VictorJuiz/thesis huggingface dataset:
Equivalent Topologies on the Contracting Boundary

The contracting boundary of a proper geodesic metric space generalizes the Gromov boundary of a hyperbolic space. It con- sists of contracting geodesics up to bounded Hausdorff distances. Another generalization of the Gromov boundary is the κ–Morse boundary with a sublinear function κ. The two generalizations model the Gromov bound- ary based on different characteristics of geodesics in Gromov hyperbolic spaces. It was suspected that the κ–Morse boundary contains the con- tracting boundary. We will prove this conjecture: when κ = 1 is the constant function, the 1-Morse boundary and the contracting boundary are equivalent as topological spaces.

Advisor: Rafi, Kasra
Metabolic and Inflammatory Biomarker Profiling in Adolescents with Obesity and Insulin Resistance

The current study characterized the postprandial inflammatory and metabolic biomarker profiles in adolescents with obesity and insulin resistance (IR) via a 6-hour oral fat tolerance test. Inflammatory and metabolic markers were assessed via immunoassays, mass spectrometry (MS), and nuclear magnetic resonance (NMR) spectroscopy. Inflammatory biomarker profiling and metabolomics revealed elevated levels of fasting and postprandial interleukin (IL)-6 and calprotectin, branched-chain amino acids and alanine (via NMR), and glutamic acid (via MS) in obesity, particularly among those with severe IR. Correlational analyses demonstrated strong associations among tumour necrosis factor-a (TNF-a), IL-6, IL-18, acylcarnitines, amino acids, biogenic amines, organic acids, phospholipids and an atherogenic lipid/lipoprotein phenotype, adiposity, IR, systemic inflammation, and hepatic enzyme levels. Taken together, adolescents with obesity and IR exhibit significant fasting and postprandial hyper-inflammation and metabolic dysfunction integral to obesity-related pathogenesis. These data may offer potentially novel sub-clinical biomarkers for early metabolic disorders in at-risk adolescents.

Keywords: Inflammation
Insulin resistance
Metabolic syndrome
Metabolomics
Obesity
Pediatrics
Advisor: Adeli, Khosrow
Somatostatin and Non-muscle Myosins: Modulators of the Canonical Pathogenesis Pathway in Alzheimer’s Disease?

Alzheimer’s disease (AD) is characterized by the emergence of two types of pathogenic structures in the brain, amyloid plaques formed by the Amyloid-beta peptide (A) and neurofibrillary tangles formed by Tau. In this study, I built on earlier work of our team and investigated two previously identified interactors of A and Tau. The earlier studies in our laboratory had made use of genetically modified cell lines and in vitro paradigms to conduct interactome studies which established the selective interaction of somatostatin (SST) with oligomeric assemblies of Aβ, and of non-muscle myosins (NMM) with wildtype Tau but not P301L mutant Tau. In this study, I investigated the significance of these earlier observations by making use of in vivo models and human post-mortem samples. My work established that SST ablation can slow amyloid plaque deposition in vivo, possibly by stabilizing oligomeric forms of A thought to form early in AD. Moreover, I learned that the association between NMM and Tau extends to human cases and may reflect a stabilizing effect of Tau on NMM. This work addressed one of the oldest biochemical questions in AD research, namely, the possible mechanism through which somatostatin might influence the A amyloidosis that is a hallmark of the disease. It also revealed that the interplay between non-muscle myosins and Tau is more intricate than our pilot in vitro studies had suggested. More work will be needed to fully reveal the influence of these stand-out interactors on the pathobiology of AD.

Keywords: Alzheimer's Disease
Amyloid beta peptide
Non muscle myosin
Somatostatin
Tau protein
Advisor: Schmitt-Ulms, Gerold
Tissue Engineered Pulmonary Valve Repair Material for use in an In-vitro Preclinical Model of Pediatric Valve Augmentation

Pediatric pulmonary valves are commonly repaired by monocusp augmentation, but current repair materials cannot grow, necessitating reintervention. Heart valve tissue engineering (HVTE) may address these limitations by producing functional living materials. Here, protocols were developed for in vitro culture of monocusp tissue comprised of pig umbilical cord perivascular cells coating aligned poly-carbonate polyurethane (PCNU) membranes. The mechanical properties of PCNU membranes were influenced by sterilization method and membrane thickness, but did not change when seeded with cells and cultured for up to 28 days. In vitro hemodynamic testing of PCNU membranes as a monocusp in a pediatric sized conduit demonstrated physiological opening and closing behaviours in response to an ISO standard condition of 20 mmHg, 100 bpm, and 1.5 L/min over two hours. These studies provide new insights for the use of PCNU for HVTE and are the first demonstration of a functional in vitro tissue engineered monocusp.

