VictorJuiz/thesis huggingface dataset:
Efficient Enumeration of Branched Novel Biochemical Pathways in the Complex Biochemical System

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.

Keywords: biochemical pathway
bioinformatics
machine learning
metabolic engineering
probabilistic technique
Advisor: Mahadevan, Radhakrishnan
Interactions of Disease-associated Nucleic Acids Repeats with Ligands and Proteins

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.

Keywords: ALS
C9orf72
neurodegenerative
neuromuscular
non-canonical structures
repeat expansion diseases
Advisor: Macgregor Jr., Robert B
Formulation of Oil Spill Dispersants using Biobased Surfactants and the Study of Flow-induced Breakup of Floating Oil Drops

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.

Keywords: Couette flow
dispersant formulation
drop breakup
floating oil
HLD (Hydrophilic-Lipophilic Difference)
oil spill
Advisor: Acosta, Edgar
Ramachandran, Arun
Genetic and Chemical Genetic Approaches to Identifying Liabilities in Malignant Brain Cancer

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.

Keywords: Chemogenomic
CRISPR-Cas9
Glioblastoma
HAP1
PTC-028
Recurrent
Advisor: Moffat, Jason
Characterization of the Microtubule Organizing Centres in Osteoclasts

Osteoclasts are highly specialized, multinucleated cells responsible for the selective resorption of bone matrix during bone remodeling and the pathological bone destruction found in osteoporosis. Our study investigated the origin of microtubules during osteoclast differentiation and bone resorption. Microtubule nucleation is generally restricted to specific subcellular sites called microtubule organizing centres (MTOCs) and is primarily fulfilled by the centrosome in metazoan cells. While mononuclear osteoclast precursor cells contain centrosomal MTOCs, previous research has suggested that functional centrosomal MTOCs do not exist in multinucleated osteoclasts. Through live-cell imaging, immunofluorescence, and ultrastructural analyses, we observed that most, if not all centrosomes donated from precursor cells remained individually functional and clustered early during osteoclastogenesis. Furthermore, by visualizing Golgi reorganization and Golgi-derived microtubules, we identified the Golgi as a possible non-centrosomal MTOC that potentially facilitates polarized microtubule arrays in osteoclasts. Together these findings show that multinucleated osteoclasts employ unique centrosomal and non-centrosomal MTOCs to organize microtubules.

Keywords: Bone
Centrosome
Golgi
Microtubule
MTOC
Osteoclast
Advisor: Harrison, Rene E
Risk Factors for Alzheimer’s Disease and Cortical Thickness in a Population-Based Sample of Middle-Aged Men and Women

Alzheimer’s Disease (AD) is a neurodegenerative disorder with a decades-long preclinical phase. Preclinical stages of AD are associated with cortical thinning. Female sex and age, as well as several genetic and modifiable metabolic factors increase risk for AD. Therefore, here I examined, in a population-based sample of younger (

Keywords: Alzheimer's disease
Cortical Thickness
Risk Factors
Advisor: Pausova, Zdenka
Protein Capture on Multiwavelength SERS Substrates: A Study on Width-Graded Plasmonic Gratings and Cytochrome C

Multiwavelength width-graded nano-gratings have been shown to localize high electric fields and thus are strong surface-enhanced-Raman-spectroscopy (SERS) substrate candidates for disease detection. The 2D geometry of graded gratings, however, produce a small sensing volume. Moreover, the bare silver (Ag) surfaces exhibit a positive charge in aqueous environments which impedes the accumulation of positively-charged analytes at the SERS hotspots of the grating surface. In this thesis, we demonstrate the efficacy of Ag surface functionalization to overcome both issues using cytochrome c (Cc) as a model biomolecule. By preparing self-assembling monolayers (SAMs) of 16-mercaptohexadecanoic acid (MHDA) on Ag, we achieved SERS detection of Cc at 1μM. Further, the MDHA SAM allows for immobilization of Cc onto the Ag surface for detection in dry phase, an approach that produced stronger Raman signals compared to those from solution phase. We conclude with promising generalization of our approach to detection of other biomolecules of interest.

