VictorJuiz/thesis huggingface dataset:
Development of a Delivery Platform for Protein-Based Regenerative and Reparative Cardiac Therapies

Cell-based therapies for heart failure have been investigated in the field of regenerative medicine, however recent discoveries have shown that cardiac progenitor-cell derived paracrine effects (the secretome) may be inducing endogenous repair, instead of an intrinsic benefit from the stem cells themselves. We hypothesize that polyurethane-based nanoparticles will enable the delivery of therapeutic components of neonatal cardiac progenitor cell secretomes (BMP-4 and Ang1-7) and will induce characteristics representative of repair in damaged heart tissue. Polyurethane-based nanoparticles with a diameter of 190 ± 2 nm (polydispersity index < 0.2) and a zeta potential of -40 ± 1 mV were generated through an emulsion inversion technique. Through optimization of the concentration, coating duration, and coating efficiency, BMP-4 and Ang1-7 were coated onto the surface of the nanoparticles. Treatment with the coated nanoparticles significantly reduced expression of senescence associated b-galactosidase, a marker for senescence which is an important contributor to heart failure. On-going future work will further investigate the biological function of the nanoparticles with their biological payload, characterize both the particle and the biomolecule stabilities, and investigate co-delivery of multiple biomolecules simultaneously, in both in vitro cardiac cell and in vivo heart tissue models.

Keywords: Cardiac
Nanoparticles
Protein
Regenerative medicine
Advisor: Santerre, Paul
Maynes, Jason T
Intrinsic Photophysical Properties of Gaseous Acriflavine Ions

Fluorescence is a widely used analytical technique in several disciplines of science. In this work, mass-selected ions are trapped in a quadrupole mass spectrometer for laser-induced fluorescence, and the photophysical properties of the fluorophore acriflavine - including steady state emission and time-resolved fluorescence lifetime - are characterized in the gas phase to learn more about its intrinsic photophysics in the absence of solvent interactions. The steady state emission spectrum of gaseous acriflavine displays two peaks, which I attribute to emission from two excited electronic states, showing that Kasha’s Rule does not always hold for warm gaseous molecular ions. The effects of excitation wavelength and internalenergy on the measured emission spectrum are investigated to further understand the flow of energy in the excited state of the acridine scaffold. This work provides experimental data that can be used to improve our models and understanding of excited states, and energy flow among these states.

Keywords: Acriflavine
Excited State
Gaseous Ions
Laser Induced Fluorescence
Mass Spectrometry
Photophysics
Advisor: Jockusch, Rebecca
Effects of Antenatal Glucocorticoids on MiRNA Levels in the Prefrontal Cortex of the Newborn Guinea Pig

Antenatal corticosteroid (ACS) treatment in cases of preterm birth (<37 weeks of gestation) significantly decreases neonatal morbidity and mortality, as it replaces an important endogenous surge in glucocorticoids that occurs in late gestation. While there are minimal short-term risks of ACS treatment, studies have demonstrated long term behavioural and structural impacts of ACS treatment on adult offspring. The underlying mechanisms of these effects are still unclear. One potential explanation is modulation by epigenetic mechanisms, including miRNA. This project seeks to identify differences in miRNA expression patterns in the medial prefrontal cortex of postnatal day 1 female guinea pig offspring that had been exposed to a single course of ACS treatment. A miRNA microarray showed no significant differences between control and treated animals. This is an important finding as it helps us understand the role epigenetic factors play at different time points of development in the modulation of the programming effects of ACS treatment.

Keywords: developmental epigenetics
fetal programming
glucocorticoids
miRNA
prefrontal cortex
pregnancy
Advisor: Matthews, Stephen G
Self-Reported Medical Cannabis Use and Inflammatory Cytokines and Chemokines in Chronic Pain Patients

This dissertation investigated the association between medical cannabis (MC) use and inflammatory immune markers among chronic pain (CP) patients. Validated questionnaires, self-reported effectiveness of MC, and patient blood samples were collected. Fifty-six patients (64% females) were included with dried cannabis (53%) and THC-dominant products (70%) most commonly consumed. Majority of patients (83- 96%) self-reported symptom relief and and 76% reported a significant decrease in analgesic medication usage (p = <0.001). Compared to males, females had lower concentrations of some pro-inflammatory cytokines, cortisol, and significantly lower eotaxin levels (p=0.04). The regression analysis indicated that female sex was associated with decreased eotaxin (p = <0.01) concentrations. Blood CBD levels were associated with lower VEGF (p=0.04) concentrations and THC-COOH was a factor related to decreased TNF-α (p=0.02) and IL-12p70 (p=0.03). These findings suggest cannabis improves CP symptoms, reduces analgesic consumption, and has a potential immunomodulatory effect associated with patient sex and product type.

