VictorJuiz/thesis huggingface dataset:
Computational Modeling of Closed-loop Geothermal System

Emerging closed-loop geothermal systems have the potential to offer dispatchable energy without the limitations of conventional geothermal technology. However, to be competitive, closed-loop geothermal requires a fluid that exceeds water with respect to heat capacity and thermosiphon effect. Employing phase change slurries (PCS) is one strategy to enhance the performance of closed-loop systems. A model was built to assess the viability of PCS-based closed-loop geothermal, the result of which shows 12.5% enhancement in thermal output compared to the water base case and achievement of additional energy by removing the need for pumping. To take advantage of the uniquely high-pressure and high-temperature conditions within the loop, idea of biofuel processing inside the loop has been proposed. A numerical model was built to assess the viability of this idea. An economic analysis of results shows that biofuel processing in the geothermal loop could potentially outperform electricity generation from water-based geothermal loop.

Keywords: biodiesel processing
biofuel processing
closed-loop geothermal
geothermal energy
phase change materials
renewable energy
Advisor: Sinton, David
Characterization of the Phage Protein LES4-4 and its Impact on Quorum Sensing in Pseudomonas aeruginosa

Bacteria protect against virus infection using a variety of anti-phage defence systems, many of which are regulated by quorum sensing. While findings have been limited to phage proteins that inhibit individual defences, recently an anti-quorum sensing protein (Aqs1) was discovered to inhibit LasR, a global transcriptional regulator of quorum sensing. This suggests that phages can prevent the activation of numerous defences simultaneously. LES4-4 is a phage protein that shares 61% protein sequence identity with Aqs1. Herein I show that LES4-4 interacts with PilB, the Type IV assembly ATPase. The interaction with PilB resulted in inhibition of twitching motility, increased resistance against pilus-dependent phage infection, and reduction of pili on the cell surface. In addition, a bacterial two-hybrid assay indicates that LES4-4 binds Vfr, a positive transcriptional regulator of LasR – suggesting that LES4-4 may also disrupt quorum sensing in bacteria.

Keywords: Anti-phage defence
Bacteriophage
Cell signaling
Phage genes
Pseudomonas aeruginosa
Quorum sensing
Advisor: Maxwell, Karen L
Investigating Metabolomic and Transcriptomic Signatures of Metabolic Dysfunction in Antipsychotic-naïve Patients

Psychosis spectrum disorders (PSDs) are characterized by metabolic dysfunction, arising from intrinsic and external factors, including antipsychotic (AP) treatment. Transcriptomics and metabolomics may help explore underlying causes of the metabolic comorbidity. The thesis comprises two studies. In study one, peripheral transcriptomic datasets of AP-naïve first-episode psychosis patients, early dysglycemia patients, along with hypothalamic and hippocampal datasets of central insulin perturbation rodent models were meta-analyzed to identify overlapping gene expression signatures. Overlapping gene expression signatures included pathways of endoplasmic reticulum stress, mitochondrial dysfunction, lipid metabolism, inflammation, and neuroplasticity. In study two, 25 AP-naïve cases and 6 controls underwent metabolomic and metabolic measures at baseline. Cases were followed over 12 weeks of AP treatment. Fatty acids distinguished AP-naïve cases from controls. Baseline adrenic acid was higher for cases who gained weight. Transcriptomics and metabolomics may identify biomarkers of metabolic dysfunction intrinsic to PSDs and predict individuals at risk for AP-induced weight gain.

Keywords: Antipsychotics
Diabetes
Metabolomics
Psychosis
Transcriptomics
Weight Gain
Advisor: Hahn, Margaret
Agarwal, Mahavir
Investigating the Molecular Function of MATR3

MATR3 is an RNA binding protein that plays a role in alternative splicing. Previous studies have shown that MATR3 binds to intronic regions flanking repressed exons and may be involved in cryptic splicing. Here, I demonstrate that MATR3 plays a role in cryptic splicing repression. I show that the RRM2 domain is required for this function, while the RRM1 and the ZF domains are not. I demonstrate that MATR3 binds its splicing targets using its RRM2 domain. I found that the disease-linked M548T mutation, which resides in the RRM2 domain, is unable to rescue cryptic exon repression, and this may be driven by its decreased solubility and/or its impaired RNA binding ability. Altogether, understanding the molecular functions of MATR3 can provide insights into how dysregulation of MATR3-dependent splicing and mutations in MATR3 influence transcript diversity and disease.

