VictorJuiz/thesis huggingface dataset:
Investigation of Dilation and Constriction Features of a Hypercapnic BOLD-fMRI Cerebrovascular Reactivity Challenge

A cerebrovascular reactivity (CVR) challenge provides the means of assessing response to a hypercapnia challenge and is used to study cerebrovascular dysfunction. This thesis uses blood oxygenated level dependent imaging during CVR to investigate individual vascular responses. We hypothesize that 1) regional vasodilation responses can be estimated using a model-free non-parametric method, 2) vasoreactivity will differ by brain region, and 3) sequential CVR estimates will be correlated. A CVR challenge was conducted in three cohorts: individuals that are pilots by occupation, patients with sleep apnea, and patients with small vessel disease. CVR was assessed in subcortical grey and white matter, and different arterial territories. Our results indicate that vasoreactivity differs by tissue type and arterial territory. We also show an association between successive CVR challenges. This work shows that distinct features of a CVR challenge can be isolated to provide additional CVR metrics to better utilize CVR in clinical and research settings.

Keywords: BOLD-fMRI
Cerebrovascular Reactivity
Physiology
Advisor: MacIntosh, Bradley J
Cardiovascular Physiology in Individuals with Obesity

Obesity is an increasingly prevalent risk factor for cardiovascular diseases including heart failure with preserved ejection fraction (HFpEF) however the hemodynamic phenotype associated with the spectrum of obesity, independent of cardiovascular disease is not fully characterized. We evaluated associations between body mass index (BMI) and cardiopulmonary hemodynamics among subjects with noncardiac dyspnea who underwent RHC during rest and exercise. We report a trend to increased pulmonary artery wedge pressures at rest and during exercise in subjects with a BMI between 30-40 kg/m2. Physiologic alterations including a depressed mixed venous oxygen saturation and an elevated arteriovenous oxygen content difference at rest were observed across studies in subjects with a BMI between 30-40 kg/m2. Together, this information suggests that obesity alone may be associated with impaired cardiac diastolic function. Both studies support the notion that obesity is associated with a hemodynamic phenotype that may predispose to HFpEF development.

Keywords: Cardiac Catheterization
Exercise
Heart Function
Hemodynamics
Obesity
Advisor: Mak, Susanna
Examination of the Pathophysiology and Functional Impact of Decompressive Surgery in a Preclinical Model of Severe Degenerative Cervical Myelopathy

Degenerative Cervical Myelopathy (DCM) is the commonest cause of spinal cord impairment worldwide and is caused by arthritically-related compression of the cervical spinal cord. Decompressive surgery (DEC) is recommended for patients with moderate and severe neurological impairment. Despite the effectiveness of this intervention, a subpopulation of severe DCM cases continue to harbor residual neurological complaints. Based on proof-of-concept work in our laboratory, I examined the hypothesis that DEC following severe DCM results in Ischemia-Reperfusion Injury (IRI) which could attenuate neurological recovery. I investigated the transcriptomic profile of IRI by undertaking quantitative meta-analyses of published studies. Furthermore, I characterized the effects of DEC in a mouse model of severe DCM using functional, histological and molecular readouts. We demonstrated DEC, like IRI, elicited increased astrocytic reactivity, neuronal death, blood-spinal-cord barrier disruption, and synaptic changes. This suggests that IRI may play a role in DEC-associated complications that can be therapeutically targeted in DCM.

Advisor: Fehlings, Michael G
Structure of the SMURF2HECT Domain with a High Affinity Ubiquitin Variant

Therapeutic targeting of the ubiquitin (Ub) proteasome system (UPS) is currently of significant interest. The HECT domain of E3 ligases is one family of UPS enzymes that have yet to be successfully targeted, which have prominent roles in human disease including the closely related SMURF1 and SMURF2. Recent work has resulted in the engineering of a protein-based ubiquitin variant (UbV S2.4) that specifically bound and inhibited SMURF2 but not SMURF1. Here, to better understand the molecular basis of this specificity, the SMURF2HECT-S2.4 complex was solved to 2.5 Å. Structural analysis revealed several critical UbV residues responsible for SMURF2HECT binding. Additional structural modeling revealed two important residues on the binding surface of SMURF2HECT that are different from SMURF1HECT, which provide an explanation for the specificity of UbV S2.4. Taken together, these results underscore the utility of UbVs in probing structure-function relationships of UPS enzymes, which will facilitate the development of therapeutics.

