open airway surgery
otolaryngology
resident education
simulation
tracheostomy

The challenges of resident work-hour restrictions, low case volumes and growing concerns over patient safety limit learning opportunities for surgical trainees in the operating room. Surgical simulation can provide trainees with valuable opportunities to develop technical skills without risk to patient safety. Current synthetic airway simulators lack realistic tissue characteristics and anatomical accuracy. The objective of this thesis was to develop and validate a realistic airway simulator for training in tracheostomy and laryngotracheoplasty using anterior costal cartilage and thyroid ala cartilage grafts. A late adolescent/adult airway simulator was developed using image segmentation techniques, three-dimensional modeling/printing, and silicone casting. Nine expert otolaryngologists-head and neck surgeons evaluated the synthetic simulator as realistic/anatomically accurate (face validity), comparable to a live porcine model (gold standard in open airway simulation) and having perceived effectiveness as a training tool (content validity). The synthetic airway simulator has the potential to enhance tracheostomy and open airway surgical education.
Effects of Anti-αIIb-mediated Fetal Neonatal Alloimmune Thrombocytopenia on Fetal Hematopoietic Stem Cells and Embryonic Development
Keywords: fetal neonatal alloimmune thrombocytopenia
hematopoietic stem cell
megakaryocytes
placenta
platelets
αIIbβ3 integrin

Fetal neonatal alloimmune thrombocytopenia (FNAIT) is characterized by an aberrant maternal immune response against fetal platelet antigens that can result in severe bleeding and miscarriage. Platelet receptor αIIbβ3 integrin is commonly targeted however there are disproportionately fewer reports of FNAIT against the αIIb subunit despite an equal prevalence of polymorphisms in the population, possibly due to increased fetal death. αIIb is also expressed on hematopoietic stem cells (HSCs). Whether they are targeted by alloantibodies, or contribute to increased disease severity is unknown. Using murine models, I revealed fetal death is prevalent in anti-αIIb-mediated FNAIT and significantly more frequent than in anti-β3-mediated. I found significantly reduced αIIb+ and αIIb- HSC, and HSC progenitor populations in fetal liver, placenta and fetal blood in FNAIT, in addition to a 3-fold decrease in hepatic megakaryocyte populations. These findings may explain the dearth of anti-αIIb-mediated FNAIT cases and the mechanisms of increased disease severity.
The Development of a Local Food Environment Policy Framework and its Application in Several Ontario Municipal Jurisdictions
Keywords: Canada
food environment
food policy framework
municipal governments
Ontario
US

Governments can influence diet quality through policies that improve the state of the food environment. While national and state/provincial obesity prevention efforts have been well documented, monitoring at the municipal level has not been widely explored. This thesis aimed to develop a framework and inventory to monitor municipal food environment policies and government action, and apply it in three municipal jurisdictions in Ontario, Canada. The collection of implemented policies within US and Canadian municipalities suggest that local governments have the authority and capacity to introduce novel policies in many food environment domains to promote healthy food choices. Currently, municipal governments in Ontario are using a variety of approaches to create healthy food environments, but local government and non-government experts agreed there are areas for further improvement. These findings will help municipalities identify the strengths and opportunities to address weaknesses in their food environments to improve population health.
Novel High-throughput Drug Screening Application Using Human Cardiomyocytes In Mechanically Controlled Environment
Keywords: cardiomyocytes
drug screening
high-throughput
iPSC-CM maturation
mechanical stiffness
silicone polymer

Drug side-effects endanger patients and cause drug recalls from the market. High-throughput screening (HTS) tests with human cardiomyocytes (CMs) can detect drug side-effects earlier in the drug development process, but no available HTS test assesses CM contraction amplitude. We established 96-well substrates with modulus corresponding to both, healthy and diseased heart tissue that ‘wrinkle’ upon cell force exertion. Stem cell-derived CMs were used to quantify frequency, amplitude, and regularity of contraction in response to substrate modulus, drugs with known effects on heart function, and electrical pacing. The wrinkling device was benchmarked against an industry-standard impedance assay. Wrinkling substrates tuned to the modulus of heart enhanced CM maturity, including sarcomere alignment (α-actinin staining), which correlated with higher degree of CM responsiveness to drug treatment. Thus, the wrinkling assay fills the gap of HTS tests for the measure of CM contraction amplitude and enhances the sensitivity of in vitro drug tests.
Involvement of Lipids in the Physicochemical and In Vitro Characteristics of Polymer-lipid Nanoparticles in Cancer Cell Models
Keywords: breast cancer
ethyl arachidate
factorial design
fatty acid binding protein
glioblastoma
polymer lipid nanoparticle