Advisor: Park, Jeehye
Community Pharmacists as Antimicrobial Stewards: A Focus on Acute Otitis Media

Background: Programs that optimize antibiotic use in primary care are important since most antibiotics are prescribed for outpatients. Although community pharmacists are gatekeepers for antibiotics, they are often absent from antimicrobial stewardship programs. Methods: This quasi-experimental uncontrolled before-and-after study was conducted with pharmacists in two community pharmacies. Patient participants were 6 months to 12 years of age presenting with an antibiotic prescription for acute otitis media (AOM). Study interventions included one-on-one pharmacist education, clinical decision support tools, and personalized monthly audit and feedback. Pharmacists were encouraged to adapt prescriptions as permitted. The primary outcome was the percentage change in guideline-congruent AOM antibiotic prescriptions attributable to pharmacist intervention. Results: The overall guideline adherence for AOM antibiotic regimens increased by 28% in the post-intervention study arm (p<0.0001), which was driven by optimization of the dose of antibiotic and duration of therapy. Conclusion: A community pharmacy-based intervention can leverage pharmacist expertise to improve antibiotic use for AOM.

Keywords: acute otitis media
antimicrobial stewardship
community pharmacy
pharmacists
Advisor: Battistella, Marisa
Spatial Heterogeneity and Immune Microenvironment of Early Invasive ER+ Breast Cancer

Estrogen receptor-positive (ER+) breast cancer makes up approximately 80% of all breast cancer cases. This subtype is known to have distant recurrences for a subset of a patient after adjuvant endocrine therapy, which can partially be attributed to the heterogeneity of the disease, requiring revision of the treatment approach. The increase in popularity of immunotherapy resulted in some cancers such as ER+ breast cancer being overlooked as immunologically cold. This study characterizes the immune microenvironment in the tumour and tumour microenvironment (TME) compartments using the GeoMx Digital Spatial Profiler. Using spatial analysis, metric of heterogeneity and multi-omic approach this study demonstrates that ER+ breast cancer presents with a rich immune microenvironment, one that can be leveraged by future immunotherapies. Significantly higher expression of CD127 in the tumour compartment versus the TME was observed, along with variable ERα expression in ER+ breast cancer that may be associated with a variable immune response.

Keywords: ER+ Breast Cancer
GeoMx Digital Spatial Profiler
Immunology
Regulatory T cells
Tumor Microenvironment
Advisor: Spears, Melanie
Bartlett, John
Expansion and Characterization of Tumour Derived T Lymphocytes from Undifferentiated Pleomorphic Sarcoma

Sarcoma is a group of rare bone and soft tissue tumours with over 50 distinct subtypes. Survival rate of metastatic sarcoma is poor due to the lack of efficacious treatments and therapeutic strategies such as adoptive cell therapy (ACT), which utilizes TDLs, has drawn significant interest due to its precedence in treating metastatic melanoma. However, the low abundance of sarcoma TDLs may be a limiting factor during ACT, which necessitates a large quantity. Additionally, IL-2’s use during ACT promotes FOXP3+ and terminal T cells and may further exacerbate this challenge. As such, this study optimized the Tumour Fragment and Rapid Expansion protocols to robustly expand sarcoma TDLs. Non-IL-2 gamma chain cytokines were also identified as promising IL-2 alternatives to promote T helper and CD8 TDLs with clinically favorable memory phenotype and pro-inflammatory functionality. Future approaches to ACT could explore IL-7+IL-15+IL-21 to expand TDLs, and PD-1 and TIM-3 blockades as adjuvants.

Keywords: Adoptive Cell Therapy
Cytokine
Immunotherapy
Sarcoma
T cell
TIL
Advisor: Andrulis, Irene L
Wunder, Jay S
Doubling Down: CRISPR-Cas9-mediated Generation of Cellular MECP2 Duplication Syndrome Models

Methyl CpG binding protein 2 (MeCP2) is a transcriptional regulator primarily expressed inneurons. A duplication of the MECP2 locus underlies MECP2 duplication syndrome (MDS), an X-linked recessive neurodevelopmental disorder. Strikingly, cellular studies have been limited to investigating MeCP2 overexpression models and patient cells, since no tandem duplication models currently exist. Here, I outline the CRISPR-mediated generation of the first cellular MDS model recapitulating the IRAK1-MECP2 tandem duplication shared across patients. I first test the feasibility of the CRISPR strategy in HEK293 cells, and then apply it to generate and characterize structural variations (SVs) in diploid HAP1 cells. Moving to a disease-relevant neuroblastoma cell line, I pinpoint the challenges of extending the technique across different cell types. Importantly, this project highlights the powerful potential of CRISPR-Cas9 technology in generating SVs, particularly duplications, of the MECP2 locus, establishing a framework to not only investigate MDS but duplication mutations at large.