Keywords: NEDD4
Protein Engineering
Protein Purification
SMURF
UbV
X-ray Crystallography
Advisor: Sidhu, Sachdev SS
Uncovering the Interactome of a Metabolism Proteome Signature in Lung Cancer

Lung cancer has the highest mortality rate of all cancers, and yet there has been limited progress towards new therapies from widespread DNA and RNA sequencing of lung tumours. Many patients lack the currently targeted driver mutations. The proteome manifests disease phenotype, so its characterization using interactome analysis may lead to identification of new actionable therapeutic targets. Proteome profiling of lung tumours identified C10, a signature comprising seven metabolism proteins that were highly correlated and upregulated in expression relative to normal lung. C10 behaves as a driver of cancer with prognostic impact, but the way in which the C10 proteins functionally interact is unknown. To investigate the function of C10, protein-protein interactions of C10 interactome proteins were analyzed using two complementary mass spectrometry-based methods. Four interactions with C10 were recapitulated and C10 was shown to be linked to serine metabolism and calcium homeostasis through an interaction at mitochondria-associated membranes.

Keywords: AP-MS
BioID
Interactome
Lung Cancer
Metabolism
Proteomics
Advisor: Moran, Michael F
Association of Frailty with Clinical Outcomes in Myeloproliferative Neoplasms: A Population-based Study from Ontario, Canada

Impact of frailty on clinical outcomes in myeloproliferative neoplasms (MPN) is unknown. In a retrospective, population-based study, we measured association of frailty with all-cause mortality and thrombosis in MPN patients identified from Ontario Cancer Registry between 2004 to 2019 (Total=10,336: essential thrombocythemia=5,108; polycythemia vera, n=3,843; myelofibrosis, n=1,385). Baseline frailty measured using the Johns Hopkins Adjusted Clinical Groups® frailty indicator or the McIsaac’s cumulative deficit frailty index (mFI) was independently associated with increased risk of mortality after adjusting for age, sex, and comorbidities in multivariable Cox proportional hazard model in MPN. Using mFI, compared to fit patients, the HRs for all-cause mortality for prefrail and frail patients were: 1.6 (1.3-1.9), and 3.6 (2.9-4.4) in ET; 1.3 (1.1-1.5) and 2.7 (2.1-3.4) in PV, and 1.2 (1.0-1.5) and 2.0 (1.5-2.7) in MF. In multivariable Fine-Gray regression, frailty was associated with increased risk of thrombosis in MPN.

Keywords: Frailty
Myeloproliferative
Advisor: Alibhai, Shabbir
Gupta, Vikas
Magnetic Locking Mechanism to Enable Multiple Curvatures in a Tendon-driven Continuum Robot

Tendon-driven continuum robots have potential for surgical applications, but as each robot segment bends only with constant curvature, multiple segments are needed to achieve the dexterity required to follow surgical paths. When adding robot segments, additional on-board actuating tendons are required, enlarging the device’s diameter and rendering it unsuitable for surgery. In this work, a magnetically-actuated locking mechanism on board a tendon-driven continuum robot was developed to enable multiple curvatures in a single robot segment, thus reducing the number of segments necessary to achieve complex robot shapes and reducing the number of actuating tendons required. It is shown that one locking mechanism can be used to achieve two curvatures in a single robot segment and that two locking mechanisms can be independently actuated, demonstrating the potential to achieve three curvatures in a robot segment. This work may facilitate future miniaturization of tendon-driven continuum robots, enabling their use in surgical applications.

Keywords: Continuum robot
Magnetic actuation
Magnetic locking mechanism
Medical robotics
Advisor: Diller, Eric
Mechanism and Microtubule Requirements of Macrophage-derived Giant Cell Formation

Macrophages are effector cells of the innate immune system that are important for the phagocytosis of foreign organisms. Under certain circumstances, macrophages can fuse into multinucleated giant cells (MGCs). My MSc work investigated the formation of MGCs and the role of microtubules in this process. We used the mouse macrophage RAW 264.7 cell line to establish an in vitro system to compare the formation mechanics between osteoclasts and LPS-induced giant cells. Live cell imaging revealed that osteoclasts formed by cell fusion events, whereas LPS-induced giant cells arose from incomplete cytokinesis. To investigate a role for microtubules in the multinucleation process, osteoclasts and LPS-induced giant cells were treated with the microtubule depolymerizing drug nocodazole during their formation. Interestingly, we detected increased acetylated (stabilized) microtubules in LPS-induced giant cells, compared to osteoclasts. Thus, incomplete cytokinesis observed during LPS-induced giant cell formation may be due to enhanced microtubule stabilization inducing more cell division events.

