VictorJuiz/thesis huggingface dataset:
Exploring NADPH Levels during ER Stress using Novel HomoFRET Sensors
Keywords: Deep Learning
ER Stress
Fluorescence Anisotropy
Microscopy
Type 2 Diabetes

In beta-cells, insulin misfolding occurs at rates as high as 20%. Misfolded insulin aggregates lead to endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). The adaptive UPR works to refold insulin, but if unsuccessful leads to programmed cell death. Proper insulin refolding requires reducing equivalents, which the ER lacks, thus external support in the form of NADPH is needed. This thesis investigates the role of NADPH in supporting insulin refolding in the ER. A novel homoFRET reporter, Apollo-IRE1, was developed to monitor the progression of ER stress. Apollo-IRE1 functionality was validated with chemical ER stressors. Additionally, our lab’s reporter, Apollo-NADP+, was used to track organelle NADPH levels during ER stress. Mitochondrial NADPH, not cytoplasmic NADPH, was found to be consumed during ER stress. The consumption of mitochondrial NADPH during ER stress demonstrates a potential supportive role of NADPH in the beta-cells protein refolding process.
Morphology and Mechanical Properties of In-situ Fibrillated Polyethylene Based Composites
Keywords: in-situ fibrillation
photocrosslinking
polyethylene
polymer composites
polymer processing
spunbond

Spunbond fibrillation, an industrial scaled technology, is utilized in a wide range of applications such as medical products, textiles, and others. Here, an in-situ fibrillated method was proposed to fabricate the fiber-in-fiber polymer composite using spunbond technology. In the study, we investigated four researches: Chapter 2 explored the influence of morphology of PBT domains on the crystallization, rheological, and mechanical properties of PBT/HDPE composites; Chapter 3 investigated the effectiveness of the coupling agent on the surface compatibility between PBT and PE interfaces and its mechanical behaviour; Chapter 4 discussed the impacts of the UV curing time and the second phase content on the morphology, and mechanical behaviours of the EPDM/PE composites; and Chapter 5 studied the morphology of the E-beam cured EPDM/PE (and mPE/PE) composites. The in-situ fibrillar strengthened/ toughened composites are promising for applications such as automotive, astronomy, medical services, and consumer goods, and so on.
Readout Transimpedance Amplifiers Monolithically Integrated with Quantum Dot Structures in a Production 22-nm FDSOI CMOS Technology
Keywords: FDSOI CMOS
Quantum Computing
Quantum Dot
Qubit Readout
Spin Qubits
Transimpedance Amplifier

This thesis investigates the design of spin qubit readout systems in a production 22-nm FDSOI CMOS technology for monolithically integrated quantum processors operated at temperatures above 4 K. At 300 K, the readout amplifier was measured to have a transimpedance gain of 108 dBΩ with 8 GHz of bandwidth, S22 output matching
Space–time Codes from Sum-rank Codes
Keywords: Rank-Metric Codes
Space–Time Codes
Sum-Rank Codes
Wireless Communication

Just as rank-metric or Gabidulin codes may be used to construct rate–diversity tradeoff optimal space–time codes, a recently introduced generalization for the sum-rank metric—linearized Reed–Solomon codes—accomplishes the same in the case of multiple fading blocks. In this thesis, we provide the first explicit construction of minimal delay rate–diversity optimal multiblock space–time codes as an application of linearized Reed–Solomon codes. We further provide sequential decoders for these codes and, more generally, space–time codes constructed from finite field codes. These decoders then enable a study of the performance of the constructed codes in simulation whereby we demonstrate that they can outperform full diversity alternatives at low SNRs as well as utilize significantly smaller constellations.
Are Fatty Acid Amide Hydrolase Levels Elevated in Social Anxiety Disorder? Preliminary Findings of a PET Study using [C-11]CURB
Keywords: endocannabinoid
fatty acid amide hydrolase
neuroscience
PET imaging
social anxiety

