VictorJuiz/thesis huggingface dataset:
Elucidating the Regulation of ADAM17 Mediated Shedding of CX3CL1 from Vascular Endothelial Cells

CX3CL1 is an inducible chemokine that functions either as a transmembrane adhesion molecule, or when cleaved, as a soluble chemoattractant for leukocytes. Exposure to inflammatory mediators induces extensive proteolysis of CX3CL1 by the transmembrane protease ADAM17 in endothelial cells. The mechanisms governing this shedding remain undefined. Using single particle tracking, we found that CX3CL1 and ADAM17 were segregated at the plasma membrane. After stimulation with ADAM17 activator, PMA, CX3CL1 mobility remained unchanged while a small amount of ADAM17 was released from confinement. A modest increase in freely diffusing ADAM17 was observed after disruption of the actin cytoskeleton. Our data suggest that PMA has a modest effect on ADAM17 mobility and that the remodeling of actin cytoskeleton is unlikely to be the main mechanism of ADAM17-mediated proteolysis of CX3CL1. Even though Î˛1 integrin activation has been suggested to regulate ADAM17 activity, our data suggests that it is insufficient for PMA-induced CX3CL1 shedding.

Keywords: ADAM17
CX3CL1
Endothelial Cells
Single Particle Tracking
Vascular Inflammation
Advisor: Robinson, Lisa
Assessing the Relationship of White Matter Hyperintensities and Grey Matter to Neuropsychiatric Symptoms in Alzheimer's Disease and Mild Cognitive Impairment

Neuropsychiatric symptoms (NPS), including apathy, irritability and depression, are frequently encountered in patients with Alzheimer's disease (AD). Focal brain lesions, particularly in the frontotemporal regions, have been linked to the development of NPS. Cerebrovascular disease (CVD) can cause focal lesions and is common among patients with AD. CVD can be detected on MRI as white matter hyperintensities (WMH). The current study aimed to evaluate WMH burden and regional cortical atrophy in MCI and AD and determine their relationship with NPS. WMH and grey matter lobar volumes were measured and NPS were assessed using the Neuropsychiatric Inventory. We found lower frontal, temporal and parietal GM volume and higher frontal WMH volume to be associated with NPS, with GM atrophy associated with symptom progression over 2 years. This study could provide a better understanding of the pathophysiology of NPS in AD and other dementias.

Keywords: Alzheimer's disease
grey matter
mild cognitive impairment
neuropsychiatric symptoms
white matter hyperintensities
Advisor: Tartaglia, Carmela
The Behavioural and Neural Correlates of Social Cognition: A Dimensional Approach in Youth with Mental Illness

Heterogeneity in social cognitive performance and social function is a major obstacle in the identification of consistent biomarkers of impairment for schizophrenia spectrum disorders (SSD), autism spectrum disorders (ASD), and bipolar disorder (BD). Improved etiological subtyping and a better understanding of mediating mechanisms in neural circuits could facilitate targeted treatment development based on underlying pathology. This thesis explores the usefulness of Similarity Network Fusion (SNF), a transdiagnostic and data-driven clustering approach, in uncovering more neurobiologically homogenous groups of individuals with social cognitive impairments. The integration of multi-modal neuroimaging, social cognitive, neurocognitive, and demographic data reveal four distinct groups of participants across SSD, ASD, BD, and healthy youth with differing neuroanatomical profiles in key nodes of the fronto-parietal and cortical midline circuits. Our findings suggest that structural neural circuit deficits may help explain poor social cognitive performance in SSD, ASD, and BD.

Keywords: Clustering
Similarity Network Fusion
Social Cognition
Structural MRI
Subtyping
Youth Mental Health
Advisor: Voineskos, Aristotle N
Maximizing Survival Through the Staged Surgical Management of Hypoplastic Left Heart Syndrome and its Related Malformations