Advisor: Simmons, Craig A
Development and Evaluations of a Polydimethylsiloxane Polyurethane Surface Engineered Sponge for Enhanced Emulsified Crude Oil Removal from Water

Oil spills are environmentally hazardous because of the toxicity of chemical constituents. Cleaning emulsified crude oil has always been challenging. Adsorbent materials can be implemented to remove oil and toxins from oily water to reach Canadian standards before discharging to the environment. This work develops and evaluates a surface-engineered sponge (SEnS) with a PDMS-PU polymer blend coating. The PDMS concentration in the coating is optimized to reduce cost, and the highest single pass oil removal efficiency attained was 62%. Toxicology tests of Artemia brine shrimp provide researchers with a foundation of the decanting standard. The mortality rate decreased from 86% in starting emulsion to 13% in filtered water and down to 0% when diluted by 90% seawater. The operating environment was also investigated by modeling two diffusion models. The efficiency of PDMS-PU coating in removing oil droplets and toxins provides the potential for implementing SEnS into an oil-water-separation system.

Advisor: Bilton, Amy
Design of Nanoparticle-loaded Etafilcon A Contact Lenses for the Controlled Release of Dextran

Dry eye disease is a growing health problem, and contact lens wear is a contributing factor to its increasing prevalence. Controlled delivery of dry eye drugs from contact lenses may be an effective way to treat and manage dry eye symptoms, and especially those caused by contact lens wear. Among dry eye treatments, dextran is a polysaccharide that is a popular active ingredient in artificial tears due to its lubricating properties. This thesis describes the formulation of dextran-loaded alginate nanoparticles, and their integration into etafilcon A contact lenses by a polyvinylpyrrolidone (PVP) coating method. The release properties of alginate and dextran are quantified and controlled by varying the PVP concentration on the surface of the nanoparticles and in the bulk of the lens, as well including polymer or surfactant additives in the storage solution. These strategies may be employed to achieve desired release profiles.

Keywords: Alginate
Contact lens
Controlled release
Dextran
Dry eye
Nanoparticles
Advisor: Gu, Frank
Associations of Linear Growth in the First 2 Years with Bone Mass at 4 Years of Age in Children in Dhaka, Bangladesh

Despite attention towards growth faltering in low-and middle-income countries, less is known about childhood bone mass. In a cohort of 4-year-old children in Bangladesh, we aimed to estimate associations between length (conditional length-for-age z-scores, cLAZ) and weight (conditional weight-for-age z-scores, cWAZ) gain measured in 3 intervals (ages 0-6, 6-12, 12-24 months) and bone outcomes (total-body-less-head bone mineral content, BMC, areal bone mineral density, aBMD, and bone area) at age 4-years (n=599). Positive associations of cLAZ in each interval with bone outcomes were rendered null after adjustment for concurrent height at 4-years. cWAZ between 12-24 months was independently associated with BMC (7.5g; 95%CI:3.1,11.8) and aBMD (0.008g/cm2; 95%CI:0.002,0.014) after adjusting for weight and height at 4-years. The associations between linear growth (birth to 2-years) and bone mass are explained by concurrent height. However, weight gain in the second year of life might improve bone mass, irrespective of length growth, in this setting.

Keywords: Bangladesh
Bone mass
Children
Linear growth
Weight gain
Advisor: Roth, Daniel DR
Ocean Current Energy Conversion for Powering Distributed Sensors

This thesis examines the concept of harvesting energy from the environment surrounding distributed ocean sensors to overcome the limitations of battery power. Our research was focused on demonstrating the feasibility of a device that can be installed with moored sensors and harvest energy from ocean currents. We first confirmed the thermodynamic feasibility of this concept, and then proceeded to design an ocean current energy conversion device. We developed a theoretical model of the performance of the device, and also built a full-scale prototype. We tested the prototype in a tow tank and were able to confirm both that the device is functional and that its actual performance aligns with the modelled performance. Highlighted performance includes producing at least 1 W of electrical power from water speeds of ≥0.27 m/s (~1 km/h). The results of our research give a very positive indication for the feasibility of this concept and continued development is recommended.