Background: Upregulation of the major catabolic enzyme for anandamide, fatty acid amide hydrolase (FAAH), has been implicated in animal models of anxiety disorders, however no in-vivo human data exist. We tested the hypothesis that FAAH levels would be elevated in social anxiety disorder (SAD). Methods: FAAH levels were measured with the positron emission tomography probe [C-11]CURB in 12 participants with SAD and 34 healthy controls. The Liebowitz Social Anxiety Scale was used to evaluate SAD symptom severity. Results: [C-11]CURB binding was marginally elevated in whole brain in SAD; effects were significant in the dorsal striatum (p=0.006) and hippocampus (p=0.04). [C-11]CURB binding was positively associated with SAD symptom severity. Conclusion: Our preliminary findings suggest that FAAH levels might be elevated in SAD, particularly in individuals with more severe symptoms. Replication of these findings in a larger sample is warranted and has implication for treatment strategies targeting FAAH.
Clinical and Neuroimaging Correlates of Cardiorespiratory Fitness in Adolescents with Bipolar Disorder
Keywords: Adolescents
Bipolar Disorder
Cardiorespiratory Fitness
Depression
Neuroimaging
Physical Activity

Cardiovascular disease (CVD) is more prevalent, and occurs prematurely, in individuals with bipolar disorder (BD) vs. the general population. Cardiorespiratory (i.e. aerobic) fitness (CRF) is a key modifiable CVD risk factor and is also associated with brain structure and function. There is an important gap in the literature on this topic in relation to BD, particularly in adolescents. 54 adolescents with BD and 53 healthy controls (HC) completed semi-structured interviews, self-report questionnaires, and 20 minutes of cardiorespiratory exercise. Power/weight (watts/kilogram) within 60-80% of estimated maximum heart rate (HR) on a bicycle ergometer served as a proxy for CRF. Structural magnetic resonance imaging analysis was done using FreeSurfer. CRF was reduced among adolescents with BD, particularly females, related in part to depression symptoms and inactivity. CRF is differentially associated with brain structure in frontal, parietal and occipital regions in adolescents with BD. Studies engaging CRF as a treatment target are warranted.
Analysis and Evaluation of a Minimally-invasive Cavopulmonary Assist Device
Keywords: Cavopulmonary Assist
Congenital Heart Defects
Fontan

A cavopulmonary assist device is a medical device intended to improve blood flow to the heart to bridge patients with failing Fontan circulations to heart transplants. This work redesigns a previously-designed cavopulmonary assist device to design constraints of a cross-sectional area of less than 166 mm2, pressure gains within 2-6 mmHg, and wall shear rates (WSRs) less than 5000 s-1. Hemodynamics and misalignment-induced effects were investigated across one idealized and three patient-specific Fontan geometries over a range of conditions, showing that target pressure gains are achieved, endothelial damage is limited, and WSR and recirculation increase with misalignment. A cannula prototype was fabricated for evaluation in a custom mock circulatory loop. This previously-constructed loop was re-tuned to better model failing Fontan conditions with a new cannula test section manufactured to match adult anatomy. Flow and pressures in the loop show good agreement with failing Fontan conditions, particularly for large flow rates.
Efficient Simulation of Driven Finite Periodic Structures using the Finite-difference Time-domain Method
Keywords: Edge effects
FDTD
Finite periodic structures

Infinitely-periodic geometries are efficiently modelled in the finite-difference time-domain (FDTD) method using periodic boundary conditions (PBCs). Several PBC implementations operate by maintaining a constant wave vector component in the periodic directions. This work presents the underlying mathematical background for all these methods and demonstrates their usage. However, infinitely-periodic structures modelled by PBCs are unrealizable physically. Therefore, an efficient FDTD technique for determining electromagnetic fields interacting with finite-sized periodic structures is proposed. The technique combines periodic boundary conditions—modelling fields away from the edges of the structure—with independent simulations of fields near the edges of the structure. It is shown that this algorithm efficiently determines the size of a periodic structure necessary for fields to converge to the infinitely-periodic case. Numerical validations of the technique illustrate the savings concomitant with the algorithm.
Identifying Novel Targets in Chemo-resistant Cell Populations in Glioblastoma Multiforme
Keywords: Cancer
Chemotherapy
Cholesterol
Drug Discovery
Drug Repurposing
Glioblastoma