Keywords: cannabinoids
chronic pain
cytokines
immune system
inflammation
medical cannabis
Advisor: Clarke, Hance
Stream Fragmentation Affects Movement in a Wetland-specialist fish, Grass Pickerel, Esox americanus vermiculatus

Animal movement is a fundamental process for organisms to maximize their fitness, yet it is often challenged by human activities and climate change. For species listed under the Species at Risk Act, like Grass Pickerel (Esox americanus vermiculatus)—a wetland specialist—, understanding their movement ecology can inform conservation strategies. To determine their movement ecology, passive integrated transponder (PIT) tag data for Grass Pickerel in a Niagara Peninsula watershed gathered by Fisheries and Oceans Canada from 2009 to 2013 were analyzed. Of the 2,007 tagged fish, only 16% made movements more than 500m, with a median and maximum movement distance of 1.89 km and 13.5 km respectively. Movements mostly originated from locations with high local abundance, and mobile fish were longer than stationary fish. Hence, while a long-distance dispersal ability exists in extant Grass Pickerel populations, the conditions of riverscapes in southern Ontario may prevent these dispersals from occurring.

Keywords: dispersal
fish movement
population ecology
stream ecology
wetlands
Advisor: Fortin, Marie-Josée
Mandrak, Nicholas E
Investigating the Interactions Between G Proteins and Estrogen Loss in the Mouse Skeletal System

Postmenopausal osteoporosis is the most common bone disease, as estrogen deficiency is directly related to reductions in trabecular and cortical bone. In addition to sex steroids, G proteins play important roles in bone development and maintenance. We have previously developed two transgenic mouse models that have high levels of Gαs (Gs-Tg) or Gα11 (G11-Tg) in osteoblasts. Gs-Tg mice had increased bone, whereas G11-Tg mice had osteopenia. To investigate how variations in G protein signaling in osteoblasts impact postmenopausal bone health, we ovariectomized (ovx) Gs-Tg and G11-Tg mice at 4 months of age and examined their skeletal phenotypes 5 weeks post-surgery. The high bone turnover in Gs-Tg mice made them more susceptible to bone loss with ovx. Conversely, G11-Tg mice were protected from ovx-induced bone loss. This offers new insight into predicting postmenopausal bone health in individuals with high G protein levels, in addition to potentially elucidating therapeutic targets.

Keywords: Bone
G proteins
Osteoporosis
Postmenopause
Advisor: Mitchell, Jane
Grynpas, Marc
Assessing the Performance of Passive House Multi-Unit Residential Buildings: An In-Situ Performance Verification and Comparison of Simulation Tools

In-situ performance verification of enclosure thermal performance and air tightness was conducted on a newly built Passive House (PH) multi-unit residential building (MURB) and a MURB retrofitted to the EnerPHit standard. Wall thermal performance ranged from 60% less to 33% more than the design R-value and window center-of-glass U-values were 20% more than design, both determined using ISO 9869. The air leakage was up to 75% less than the PH requirement of 0.6 ACH50 for new build and 1.0 ACH50 for retrofit. Overall, the enclosure performance was consistent with prior studies, however, exterior temperature estimates likely resulted in inaccuracies of the measured R- and U-values. Building energy simulation tools Passive House Planning Package (PHPP) and CAN-QUEST (CQ) were compared to assess the interchangeability of tools for compliance purposes, using the new PH MURB as a case study. The CQ model had 20% less cooling and 20% more heating energy use and 76% and 40% less heat gains and losses, respectively, than the PHPP Model. Due to these differences in energy use and loads, it is unclear whether the tools are interchangeable for compliance purposes.