Advisor: Bilton, Amy
Deoxygenation of Respiratory and Limb Muscles during Exercise in COPD and Healthy Adults

The overall objective of the thesis is to investigate deoxygenation of limb and respiratory muscles in chronic obstructive pulmonary disease (COPD), and to compare exercises that recruit these muscles in healthy participants.The first study, a scoping review that searched 7 databases, demonstrated that, compared to healthy participants, COPD patients display more rapid increases in vastus lateralis deoxygenated hemoglobin and blood flow; and lower muscle tissue saturation during cycling exercise. For the second study, two different exercises were compared in order to investigate alternative ways to train the inspiratory muscles. In healthy participants, we found submaximal intermittent neck flexion (INF) induced quicker and greater deoxygenation of sternocleidomastoid than inspiratory threshold loading (ITL) in healthy participants. INF induced significant metabolic activity of the sternocleidomastoid at a lower perception of effort than ITL. The merits of INF compared to ITL may be advantageous for applications of respiratory muscle training clinically.

Keywords: exercise
inspiratory
limb
NIRS
rehabilitation
training
Advisor: Reid, Darlene WDR
Rozenberg, Dmitry DR
The Role of Maternal Vitamin D supplementation in the Prevention of Infantile Rickets in Dhaka, Bangladesh

Nutritional vitamin D deficiency is the primary cause of childhood rickets worldwide; however, the role of maternal vitamin D supplementation in the prevention of infantile rickets is unknown. The primary aim of this secondary analysis of a randomized placebo-controlled trial of maternal vitamin D supplementation in Dhaka was to estimate the effects of prenatal with or without postpartum vitamin D supplementation on the risk of biochemical rickets at ages 6 – 12 months. Secondary outcomes included the characteristics of infants at diagnosis, and the relationships of antecedent maternal and infant factors with rickets. Contrary to our hypothesis, prenatal vitamin D supplementation alone did not decrease the risk of rickets at 6 – 12 months of age; however, prenatal supplementation (28000 IU/week) followed by maternal supplementation (28000 IU/week) until 6 months postpartum did significantly decrease this risk, by 84%, compared to placebo. Further research is needed to define optimal postpartum vitamin D supplementation dosing in breastfeeding women.

Advisor: Roth, Daniel E
Investigation of Stress Adaptation as a Vulnerability in Ovarian Cancer

High-grade serous ovarian cancer (HGSOC) is the most prevalent and lethal ovarian cancer subtype. HGSOC cells experience many stressors—including genotoxic, metabolic, and hypoxic stress—generating a cancer-specific stress state. The conserved integrated stress response pathway is activated by four stress kinases, including general control nonderepressible 2 (GCN2), inducing a transcriptional program driven by activating transcription factor 4 (ATF4). GCN2 and ATF4 are elevated in many cancers and associated with poor prognosis and chemotherapeutic resistance. I hypothesized that HGSOC cells rely on GCN2 to adapt to unique stress conditions. I demonstrated that the GCN2-ATF4 pathway was functional in HGSOC cell lines. Downstream signalling was inhibited using novel GCN2 inhibitors, and GCN2 knockout clones confirmed their specificity. Novel GCN2 inhibitors reduced viability of HGSOC cell lines and patient-derived organoids upon stress induction by L-asparaginase (ASNase). Combining GCN2 inhibitors and ASNase may be a promising therapeutic strategy to improve HGSOC survival outcomes.

Keywords: Asparaginase
ATF4
Cancer therapy
GCN2
Integrated stress response
Ovarian cancer
Advisor: Rottapel, Robert
Extraction of Clove Oil with Lecithin-based Microemulsions Guided by the Hydrophilic-Lipophilic-Difference (HLD) and Net-Average-Curvature (NAC) Model

Current methods for extracting herbal oils, including steam and solvent extraction, suffer from low yields, using large volumes of solvents, and for being time and energy intensive. Capillary displacement, as an emerging extraction method, uses dilute surfactant solutions to promote low interfacial tensions to reduce the capillary pressure that retains triglycerides on the seed matrix. This work adapts this strategy to extract polar oils, specifically eugenol. Polar oils are compounds with dual, surfactant- and oil-like behaviour and their high affinity for the surfactant alters the phase behavior and make separating them from the surfactant difficult. The Hydrophilic-Lipophilic-Difference and Net-Average-Curvature + polar oil models are applied to predict the influence of eugenol in lecithin-based microemulsions and as a guide to develop an extraction process called Solvent-Addition and Self-Emulsification, that including a recycling step for the aqueous phase, produced 18% yield at room temperature and pressure with 5 minutes of extraction time.

