VictorJuiz/thesis huggingface dataset:
Structural and Connectivity Analysis in Acoustic Neuroma Patients
Keywords: Acoustic Neuroma
Connectomics
Graph theory
Magnetic Resonance Imaging
Tractography
Unilateral Hearing Loss

The global incidence of acoustic neuroma (AN) tumours is increasing, with devastating implications for individuals who subsequently develop unilateral hearing loss (UHL). Recent advances to brain imaging techniques permit a non-invasive investigation of UHL pathophysiology. The goal of this thesis is to use brain imaging methods to identify structural markers of UHL in adults with ANs. In Study 1, I use a fixel-based analysis to examine white matter structure in adults with ANs and UHL. In Study 2, I use structural connectomics and graph theory to explore whole-brain topology in this group. I found that 1) at the whole-brain level, white matter structural properties do not distinguish adults with ANs and UHL from healthy controls, but that 2) there are structural connectivity patterns unique to adults with ANs and UHL. Overall, this thesis concludes that brain imaging techniques can demonstrate whole-brain topological reorganization in adults with ANs and UHL.
EEG-based Brain Networks in Children with Infantile Spasms: Localization of Network Hubs
Keywords: EEG
functional connectivity
infantile spasms
localization
wavelet phase coherence

Surgical resection can improve outcomes in infantile spasms (IS), but localization of epileptic tissue is a challenge. We aim to use phase coherence and network analysis to non-invasively identify channels of interest. Coherence-based time and frequency networks were constructed using peri-ictal EEG records from IS patients (N=15); connectivity was assessed through both global efficiency and channel-wise closeness centrality. Spasms are characterized by increased connectivity; global efficiency in the fast ripple (251-400 Hz) networks was significantly greater after the onset of spasms than it was prior to the onset. The fast ripple spasm networks have hubs of localized connectivity; these hubs are found in the posterior region in 14/15 patients. Comparisons with interictal and non-IS patients shows that fast-ripple networks are specific to the spasm and arousal states. Hubs are channels that can quickly propagate signals to the rest of the brain network, and may identify regions of spasm propagation/generation for resection.
Design and Evaluation of a Context Aware AAC Application for Pre-literate Children with Complex Communication Needs
Keywords: augmentative and alternative communication
Language Model

Nonverbal, pre-literate children must rely on communication devices to interact with others, but contemporary communication aids are inefficient as they ignore conversational context. This thesis presents the design and implementation of a conversational context-aware augmentative and alternative communication (AAC) device. A query from an AAC user’s communication partner serves as the input to our system. Keywords are extracted from the query and contextual language embeddings are leveraged to predict semantically related words. Considering both their parts of speech and their word sense (most likely meaning given the keywords), the recommended words are finally mapped to corresponding pictograms. Based on preliminary evaluations (top-n category measure of agreement between word recommendations and keywords from partner’s message; case examples; visualizations of embeddings), the context-based prediction enhancements appear to have the potential to accelerate communication. This research is the first step in incorporating modern natural language models in AAC devices.
First-line Systemic Therapy with Bevacizumab in Advanced Epithelial Ovarian Cancer
Keywords: Evaluation
Health Outcomes

First-line treatment of advanced epithelial ovarian cancer (EOC) involves a combination of cytoreductive surgery, chemotherapy, and targeted therapy. Bevacizumab is a monoclonal antibody targeting the angiogenesis pathway and has become a standard treatment option in EOC. The first part of this thesis synthesizes the current literature on first line systemic treatment in EOC, focusing on clinical trials involving bevacizumab. This includes an in-depth systematic review and meta-analysis of bevacizumab in the first-line treatment of advanced EOC in modern oncology, and a critical analysis of the current economic considerations of bevacizumab in this setting. The latter part of this thesis reflects real-world evidence on patterns of first-line systemic therapy delivery and adoption of bevacizumab for advanced EOC in Ontario using province-wide administrative data. We found overall low uptake of bevacizumab which may be influenced by provider specialty. Further studies are required to explore in more depth factors associated with these findings.
Dimensionality-reduced Neural Networks for Improved Prediction in Finite Element Analysis Applied to Sheet Metal Forming
Keywords: Artificial Neural Networks
Dimensionality Reduction
Finite Element Analysis
Machine Learning
Sheet Metal Forming