Keywords: biosensor
cytochrome c
electron beam lithography
multiwavelength
self-assembling monolayer
surface enhanced Raman spectroscopy
Advisor: Kherani, Nazir P
Classifying Schizophrenia Based on Response to Antipsychotic Medications

Clozapine is the main treatment for patients with significant psychotic symptoms despite adequate trials of non-clozapine antipsychotics. However, 40-70% of patients show suboptimal response to clozapine. We aimed to: (1) examine the relationship between delay in initiating clozapine and treatment outcomes through a literature review; (2) examine clozapine response/non-response trajectories and predictors of long-term non-response through a retrospective chart review; and (3) determine the relationships between glutamatergic neurometabolites and cortical thickness through a cross-sectional imaging study. Delay in initiating clozapine and number of hospitalizations were associated with poor clozapine response. Further, response trajectories ranged from sustained response or non-response to developed response or non-response. Finally, glutamatergic neurometabolite levels in the dorsal anterior cingulate cortex were associated with cortical thinning in the right prefrontal cortex in patients with treatment-resistant schizophrenia, independent of age, sex, treatment, and illness severity. This work advances our understanding of treatment-resistant schizophrenia from clinical and neuropathological perspectives.

Keywords: Clozapine
Outcomes
Predictors
Psychosis
Response
Schizophrenia
Advisor: Graff-Guerrero, Ariel
Gerretsen, Philip
Transforming Existing Stateful Network Protocol Applications into Effective Protocol-Specific Security Testing Tools

To discover low-level security vulnerabilities in target applications that implement stateful network protocols, security researchers usually employ manually-constructed protocol-specific testing tools. Due to the complexity and heterogeneity of network protocols, however, building such tools for every network protocol used by target programs is a challenging task. We propose a semi-automated technique for creating protocol-specific testing tools, which leverages an existing application that implements a network protocol (a source), and converts it into a testing tool that can be used for bug discovery in any target program that “speaks” the same protocol. We call our implementation of this method InSource, and, by measuring coverage gain, show that InSource can test a target just as well a manually-created protocol- specific testing tool. Furthermore, we show that InSource is effective at testing applications that use different protocols, as long as a source application for each protocol is available.

Keywords: Protocols
Security
Testing
Vulnerabilities
Advisor: Lie, David
Magnetic Swarm Control for Active Embolization

Conventional embolization strategy using agents such as polymer particles lacks the ability of active control after the particles are released into the bloodstream, thus risking damaging healthy tissues with unintended occlusion. This thesis presents a new magnetic swarm control to achieve targeted embolization by maintaining (vs. periodically lowering) the magnetic force interactions of swarm for aggregation (vs. disassembly) within (vs. outside) the confined region under continuous flow. The dynamic of swarm was studied to determine the required minimum magnetic force and the corresponding strength of magnetic field to form aggregation. A model of magnetic field and an algorithm of electric current determination were created to spatially and temporally generate a magnetic field rotating pattern to differentiate the aggregation inside and outside the target region. The magnetic system was validated on a microfluidic model and a porcine omentum tissue using swarms of 1 µm thrombin-coated magnetic particles in a physiological flow.

Advisor: Sun, Yu
The Impact of the Repeal of the 2015 Health Physical Education Curriculum on Ontario Teachers

This project analyzes how the repeal of the 2015 Health Physical Education curriculum for Grades 1-8 impacted Ontario teachers. Eight Grades 7-12 teachers from one school board in southern Ontario were interviewed. Interviews found that participants faced major constraints in teaching sex education, both before and after the repeal. All participants disagreed with the repeal of the 2015 curriculum and felt the 2018 interim curriculum did not meet the needs of students. Both elementary and secondary teachers expressed concern over teaching sexual health topics over the 2018-2019 school year due to the political tension surrounding sex education. Teachers who felt supported by their school administration felt more comfortable teaching sex education over the 2018-2019 school year than those who lacked administrative support. This study emphasizes the chaos surrounding sex education following the 2018 Ontario election, the danger of relying on outdated curriculum, and the importance of comprehensive sexuality education.

