VictorJuiz/thesis huggingface dataset:
Sustained Regional Anesthesia for Post-operative Pain Management

Acute post-operative pain is inevitable, yet current treatment strategies do not provide sufficient pain relief. While local anesthetics are widely used to achieve a regional block, they are currently delivered as a bolus liquid injection and, thus, quickly clear the injection site. Subsequently, pain relief is short-lived, and quick distribution of the drug throughout the body leads to systemic side effects. Post-operative pain management can be improved by a local, controlled and sustained drug delivery system that increases the duration of local anesthetic efficacy while minimizing side effects. Herein, a hyaluronan-methylcellulose hydrogel (HAMC) was investigated as a drug delivery vehicle to locally deliver pain medication over an extended period. By distributing particulates of a local anesthetic within HAMC, the hydrogel serves as a local drug depot and prevents fast clearance of the drug. The anesthetic-loaded HAMC system was optimized in vitro and then evaluated in rat models of nerve block.

Keywords: Drug delivery
HAMC
Hydrogel
Local anesthetic
Pain
Sustained release
Advisor: Shoichet, Molly S
Dynamic Modeling of Occupant Response to Frontal/Rear/Lateral Vehicular Collisions

Cervical injury is one of the primary concerns in vehicle collisions. In this work, two multibody dynamics models of the cervical spine of a 50th percentile male were developed using biofidelic variable intervertebral rotational stiffnesses. Furthermore, finite element simulations of a seated and restrained occupant in frontal, rear, and lateral collisions between two passenger cars were performed to determine the kinematics and kinetics response of the occupant. The resultant accelerations of the T1 vertebra were applied to the multibody dynamics models to obtain their true kinematic response. The multibody dynamics models and finite element models were used to estimate the risks of cervical injuries. Ligament injury was most likely at the interspinous ligament in frontal collision, the anterior longitudinal ligament in rear collision, and the near-side capsular ligament in lateral collision. The highest vertebral fracture risks were found in rear and lateral injuries, in the mid- and lower cervical spine.

Keywords: Biomechanics
Cervical injury
Collision
Dynamics
Finite element
Whiplash
Advisor: Meguid, Shaker A
Astroglial Plasticity within the Rat Orofacial Primary Motor Cortex Induced by Endodontic Treatment versus Tooth Extraction

Objective: To optimise the CLARITY technique that renders brain tissue optically transparent, immunolabelling and light-sheet microscopy for 3D-characterisation of astroglial cytoarchitecture and morphology within the orofacial primary motor cortex of rats receiving endodontic versus tooth extraction treatment. Methods: Rats received either extraction, endodontic-, sham- or no-treatment of the right maxillary molar teeth. After one week, 2 mm-thick brain sections of the orofacial primary motor cortex were cleared and immunolabelled with astroglial markers. 3D-images were acquired with light-sheet microscope and Imaris software was used to characterise and quantify cytoarchitecture and morphological features of astroglial processes. Results: As compared with endodontic-, sham- and no-treatment, tooth extraction produced significantly thinner and straighter astroglial processes within layer-I of a laminar motor cortex. Conclusion/significance: Tooth extraction but not endodontic treatment induces astroglial plasticity within the rat primary motor cortex that controls orofacial motor functions. Astroglia may be a therapeutic target for preventing/curing postoperative motor impairments.

Keywords: CLARITY
Dental injury
Glia
Motor cortex
Neuroplasticity
Rats
Advisor: Avivi-Arber, Limor
Children's Comprehension of Implicit Messages to Interpret Ambiguous Requests

The current study explored young children’s ability to use past linguistic information to make pragmatic inferences in a referentially ambiguous situation. Eighty-three 2.5-year-old and 3- year-old children heard a speaker convey her preference for an absent object, using either negative (i.e., “I do not like ducks”) or affirmative (i.e., “I like ducks”) sentences. When two objects become perceptually present (i.e., duck and turtle), the speaker gave an ambiguous request (“Can you give one to me?”). Results showed that three-year-old children were successful in using the speaker’s past affirmative information to reason about which object she desired, however, inferencing abilities were hindered following negative sentences. Two and a half-year-old children did not succeed with neither affirmative nor negative sentences. This work provides important insight into how young children interpret implicit verbal messages to make inferences about another person’s communicative request.