Sheet metal forming processes involve highly nonlinear relationships between process parameters which are cumbersome to model and solve. This paper presents the use of dimension-reduced neural networks (DR-NNs) for predicting different output properties in finite element sheet metal forming models. The objective of using DR-NNs is to reduce computational demand, error, and uncertainty in predictions compared to standalone neural networks. Process input parameters such as material properties, and sheet dimensions were transformed to a smaller set of principal components using linear and non-linear dimensionality reduction methods. The principal components were fed as inputs to the neural networks for predicting mechanical and thermal phenomena such as springback and temperature distribution. The DR-NNs were compared against a neural network and showed improvements in terms of lower computational time, prediction error, and prediction uncertainty.
Investigating ICU-acquired Weakness in a 3D Human Skeletal Muscle Microtissue Platform
Keywords: ICU
ICUAW
Muscle atrophy
Regenerative medicine
Skeletal muscle
Tissue engineering

Numerous pathologies can lead to progressive muscle weakness and atrophy as secondary consequences. Intensive care unit acquired weakness (ICUAW) is a clinically detected muscle weakness in critically-ill patients, often resulting in persistent disability. We investigated how humoral factors contribute to ICUAW by treating genetically identical 3D-human skeletal muscle microtissues(hMMTs) with sera collected along the treatment of critically-ill patients that may develop ICUAW. Treatment of hMMTs with sera collected within 72 hours of ICU admission with intubation and mechanical ventilation resulted in significantly reduced hMMT myotube diameter, sarcomere integrity and absolute passive force. Comparison of trends in hMMT form and function, when treated with early and later timepoint serum, to clinical outcomes revealed that hMMT passive force outcomes align with clinical outcomes of function measured by Medical Research Council sum score and motor functional independence measure. The next steps will include understanding which molecules are responsible for effects observed in culture.
Investigating the Functional Evolution of Shikimate Kinase-Like 1 in Marchantia polymorpha
Keywords: Marchantia polymorpha
Shikimate kinase
SKL1

Shikimate kinase-like 1 (SKL1) is an ancient gene duplicate of shikimate kinase that arose during the evolution of early land plants between 400 and 500 million years ago. Through previous studies of Arabidopsis thaliana (AtSKL1), SKL1 is known to be essential for chloroplast biogenesis. My work aimed to study the ortholog of SKL1 in Marchantia polymorpha subsp. ruderalis (MpSKL1), an ancient species of land plant. This was aimed at confirming that SKL1 evolved its function shortly after its emergence during the early stages of land plant evolution. In this thesis, I have shown that MpSKL1 is a true ortholog of AtSKL1, functioning in chloroplast biogenesis. I have also shown that SKL1 evolved through the diversification of a shikimate kinase retrogene and that it most likely retains its functions as a small molecule kinase, having evolved to phosphorylate a new substrate.
Examining the Autophagy Proximity Interactome
Keywords: Autophagy
BioID
EMC
TARS2
UHRF1BP1
Xenophagy

Macroautophagy (hereafter autophagy) is a highly conserved catabolic process involving the lysosomal degradation of macromolecules, organelles and invading microbes. The signaling and mechanisms of autophagosome formation and targeting of intracellular cargo is incompletely understood. To address this, proximity-dependent biotin identification (BioID) analysis was performed on 39 autophagy proteins to map the autophagy interactome in human cells. We identified 773 unique interactors, of which 78% were previously uncharacterized. The interactome identified novel interactors of autophagy proteins associated with essential genes and have links to human disease. From this network, proteins involved in membrane contact sites (EMC complex), mitochondrial translation (TARS2) and endosomal trafficking (UHRF1BP1, UHRF1BP1L) were found to have functional roles in autophagy. UHRF1BP1 was further characterized to be a bona fide LC3 interactor localized to Salmonella-containing autophagosomes. Altogether, this autophagy proximity interaction map will serve as a valuable resource for future analysis of autophagy.
Age-related Differences in the Relationship between Eye Movement Behaviour and Facial Recognition Memory
Keywords: aging
Alzheimer's disease
eye movements
facial recognition memory
relational memory