Keywords: Bifunctional model
Capillary Displacement
Extraction
HLD-NAC
Microemulsion
Polar oil
Advisor: Acosta, Edgar J.
Investigating Lipid Metabolites in the Serum of Psoriatic Arthritis Patients Using Solid Phase Microextraction – Liquid Chromatography – High-resolution Mass Spectrometry

Psoriatic arthritis (PsA) is an inflammatory arthritis affecting approximately a quarter of psoriasis patients. PsA is a heterogeneous disease and therefore accurate assessment of disease activity is difficult. Metabolomics – the study of all metabolites in a system – is an emerging branch of systems biology. Previous metabolomics studies have identified lipid candidate markers for PsA disease activity that require further evaluation. Liquid chromatography paired with high resolution mass spectrometry (LC-HRMS) is a commonly used analytical technique in metabolomics due to its high throughput and good coverage of metabolites. Solid Phase Microextraction (SPME) is an extraction technique via free concentration that significantly reduces matrix effects. This thesis presents the development of an LC-HRMS method, in conjunction with SPME to investigate serum lipid metabolites associated with PsA disease activity. Several lipids identified as fatty amides, fatty acids and acylcarnitines, when combined in various classifying models could predict disease activity.

Advisor: Chandran, Vinod
Structures of SUR2 NBD1 / Drug Complexes Determined with NMR Spectroscopy and Data Driven Docking

ATP-sensitive potassium (KATP) channels are formed by four inward-rectifying K+ channels and four regulatory sulfonylurea receptors (SURs). ATP binding and hydrolysis at the SUR nucleotide binding domains (NBDs) regulates opening of the KATP channel pore. The SUR NBDs are also the sites of binding for KATP channel opener (KCO) drugs, which are diverse in structure and can be broadly categorized into several classes of molecules, including benzothiadiazines (diazoxide), cyanoguanidines (pinacidil and P1075), benzopyrans (cromakalim and Y26763), and nicotinamides (nicorandil). Through NMR binding studies, the identification of specific NBD1 residues involved in binding various KCO drugs were identified. The NMR titration data were used to calculate models of NBD1/drug complexes using the data-driven docking program HADDOCK. Knowledge of the bound complex structure will be used for rational design of more effective drugs that will be used to treat diseases associated with impaired KATP channel function, including hyperinsulinism and heart disease.

Keywords: ABC Protein
ATP Sensitive Potassium Channel
KCO Drugs
Molecular Docking
NMR Spectroscopy
Sulfonylurea Receptor
Advisor: Kanelis, Voula
Lightweight Foam Structures for Aerospace Application using High-performance Polymer PPSU

Foaming of high-performance material polyphenylsulfone (PPSU) was investigated using supercritical CO2 or n-butane as the physical blowing agent. The expansion ratio, which ranges from 1.10–16 was obtained under different conditions. Using n-butane is favorable in achieving a high expansion ratio due to its higher solubility and lower diffusivity comparing to CO2. Temperature is the most important parameter determining the expansion ratio. In batch foaming, the gas saturation time is less sensitive to the expansion ratio. Optimum saturation pressure is essential as the final expansion ratio is very sensitive to the saturation pressure. Similar to saturation pressure, an optimum pressure drop rate is also needed to induce enough thermal instability but not too much to cause cell coalescence and higher open-cell content. Another important parameter is cell growth time right after pressure drop. Due to the low diffusivity of n-butane, the cells grow much slower but larger comparing to CO2 as PBA.