Glioblastoma multiforme is an aggressive brain tumour characterized by poor prognosis, with overall patient survival rates averaging less than 15 months. Current treatment methods display immediate control of the disease, however treatment-resistant cell populations persevere, and disease recurrence is inevitable. As a result, all patients eventually succumb to the effects of their disease. Therefore, there is a need for therapeutic approaches that are capable of targeting the treatment-resistant cell populations in glioblastoma in order to provide patients their most meaningful period of remission. In this study, we propose that FDA-approved agents capable of crossing the blood-brain barrier can be repurposed for use in glioblastoma. In particular, the lipid-lowering agent lomitapide shows promising therapeutic potential in glioblastoma due to its ability to alter exogenous cholesterol levels, which Villa et al. have shown GBM cells rely on for survival.
Angle of Arrival Estimation as an Ising Energy Minimization Problem
Keywords: Angle of Arrival
Compressive Sensing
Localization

A popular approach to realizing decimetre-level localization involves estimating the angle between a target and one or more anchors. In the context of wireless communication, this work implements compressive sensing to first discretize the angular domain and then optimize a suitable objective function. This thesis presents the problem using an L0-norm function that is then formulated as an Ising energy minimization problem; although NP-hard, the optimization is efficiently solved using the Digital Annealer (DA) machine. This work leverages the computational efficiency of the DA to further develop the Ising formulation by devising a unique iterative search procedure. The performance of this approach is studied extensively and compared to other state-of-the-art works. Test results show that the proposed method outperforms other approaches.
Archival Imperialism: An Analysis of Racial Hierarchy in the Six Day War Files
Keywords: Archives
Colonialism
Israel
Palestine
Recordkeeping
War

Using a theoretical framework of critical race theory, settler colonialism, and symbolic annihilation, this research investigates how records creators and archivists of the Six Day War Files Collection have constructed their own narrative of the War, thereby legitimizing a racial hierarchy between Palestinians and Israelis and sustaining Israeli imperialism. Chapter One problematizes why there is little written about Palestine from the archival perspective, despite the abundance of scholarship on the colonial power of the archive. Chapter Two analyzes the content of the Collection, investigating how records creators used symbolic annihilation to construct Palestinians as a racialized Other. Chapter Three analyzes the context of the Collection, investigating how archival practices have sustained the colonizer’s representation of the colonized and furthered racial inequality. This thesis offers a novel perspective to the current archival scholarship regarding Palestine, revealing how symbolic annihilation in the archive extends, and is an extension of, systemic annihilation.
Genome-wide Investigation of Rare Genetic Variation in Epilepsy and Autism Spectrum Disorder
Keywords: 7q11.23 duplication
Autism Spectrum Disorder
Epilepsy
Genetics
Whole genome sequencing

Epilepsy and autism spectrum disorder (ASD) are a clinically heterogeneous group of neurological disorders. Despite their known genetic basis, many cases of epilepsy and ASD remain unresolved without a molecular diagnosis. In this thesis, I describe the use of whole-genome sequencing (WGS) to conduct a genome-wide investigation of rare genetic variation in two cohorts. In a cohort of unexplained epilepsies, I identified clinically relevant rare variants in 9/28 (32.1%) participants, for whom prior genetic tests were inconclusive. In a cohort of 20 participants with a duplication of the 7q11.23 region (Dup7), I found that in the presence of the same pathogenic Dup7 variant, rare and low frequency genetic variants act additively to contribute to components of the overall Dup7-ASD phenotype. Overall, my findings demonstrate that the use of WGS enables molecular diagnosis, points to the role of multiple contributing variants in the genetic background, and yields insights into epilepsy-ASD genetics.
Synthesis of a Reversible Crosslinked Hydrogel
Keywords: degradable
dynamic
hyaluronan
hydrogel
methylcellulose
TEV protease

Detachment of fragile cell types cultured on two-dimensional (2D) surfaces detrimentally affects cell viability. Accutase treatment of neurons growing in 2D damaged fragile neuronal connections, resulting in cell death and host tissue damage in vivo. Avoiding cell detachment altogether by developing an in vitro culture system may better maintain cell viability; therefore, we present the synthesis of a reversible crosslinked three-dimensional (3D) hydrogel which would provide stability for culture/differentiation when crosslinked and injectability for transplantation following crosslink degradation. A blend of hyaluronan (HA) and methylcellulose (MC), HAMC, was chemically crosslinked with an enzyme-degradable peptide sequence using oxime click-chemistry. Specifically, HA and MC were modified with ketone and aldehyde groups, respectively, and a TEV protease-degradable peptide crosslinker was synthesized and modified with oxyamine groups. The gel components were characterized, and gels were formed that demonstrated good stability, improved injectability upon crosslink degradation, and cytocompatibility with iPSC-derived neural progenitor cells.
Electrophysiological Substrates of Cognition in the Basal Ganglia and Basal Forebrain
Keywords: decision making
neurophysiology
single units