Eye movements allow for visual exploration which serves to gather information from the environment in order to create, update, and reconstruct memories. This study examined the influence of aging on two eye movement measures and memory. The eye movement measures were monitored in two phases: a study phase during which healthy younger and healthy older adults viewed single faces from the same or different viewpoints across multiple blocks, and a test phase, in which each face was displayed from the same or a different viewpoint as seen during the study phase. The first eye movement measure showed that greater visual exploration was not associated with recognition among older adults. Furthermore, the second eye movement measure revealed, indirectly, that the development of a memory representation across time was intact among older adults. Therefore, in aging, the accumulation of visual information into a memory representation that supports recognition may be disrupted.
The Value of Advance Surgery Booking Information for Inventory Management of Surgical Supplies
Keywords: advance demand information
consumables
healthcare
inventory control
supplychain

We study the value of incorporating Advance Booking Information (ABI) of elective surgery schedules information on into the inventory replenishment decisions of surgical supplies at hospitals. Medical operations require a large variety of consumable supplies that are kept in hospital inventory and replenished regularly. The combination of stringent requirements on their availability and high usage variability contributes to the high inventory costs. We study a periodic-review stochastic inventory control problem, where the item demand is driven by the number and type of surgeries. Through exact analysis of a simplified model and extensive numerical experiments (synthetic and real data), we provide insights on and quantify the value of using ABI. In the relevant parameter regime of high backlogging and low setup costs, the value of using ABI is significant and most of the benefit can be gained through using one period of ABI beyond the ordering lead-time into the ordering decision.
Effect of Flaxseed, its Oil and Lignan Components, and of its Hull Fraction on the Murine Intestinal Ecosystem
Keywords: Fiber
Flaxseed
Flaxseed Oil
Microbiota
Mouse study
Phytoestrogen

Flaxseed (FS) is rich in oil (FSO; enriched in the kernel), secoisolariciresinol diglucoside (SDG), and dietary fiber (both enriched in the hull (FH)). FSO has anti-cancer and anti-inflammatory effects. SDG and fiber are metabolized by the intestinal microbiota to produce enterolignans and short chain fatty acids, respectively, contributing to FS benefits. The objective was to assess the effects of FS, and its FSO and SDG components at levels found in FS (Chapter 3), and of FH (Chapter 4) on the female C57BL/6 murine intestinal microbiota. In Chapter 3, FS induced greater microbial diversity, enrichment of fiber and protein metabolic pathways, and relevant taxa compared to FSO and SDG. In Chapter 4, FH induced a higher relative abundance of Bacteroides genus and serum lignans concentration compared to FS. Findings suggest that the complementary action of FS components is necessary to affect the intestinal microbiota and the production of beneficial metabolites.
Genome-wide CRISPR-Cas9 Loss of Function Screens Identify Genetic Vulnerabilities in BRCA1 Mutated Cancers
Keywords: BRCA1
CRISPR-Cas9
High throughput screening
Synthetic lethality

The breast cancer susceptibility gene (BRCA1) encodes a protein that plays a central role in DNA- damage repair and several nuclear processes. Somatic and germline mutations in BRCA1 drive breast and ovarian cancer development, however also confers a significant vulnerability to particular forms of chemotherapy. To search for genetic targets whose inhibition may interact in a synthetic lethal manner with BRCA1, we screened a BRCA1 methylated and BRCA1 wildtype ovarian cancer cell line with a genome-wide CRISPR based library. To provide a more comprehensive analysis, we additionally queried data from large-scale CRISPR-Cas9 dropout screens. Through the validation of CRISPR screening hits, here we found that the depletion of FAAP24 was selectively essential in BRCA1 deficient cell lines. We propose that targeting of FAAP24 may be a promising drug target for BRCA1 mutated cancers, although further in vitro and in vivo studies are required to extrapolate these findings.
Exploration of Alzheimer's Disease Risk Factors
Keywords: Alzheimer's disease
risk factors