Objective: Mortality during 3-stage single ventricle palliation is much greater before vs. after stage-2-palliation (S2P). We investigated how the timing of S2P and post-Norwood events affect survival. Methods: The optimal timing of S2P was determined with conditional survival analysis. Post-Norwood events and measures, as time-varying covariates (TVC), were used to generate dynamic, patient-level risk profiles. Results: In low/intermediate-risk infants, performing S2P at ≥3 months old was associated with 89±3% and 82±3% 2-year survival, respectively. In high-risk infants, 2-year survival was ≤63±5% when S2P was performed at ≤6 months old. When accounting for post-Norwood events, weights, and SaO2, TVCs displaced baseline and operative characteristics. Because risk factors occurred over time, an infant’s mortality risk varied. Conclusion: S2P should be performed after age 3 months for low/intermediate-risk infants. High-risk infants are unlikely to complete three-stage palliation. By visually depicting risk

Keywords: Dynamic risk profile
Hypoplastic left heart syndrome
Real time risk assessment
Single ventricle palliation
Timing of surgery
Advisor: McCrindle, Brian W
Lithium carbonate in a post-stroke population: preliminary analyses of neuroanatomical and neuropsychiatric outcomes, and associations with BDNF from a pilot study

Neuronal atrophy following stroke can lead to changes in grey matter volumes and associated neuropsychiatric impairments. This study aimed to investigate the therapeutic potential of lithium, a putative neurotrophic agent, in the stroke recovery process. Stroke patients recruited to the study were prescribed lithium for 60 days. Grey matter volumes, cognitive and mood outcomes, and brain-derived neurotrophic factor (BDNF) levels were assessed at baseline and end of treatment. There was no difference in global grey matter volume between baseline and termination. There was a significant interaction between lithium dose and global grey matter volume (F=14.25, p=0.004), and a positive correlation between lithium dose and verbal memory (r=0.576, p=0.05). There was no difference in serum BDNF levels between baseline and termination. Lithium pharmacotherapy may be associated with grey matter volume change and verbal memory improvement in stroke patients, suggesting potential therapeutic applications of lithium in a post-stroke population.

Advisor: Lanct么t, Krista L
Herrmann, Nathan
Management of Stroke Risk in Patients on Hemodialysis with Non-Valvular Atrial Fibrillation: A Comparison of Cardiologists and Nephrologists in Canada

Antithrombotic therapy for stroke prevention in atrial fibrillation (AF) is standard practice, but for hemodialysis (HD) patients, the benefits are unclear and risks are high. Our study objectives were to compare cardiologistsâ and nephrologistsâ stroke prevention practices in this population and their associated decisional certainty. A cross-sectional, online survey was distributed to members of three Canadian physician societies (Nephrology, Cardiovascular, Heart Rhythm), and to cardiologists at three Universities. The questionnaire included four scenarios of AF in HD patients with varying stroke and bleeding risks. Respondents selected from treatment options and rated their level of certainty. Cardiologists were 3 times more likely than nephrologists to choose anticoagulant therapy, regardless of stroke or bleeding risk. Level of certainty differed between specialties across scenarios; however, this finding is not conclusive. Due to the low response rate (9%), results must be considered tentative. Physicians in Canada are encouraged to consider these differences in prescribing.

Keywords: anticoagulant
antiplatelet
atrial fibrillation
bleed
hemodialysis
stroke
Advisor: Battistella, Marisa
Mackeigan, Linda
Predictors of Mammographic Density among Women at a High Risk for Breast Cancer

Whether mammographic density, a strong predictor of breast cancer risk, is associated with breast cancer risk factors in women at an increased risk of familial breast cancer is unclear. Therefore, this study evaluated the associations between reproductive, hormonal, anthropometric, and lifestyle risk factors and measures of mammographic density (percent density, dense area, non-dense area) among high-risk, BRCA mutation-negative women. Overall, parity and body weight were inversely associated with percent density and positively associated with non-dense area. Increasing height was positively associated with percent density and inversely associated with non-dense area. A later age at smoking and alcohol initiation were positively associated with mammographic density. Among postmenopausal women only, past smoking was inversely associated with mammographic density. In premenopausal women only, an increasing duration of smoking was inversely associated with mammographic density. These findings suggest that mammographic density is associated with several modifiable breast cancer risk factors among this high-risk cohort.