Advisor: Harrison, Rene E.
Predictors of Early and Long-term Readmission of Patients following Liver Transplantation

Background and objectives: Chronic liver disease (CLD) is on the rise, and accounts for over 2 million deaths annually. Liver transplantation (LT) is the most effective treatment for CLD but has been strongly associated with hospital readmissions and mortality outcomes. While most research focuses on predictors and reasons for readmission within the first 3 months post-LT, very few studies examine long-term readmission outcomes. The objectives of this study are: (1) to compare predictors of early (<30 day), mid-term (30-90 day), and long-term (>90 day) readmissions post-LT, (2) to assess the effects of initial readmission on survival post-LT, (3) to describe reasons for readmission post-LT within the early, mid-term, and long-term period. Methods: This is a retrospective observational study, investigating adult patients older than 18 years who underwent LT between January 1, 2010 – December 31, 2019 at Toronto General Hospital (TGH). The exclusion criteria include patients who died before LT discharge, and patients living outside of the Greater Toronto Area (GTA) at time of LT. Results: 987 patients fulfilled the inclusion criteria. Of those patients, 467 (47.3%) were readmitted at least once, with the median time from transplant discharge to initial readmission being 86 days (IQR 15-279). Of the total cohort, patients readmitted at 30 days, 90 days, and 5 years were 18.5%, 25.3%, and 55.1% respectively. Significant predictors of readmission were BMI > 30kg/m2 (HR=0.64, 95% CI= 0.42-0.98), and autoimmune/cholestatic CLD (HR=1.86, 95% CI= 1.01-3.42) at 30 days, post-LT length of stay (LOS) (HR=1.05, 95% CI= 1.02-1.08), and driving distance (HR=1.07, 95% CI= 1.01-1.14) at 30-90 days, and living donor LT (HR=1.41, 95% CI=1.06-1.89), and driving distance (HR=1.05, 95% CI=1.01-1.09) after 90 days. Readmission was significantly associated with mortality (HR=2.4, 95% CI=1.6-3.6). The main reason for readmission within the early, mid-term, and long-term period was infection, with the incidence of surgical complications (namely incisional hernias) increasing in the long-term period. Conclusion: This large single-centre study provided more information on the short-term as well as long-term predictors of readmission post-LT in a Canadian cohort. Adding to the pre-existing literature, the findings of this study show an association between readmission and mortality. Understanding the predictors of as well as reasons for readmission at specific time intervals may allow healthcare practitioners to mitigate the mortality seen post-LT.

Keywords: Hepatology
Liver Transplantation
Mortality
Readmission
Advisor: Janssen, Harry
Hansen, Bettina
Identification of Specific Clinical Risk Factors Associated with the Malignant Transformation of Oral Epithelial Dysplasia

Background: Factors that increase the risk of malignant transformation of oral epithelial dysplasia (OED) are not completely elucidated. Methods: A retrospective chart review was performed assessing risk factors for transformation, and cancer staging for transformed cases at Sunnybrook Health Sciences Centre in Toronto, Canada. Results: Two hundred-four patients were diagnosed with OED, and 16.7% underwent malignant transformation. Risk factors associated with transformation included: heavy tobacco smoking, excessive EtOH consumption, non-homogenous leukoplakia, size > 200 mm2, moderate or greater than moderate dysplasia, progression of dysplasia grades, and immunosuppression. Transformed cases followed for a dysplastic lesion were associated with a stage I cancer diagnosis, and cancer cases with no prior biopsy were associated with a stage IV diagnosis. Conclusions: In addition to commonly cited risk factors, immunosuppression was associated with malignant transformation, including the use of topical steroids. Analyzing risk factors can help clinicians define risk of progression in patients with OED.