Polymer-lipid nanoparticles (PLN) have been a focus in cancer chemotherapy research due to their potential for targeting tumour cells, overcoming drug resistance and reducing toxicity. This work explores the (1) impact of “lipid” component properties and formulation parameters on PLN physicochemical properties and in vitro cytotoxicity using statistical design-of-experiments, and (2) mechanisms of PLN cell entry and organelle distribution, and response to lysosomal environments. These analyses show effects of melting point and chemical structure of multiple fatty acids/esters, and long heat exposure on PLN properties. As a result, a robust PLN system was optimized as a doxorubicin (DOX) delivery system for human glioblastoma U87-MG-RED-FLuc cells. This PLN system demonstrated intracellular internalization by multiple cell mechanisms. Furthermore, mechanistic studies examined the role of not only the optimized PLN in glioblastoma cells, but also in a previously-studied myristic acid-based PLN in breast tumour cells on improved potency over free drug.
Design and Study of Novel Fluorinated Tags for Elucidation of Protein Conformational Dynamics by 19F NMR
Keywords: 19F NMR
Small molecule
Tag

Here we explore a variety of monofluorinated and trifluoromethyl reporters in an effort to derive optimal tags for purposes of fluorine NMR studies of proteins. By examining fluorine NMR spectra in MeOH and water mixtures, we compared chemical shift sensitivity to solvent polarity. A bromo-acetamide functionalized monofluorinated pyridinol, which was designed to be specifically reactive towards thiols, was observed to exhibit an unprecedented range of chemical shift dispersions of 2.56 ppm in these solvents. A trifluoromethylated analog exhibited a chemical shift range of 1.67 ppm albeit with higher intensity and reduced linewidth. This may be contrasted with conventional fluorinated tags such as BTFA and BTFMA, whose dispersions are on the order of 0.57 and 1.03 ppm, respectively. We anticipate that these next-generation tags will greatly enhance prospects for fluorine NMR studies of proteins and fluorine NMR based drug discovery.
C-Terminus of HSP70 Interacting Protein as a Regulator of Parkin Translocation
Keywords: BAG4
Chaperones
CHIP
Parkin
Parkinson's disease
PINK1

Several genes implicated in Parkinson’s disease encode for proteins involved in the PINK1-Parkin pathway of mitochondrial clearance. The co-chaperone BAG proteins were previously shown to regulate this pathway as well as the co-chaperone CHIP. In this thesis, I determined which BAG proteins physically interact with CHIP and identified a novel interaction between CHIP and BAG4, a known regulator of Parkin translocation to the mitochondria. This interaction was dependent on the TPR domain of CHIP. Further, I demonstrated that CHIP is a potential regulator of the PINK1-Parkin pathway in that CHIP interacted with PINK1 and CHIP overexpression reduced Parkin translocation. I found that neither BAG4 nor the CHIP-BAG4 interaction were necessary for the effect of CHIP on Parkin translocation. I also found that CHIP knockdown did not increase Parkin translocation. This thesis provided initial work on how CHIP may regulate Parkin translocation and how co-chaperones control cell systems underlying Parkinson’s disease.
Type 1 Interferon Limits Phagocyte Antimicrobial Function by Modulating Lysosomal Cholesterol
Keywords: Bacteria
Cholesterol
Interferon
Lysosome
Phagocyte

Listeria monocytogenes is a foodborne bacterial pathogen that is responsible for causing listeriosis in humans and animals. These infections can lead to severe disease such as meningitis and encephalitis, with a high mortality rate especially in the elderly and immunocompromised individuals. Prior studies have revealed that these bacteria can induce a type 1 interferon response that is deleterious to the host during systemic infection, while also affecting the intracellular life cycle of L. monocytogenes. However, the impact of type 1 interferon on innate cellular defenses to bacterial infections remain unclear. Here, we show that type 1 interferon can negatively impact the antimicrobial activity of macrophages. Type 1 interferon was found to cause cholesterol accumulation in lysosomes that alters their fusion with phagosomes, and also their ability to fuse with the plasma membrane in response to membrane damage. These findings help to explain how L. monocytogenes exploits type 1 interferon responses during infection.
The Impact of Maternal High Fat Diet and Caffeine Exposure on Maternal and Offspring Health
Keywords: Development
Diet
Maternal Fetal Medicine
Neuroscience
Obesity