Keywords: breast cancer
family history
lifestyle
mammographic density
Advisor: Kotsopoulos, Joanne
Examining the Heterogeneity in Schizophrenia Using Top-Down and Bottom-Up Approaches

Schizophrenia is a heterogeneous disorder. Demographic, clinical, neurobiological and methodological sources of heterogeneity have all likely impeded biomarker discovery. The objectives of this work were to use a ‘top-down’ and ‘bottom-up’ approach respectively to begin to disentangle 1) the effect of sex on structural connectivity 2) and the effect of variable spatial organization of the brain on functional connectivity in schizophrenia. In study 1, larger differences in white matter diffusion-based measures between patients and controls were observed in females compared to males. One interpretation of this result is that female patients require a larger biological hit to manifest schizophrenia symptoms. In study 2, correcting for variability in the topography of the brain reduced or eliminated several functional connectivity differences between schizophrenia patients and controls. These findings provide new windows of understanding into the heterogeneity of brain structure and function in people with schizophrenia.

Keywords: Diffusion Tensor Imaging (DTI)
Meta-Analysis
Resting-State Functional Magnetic Resonance Imaging (rsfMRI)
Schizophrenia
Sex
White Matter
Advisor: Voineskos, Aristotle N
Automated Immunohistochemical Analysis of the Orbitofrontal Cortex in Patients with Schizophrenia, Bipolar Disorder and Major Depressive Disorder

Previous studies have found evidence for orbitofrontal cortex (OFC) pathology in major depressive disorder (MDD), bipolar disorder (BP) and to a lesser extent schizophrenia (SCZ). However, given that the OFC is a large heterogeneous area, it is difficult to assess how findings from small subareas translate to the entire region. The aim of this thesis is to analyze the entire OFC in patients with MDD, BP and SCZ. Using a novel approach with layer-specific immunohistochemical markers and an automated counting protocol, we were able to analyze the cortical width, cell density, cell area and distance from pia in the entire OFC of 60 post-mortem brain samples (15 control, 15 MDD, 15 BP, 15 SCZ). We did not find strongly significant differences between patients and control subjects. Our findings suggest that inconsistencies in the literature may arise from sampling only small areas of the cortex in a limited number of subjects.

Keywords: CUX2
Immunohistochemistry
Post-mortem brain tissue
ZNF312
Advisor: Wong, Albert
Integrated Laser-Induced Fluorescence Detection for Parallelizable Microfluidic Single Cell Analysis

Microfluidic devices employing on-chip capillary electrophoresis (ÂľCE) have the potential to analyze single cells at high throughput while demanding less sample volume. However, to date, detecting the lower limit of the biological dynamic range involves coupling the fluorescence into confocal set-ups using externally cooled photomultiplier tubes (PMTs) which inhibit parallelization of the analysis. The integration of photodetector elements directly on-chip is desirable, but thus far, demonstrated systems are unable to detect targets without increasing target concentration by chemical techniques such as polyermase chain reaction (PCR). To address these demands, this work will investigate a laser-induced fluorescence (LIF) detection scheme using a high-index micro-ball lens embedded in a carbon-blackened polydimethylsiloxane (PDMS) panchromatic filter. The lens-filter layer enables simultaneous excitation rejection and fluorescence enhancement to couple fluorescence from a microfluidic channel to a surface detector. Furthermore, a method is proposed to optimize signal-to-noise ratio (SNR) in these higher dark current environments towards the goal of multiplexable and parallelizable integrated LIF detection.

Keywords: integrated
laser-induced fluorescence
microball
microfluidics
micro-optics
on-chip
Advisor: Lilge, Lothar
Exploring the Role of BDNF and NTRK2 Genetic Polymorphisms on Eating Behaviours in Young Children

Background: Genetic studies in obesity and eating disorders have identified brain-derived neurotrophic factor (BDNF) and neurotrophic receptor tyrosine kinase 2 (NTRK2) as candidate genes. We investigated the role of BDNF and NTRK2 SNPs on eating behaviours in young children. Methods: Data was obtained from a preschool-aged cohort. SNP and haplotype analysis were carried out for two phenotypes: Snack Delay Task (n=158), a behavioural measure of impulsive responding to food and Child Eating Behaviour Questionnaire (CEBQ) (n=160), a psychometric measure of eating behaviours. Results: NTRK2 rs1047896 and haplotypes containing this SNP predicted performance on Snack Delay Task. We also detected an association between NTRK2 rs1078947 and Food Approach Score from the CEBQ that was trending towards significance. Nominal epistatic effects were observed between BDNF rs6265 and NTRK2 rs1187325 on Food Approach Score. Conclusion: NTRK2 SNPs demonstrated novel associations with measures of impulsive eating and food approach behaviours. Findings should be replicated in larger samples.