Advisor: Lee, Patrick C.
A Randomized Investigation of Icosapent Ethyl in Outpatients with COVID-19: Results from the VASCEPA-COVID-19 CardioLink-9 Trial

Coronavirus disease 2019 (COVID-19) has had immense global implications on morbidity and mortality. At present, the development of therapeutic agents to combat COVID-19-related insults are considerably restrained. Safe and effective treatment options are urgently needed to reduce disease proliferation, inflammation and symptomatology. In response, the open-label VASCEPA-COVID-19 trial randomized 100 symptomatic COVID-19-positive outpatients in Toronto, Canada, to icosapent ethyl or usual care. Over a 14+3-day follow-up period, treatment with icosapent ethyl (4 g twice per day for 3 days, followed by 2 g twice per day for 11 days) was shown to significantly reduce high-sensitivity C-reactive protein, as well as, improve symptomatology. This study provides novel evidence of icosapent ethyl to have an early anti-inflammatory impact in a modest sample size of COVID-19 ambulatory patients, including the first demonstration of a well-tolerated icosapent ethyl loading dose. ClinicalTrials.gov Identifier: NCT04412018.

Keywords: Anti-Inflammatory
Coronavirus Disease 2019 (COVID-19)
High-sensitivity C-reactive Protein
Icosapent Ethyl
Omega-3 Fatty Acids
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
Advisor: Verma, Subodh
Ultra-strong, Lightweight, and Thermally Conductive Hybrid Graphene Nanoplatelets and Glass Fibre Reinforced Polypropylene-Based Composites

In this work, ultra-strong, lightweight, and thermally conductive hybrid polypropylene-based composites reinforced with graphene nanoplatelets (GnP) and glass fibre (GF) were fabricated and characterized; demonstrating their ability to be tailored for high-performance applications in the automotive industry. GnPs expedited the crystallization of the polymer matrix by serving as seeds for heterogeneous nucleation, while inducing β-crystals. The hybrid composites yielded improved properties greater than the sum of the properties of the individual reinforcing materials, showing a synergistic effect. The synergistic effect was maximized with 0.5wt.% GnP and increased with lower concentrations of GF, whereby the greatest effect was approximately 54% and 65% for the Tensile and Flexural Modulus, and 37% and 39% for the Tensile and Flexural Strength, respectively. Moreover, an 18% weight reduction was achieved with PPGnP0.5GF40 while maintaining the desirable mechanical strengths of PPGF60. Furthermore, the thermal conductivity was maximized with PPGnP5GF50, exceeding that of Neat PP by 201%.

Keywords: Graphene Nanoplatelets
Injection Molding
Mechanical Properties
Polypropylene
Structure-Property Relations
Thermal Conductivity
Advisor: Lee, Patrick C
An Optimization Technique for Volumetric Modulated Arc Therapy (VMAT)

This thesis presents a novel methodology for the development and evaluation of an IMRTto-VMAT (intensity-modulated radiation therapy to volumetric-modulated arc therapy) mapping system, modeled as a quadratic unconstrained binary optimization (QUBO) problem. The mapping system uses an IMRT solution as an initial point and decomposes the optimization process into several parallel QUBO problems. In each independent sub-problem, our method distributes the sequences of the IMRT plan into new candidate beam angles by solving a QUBO problem. This optimization considers all the machine limitations for VMAT delivery. We have implemented this approach on a specialized hardware platform designed for QUBO problems to accelerate optimization. The proposed approach demonstrates results with delivery times up to 20× shorter than the IMRT results provided by matRad, without compromising the quality of treatment plans in complex cases and improving the quality of the plan in simpler cases.

Advisor: Sheikholeslami, Ali
Examining the Role of RNF8 in R-loop Resolution in BRCA1-deficient Breast Cancer Cells

BRCA1 repairs DNA double-strand breaks (DSBs) through homologous recombination, therefore, loss of BRCA1 leads to increased genomic instability and tumorigenesis. Our lab observed that loss of Rnf8 in female mice with mammary-specific deletion of Brca1 rescued these mice from the development of mammary tumors. In vitro, our lab previously found that human breast cancer cell lines lacking BRCA1 displayed elevated levels of DSBs with depletion of RNF8, leading to cell death. In this study, using DRIP and ChIP, we demonstrated that loss of RNF8 in BRCA1-deficient cells led to R-loop accumulation and that RNF8 was enriched at R-loop prone genomic loci. We performed IP/MS to identify whether RNF8 interacted with known R-loop suppressors. We validated one interactor, XRN2, however, we found that XRN2’s recruitment to R-loops was not significantly impaired in the absence of RNF8. It remains to be determined if RNF8 is directly or indirectly involved in R-loop resolution.

Keywords: BRCA1
Breast Cancer
DNA Damage
R-Loops
Advisor: Hakem, Razq