Maternal malnutrition and resulting metabolic state is detrimental to offspring survival and increases offspring disease risk. Despite prevalence of maternal obesity and caffeine use during pregnancy, the effects on fetal outcomes are unclear. In this study, mice were fed with 60% high fat diet and/or 0.3g/L caffeine in water for 5 weeks prior to mating and through gestation and lactation. Caffeine effectively reduced high-fat diet induced weight gain however resulted in detrimental effects on offspring survival. Neurodevelopment and anxiety-like behaviours were altered in offspring born from obese dams using caffeine and this was correlated with reduction in maternal-pup interaction. These results highlight the differential effects of maternal caffeine on offspring health which are nutritional status dependent and may be mediated by changes in maternal care.
Exploring Phosphorylation-independent Pathway of STAT5 Activation for Development of Small Molecule Inhibitors of STAT5
Keywords: Cancer
cancer biology
Medicinal chemistry
rational drug discovery
STAT5B
STAT5B N624H

STAT5B is critical in the molecular pathogenesis of multiple blood cancers. The activation of STAT5B involves cytokine stimulation of a cell surface receptor. The intracellular receptor tail recruits a tyrosine kinase, which phosphorylates a tyrosine residue that is C-terminal to the SH2 domain of STAT5B followed by dimerization of STAT5B, and subsequent translocation to the nucleus to regulate gene expression. Currently, several therapeutic strategies are designed around inhibiting STAT5B phosphorylation, thereby preventing dimerization and downstream activation. However, recent studies have suggested a phosphorylation-independent mode of dimerization for STATs. Here we have examined the paradigm of phosphorylation-independent STAT5B dimerization. These studies suggest that in-vitro STAT5B dimerization is cysteine-mediated. We examined phosphorylation-dependent dimerization of STAT5B and utilized this to develop biophysical assays for screening differences in inhibitor binding. Finally, we examined the structural changes in the most frequently occurring disease-causing missense mutation, STAT5BN642H, which promotes phosphatase resistance and therefore enhances dimer lifetime.
Generation and Characterization of Clinical Grade Induced Pluripotent Stem Cells (iPSCs) from Human Umbilical Cord Tissue Mesenchymal Stromal Cells (CT-MSCs)
Keywords: Reporgramming
Stem Cells
Umbilical Cord

Induced pluripotent stem cells (iPSCs) have had tremendous potential in the field of cell-based therapies, due to their unlimited capacity for proliferation and differentiation into any cell linage. For clinical use, it is important to make sure the cells are grown under Good Manufacturing Practice (GMP) by using an optimal starting cell source, an integration-free reprogramming method, and culturing the cells in feeder-free and xenogenic-free cell culture techniques. Mesenchymal stromal cells (MSCs) derived from the human umbilical cord tissue are a promising source for creating iPSCs as these cells can be stored for many years without the loss of viability and their collection is non-invasive. I have established a clinical grade protocol that produced feeder-free and integration-free human iPSCs from human umbilical cord MSCs. The iPSCs lines were successfully characterized through karyotyping, expression of pluripotency markers (OCT4, SOX2 and NANOG), and the formation of embryoid bodies (EBs) and teratomas.
Replica Exchange MCMC Engine for Combinatorial Optimization Problems
Keywords: Combinatorial Optimization
Field-Programmable Gate Array
Graphics Processing Unit
Ising Model
Markov Chain Monte Carlo
Replica Exchange

A replica exchange Markov Chain Monte Carlo engine is proposed and implemented with automatic temperature adjustment for solving combinatorial optimization problems. The automatic temperature adjustment ensures that the process is optimized at every stage. This approach is performed by dynamically adjusting temperatures of all replicas, in addition to the capability of automatically inserting new replicas or removing any existing ones to improve the resource efficiency and execution time. The proposed replica exchange algorithm is integrated with parallel evaluation of energy increment and update scheme to increase the time to solution. The replica exchange algorithm alone, is able to achieve a 4-5x speedup in time to solution, over a simulated annealing based optimizer, in addition to eliminating the need for an annealing schedule. The engine is developed in hardware with a capacity of running up to 64 replicas in pipeline, each running a 1024 fully-connected network in parallel.
The Role of Allosteric Networks in Facilitating Enzymatic Catalysis of the Homodimer, Fluoroacetate Dehalogenase
Keywords: Allostery
Dynamics
Enzyme
Kinetics