Advisor: Levitan, Robert D
Epigenetic Vulnerabilities in Triple-Negative Breast Cancer

Breast cancer is the most commonly diagnosed cancer amongst Canadian women. To date, three main histopathological subtypes based on the expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 with different clinical outcomes dictate the treatment approach. Among these, the Triple-Negative Breast Cancer (TNBC) subtype does not express any of the hormone receptors and has the least survival rate due to lack of targeted therapy and poor prognosis. Recently, a category of highly selective and potent drug-like molecules ideal to assess therapeutic potential of new targets, known as chemical probes, have been designed to target epigenetic enzymes. Here, we determined the impact of 56 epigenetic chemical probes on the proliferation of TNBC cell lines. We identified distinct response across these cell lines after inhibition of the bromodomains, methyltransferases, methyl lysine transferases and lysine demethylases. Our results revealed epigenetic targets that could lead to potential therapeutic opportunities.

Keywords: breast cancer
chemical probes
drug screen
epigenetics
SGC
TNBC
Advisor: Lupien, Mathieu
Predicting the Volatility Index Returns Using Machine Learning

We probe how predictable the short term future behaviour of the Chicago Board Options Exchange (CBOE) Volatility Index (ticker symbol VIX) is given past market price data within the constraints of a simple classic machine learning framework. We use past VIX and SPX price time windows as input to predict the movement direction, i.e. sign of the return, of VIX over the next 1 to 6 weekdays. For successful cases of pre- dicting return direction from one particular weekday to another particular future weekday, we have moderately reliable accuracies of between about 55% and 65% depending on the particular time bridge. We find that 1 day returns are difficult to predict except for a few particular cases, and as the prediction window grows we have models that can predict more and more accurately up to a consistent 62% for both 5 days and 6 days in the future.

Keywords: ensemble method
finance
machine learning
VIX
volatility index
XGBoost
Advisor: Seco, Luis
Coupling Synthetic Antibodies with Mass Cytometry Allows the Development of a Highly Tailored, Multi-Parametric Single Cell Analysis Strategy

Increased appreciation for the inherent heterogeneity in cell populations has prompted a demand for more parameters at the single cell level. Synthetic antibody technology allows the rapid development of monoclonal antibodies with exquisite specificity towards any cellular epitope of interest, surpassing traditional hybridoma techniques. A new technology termed mass cytometry (CyTOF) improves on conventional fluorescence detection by labeling antibodies with metal isotope tags, significantly increasing the parameters that can be distinguished simultaneously. In this thesis, the convergence of synthetic antibody technology with mass cytometry is proposed. A comprehensive set of synthetic antibodies towards the Eph Receptor family is amended and tested for use in CyTOF. After validation, this toolset is applied to the study of cancer heterogeneity in Glioblastoma Multiforme. Subsequent analysis by ViSNE and SPADE unearths a putative brain tumour initiating cell population, illustrating an example of the potential afforded through combining these technologies.

Keywords: BTIC
cyTOF
glioblastoma
mass cytometry
single cell analysis
synthetic antibodies
Advisor: Moffat, Jason
Sidhu, Sachdev
The effects of noise-robustness of in-car voice-controlled systems on user perceptions and driving behaviour

In-car voice-controlled infotainment systems are becoming increasingly common in automobiles, but the effects on users when their accuracy degrades in the presence of background noise has not been examined. This thesis compares use of both noise-sensitive and noise-robust simulated voice-controlled infotainment systems under three background noise conditions. It was found that the sensitive system was perceived to be less useful and satisfying even when it performed identically to the robust system. No differences were observed between the systems in several driving performance metrics (with the exception of brake response), but the use of either system impaired driving performance compared to baseline. Glances and subjective workload demonstrated advantages to the robust system. Increased heart rate was observed with the robust system. The results demonstrate that noise robustness is a key factor in user acceptance, and may mitigate visual distraction generated by voice-controlled systems; however, the effects on driving performance are inconclusive.