Keywords: Dysplasia
Oral Cancer
Pre-cancer
Advisor: Magalhaes, Marco
The Correlation between Flowering Time and Herbivory Tolerance Depending on the Timing of Attack and Competition Intensity during Recovery

Herbivory tolerance is thought to be genetically correlated with flowering time in annual plant Brassica rapa. When damage occurred, plants with late-flowering genotypes would have more time to recover before reproduction, hence be tolerant to damage. In addition, tolerance is under the influence of factors like the timing of the attack and the competition intensity during recovery. In chapter 1, I found out that late-flowering B. rapa tolerated damage better than the early-flowering ones, and tolerance was higher when the damage occurred early. In chapter 2, I mimicked different levels of post-damage competition intensity by creating different neighborhood damage levels. The results showed that when the competition was relaxed or extremely intense, the early- and late-flowering B. rapa achieved similar levels of tolerance. However, when the competition was moderate, the early-flowering ones had higher fitness after

Keywords: flowering phenology
herbivory tolerance
plant ecology
Advisor: Weis, Arthur E
Left Ventricular Diastolic Function in Middle-aged Endurance Athletes: Considering the Effects of Training Volume, Exercise Modality and Sex

While middle-aged individuals are the largest and fastest growing cohort of endurance sport, the impact of chronic, intensive endurance training on resting left ventricular (LV) diastolic remodeling and the effect of exercise modality (running, cycling and triathlons) and sex is poorly understood. METHODS: Endurance (EA; n = 66, 67% male) and recreational (RA; n = 32, 59% male) athletes completed a detailed exercise history questionnaire, graded exercise to exhaustion on a treadmill and a resting transthoracic echocardiogram. RESULTS: EA displayed lower mitral A velocity, higher E/A ratios and faster time to peak strain rates compared to RA with negligible differences in diastolic function between exercise modalities. DISCUSSION: The observed LV diastolic function in EA may be a function of an increased preload and LV compliance. CONCLUSION: Chronic endurance training may have a limited influence on resting diastolic function displaying only incremental benefits with a greater training burden.

Keywords: athletes
cardiac
endurance
function
middle-age
Advisor: Goodman, Jack
Bentley, Robert
Multi-dipole Magnetic Localization for State Estimation of Ingestible Capsule Devices Bearing Dual-dipole Magnetic Mechanisms for Sampling the Gut Microbiome

Wireless capsule endoscopes (WCEs) are a class of ingestible, robotic devices designed for imaging the digestive tract during diagnostic procedures. Sightless localization of these devices is achieved in 5DOF by embedding a single permanent magnet within the device and detecting its emitted magnetic field remotely via magnetic field sensors. The work in this thesis applies magnetic localization techniques to track two WCE-based, dual-dipole magnetic sampling capsule devices (SCDs) across ten degrees of freedom; providing full device pose and actuation state estimation in real time. A magnetic field sensing system is developed to localize the SCDs designed for obtaining targeted samples of the gut microbiome. The unique ability to determine 6DOF pose and actuation state is achieved by tracking the relative positions and orientations of the two embedded permanent magnets. The localization speed and accuracy of this system are analyzed and compared across three different SCD models.

Keywords: Capsule
Localization
Magnetic
Microbiome
Microrobot
Sampling
Advisor: Diller, Eric
Predicting Relapse and Long-term Renal Outcomes in Patients with Relapsing and Remitting FSGS: A Retrospective Observational Cohort Study

Primary focal and segmental glomerulosclerosis (FSGS) is the leading glomerulonephritis related cause of renal failure in developed countries. Change in twenty-four-hour urinary protein excretion is the key biomarker defining remission and relapse. Predictive models for relapses and progression to renal failure are lacking. We hypothesized that two time-to-event, multivariable, survival models employing clinical variables may be utilized to predict the risk of relapse from the time of remission and predict progression to renal failure from the time of first relapse.Risk prediction models were created to (1) estimate the absolute risk of relapse among primary FSGS patients at 12, 24 and 60 months after their first remission and, (2) among patients suffering a relapse, to estimate the absolute risk of renal failure at 60 months. The model assessing relapse had poor discrimination, but reasonable calibration at 24 and 60 months. The model assessing renal failure had good discrimination with reasonable calibration.