Cognitive and non-motor behavioral functions have recently been described to heavily engage basal ganglia (BG) and subcortical circuitry and nuclei. Functionality at the neural level may be examined by analyzing single unit spiking activity and/or the aggregate activity of a population of neurons in various frequency bands known as local field potentials. This thesis addresses the role of the subthalamic nucleus (STN) in a cognitive 2-item choice decision-making task; and the role of the nucleus basalis of Meynert (nbM) in an auditory oddball attention task. Utilizing intraoperative electrophysiological recordings and behavioral testing in patients undergoing deep brain stimulation surgery, we expand upon the current understanding of the physiological function of the STN, subcortical beta, and the nbM in cognitive functions. The research presented here carries clinical implications for progressing DBS technologies as well as bettering our understanding of cognitive/non-motor deficits in patients with basal ganglia dysfunction.
A Streaming Accelerator for Heterogeneous Multicore-FPGA Processing of Graph Analytics Applications
Keywords: accelerator
analytics
fpga
graph
heterogeneous
streaming

This work explores the acceleration of graph processing on a heterogeneous platform that tightly integrates an FPGA with a multicore processor to share system memory. The key research challenge addressed is that of designing an accelerator that exclusively accesses graph data in system memory, enabling the concurrent use of both the accelerator and software. Specifically, the work proposes a streaming accelerator design for the scatter phase of iterative scatter-gather graph processing. The streaming design is implemented and evaluated on the second-generation Intel Heterogeneous Architecture Research Platform (HARPv2). Evaluation of three key graph processing kernels using a combination of synthetic and real-world graphs shows that this design achieves highperformance, up to 1100 MTEPS. Further, the accelerator has high FPGA–to–Memory bandwidth utilization, over 90%. The streaming accelerator also features fine-grain granularity sharing with the CPU that enables integration with efficient load-balancing schemes, such as work-stealing.
Circadian Oscillations of the Mouse and Human Epigenome
Keywords: Aging
Circadian rhthmicity
Complex diseases
DNA modification
Epigenetics

Circadian rhythmicity in biological processes is an evolutionary adaptation in response to Earth’s rotation. Epigenetics refers to chemical modifications of histones and DNA, for the regulation of the genome. Although previous evidence suggested the involvement of DNA modification in the circadian machinery, direct confirmation has been elusive. This thesis presents evidence for oscillating modified cytosines with circadian periodicity in both mouse and human genomes. Furthermore, oscillating modified cytosines (osc-modCs) are associated with cytosines that change their modification status with age. Linking circadian patterns with linearly changing epigenomes over years provides new insights into the mechanisms of aging. Finally, we investigated plausible roles of osc-modCs in malignant, psychiatric, and metabolic diseases. Intriguingly, osc-modCs significantly overlapped with the cytosines exhibiting differential modification in these diseases. In summary, my findings indicate that fine tuning of evolutionary advantageous adaptations such as circadian rhythmicity may contribute to the decline in the fitness of the organism.
Ontario Pharmacy Smoking Cessation Program: A Descriptive Analysis, 2011-2016
Keywords: administrative claims data
Pharmacy
smoking cessation

The Ontario Pharmacy Smoking Cessation Program was introduced in September 2011 and reimburses pharmacies for providing counseling services to residents eligible for Ontario Drug Benefits. Using healthcare administrative data through to November 2016, we described patient (demographic, healthcare) and program (enrolment, follow-up services, smoking cessation medication and success) characteristics. Analyses were completed overall and by age (≥65 [seniors] versus
Efficient Enumeration of Branched Novel Biochemical Pathways in the Complex Biochemical System
Keywords: biochemical pathway
bioinformatics
machine learning
metabolic engineering
probabilistic technique