Keywords: Absent Reference
Desire Reasoning
Language Development
Verbal Negation
Advisor: Ganea, Patricia A
Developing an Intelligent Robot Control Architecture for Autonomous Exploration in Urban Search and Rescue

The urban search and rescue (USAR) task is a very time sensitive operation which occurs in environments with high uncertainty. The task of a robot in USAR is to explore unknown and cluttered environments and identify any potential victims within the environments. In this thesis, an autonomous controller is presented which utilizes a hierarchical partially observable Markov Decision Process approach to model the environment uncertainty inside a robot’s decision-making scheme. Additionally, an intelligent exploration technique for USAR which utilizes deep reinforcement learning is proposed. The aim of these two techniques is to allow a robot to perform the full USAR task autonomously without the assistance of a human operator and to also follow an efficient exploration strategy which assists in the faster discovery of potential victims. Several experiments were conducted in USAR-like environments to validate the performance and robustness of each technique.

Keywords: autonomous robot exploration
deep reinforcement learning
partially observable Markov Decision Process
urban search and rescue
Advisor: Nejat, Goldie
Enzymatic Oxidation for Value-Added Applications of Hemicellulose Streams

Hemicellulose is a largely untapped resource generated as a by-product of forestry and agriculture industries amenable to enzymatic activation for value-added applications. Hemicellulose can be modified to prepare dialdehyde polyol cross-linkers as an alternative to toxic petroleum derived chemicals such as glyoxal which is commonly used for polyol film strengthening and hydrogel formation. A chemo-enzymatic pathway was developed to convert galactoglucomannan oligosaccharides into dialdehyde polyol cross-linkers using lactose as a model. Enzymatic oxidation using glucooligosaccharide oxidase introduced a reducing end acid with high conversion in 6.5 hours. Amidation using an ethylendiamine linker achieved a 37% yield of dilactobionamide in 4 hours. This configuration allowed oxidation of terminal galactose units using galactose oxidase yielding nearly complete conversion to a dialdehyde in 6 hours. Initial cross-linking of poly(vinyl alcohol) was attempted in DMSO with some promise. Activation by galactose oxidase also enabled increased reactivity of lactose toward diamines for thermoset resin applications.

Keywords: Biorefinery
Carbohydrate-Active Enzymes
Cross-linker
Hemicellulose
Lignocellulose
Thermoset resin
Advisor: Master, Emma R
Swallowing Misandry: A Survey of the Discursive Strategies of r/TheRedPill on Reddit

The Red Pill (r/theredpill) (TRP) subreddit lies at the heart of an interconnected network of misogynistic blogs and websites known as the manosphere. It disseminates radical anti-feminist and discriminatory content across Reddit and the broader internet. Acknowledging the community’s staggering size - with membership that numbers in the hundreds of thousands - this research fills a gap in standalone investigations into the toxic subreddit. Using mixed-methods critical discourse analysis (CDA), qualitative and quantitative research methods identify how misogynistic ideologies are constructed, consumed, and exchanged by RedPills on their virtual platform, Reddit. This study does not seek to define their discursive strategies as uniquely RedPill. Instead, it situates them in the context of a growing community based in gendered rage and the validation of violence. As result, it reveals the complex affordances Reddit provides, to create, engage, and disseminate RedPill discourses online.

Keywords: Anti-Feminism
Geek
Internet
Misogyny
Reddit
Trolling
Advisor: Keilty, Patrick
3R Ambassadors and the Governance of Recycling Practices in Toronto

The mainstreaming of environmental concern has projected environmental intervention and regulations into all aspects of contemporary everyday life. Yet everyday environmentalisms are often critiqued as ineffectual neoliberal instruments that depoliticise environmental action, and narrow the possibilities of systemic change. In this thesis, I explore the logics of everyday environmentalisms through recycling volunteers in Toronto. Volunteers demonstrated neoliberal tendencies in their narratives of social change, and through affective responsibilisation. But for the most part, volunteers drew meaning from place-based social ties and attachments. Furthermore, volunteers’ experience were often more than about the environment. In some cases, the recycling project was also bound up with multiple politics; for instance, over decision-making or resource allocation authority, the various ways one participated within a supposedly technocratic waste regime, and re-directing flows of discarded materials. Taken together, the case of Toronto’s 3R Ambassadors show that such mundane practices embody possibilities and potential for everyday environmental governance to circumvent dominant neoliberal logics.