Specific demographic and biological factors are known to contribute to the risk of Alzheimer’s disease (AD) such as: sex, age, formal education, and levels of cerebral spinal fluid (CSF) biomarkers. The present study explored the prevalence of thirteen proclaimed AD risk factors within a large sample of older adults that were cognitively healthy, in progressive stages of AD, or diagnosed with AD. Apolipoprotein E (APOE) ε4/ε4 gene status was demonstrated as a strong predictor of AD and cognitive dysfunction. Cognitively impaired participants showed shifts in CSF amyloid-β42, phosphorylated tau, and total tau biomarkers towards abnormal levels. Age and education, independent of AD status, had the greatest impact on cognitive, memory, and psychological performance outcomes. Altogether, the results highlighted risk factors that were more commonplace in persons with AD which established important risk factors for future research to concentrate.
Development of a 96-well Platform to Increase Throughput of a Muscle Endogenous Repair Model
Keywords: 96-well
Endogenous Repair
In Vitro Model
MEndR
Muscle Regeneration
Myotube

Identification of pharmacological candidates for enhancing muscle endogenous repair has been limited due to a lack of suitable in vitro models. To address this issue, our team previously developed a predictive in vitro skeletal muscle repair model consisting of muscle stem cells engrafted on a thin sheet of myotubes. This model has great potential for stratification of drug candidates that can enhance muscle endogenous repair, however its application is currently limited by its throughput capacity. To increase this model’s throughput, here we describe a platform capable of bulk generation and characterization of myotube sheets. Higher-throughput manufacturing is achieved by miniaturizing cellulose scaffolds, placing them in statically charged 96-well-plates, and adsorbing the enzyme responsible for triggering gelation of extracellular matrix on scaffolds. Higher-throughput characterization was achieved through development of methods facilitating automated image acquirement. The development of this platform brings us closer to identifying compounds that can enhance muscle endogenous repair.
Induction of Heat Shock Proteins in Differentiated Human SH-SY5Y Neuronal Cells by Caffeine and Cafestol
Keywords: Cafestol
Caffeine
HSPA1A
HSPA6
Hsps
SH-SY5Y Neuronal Cells

During aging, protein quality control fails, leading to the accumulation of misfolded, aggregation-prone proteins which are characteristic of neurodegenerative diseases for which few effective therapies exist. Enhancement of protein quality control mechanisms is a potential treatment strategy, specifically upregulation of heat shock proteins (Hsps) that function to counteract misfolded proteins. Non-toxic inducers are required that can be ingested regularly and cross the blood-brain barrier to trigger Hsp induction in neurons that are affected in neurodegenerative diseases. Caffeine is a non-toxic compound taken daily that crosses the blood-brain barrier. The effects of two coffee components namely, caffeine and cafestol, are examined on the induction and intracellular localization of Hsps in differentiated human neuronal cells grown in tissue culture. Cafestol, but not caffeine, induced HSPA1A (Hsp70-1) and the little studied HSPA6 (Hsp70B’) which localized to the nucleolus where these Hsps could protect ribosome biogenesis, a critical feature of neuronal protein synthesis.
The Effect of Important Food Sources of Fructose-containing Sugars on Adiposity: A Systematic Review and Meta-analysis
Keywords: Food sources of sugars
Fruit
Obesity
SSB
Systematic Review and Meta-analysis
Weight gain

Sugar-sweetened beverages (SSBs) are associated with increased weight gain. It remains unclear if other food sources of fructose-containing sugars show a similar relationship. We conducted a systematic review and meta-analysis of controlled trials to assess the effect of different food sources on body weight (primary outcome) and other adiposity measures. We identified 119 controlled trials (368 trial comparisons, N=5,263). Total fructose-containing sugars increased body weight (MD, 0.29kg [95% CI, 0.05 to 0.53]; moderate-certainty evidence) and body fat (MD, 0.0.47% [95% CI, 0.09 to 0.85]; low-certainty evidence) in addition trials (energy from sugars added to diet) with no effect in substitution (energy matched comparisons), subtraction (energy from sugars subtracted from diet), or ad libitum trials. There was evidence of interaction by food source with SSBs and mixed sources increasing body weight in addition trials. Energy control and food source appear to be mediators of the effect of fructose-containing sugars on adiposity.
Establishing Zebrafish Embryonic Axial Curvature as a Scoliosis Surrogate Model to Screen for Pathogenic Mechanisms and Therapeutic Strategies
Keywords: chemical screening
idiopathic scoliosis
neuroinflammation
oxidative stress
therapy discovery
zebrafish