Keywords: Cognitive workload
Driver distraction
In-vehicle technologies
User acceptance
Voice recognition accuracy
Advisor: Donmez, Birsen
A study of the statistical properties of scattered radiation under optical coherence tomography conditions: scattering medium characterization via the power spectrum and the probability density function

This thesis explores theory and data processing techniques that have the potential to extract much more information about a sample than can be gathered from standard optical coherence tomography (OCT) structural images. First, work is done towards making non-invasive glucose measurements via OCT and dynamic light scattering (DLS) techniques. A recently developed theory which models the power spectrum of the radiation scattered from flowing Brownian particles under OCT conditions is described, along with the experiments conducted that validate it. Second, it is demonstrated that the scattering of radiation from tissue-simulating phantoms has non-Gaussian features when there are a small number of scatterers in the OCT scattering volume, and that the statistics are well-described by the K distribution, which allows for scatterer concentration measurements. Subsequent preliminary experiments were conducted on human tissue, and the results show promise for differentiating between different tissue types.

Keywords: Brownian motion
Dynamic light scattering
Optical coherence tomography
Scattering
Speckle
Viscosity
Advisor: Vitkin, I. Alex
The relationship between seizure adequacy and response to magnetic seizure therapy in patients with treatment-resistant depression

Magnetic Seizure Therapy (MST), an alternative to electroconvulsive therapy (ECT), is under investigation for the treatment of depression, and the optimal treatment frequency is still unknown. Electrophysiological (EEG) recordings during treatment seizures can predict response to ECT, but the relationship between seizure characteristics and treatment outcome in MST remains unclear. This study aims to investigate the effect of stimulation frequency on seizure characteristics in MST, and to elucidate the relationship between seizure characteristics and MST treatment outcome. The results indicate that 100 Hz seizures had the lowest quality characteristics than the 25 and 50 Hz groups, particularly with measures of seizure duration. Moreover, shorter polyspike durations and slow-wave amplitudes are correlated with better treatment outcome, but these measures do not significantly differ across frequency groups. The results suggest MST may not have the same mechanisms of action compared to ECT, and that frequency is not an important modifier of treatment response.

Keywords: Biomarkers of Response
Brain Stimulation
Depression
Electroconvulsive Therapy
Magnetic Seizure Therapy
Treatment-Resistant Depression
Advisor: Blumberger, Daniel M.
Mechanical Anisotropies in Jetted Photopolymer Structures

Material jetting is a type of additive manufacturing that 3-D prints with a photopolymer resin through a series of small jets in a layer-by-layer process. Resulting structures were found to be anisotropic in nature with regard to print orientation due to differences in levels of bonding between successive print layers. The mechanical property anisotropies were quantified at both micro and macro length scales through nano- and micro- indentation and uniaxial tensile testing. The dependence and trends in anisotropy were found to be linked to the size scale of the testing method relative to the layer thickness. Under tensile testing, going from sample print orientations of 0째 to 90째, approximately 20% drops in modulus and strength, and a 75% drop in ductility were seen. The effect of how these anisotropies are then exemplified in more complex architectures, such as a microtruss, was investigated and found to correlate with the tensile results.

Advisor: Hibbard, Glenn D
Perovic, Doug D
Engineering Non-Wetting Antimicrobial Fabrics

This research presents novel techniques and a review of commercially available fabrics for their antimicrobial potential. Based on previous research into the advantages of superhydrophobic self-cleaning surfaces against bacterial contamination, insights into what can make a superhydrophobic fabric inherently antimicrobial were analyzed. Through comparing the characterization results of scanning electron microscopy (SEM) and optical profilometry to microbiology experiments, hypotheses into the relationship between the contact area of a bacterial solution and the extent of contamination is developed. Contact scenario experiments, involving the use of fluorescence microscopy and calculating colony forming units, proved that the contamination potential of any fabric is due to the wetting state exhibited by the fabric, as well as the extent of surface texturing. Transmission experiments, utilizing a novel technique of stamping a contaminated fabric, outlined the importance of retention of solutions or bacteria during interactions within the hospital environment on the extent of contamination.

Keywords: antimicrobial
bacterial adhesion
fabric
Advisor: Hatton, Benjamin D
Naguib, Hani E