Keywords: Comprehensive Sexuality Education
Doug Ford
Health Physical Education
Ontario
Sex Education
Sexuality Education
Advisor: Bialystok, Lauren
Identification and Characterization of T Cell-inflamed vs non-T Cell-inflamed Tumours based on Chemokine Expression Reveals Distinct Immunophenotypes in Primary and Metastatic Tumours in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate of all solid tumours. Despite progress in other cancers, immunotherapy remains ineffective against this malignancy. This is, in part, due to a paucity of CD8+ T cells in most pancreatic cancer tumours. Here, we investigate the role of chemokines in CD8+ T cell infiltration in PDAC. Analysis of 79 primary resections uncovered a panel of chemokines associated with infiltration, consisting of CCL4, CCL5, CXCL9, and CXCL10. Segregating 113 resections based on expression of this panel, those with higher expression had increased immune activation signatures; including MHC I presentation, dendritic cell (DC) activation, and Batf3-driven DC presence, with no differences in mutational nor neoantigen load. Results were consistent across three independent cohorts, including 107 liver metastases, suggesting conserved immunobiology between primary and metastatic sites. Taken together, these results suggest a potential role for these chemokines in CD8+ T cell recruitment in PDAC.

Keywords: Bioinformatics
Chemokines
Immunology
Metastases
Pancreatic Cancer
T lymphocytes
Advisor: Gallinger, Steven
Investigating the Roles and Regulation of Testis-specific eIF4Es during Drosophila Spermatogenesis

Translational regulation is an important mechanism for controlling gene expression, and is associated with maintaining cellular homeostasis and regulating aspects of development. Eukaryotic initiation factor 4Es (eIF4Es) are mRNA cap-binding proteins required for the initiation of translation. Although most eukaryotic genomes encode several paralogs of eIF4E, their roles and regulation remain largely uncharacterized. Drosophila melanogaster has eight paralogs and four of them are enriched in the testis (eIF4E-3, -4, -5 and -7). These paralogs are expressed at distinct stages of spermatogenesis, suggesting they have differential roles. Further characterization of eIF4E-5 demonstrated that it is involved in polarization and individualization of spermatids, likely via localized translation of aPKC and Soti. In addition, eIF4E-5 works in the same pathway as Orb2 to regulate these cellular processes. Overall, my results suggest that the Drosophila male germline serves as an excellent model to examine mechanisms regulating eIF4Es in translation initiation.

Keywords: Drosophila
eIF4E
gene expression
spermatogenesis
translational control
translation initiation
Advisor: Brill, Julie A
Novel Industrial Scale Radio Frequency Inductively Coupled Plasma Torch

A novel industrial scale radio frequency inductively coupled plasma (RF-ICP) torch design is proposed which uses a conical geometry. The objective of this thesis is to investigate whether this geometry can provide reduced gas power consumption and a higher quantity of spheroidized (i.e., melted) particles. The investigation is conducted using computational fluid dynamic simulations in ANSYS Fluent by simulating the injection of powder particles into the plasma discharge produced by the RF-ICP torch. Simulations are performed to optimize the conical torch and compare its performance to a conventional RF-ICP torch. It is found that the new conical torch achieves spheroidization ratios up to 2 times higher than the conventional torch, due to higher temperatures and an induction zone closer to particles. Additionally, it runs at 42% lower gas consumption and can achieve industrially acceptable spheroidization ratios at half the power level of the conventional torch.

Keywords: computational fluid dynamics
heat transfer
industrial
nanoparticle synthesis
powder spheroidization
radio frequency inductively coupled plasma
Advisor: Mostaghimi, Javad
Receipt of Overactive Bladder Drugs and Incident Dementia: a Population-based Case-control Study

Second-line treatment for overactive bladder (OAB), consists of muscarinic antagonists or β-3 agonists. There is limited knowledge about the differential risk of incident dementia associated with receiving the various OAB drugs available. We conducted a population-based case-control study, where cases with incident dementia were age- and sex-matched to controls from the general population. We performed multivariate conditional logistic regression to estimate the odds of incident dementia associated with receiving individual OAB antimuscarinics, relative to a β-3 agonist, mirabegron. Patients had an increased odds of incident dementia associated with receiving antimuscarinic drugs, solifenacin (OR 1.24; 95% CI 1.08-1.43) and darifenacin (OR 1.30; 95% CI 1.08-1.56), compared to those receiving mirabegron, in the six months prior to diagnosis. In the six months to one year prior to diagnosis, receipt of any OAB antimuscarinic was associated with increased odds of incident dementia (OR 1.29; 95% CI 1.09-1.54), compared to receipt of mirabegron.