Idiopathic scoliosis (IS) is characterized by abnormal spinal curvatures arising without observable vertebral or physiological anomalies. Genetic heterogeneity and historical lack of relevant animal models have hindered understanding of mechanisms driving disease. Consequently, scoliosis treatments rely on invasive mechanical spinal corrections. Our lab first demonstrated that zebrafish faithfully recapitulate hallmarks of human IS. We identified disruptions in cerebrospinal fluid flow/homeostasis and neuroinflammation as drivers of zebrafish IS, and found that pharmaceutical immunomodulation suppresses spinal curvature. As scoliosis develops and progresses slowly, an embryonic phenotype linked to scoliosis would facilitate small molecule suppressor screening for mechanisms underlying spinal curvature, while revealing targets amenable to therapy development. Herein I establish zebrafish embryonic ventral tail curvature as a functional scoliosis surrogate model. In exploiting this discovery, I identified novel chemical therapy in a new zebrafish model of IS and implemented a high-throughput embryonic screening platform providing potentially translatable biology and therapeutic targets.
A Deep Learning-based Cyberattack Detection and Mitigation System for Transmission Protective Relays
Keywords: Anomaly Detection
Cyberattack Detection Systems
Cyberphysical Systems
Deep Learning
Operational Technology
Transmission Protective Relays

There is a pressing need for the development of cyberattack detection and mitigation systems for substations and in particular protective relays, a critical component of substation operation. Multiple false transmission line trippings initiated by coordinated cyberattacks on protective relays can cause large scale power disturbances and cascading failures. This thesis presents a deep learning-based cyberattack detection and mitigation system (CDMS) for transmission line protective relays. The proposed CDMS consists of a convolutional autoencoder based anomaly detector that is first trained with power measurements representing various types of fault and fault-free conditions. The CDMS is then employed to detect measurements that are maliciously injected by an attacker. The proposed CDMS is evaluated under a variety of cyberattack scenarios and is capable of blocking most attacks without interfering with normal relay operations. This thesis also evaluates the security and robustness of the machine learning model within the CDMS under a white-box attack.
Spatial Variation of Circadian Gene Expression in the Rodent Brain
Keywords: Brain
Circadian rhythm
Melatonin

The brain plays a major role in the coordination of circadian rhythms in the body. However, it has been demonstrated that circadian transcriptome oscillations in the bulk brain exhibit dampened amplitude compared to peripheral organs. This paradoxical phenomenon can be explained by the complexity of anatomical structures within the brain which may exhibit phase differences in the expression of circadian genes. To address this question, we investigated Per2 and Arntl expression during the circadian cycle in thousands of isometric voxels in the rat brain. We identified a previously uncharacterized spatiotemporal organization of circadian rhythms in the brain. The acrophase time of Per2 and Arntl expression is incrementally delayed with increasing distance from a caudomedial region of the brain. Our results confirm circadian heterogeneity of the brain and point at a new mechanism of phase regulation across brain regions.
A Novel Memory Paradigm to Examine Behavioural Pattern Completion and Pattern Separation
Keywords: episodic memory
humans
pattern completion
pattern separation

Pattern completion and pattern separation are distinct computational mechanisms that support episodic memory. Human studies manipulate image completeness to index behavioural pattern completion (BPC). Study-test image similarity is manipulated for behavioural pattern separation (BPS), which is assessed in the Mnemonic Similarity Task (MST). The MST, however, does not directly index BPC, and rather attributes generalization of similar items (lures) as previously studied to BPC. The goal of the current study was to modify the MST to directly assess BPC (by varying image completeness at test) and BPS (by varying image similarity at test) in one session. Participants (n=51) made ‘old’/‘new’ judgements to distinguish among studied and novel images. Results showed a positive correlation between BPS and BPC and no correlation between lure generalization and BPC. Our findings indicate that BPS and BPC may share underlying neural mechanisms. Contrary to previous interpretations of MST performance, these results suggest that lure generalization and BPC are independent.