Keywords: ESKD
ESRD
Focal Segmental Glomerulosclerosis
FSGS
Relapse
Remission
Advisor: Naimark, David
Process Development for Double and Multiple Fortification of Salt with Ferric Pyrophosphate and Iron Absorption Enhancers

A process was developed to fortify salt using ferric pyrophosphate (FePP), to treat micronutrient deficiencies (in iron, zinc, iodine, B9, B12) causing prenatal complications. Extrusion and microencapsulation produced premixes for double (DFS) and multiple-fortified salt (MFS). Reduction in colour-masking was predicted, since FePP is off-white. FePP is significantly less bioavailable than ferrous fumarate, therefore, absorption enhancers were utilized. Formulations developed by ETH Zurich were 1:citric acid (CA), trisodium citrate (TSC); 2:CA, sodium pyrophosphate; 3: reduced levels CA, TSC; 4: disodium EDTA. 25% titanium dioxide was required to colour-mask the extrudates. Soy stearin (SS) coating at 15% w/w prevented iodine loss (from iron-iodine interaction) in fortified salts. All samples made with University of Toronto retained >50%iodine at 25, 35, 45oC after 6 months. Pilot testing of the process at JVS Foods, Jaipur confirmed the laboratory results. With 10g salt consumption/day, DFS and MFS can deliver 50-200% RDA for the added micronutrients.

Keywords: bioavailability enhancers
double fortified salt
ferric pyrophosphate
fortification
iodine retention
multiple fortified salt
Advisor: Diosady, Levente L
Investigating Targeted Therapies for Genetic Heart Disease

Hypertrophic cardiomyopathy is a phenotypically and genetically heterogeneous disease caused by MYH7 and MYBPC3 mutations. The objective of this study was to 1) create a model using patient hiPSC-cardiomyocytes from children with HCM and demonstrate rescue of phenotype via gene correction, and 2) identify differences in response to targeted and non-targeted drugs across different mutations. hiPSC-derived cardiomyocytes were generated from 4 pediatric HCM patients harbouring myosin mutations, and the mutations were corrected using CRISPR/Cas9 gene editing. The morphological, contractile, biochemical, and arrhythmogenic phenotype were compared between patient, gene-corrected, and healthy control hiPSC-CMs. We demonstrate the recapitulation of the HCM phenotype, with varying severity, in all four patient lines, which can be successfully rescued with gene correction. Targeted myosin inhibitor was effective in rescuing phenotype compared to a non-targeted drug. This provides a platform to functionally validate new variants and assess the ability of myosin-targeted drugs to rescue the HCM phenotype.

Keywords: Cardiology
Genetics
Stem Cell
Advisor: Mital, Seema
ctFS: Eliminating File Indexing with Contiguous File System on Persistent Memory

Persistent byte-addressable memory (PM) is poised to become the norm of future computer systems. PMs are significantly faster than disk storage; moreover, accesses to PMs are governed by the Memory Management Unit (MMU) just as accesses to volatile RAM (Random Access Memory) are. These unique characteristics shift bottlenecks to operations like block address lookup – for example, in write workloads, up to 45% of the overhead in ext4-DAX is due to building and searching extent trees to translate file offsets to addresses on persistent memory.We propose a novel contiguous file system - ctFS, which obsoletes the use of any indexing structures such as extent trees in the file system. Instead, ctFS represents each file as a contiguous region of virtual memory, hence a lookup from the file offset to the address is simply an offset operation.

Keywords: File System
Persistent Memory
Advisor: Yuan, Ding
Extending Data Flow Architectures for Convolutional Neural Networks to Object Detection and Multiple FPGAs

This thesis augments and extends the state-of-the-art CNN inference accelerator for FPGAs, HPIPE. We first focus on the infrastructure of the accelerator, where we build an extra hardware unit to implement the Sigmoid function and automated unit tests to validate the functionality of the accelerator. We then study how to leverage the AI-optimized Stratix 10 NX FPGAs to achieve up to 7X speedup for convolution operations. Next, we extend HPIPE by integrating it with a hardware-friendly non-maximum suppression (NMS) unit to accelerate object detection and provide the highest-performing single-shot detection-based (SSD-based) object detection accelerator for FPGAs. Finally, we build an automated CAD flow to partition CNNs across multiple FPGAs that communicate via 100 Gb Ethernet. We show through a prototype system that doubling the number of FPGAs results in 2X performance improvement on three CNNs: MobileNet-V1, MobileNet-V2, and ResNet-50.

Keywords: Convolutional Neural Networks
Data Flow Architecture
FPGA
Hardware Acceleration
Machine Learning Acceleration
Tensorflow
Advisor: Betz, Vaughn