Advisor: Touchie, Marianne
Study of 48-to-1 V Multi-inductor Hybrid Converters

The 48 V DC bus is an intermediate power bus in all telecommunication systems. The traditional approach is to employ cascaded converters to step-down the supply voltage from 48 V to 5/12 V, and 5/12 V to 1 V at the point of load. This usually results in inefficient power conversion. To achieve high efficiency, this thesis is aimed to determine the best multi-inductor hybrid converter (MIHC) configuration, for a direct 48-to-1 V conversion, 90 A, 200 kHz application. The simulated 6-to-1 level is found to be the best topology. The gate drive loss and inductor conduction loss outweigh the benefits of the 8-to-1 level configuration. The 6-to-1 level MIHC is also verified experimentally to outperform the 2-to-1 topology in 48-to-1 V conversion with a peak efficiency of 90 % at 5 A, and 65% at 25 A. The 6-to-1 MIHC topology provides a good trade-off between circuit complexity and power conversion efficiency.

Keywords: 48-to-1 V DC-DC converter
Multi-inductor Hybrid Converter
Advisor: Ng, Wai Tung
Real-Time Motion Compensation of Magnetic Resonance Thermometry and Adaptive Targeting Algorithms for Focused Ultrasound Controlled Hyperthermia in Sarcomas

Sarcomas are the most common extracranial solid tumours in children and have poor prognoses due to resistance to conventional treatments. Magnetic resonance-guided high-intensity focused ultrasound (HIFU) can non-invasively administer localized hyperthermia which can improve the efficacy of chemotherapy, radiation, and immunotherapy in various cancers. One of the challenges preventing the widespread clinical adoption of MRgHIFU is that thermometry is prone to motion artifacts that corrupt data. The objective of this work is to optimize MRgHIFU-controlled hyperthermia by implementing motion compensation and adaptive tumour targeting algorithms. During targeted drug delivery in a murine sarcoma model, motion artifacts resulted in underheating of the tumour, leading to less drug being released. In preparation for translation, a motion compensation algorithm demonstrated powerful artifact removal during robot-controlled motion in a phantom on a clinical MRgHIFU system. An adaptive targeting algorithm was implemented to correct a mistargeted HIFU focus with high accuracy and precision in gelatin phantoms.

Keywords: High Intensity Focused Ultrasound
Hyperthermia
Magnetic Resonance Thermometry
Motion Compensation
Sarcomas
Thermosensitive Drug Delivery
Advisor: Drake, James M
Waspe, Adam C
Designing Epitope-specific CDR-H3 Loops via Deep Learning

Antibodies are great therapeutic candidates because of their ability to recognize and bind disease-related antigens with high specificity and affinity. Such binding is driven by the interaction between a subset of residues in the antigen, which collectively form the epitope, and loops within the antibody that are known as complementarity-determining regions (CDRs). One CDR loop in particular, the CDR-H3 loop, has a high degree of sequence and structural diversity, allowing such binding to be diverse and specific. Currently, approaches for the design of CDR-H3 loops are not antigen-specific. Here, I developed a pipeline to design backbones and sidechains for CDR-H3 loops that target specific epitopes. To determine the Cα position of the backbone, a Generative adversarial network (GAN) was trained to predict a Cα distance matrix defining the structure of the loop and its relative position to antigen residues. The resulting distance matrices show a high degree of similarity to the ground truth matrices (median 1.2Å difference). Using these generated matrices, the 3D positions of all Cα atoms were recovered. The full backbone and sidechains were subsequently reconstructed using existing physics-based methods such as Rosetta, yielding antibodies that were predicted to bind to the specified epitopes. This novel method has the potential to surpass or supplement current antibody development methods and can have numerous applications in biomedical sciences.

Keywords: Antibody
CDR-h3
deep learning
GAN
Advisor: Kim, Philip PK
Local Metabolism of Progesterone Regulates Cervical Remodelling and Timing of Labour Onset