The main challenge of novel biochemical pathway identification remains in dealing with the combinatorial growth of nodes and branches in the putative reaction network generated when searching the branched pathways. In this thesis, a pathway computation tool, Anneal Path, is presented. It targets chemical diversity and explores a larger theoretically possible chemical space. The pathway network has been modeled through a loopless directed hypergraph, where a list of starting compounds and a target compound are connected with a series of hyper-edges, each representing a multi-molecular reaction. The pathway identification program Anneal Path efficiently enumerates chemically possible branched novel biochemical pathways with complicated pathway-topologies. It has been shown that this Anneal Path can identify a large set of branched pathways more efficiently than purely similarity based search methods. A GUI (graphical user interface) driven application has also been programmed to allow visualizing the novel chemical structures and results pathways.
Interactions of Disease-associated Nucleic Acids Repeats with Ligands and Proteins
Keywords: ALS
C9orf72
neurodegenerative
neuromuscular
non-canonical structures
repeat expansion diseases

The amyotrophic lateral sclerosis (ALS)-associated hexanucleotide, d(GGGGCC), repeat expansions within the chromosome 9 open reading frame 72 (C9orf72) gene are characterized with TAR DNA binding protein (TDP-43) positive inclusion and methylation marks at CpG islands in promoter and other regions. We characterized the binding interactions of TDP-43 with C9orf72 repeat expansion sequences and the effect of 5mCpG methylation. We demonstrated polymorphic quadruplex formation and thermostability by using circular dichroism and UV spectroscopy. We showed that TDP-43 proteins preferentially bind to G-rich RNA and R-loops by using electrophoretic mobility-shift assays. 5mCpG methylation further stabilized structures and affected TDP-43 binding interactions with C-rich DNA. Using in vitro assays, we found ethidium bromide and actinomycin D (ActD) preferentially bind CTG hairpins over CAG hairpins and showed the least affinity to the inverted repeat control DNA. These tool compounds can be used to screen and identify other potential small-molecule modulators of repeat instability.
Formulation of Oil Spill Dispersants using Biobased Surfactants and the Study of Flow-induced Breakup of Floating Oil Drops
Keywords: Couette flow
dispersant formulation
drop breakup
floating oil
HLD (Hydrophilic-Lipophilic Difference)
oil spill

This thesis deals with two challenges related to oil spills. First, the Hydrophilic-Lipophilic Difference (HLD) framework was used to develop a lecithin formulation containing food-grade lipophilic and hydrophilic linkers in combination with a non-volatile, mineral oil solvent with food additive status. The HLD parameters of the components were used to determine the lecithin-linker formulations and the interfacial tensions were of the order of 10-2 mN/m and emulsification effectiveness in the range of 75- 85%. The second part of this thesis addresses the breakup oil drops floating on water/aqueous medium under simple shear flow, using a counter-rotating circular Couette device. It was observed that floating drops produce fine droplets via tip-streaming in viscosity matched systems too. At a solvent to bitumen (S/B) ratio of 2, diluted bitumen drops formed a rigid network upon spreading on the interface, but at lower S/B ratios (0.5), they formed drops that rotated like rigid structures.
Genetic and Chemical Genetic Approaches to Identifying Liabilities in Malignant Brain Cancer
Keywords: Chemogenomic
CRISPR-Cas9
Glioblastoma
HAP1
PTC-028
Recurrent

Glioblastoma (GBM) remains the most common primary malignant brain tumor in adults. Patients face a dismal prognosis despite efforts to identify novel therapeutic targets. Following conventional therapy, patients relapse with treatment-refractory GBM, which remains largely unexplored. This thesis explores the functional genetic landscape of recurrent GBM (rGBM) using unbiased CRISPR-Cas9 knockout screening. Negative selection screens in two patient-derived rGBM cell models provided evidence for the essential role of EGLN1, PTP4A2 and TIMELESS in treatment-refractory GBM. Pursuing the idea of identifying targets in rGBM, I explored modulators of BMI1, a master-regulator of brain cancer tumorigenesis. I carried out a chemical genetic screen to identify perturbations that sensitize cells to the effects of PTC-028, a small molecule thought to inhibit BMI1. I validated the loss of WNK1 gene as the strongest positive chemical-genetic interaction with PTC-028. In summary, this thesis describes new rGBM genetic vulnerabilities and sheds light on the mode of action of PTC-028.