Keywords: community building
everyday environmentalisms
neoliberalisms
recycling
volunteer
Advisor: Maclaren, Virginia W
THE EFFECTS OF PHONOLOGICAL SHORT-TERM MEMORY AND EXECUTIVE WORKING MEMORY ON READING COMPREHENSION IN ELEMENTARY STUDENTS: A LONGITUDINAL STUDY

This longitudinal study looked at the contributions of executive working memory (EWM) and phonological short-term memory (PSTM) to reading comprehension in ELL elementary students while controlling for English language proficiency. Participants were assessed once a year, in grades 4-6. Results revealed that EWM contributed to reading comprehension above and beyond PSTM across the three years. The mediating effect of English language proficiency on the association between EWM and reading comprehension was also studied. Results showed that the association between EWM and reading comprehension was partially mediated by English language proficiency in Year 1, and fully mediated in Years 2 and 3 respectively. Growth model analysis did not show a developmental trajectory in reading comprehension across the three years. To conclude, EWM had a unique contribution to reading comprehension, which was greater than PSTM. Language proficiency had a mediating effect on EWM’s contribution to reading comprehension.

Keywords: ELL students
English language proficiency
Executive working memory
Phonological short-term memory
Reading comprehension
Advisor: Geva, Esther
TARGETING THE MITOCHONDRIAL RNA POLYMERASE AS AN ANTICANCER STRATEGY IN ACUTE MYELOID LEUKEMIA

AML cells have unique mitochondrial characteristics such as increased mitochondrial mass, mitochondrial DNA content, a higher reliance on oxidative metabolism and lower spare reserve capacity compared to normal hematopoietic progenitors. This project focuses on a novel non- mutant therapeutic target, the mitochondrial RNA polymerase (POLRMT) which indirectly controls OXPHOS by transcribing 13 essential subunits of the mitochondrial electron transport chain. In my anticancer strategy, I leveraged the metabolic vulnerability of AML in order to preferentially inhibit POLRMT and mitochondrial function in AML with the tool molecule 4’- azidocytidine. In AML cells, 4’-AC reduced mitochondrial gene expression resulting in the depletion of mitochondrial-encoded ETC subunits, the functional impairment of oxidative phosphorylation, and a time- and dose-dependent decrease in cell number. Genome-wide consequences of 4'-AC treatment were assessed with RNA sequencing and in vivo anticancer conseqeunces of 4'-AC treatment were assessed in a mouse xenograft model.

Advisor: Laposa, Rebecca
Resolving the synovial fluid proteome and peptidome for disease-specific mediators of inflammatory arthritis

Early administration of therapeutic agents is a leading approach to impede the progressive destruction of articular joints plagued by inflammatory arthritis (IA). Unfortunately, diagnostic tools for the detection of IA during its pre-clinical stage are greatly lacking. Soluble biomarkers originating from sites of synovitis may reveal the molecular constituents of aberrant signalling pathways leading to the development of arthritis. Our objective was to facilitate the discovery of putative biomarkers of IA and its subtypes, rheumatoid arthritis (RA) and psoriatic arthritis (PsA), by mining for proteins and peptides secreted into the synovial fluid (SF). Using a label-free, mass spectrometry (MS)-based approach, 419 proteins and 288 peptides were identified in IA SF. When supplemented with bioinformatic analysis, 11 and 16 high-priority protein and peptide candidate biomarkers were identified, respectively. Investigations into the biological and molecular relevance of selected candidates has revealed possible pathogenic roles in IA and its specific subtypes.

Keywords: Mass spectrometry
Peptidomics
Proteomics
Psoriatic arthritis
Rheumatoid arthritis
Synovial Fluid
Advisor: Chandran, Vinod
Diamandis, Eleftherios P
Method for the Selection of High Quality Sperm via Two-dimensional Slither Swimming

Sperm locomotion is central to natural conception and assisted reproduction. Most sperm selection technologies rely on sperm motility in bulk fluid. In vivo, however, sperm tend to accumulate and transit near surfaces, often using a two-dimensional slither swimming mode, where the entire body of the sperm is confined within 1 μm of the surface. The most significant contribution of this thesis is the finding that a subpopulation of sperm capable of slither swimming possess enhanced DNA integrity compared to the motile and raw sperm populations. This result is found in both high-quality donor as well as low-quality patient semen samples. Selection of sperm based on their ability to swim in a slither mode was made possible in this work by the development of a microfluidic platform, which additionally offers a means to readily implement this sperm selection strategy in clinical workflow.