Withdrawal of pro-gestational hormone progesterone (P4) is necessary for labour onset in human and rodents. In murine cervix P4 withdrawal is mediated by enzymes 5-alpha-reductase (Srd5a1) and 20-alpha-hydroxysteroid-dehydrogenase (20αHSD/Akr1c18). I hypothesize that 1) inflammation (physiologic or infection-induced) alters the levels of both enzymes in mouse cervix, impacting local P4-metabolism; 2) Selective Progesterone Receptor Modulator (SPRM), Promegestone (aka R5020), non-metabolizable by 20αHSD, can prevent preterm labour (PTL) in mice by maintaining P4 signaling. I found significant induction (p<0.01) of Srd5a1 and Akr1c18 mRNA and protein levels during infectious (Lipopolysaccharide (LPS)-induced) PTL in mice which was inhibited by prophylactic R5020 administration. Transcript levels of cervical ripening enzymes Adamts1 and Has2, as well as pro-inflammatory markers Il1b, Il6, Cxcl1, and Ccl2 were induced during PTL (p<0.05) and inhibited with R5020 pre-treatment (p<0.05). I concluded that prophylactic R5020 administration prevents LPS-induced inflammation and cervical ripening in mice, thus presenting a promising novel therapeutic for women at risk of preterm birth.

Keywords: Cervical Ripening
Inflammation
Labour
Preterm Birth
Progesterone
Promegestone
Advisor: Shynlova, Oksana
Lye, Stephen
Development of a CRISPR Screen to Identify Molecular Regulators of Photoreceptor Intercellular Material Transfer

A widely investigated therapeutic strategy for retinal degeneration is transplantation to restore photoreceptor function. Recent studies suggest that vision rescue from photoreceptor transplantation is due to material transfer (MT) of cytoplasmic proteins from donor to host photoreceptors. However, the mechanisms of MT are largely unknown. Our lab has established an in vitro co-culture assay to track cell contact-dependent mitochondria transfer. Using this system, we designed and investigated a genomic CRISPR/Cas9 screening strategy for an unbiased, large-scale investigation of genes regulating MT in acceptor photoreceptors. We generated retinal explant derived CRISPR/Cas9 edited photoreceptors with the capacity to efficiently accept mitochondria in the co-culture assay. We optimized culture components to increase the feasibility of this challenging primary cell-based strategy. Our findings have advanced the development of an approach for discovery of mechanisms underlying photoreceptor MT. Further understanding of MT regulators can lead to therapeutic applications of MT for treatment of retinal diseases.

Keywords: cell communication
CRISPR
material transfer
photoreceptors
primary cells
retina
Advisor: Wallace, Valerie A
Psychometric Evaluation of the Patient Reported Outcomes of Fracture Healing Questionnaires for Children with Upper Extremity Fractures (PROOF-UE)

Objective: To evaluate the psychometric properties of a new patient reported outcome measure, the Patient Reported Outcomes of Fracture Healing questionnaires for children with upper extremity fractures (PROOF-UE).Method: Children with upper extremity fractures and their parents completed the child and parent versions of PROOF-UE questionnaires up to 4 time points during fracture healing until full recovery: early healing, intermediate healing, fully healed, and 1-2 weeks after fully healed. Test-retest reliability, internal consistency, construct validity (known-groups and convergent validity), and responsiveness were evaluated. Results: The PROOF-UE showed acceptable test-retest reliability (ICC2,1: 0.54-0.84; ICC2,1: 0.66-0.98) and internal consistency (Cronbach Alpha: 0.76-0.90; 0.83-0.88) for parent and child versions, respectively. Fractures associated with neurologic or vascular injury or other complications scored significantly less than fractures with no complications. The PROOF-UE total and domain scores correlated as hypothesized with the QuickDASH and corresponding domain scores of the PODCI. The PROOF-UE was also found to be responsive to change (SRM: 0.32-1.4; 0.55-1.40 for parents and children’s questionnaires, respectively). Conclusion: The PROOF-UE is a promising outcome measure to evaluate children’s upper extremity fractures treatments.

Keywords: Children's Fracture
Outcome Research
Patient priorities
Patient Reported Outcome Measure (PROM)
Psychometrics
Upper Extremity Fractures
Advisor: Narayanan, Unni G
Neurodevelopmental and Protein Analysis in the Maternal Immune Activation Mouse Model of Neurodevelopmental Disorders

Neurodevelopmental disorders are a class of psychological disorders which alter brain development and function. The cause of these disorders is believed to include a variety of factors including genetics, environmental contaminants and issues related to pregnancy including maternal immune activation (MIA). To study MIA and its implications in neurodevelopmental disorders, we decided to inject an immunostimulant called polyinosinic: polycytidylic acid (POLY IC) into pregnant mice (CD-1) to illicit an immune response. We examined the phenotypical and molecular outcomes of the MIA offspring throughout different developmental periods. We found a decrease in global prepulse inhibition in adult MIA mice at twelve weeks of age. MIA also resulted in differences of protein expression related to microglial activity, the complement system, post synaptic densities and metabolism.