Keywords: Adrenergic beta-3 Receptor Agonists
Case-Control Studies
Dementia
Muscarinic Antagonists
Urinary Bladder
Overactive
Urological Agents
Advisor: Nam, Robert K
Examining the Efficacy and Mechanism of a Peptide Modified Hydrogel for Wound Healing Applications

Wound healing is a pandemic, challenging doctors, patient quality of life, and healthcare dollars. Current research is focused on developing a multi-modal approach which seeks to heal wounds during all phases of healing, as opposed to tackling one. Using the QHREDGS (Q- peptide)-hydrogel, we seek to elucidate the mechanistic effect of the Q-Peptide on the immune system, specifically evaluating macrophage polarization and how this may affect scar formation. When cultured in the presence of the Q-Peptide, bone marrow derived macrophages differentiated into a novel polarization that is favourable in promoting wound healing. Further, in a clinically relevant model of healthy human healing, the Q-Peptide accelerated and attenuated scarring. This research suggests that the Q-Peptide hydrogel supports wound healing by enacting a response on all phases of healing, adding motivation driving the clinical translation of this biomaterial.

Keywords: Biomaterials
Hydrogel
Immune-modulating
QHREDGS
Wound Healing
Advisor: Radisic, Milica
Immuno-mass Spectrometric Identification of Predictive Biomarkers of Response and/or Toxicity to Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) are humanized antibodies that target specific inhibitory molecules, such as programmed cell death protein 1 (PD-1) and its ligand, PD-L1. The limitations of ICIs are high cost, limited response rate and development of immune-related adverse events (irAEs). Predictive and monitoring biomarkers of ICIs are an unmet need. We hypothesized that patients who develop irAEs will produce specific autoantibodies indicative of an autoimmune-like response. We developed a novel methodology that involves immunoaffinity purification of serum autoantibodies, incubation with target autoantigens and mass spectrometric identification of autoantibody targets. Using our methodology and electrochemiluminescence immunoassay for validation, we found that patients treated with pembrolizumab have anti-thyroglobulin antibody titers that are significantly associated with irAE development. Furthermore, we identified several potential autoantibody targets in a patient with ICI-induced myocarditis. Predictive biomarkers of ICIs will save significant resources, ensure proper patient selection for treatment, and spare certain patients from irAEs.

Keywords: Biomarkers
Immunotherapy
Mass Spectrometry
Advisor: Diamandis, Eleftherios P
Genome-wide Investigation of Short Tandem Repeat Variation in Autism Spectrum Disorder

Short tandem repeats (STRs) may contribute to the genetic etiology of autism spectrum disorder (ASD) since several pathogenic STRs are ASD risk factors. Screening for STR variation may uncover novel risk loci, however, this was previously hindered by the difficulty of aligning repetitive sequences in whole genome sequencing (WGS) data. Recently, several tools have been developed to genotype STRs from WGS data. In this study, a STR genotyping pipeline was created to perform a genome-wide screen for repeat variation in an ASD genomic database, MSSNG. This work uncovered 4925 STRs, and variation was identified in ASD-risk loci, repeat disorder genes, and other pathogenic loci. In particular, repeat expansions upstream of the CRYBB2 gene were seen significantly more frequently in individuals with ASD than a control population. These findings suggest that this STR genotyping pipeline can detect repeat variation in ASD, and may lead to the discovery of novel candidate loci.

Advisor: Scherer, Stephen W
Yuen, Ryan KC
End-to-end Network Slicing for Flash Crowds in Multi-region Cloud Platform

End-to-end network slicing is an auspicious paradigm, which promises to lead the way towards efficiently addressing the problems of legacy networks. Based on softwarization and virtualization, it is capable of enabling network as a service (NaaS) and allow the coexistence of multiple networks on the same physical infrastructure. These features make network slicing suitable for mission-critical scenarios, including flash crowds and emergency situations, and foster the required system performance. In this thesis, we design and implement an end-to-end network slicing platform aiming to deploy agile, flexible and scalable network architecture. We provide insights into the emergency scenarios and elaborate on the system requirements that it needs to fulfill. In order to evaluate the performance of NaaS, we implement a wireless testbed featuring fully virtualized systems, and conduct a series of experiments. We present evaluations to validate the proposed slicing model and demonstrate its applicability for flash crowds.

Keywords: 5G
End-to-end network slicing
Flash crowds
Management and Orchestration
Network Function Virtualization
Software Defined Networking
Advisor: Leon-Garcia, Alberto