Keywords: fertility
intracytoplasmic sperm injection
in vitro fertilization
planar swimming sperm
slither swimming sperm
sperm selection
Advisor: Sinton, David
The Association of COG5 and SRD5A3 Gene Mutations to ER Stress Activation and their Role in Retinal Degeneration

Five individuals were diagnosed with Leber’s congenital amaurosis, an early-onset inherited vision disorder. Two unrelated individuals have a homozygous mutation in SRD5A3 (p.W19X). The remaining three are siblings that have compound heterozygous mutations in COG5 (p.M32R; p.S777Q_fs*14). Both SRD5A3 and COG5 play critical roles in glycosylation, which if disrupted could result in ER stress. Transfection of wild-type or mutant variants of SRD5A3 or COG5 in vitro found no link between SRD5A3 and ER stress. However, PERK was significantly upregulated in response to compound transfection of the mutant COG5 variants. Immunocytochemical staining revealed that the compound COG5 mutants lead to a significant increase in Golgi fragmentation and DNA damage. Treatment of the transfected cells with PERK inhibitor, GSK2606414, reduced DNA damage levels to that of the control. This study is the first to associate COG5 disruption with ER stress and has identified a potential therapeutic target for patients with COG5-related disorders.

Keywords: DNA Damage
Endoplasmic reticulum
Golgi
Leber congenital amaurosis
PERK
Unfolded protein response
Advisor: Monnier, Philippe
Héon, Elise
The Influence of the Hypogastric Nerve in the Bladder Inhibitory Reflex Induced by Saphenous Nerve Stimulation in Anesthetized Rats

Saphenous nerve (SAFN) stimulation has been shown to modulate bladder activity however, the reflex mechanism remains unknown. This study analyzed the influence of the hypogastric nerve (HGN) in the SAFN-bladder activation pathway. The SAFN was stimulated for 40-minutes (50 and 100 µA intensity) in 33 female rats during continuous cystometry. Animals were divided into four experimental groups: (1) HGN intact, saline, (2) HGN transected, saline, (3) HGN intact, acetic acid, and (4) HGN transected, acetic acid (HGNt-a). Stimulation in HGNt-a animals elicited significant changes in urodynamic activity and, in all groups, SAFN stimulation suppressed reflex bladder contractions (25-50% incidence rate). Results suggest that HGN efferent fibers are not critical in this inhibitory mechanism; rather, HGN afferent fibers provide an excitatory input that counters bladder inhibition during SAFN stimulation. From a clinical perspective, SAFN stimulation may be relevant for treating urinary symptoms associated with interstitial cystitis.

Keywords: Bladder
Hypogastric Nerve
Saphenous Nerve
Saphenous Stimulation
Advisor: Yoo, Paul B
Aprepitant for the Prevention of Acute Chemotherapy-Induced Nausea and Vomiting in Children: Overcoming Barriers

Aprepitant is an effective antiemetic for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) in children. This thesis presents an updated clinical practice guideline for the prevention of acute CINV that recommends children receiving highly emetogenic chemotherapy be given an antiemetic regimen that includes aprepitant. However, aprepitant-antineoplastic drug interactions and lack of a commercially available aprepitant oral liquid formulation limit its utility. A systematic review of aprepitant-drug interactions was undertaken to identify clinically significant interactions. Significant pharmacokinetic interactions were found between aprepitant and the following antineoplastic agents: bosutinib, cabazitaxel and cyclophosphamide. A crossover study was conducted in healthy adult volunteers to establish the relative bioavailability of an extemporaneous aprepitant oral suspension compared to the commercially available capsule. Relative bioavailability of the oral suspension was found to be 82.3%, demonstrating sufficient absorption of aprepitant to have an antiemetic effect. Overall, these projects have addressed barriers to aprepitant use in children.

Keywords: aprepitant
chemotherapy-induced nausea and vomiting
clinical practice guidelines
drug interactions
pharmacokinetics
Advisor: Dupuis, L. Lee
Laboratory Methods to Improve Quantification of Microplastic Ingestion by Marine Organisms Under Climate Change Stressors

Human impacts on the environment pose serious threats to the planet’s oceans. This thesis presents methods to quantify microplastic ingestion by marine organisms under ocean warming and acidification. First, a study utilizing a novel high-throughput screening device with CO2 concentration and temperature gradients was completed to quantify microplastic ingestion by copepod, Tisbe biminiensis, under multiple temperature and CO2 levels. Due to limitations in the methods of that study, three additional methods were developed: (i) a low-cost customizable climate-change incubator capable of regulating temperature and CO2 for larger volumes and longer exposures; (ii) a fluorescent microplastic dyeing method enabling tracking of different microplastic types and shapes in exposure studies; and (iii) a digestible fluorescent microplastic coating method enabling enumeration of microplastic ingestion. The methods developed here enable screening impacts of multiple stressors, and improve realism in microplastic experiments, to properly depict future ocean conditions and their subsequent effects on marine life.