Advisor: Liu, Fang
The Outcomes of Endodontically Treated Teeth Restored with Custom-made Cast Post-and-core Restorations: A Retrospective Cohort Study

Introduction: Custom-made cast post-and-core (CMCPC) restorations have long been used to restore structurally deficient endodontically treated teeth (ETT). However, the evidence regarding their impact on the outcomes of ETT is largely inconclusive. This study evaluated the long-term treatment outcome of ETT restored with CMCPC. Methods: This retrospective cohort study examined the dental records of patients with CMCPC placed at a specialty private practice in Toronto, Canada, between 1999 and 2021. The proportion of ETT with complete periapical healing and those that survived were estimated, and prognostic factors were investigated using multiple logistic and Cox regression analyses, respectively (P<.05). Results: A total of 500 and 1000 teeth met periapical healing and survival criteria, respectively. The periapical healing rate was 88.8% and was associated with the presence of baseline periapical radiolucency [OR=0.1, 95% Confidence Intervals (CI):0.05–0.2; P<.001]. The survival, after a mean follow-up time of 68.9±54.07 months (range:0.5–251.9), was 87.9% and was associated with <75% of root length in bone [Hazard Ratio (HR) =2.6; 95%CI:1.0–6.6; P=.033], type and quality of final restoration [HR=2.09; 95%CI:1.1–3.9; P=.020; HR=2.3; 95%CI:1.2–4.5; P=.008, respectively], and the presence of periapical radiolucency at the latest recall (HR=3.2; 95%CI:1.7–6.3; P<.001). Conclusions: The outcome of ETT restored with CMCPC was assessed to be very good. CMCPC may be regarded as a viable restorative option for ETT with reduced coronal structure.

Keywords: Apical periodontitis
cohort study
post and core technique
root canal therapy
treatment outcome
Advisor: Azarpazhooh, Amir AA
Clinical Evaluation of Adults Undergoing Elective Surgery Utilizing Intraoperative Incisional Wound Irrigation: A Pilot Randomized Controlled Trial

Introduction: Surgical site infections (SSIs) occur in up to 20% of patients postoperatively. Intraoperative incisional wound irrigation may reduce SSIs; however, uncertainty remains in the type, volume, and method of irrigation to use. A feasibility study of irrigation with povidone-iodine versus saline versus no irrigation to reduce SSIs was conducted. Methods: Over six months, a multicentre 3-arm randomized controlled trial (RCT) was conducted to assess feasibility of: 1) accrual; 2) compliance with the intervention; 3) collection of patient-reported outcomes (PROs) for quality of life and SSIs; and 4) the rate of SSIs. Results: Overall, 32.3 (standard deviation 6.9) participants were accrued monthly across three sites. Of 177 procedures, 170 (96%) received the correct intervention. At postoperative day 30, 81.5% of PROs were completed and SSIs were reported by 20 (14.3 % (95% Confidence Interval (CI): 8.5% - 20.1%)) of participants. Conclusion: A definitive RCT is feasible to conduct with modifications.

Keywords: feasibility
randomized controlled trial
surgical site infection
wound irrigation
Advisor: Karanicolas, Paul J
Autonomous Vehicles: How they can Transform Perceived Travel Times and Toronto’s Transportation Network in the Process

Since almost the introduction of the automobile itself, people have long fantasized about the possibility of a self-driving car, allowing its passengers to read, sleep, or whatever else they wanted to do. Until recently, it was just that- a fantasy. However, recent developments suggest that Autonomous Vehicles (AVs) may soon become a reality, potentially bringing a massive shift in how we perceive travel times. This thesis examines how AVs might impact our perceptions of travel time and the kinds of activities that this time would be used for via a Stated Preference (SP) survey conducted in the Greater Toronto and Hamilton Area (GTHA). In addition, this thesis aims to better understand the factors that may influence AV adoption under different ownership structures. The results provide planners and engineers with an idea of the potential effects of AVs on travel demand and inform policy to help navigate this future.

Keywords: Autonomous Vehicles
Mode Choice
Perceived Travel Time
Toronto
Transportation Demand
Travel Behavior
Advisor: Habib, Khandker N