Many oligomeric enzymes act through half-of-the-sites reactivity, in which the substrate engages with only one protomer at a time. In the case of the homodimeric enzyme, fluoroacetate dehalogenase, vacancy of one protomer is required for catalytic function. Substrate binding to one protomer induces disorder in the empty protomer, entropically driving the reaction forward. The enzyme utilizes a regulatory cap domain above the substrate access channel which prohibits substrate access to the empty protomer. At high substrate concentrations, a second substrate binds to a site along the binding channel of the occupied protomer, inhibiting catalysis. A key mutation of this site, K152I, effectively halts second site binding, resulting in abrogation of substrate inhibition and an order of magnitude drop in catalytic rate. At low substrate concentrations, the allosteric pocket acts as a conduit to desolvate the substrate. These results illustrate the role of dynamics along allosteric networks in facilitating chemical function.
A Hamiltonian Engine for Radiotherapy Optimization
Keywords: Graphics Processing Unit
Intensity-modulated radiation therapy
Ising model
Markov Chain Monte Carlo
Optimization
parallel computing

We apply a new hardware and software platform called Hamiltonian Engine for Radiotherapy Optimization (HERO) to the problem of beamlet intensity optimization in Intensity-modulated radiation therapy (IMRT). HERO solves large general-form binary optimization problems by decomposing them into sub-problems and approximating them by a quadratic pseudo-boolean function. Optimizing the resulting function becomes a quadratic unconstrained binary optimization (QUBO) problem which is widely studied and has numerous applications in different fields. In addition, we propose a new method to compute the IMRT objective function using a binary search approach. We exploit a GPU to perform the evaluations and also present a novel update scheme to perform groups of related evaluations together with better computational efficiency. We evaluate HERO on 10 prostate IMRT cases with clinical objectives, each involving approximately 700 beamlets. HERO solves most of the cases in about 2 minutes, with significantly lower objective function scores than the simulated annealing.
Characterization of Unmanned Aerial Vehicle’s Single and Co-axial Propellers Performance Considering Geometrical and Environmental Factors
Keywords: Coaxial Propellers
Computational Fluid Dynamics
Drone
Single Propeller

Many studies have investigated the behavior of coaxial propellers for drones considering different design configurations and various external geometrical and environmental factors. However, to date, most studies have been focused on a limited number of influential factors, and no comprehensive study into the complex interactions between design configuration, operating condition, and overall propeller performance has been carried out. In this study, a parameterized CFD model is developed to characterize the performance of single and coaxial propellers based on the individual and compound effects of geometrical and environmental factors such as propeller diameter, number of blades, and inflow velocity magnitude and direction. Through this study, it was found that in a coaxial configuration, corotating propellers generate 60% more thrust than contrarotating propellers in close stacking distance between two propellers. However, by an increase of distance, contrarotating propellers show a higher thrust and efficiency compared with corotating propellers by 6% on average.
Canadian Election Integrity Initiatives and Domestic Disinformation: Investigating the 2019 Canadian Federal Election Across Sectors
Keywords: Disinformation
Election integrity
Elections Modernization Act
Media literacy
Political advertising
Social media

This thesis examines several efforts to address the threat of online disinformation to the 2019 Canadian federal election, and considers the degree to which election integrity initiatives by government, industry, and civil society stakeholders accounted for the role of domestic actors within the disinformation ecosystem. While much contemporary discourse on disinformation and election integrity focuses on foreign influence, the phenomenon also implicates domestic actors like political parties, third party groups, mainstream and partisan media, and average social media users. Through qualitative analysis of key legislative, policy, and public awareness initiatives, this thesis draws out common themes, strategies, and perspectives in Canada’s approach to disinformation across sectors, alongside a supplementary analysis of Canadian mainstream media coverage related to the election. It concludes with a critical policy analysis that considers whether Canadian election integrity initiatives sufficiently account for domestically-driven disinformation, particularly given increased political polarization and far-right influence in Canada.