Keywords: Climate Change
Microplastic Pollution
Multiple Stressors
Ocean Acidification
Ocean Warming
Advisor: Sinton, David
Exploring Approaches to Enhance the Anti-Leukemic Function of Double Negative T Cell Therapy

Chemotherapy resistance in acute myeloid leukemia (AML) is a prevalent problem that contributes to disease relapse and patient death; hence, novel therapies are needed to improve patient outcomes. Our lab has shown that allogeneic double negative T cells (DNTs) target the majority, but not the entirety, of primary AML blasts in vitro and in patient-derived xenograft models. Given the differences in the modes of action of DNTs and chemotherapy, we sought to determine if DNT therapy can be combined with conventional chemotherapy to target chemotherapy-resistant disease. To this end, we employed a xenograft model and in vitro assays. To further understand AML resistance or susceptibility to DNTs, we conducted a CRISPR screen to discover genes that may influence DNT-mediated cytotoxicity of AML. Overall, our results demonstrate the enhanced efficacy of DNT therapy following conventional chemotherapy and also shed light on mechanisms involved in the interactions between DNTs and AML.

Keywords: acute myeloid leukemia
adoptive cellular therapy
cancer immunotherapy
chemotherapy
CRISPR screen
Advisor: Zhang, Li
A Descriptive Analysis of Older Adults Who Initiated Denosumab in Ontario, 2012/02 – 2015/03

Denosumab was added to the Ontario Drug Benefit formulary for patients at high risk of osteoporotic fractures in 2012/02. We described patients who initiated denosumab from 2012/02-2015/03, stratified by community and long-term care (LTC) residence. We identified 46,797 patients (97% female; 13% LTC), averaging 1,263±187.1 new patients monthly. Patient characteristics remained relatively stable, yet one-fifth had no prior osteoporosis drug use, which increased over time. Community-dwelling patients had a higher prevalence of bone mineral density testing, yet were younger, and had a lower prevalence of hospitalizations and hip fractures, compared to LTC patients. Patients received an average of four denosumab doses and persisted for 1.7±1.1 years: 75.2% ≥1 year, 59.8% ≥2 years, and 49.2% ≥3 years. Of those who stopped, 58.4% returned ≤4 years. New exposure to denosumab is increasing steadily in Ontario, yet further research examining how patient characteristics impact the safety and effectiveness of denosumab is warranted.

Keywords: denosumab
osteoporosis
pharmacoepidemiology
rheumatology
Advisor: Cadarette, Suzanne M
Regulation of SH3PX1 by dNedd4-long at the Drosophila melanogaster neuromuscular junction

Drosophila Nedd4 (dNedd4) is a HECT E3 ubiquitin ligase present in two isoforms: short (dNedd4S) and long (dNedd4Lo), with the latter containing two unique regions (N-terminus and Middle). While dNedd4S promotes neuromuscular synaptogenesis (NMS), dNedd4Lo inhibits it and impairs larval locomotion. To explain how dNedd4Lo inhibits NMS, mass spectrometry was performed to search for binding partners and identified SH3PX1, which binds dNedd4Lo unique Middle region. SH3PX1 contains SH3, PX and BAR domains, and regulates active zone ultrastructure and presynaptic neurotransmitter release at NMJs. Here, I demonstrate direct binding of SH3PX1 to the dNedd4Lo Middle region via the SH3PX1-SH3 domain. Overexpression of dNedd4Lo in the muscle, but not presynaptic terminals, reduces levels of SH3PX1 at the SSR. While dNedd4Lo does not genetically interact with SH3PX1 to regulate larval locomotion, larvae that overexpress dNedd4Lo and are heterozygous for SH3PX1 display increased neurotransmission compared to dNedd4Lo or SH3PX1 mutant larvae alone.

Keywords: sorting nexin
synaptogenesis
ubiquitin ligase
Advisor: Rotin, Daniela