Advisor: Cohn, Ronald D
N-acetylcysteine in the Rotenone Model of Mitochondrial Complex I Dysfunction in THP-1 Monocytes

Mitochondrial Complex I dysfunction and oxidative stress have been consistently reported in bipolar disorder (BD). Neuronal cell lines and rotenone, an inhibitor of Complex I, were previously used to model Complex I dysfunction in the brain. We used rotenone and THP-1 cells, a human monocytic cell line, to model Complex I dysfunction and oxidative stress potentially present in the peripheral blood mononuclear cells of BD patients and to explore N-acetylcysteine (NAC) in preventing the mitochondrial effects of rotenone. Rotenone upregulated NDUFS7, a Complex I subunit dysregulated in BD, and induced production of mitochondrial superoxide. NAC pre-treatment prior to rotenone exposure prevented NDUFS7 upregulation but had no effect on mitochondrial superoxide production. Our results suggest a reactive oxygen species-linked adaptive mechanism to mitochondrial Complex I dysfunction, providing insights to how NAC antioxidant therapy may be effective in BD.

Keywords: Bipolar disorder
Complex 1
Mitochondria
N-acetylcysteine
NDUFS7
Advisor: Andreazza, Ana C
Methods for Modulation of Surface Calreticulin and Subsequent Phagocytosis

An increase in surface calreticulin (CRT) can promote recognition of cells by macrophages and the immunogenicity of cell death, and is a desirable response in current chemotherapeutics. Using standard hematopoietic cell lines, Jurkat, THP-1 and HL-60, a range of small molecules postulated to increase surface CRT were tested. Overall, raphin1, sephin1, nelfinavir and ritonavir showed promise for increasing surface expression of CRT, which led to an increase in both THP-1 and RAW 263.7 mediated phagocytosis with raphin1 and ritonavir. A second method of increasing surface CRT was also explored. THP-1 pre-treated with P-3Fax-Neu5Ac were found to have a reduction in terminal α2, 3 and α2, 6 N-acetylneuraminic acids, exposing an obscured Tri/ Mii glycan, which allowed for increased binding of exogenous CRT, and subsequent phagocytic uptake by differentiated THP-1 macrophage-like cells.

Keywords: Calreticulin
Glycans
Macrophage
Phagocytosis
Advisor: Walker, Gilbert C
Three-dimensional Imaging of Bacterial-induced Dental Caries using Truncated-correlation Photothermal Coherence Tomography and Computationally Optimized Modalities

Dental caries is a highly prevalent chronic disease which is easily treatable when detected early in its formation. The primary diagnostic imaging modality used by clinical dentists, radiography, is insensitive to early caries and unsuitable for frequent use due to the health risks associated with ionizing radiation. Photothermal imaging shows great promise in the caries detection field thanks to its non-ionizing nature and the co-operative optical and thermal properties of healthy and diseased dental tissue making it highly sensitive to early caries. In this thesis, two existing photothermal modalities: Truncated-Correlation Photothermal Coherence Tomography (TC-PCT) and Enhanced Truncated-Correlation Photothermal Coherence Tomography (eTC-PCT) as well as a newly introduced TC-PCT phase algorithm: the Linear Iso Phase (LIOP) are applied to bacterial-induced dental caries imaging of human teeth. The findings demonstrate higher sensitivities to early-stage caries than micro-CT, the non-destructive gold stand of caries detection, while operating as clinically safe energy levels.

Keywords: Dental Caries
Linear Iso Phase (LIOP)
Signal Processing
Thermophotonics
Truncated-Correlation Photothermal Coherence Tomography (TC-PCT)
Advisor: Mandelis, Andreas
Surfactant-oil-Water (SOW) Behaviour of Surfactant Mixtures Containing Naphthenic Species

Recent studies have indicated naphthenic acid (NA) and its salt form, sodium naphthenates (NaN), both of amphiphilic nature, are the main agents in the formation of emulsions during the bitumen production process. Although similar fatty acids have shown ultra-low (< 0.1 mN/m) interfacial tensions (IFT) in surfactant-oil-water (SOW) systems, NA and NaN do not achieve such levels of IFT. In this work, HLD-NAC simulations guided a stoichiometric neutralization of the NA to find an ultra-low IFT interval. As experiments did not achieve ultra-low IFT, we explored potential explanations for the deviation. The work defined that NaN partitioned to the oil phase upon production. On the other hand, simulated neutralizations showed that by increasing NaNconcentration in the aqueous phase, forcing NaN to stay in it, the system could experience IFT reductions. However, NaN was then also lost to the oil phase. The zipper-like linker self-assembly, using a mixture of two balanced surfactants AOT-SDHS, was partially confirmed as a mechanism to enhance the interaction of the NA-NaN at the interface and even increased the retention of NaN in the aqueous phase. From the scenarios experimentally explored as a function of HLD (>0, ~0, and < 0), the systems with intrinsic HLD ~0 and < 0 suggested better NaN retention and potential NaN recovery even without neutralization. Emulsion stability studies confirmed the findings, achieving the separation of the water-in-oil emulsions in 15 minutes and were congruent with the HLD-NAC simulation once the critical aggregation concentration was revisited.

Keywords: HLD-NAC
hydrophilic linker
interfacial tension
lipophilic linker
Microemulsions
Naphthenic Acid
Advisor: Acosta, Edgar J
Clinical Evaluation of the ONETest, a Target-capture Next Generation Sequencing Platform for the Identification of Respiratory Pathogens

We clinically evaluated the diagnostic capabilities of a target capture next generation sequencing (NGS) platform called the ONETestTM. The ONETest facilitates the simultaneous detection of respiratory pathogens through a comprehensive pipeline that includes specimen processing, NGS, and bioinformatic analysis. Clinical specimens (n=655) were collected from November 2019 to April 2020 at two hospitals in Toronto, Ontario, and another 251 specimens were collected in December 2020 from healthy community participants. All specimens were evaluated using the ONETest and conventional diagnostic techniques. Agreement statistics indicate a high level of agreement between the ONETest and conventional diagnostic techniques. The overall sensitivity, specificity, positive predictive value and negative predictive value of the ONETest was 90.9% [95% CI 87.8% - 93.4%], 97.6% [95% CI 97.1% - 98.0%], 77.7% [95% CI 73.9% - 81.2%], and 99.1% [95% CI 98.8% - 99.4%], respectively. These findings highlight the efficacy of the ONETest to detect respiratory pathogens accurately.

Keywords: Diagnostics
Infectious Diseases
Next generation sequencing
Respiratory
Advisor: Mubareka, Samira
Modelling Hyperexcitability in Human Cerebral Organoids: A Platform for Epilepsy Drug Testing

Epilepsy is a complex neurological condition characterized by recurrent seizures, that affects 1% of the population. A third of people with epilepsy do not respond to drugs and there is not one drug that treats all; thus, better models of epilepsy are needed for drug development. Human cerebral organoids resemble the 3D complexity of the human brain and have the potential to augment current drug development pipelines. In the present work, human cerebral organoids are used along with electrophysiological methods to explore various means of inducing seizures. The resulting activity is characterized through signal processing and manual event analysis. Furthermore, this hyperexcitable activity is investigated in its response to current anti-seizure drugs. These findings demonstrate the presence of hyperexcitable changes in the cerebral organoid tissue, which supports the use of organoids as a platform for modelling epilepsy, as well as provides a framework for testing anti-seizure drug efficacy.

Keywords: brain
cannabis
epilepsy
organoid
pharmacology
seizures
Advisor: Carlen, Peter L
The Impact of COVID-19 Restrictions on Healthcare and Caregiving Access among Community-dwelling Adults Living with Spinal Cord Injury in Southwestern Ontario

Restrictions implemented during the novel coronavirus (COVID-19) pandemic may disproportionately affect healthcare and caregiving access among individuals living with disabilities. A unique longitudinal survey was used to examine changes to healthcare and caregiving access among community-dwelling adults living with spinal cord injury (SCI) in southwestern Ontario, Canada before and during the COVID-19 pandemic. The results of this research demonstrated that most of the participants were able to access virtual care, but not in-person healthcare services during the COVID-19 pandemic. Longer time since injury was associated with accessing in-person healthcare services and attending all scheduled appointments. A large proportion of participants reported increased spousal participation in caregiving services early during the pandemic and understaffed formal caregiving agencies. Findings from the current study highlight the need for improved healthcare and caregiving access for individuals living with SCI during the COVID-19 pandemic and can be used to inform ongoing and future pandemic responses.

Keywords: caregiving access
COVID-19
healthcare access
spinal cord injury
Advisor: Chan, Brian CF
Wodchis, Walter P
Envelope Tracking Power Supplies for 5G RF Amplifiers

Envelope tracking is a technique to improve the power efficiency in 5G wireless networks. Center to this technique is a supply modulator which adjusts the supply voltage to the radio-frequency power amplifier (RF PA) according to the incoming modulated signal. In this thesis, a hybrid parallel supply modulator design is proposed. It consists of a linear amplifier connected in parallel to a non-inverting buck boost converter. The linear amplifier is responsible for providing the AC current while the buck boost converter is responsible for providing the DC current. Simulation results show that the proposed supply modulator can achieve an efficiency of over 80% with a maximum output voltage of 4.79 V, a maximum output power of 3.82 W, and an envelope bandwidth of up to 100 MHz.

Keywords: Envelope Tracking
Supply Modulator
Advisor: Ng, Wai Tung W.T.
Investigating the Effect of Sensory Input on Muscle Function

Central sensitization (CSens) is a pain mechanism marked by hypersensitivity to stimuli. It is believed that neuroplastic changes caused by increased nociceptive input may allow sensory information to affect motor pathways. This study investigated the relationship between CSens and muscle function. Fifteen healthy participants underwent two interventions where capsaicin either induced CSens or was blocked with lidocaine. Three measurements were taken from the soleus and tibialis anterior muscles: shear wave elastography to monitor changes in muscle stiffness; surface electromyography to measure motor unit recruitment order, and F-wave amplitude and persistence to measure motor neuron excitability; torque recordings to determine force steadiness. An increase in the stiffness of the tibialis anterior was observed following the application of capsaicin. The amplitude and persistence of the F-waves were not significantly different after either intervention. Furthermore, although there was a change in motor unit recruitment, force steadiness did not change during the torque recordings.

Keywords: Chronic Pain
Electromyography
Pain Processing
Skeletal Muscle
Ultrasound
Advisor: Kumbhare, Dinesh
Popovic, Milos
The Role of Neuroepithelial Bodies and 5-Hydroxytryptamine During Inflammation in the Airways

Neutrophils activated by foreign pathogens generate reactive oxygen species (ROS) via NADPH oxidase (NOX) 2 and myeloperoxidase (MPO), inducing the release of neutrophil extracellular traps (NETs) that kill airway epithelial cells. Single pulmonary neuroendocrine cells (PNECs) of the neuroepithelial bodies (NEBs) present in airways secrete serotonin (5-hydroxytryptamine, 5-HT), a competitive substrate of MPO. We hypothesized that 5-HT secreted by NEBs into the lumen inhibits NET formation and protects epithelial cells against NET-mediated cell death. To test this hypothesis, neutrophils isolated from the peripheral blood of healthy human donors were exposed to 5-HT and stimulated to undergo NETosis. Both exogenous and 5-HT released by neuroendocrine H727 cells suppressed NOX-dependent ROS production and NETosis. Cell death and detachment assays showed that airway epithelial A549 cells are highly susceptible to NET-mediated killing. Therefore, we conclude that 5-HT inhibits NOX-dependent NETosis by suppressing ROS production and protects epithelial cells from NET-mediated damage.

Advisor: Palaniyar, Nades
Gauda, Estelle
Design Optimization of a Wind-Powered Aeration System for Enhancing Rural Aquaculture

Aeration is a critical process of commercial aquaculture and is required for maintaining sufficient dissolved oxygen (DO) levels for producing high yields of fish. However, many producers in low-income countries do not use active aeration due to high costs or lack of electrical availability. This project optimizes the design of a wind-powered system for passively increasing DO concentration in aquaculture ponds for use in these regions. The design consists of a vertical-axis wind turbine coupled to a subsurface impeller positioned in a draft tube. CFD-based optimization experiments were conducted to maximize the turbine efficiency and to increase the rate of water circulation. The optimized system was tested in an aquaculture pond to evaluate the impact of the system on DO levels. The optimized aeration system operated at a 12% greater rotational speed than the original design, improved distribution of DO and elevated the overall concentration by an average of 18%.

Keywords: Aeration
Aquaculture
Savonius
Advisor: Bilton, Amy