VictorJuiz/thesis huggingface dataset:
RanBP2 Regulates the Translation of the IL6 Reporter and Nuclear mRNA Export of Reporters Containing a 5’ Splice Site Motif
Keywords: ANE1
IL6
miRNA regulation
mRNA export
mRNA translation
RanBP2

Previously, a sequence element resembling a consensus 5’ splice site (5’SS) motif was found to function as a nuclear retention element when found in the 3’ untranslated region (UTR) of the fushi taratsu (ftz) reporter mRNA. I have identified RanBP2 as one of the protein factors that is involved in the nuclear retention of 5’SS-containing transcripts such as ftz. Mutations in RanBP2’s N-terminal region confer genetic risk for the pediatric neurological disease called acute-necrotizing encephalopathy (ANE1). ANE1 patients experience pathological cytokine protein production after flu infection. RanBP2 has previously been found to translationally regulate mRNAs encoding for secretory proteins. I have now shown that RanBP2 can repress the translation of the IL6 reporter mRNA, which is one of the secreted cytokine proteins aberrantly up-regulated in ANE1 patients. I’ve shown that RanBP2 requires the let7 miRNA binding site within the IL6 3’UTR to carry out this translational regulation.
Elucidating the Roles of H3K4 Methyltransferases in Caenorhabditis elegans Small RNA Pathways
Keywords: Epigenetics
H3K4
Histone methylation
Histone methyltransferase
Small RNA pathways

Endogenous small RNA pathways utilize several classes of small RNAs to direct gene regulation, both in the cytoplasm at the post-transcriptional level and in the nucleus at the transcriptional level. One mechanism of small RNA/AGO-mediated transcriptional regulation is the alteration of histone modification profiles, which thereby alters chromatin conformation and accessibility of gene promoters to the transcriptional machinery. Defects in components of nuclear endogenous RNAi pathways, such as AGOs, have been shown to lead to heritable changes in the distribution of histone methylation in Caenorhabditis elegans and other organisms. However, the mechanism by which small RNA pathways regulate histone methylation is not well understood. I investigated the mechanism by which small RNA pathways affect and engage with H3K4 methylation pathways in C. elegans. While I did not uncover effects on H3K4 methylation or roles for H3K4 methyltransferases in epigenetic resetting or heritable silencing of an RNA interference target, this study has revealed a previously uncharacterized putative histone methyltransferase as an H3K4 methyltransferase.
Psychiatric Utilization Prior to Cancer Diagnosis: Implications for Survival Outcomes and Suicidal Death Among Incident Solid Organ Cancer Patients
Keywords: Cancer
Oncology
Psychiatric Utilization
Psychiatry

Background: A cancer diagnosis is associated with psychiatric morbidity. I assessed the impact of pre-cancer psychiatric utilization (PU) on cancer-specific mortality (CSM), and the effect of cancer on suicidal death. Methods: Solid-organ cancer patients were assigned a PU gradient (PUG) score, 0 – none; 1 – outpatient; 2 – emergency department; 3 – admission. A multivariable cause-specific hazard model (CSHM) assessed the effect of PUG score on CSM. To assess the effect of cancer on suicide, patients were matched to non-cancer controls and compared using marginal CSHM. Results: Compared to PUG 0, PUG 1 patients had increased risk of CSM (HR 1.05, 95%CI 1.04-1.06), as did PUG 2 (HR 1.36, 95%CI 1.30-1.42) and 3 (HR 1.73, 95%CI 1.63-1.84). Cancer patients were more likely to die of suicide than controls (HR 1.34, 95%CI 1.22-1.48). Conclusions: Pre-cancer PU is independently associated with worse CSM. A cancer diagnosis is associated with increased suicide risk compared to controls.
Hardware Classification of Circulating Tumour Cells and Clusters
Keywords: Circulating tumour cells
CTC
CTC Clusters
Hall sensor

Circulating tumour cells (CTCs) are rare cancerous cells that disperse into the bloodstream from a primary tumour. Study of heterogenous CTCs have the potential to yield insights into the development and treatment of cancer. It is therefore of interest to develop non-invasive methods to sort and enumerate small numbers of rare CTCs into subpopulations to aid the characterization of these cells. This thesis reports a new integrated microfluidic device that counts and profiles CTCs according to their biomarker expression. Single cells and clusters of cells in blood are detected using Hall sensors made from monolayer graphene. The Hall sensors are integrated with magnetic separation methods to profile CTCs based on their epithelial surface markers. The integrated devices automate the non-invasive capture, selective release and enumeration of rare cells in blood. The capabilities of the integrated sensors are confirmed using experimental work with cell lines and with a xenografted mouse study.
Urban to Rural Migration for Employment Reasons: An Examination of Immigrant Settlement Needs in Rural Ontario
Keywords: Immigration
Integration
Newcomers
Rural
Settlement
Skilled employment

Canada depends on immigration to contribute to the growing economy and to stabilize the population. Although the majority of immigrants to Canada are highly skilled and educated, they experience high rates of unemployment and underemployment, typically in urban areas. Meanwhile, small towns and rural areas require more skilled labour to satisfy economic and demographic declines. Working in partnership with the Newcomer Centre of Peel (NCP), this research examines the potential of NCP’s Rural Employment Initiative, which seeks to connect talented newcomers with employment opportunities in rural areas of Ontario. Using focus groups with 50 skilled newcomers interested in urban to rural relocation, this research examines perceived newcomer settlement and integration needs and challenges to be faced in rural areas. Findings show employment and welcoming communities are fundamental to newcomer integration, and collaboration between stakeholders is necessary to ensure that these economic and socio-cultural integration needs of newcomers are met.
Is Hospital Type Associated with Application of Best-evidence Treatment Recommendations for Children’s Low-risk Distal Radius Fractures Treated in Ontario Emergency Departments?
Keywords: children
Evidence
Fracture
hospital
radius
wrist

Objectives: Investigate the association of hospital and physician type with the application of best-evidence treatment for low-risk distal radius fractures in children aged 2-14 treated in Ontario emergency departments from 2003-2015. Methods: Retrospective population-based cohort study using administrative data. Multivariable log binomial regression was used to quantify associations between hospital and physician type and best-evidence treatment. Results: 70,801 fractures were analyzed. Only 21% received best-evidence care. Significant associations were identified between best-evidence treatment and paediatric (RR 1.16, 95%CI 1.07-1.26), community (RR 1.13, 95%CI 1.06-1.20), or small (RR 1.86, 95%CI 1.72-2.01) hospitals, and treatment by FP/GP (RR 1.09, 95%CI 1.02-1.16), paediatrician (RR 1.22, 95%CI 1.11-1.34), or subspecialty paediatric emergency medicine training (RR 1.73, 95%CI 1.56-1.92). Conclusion: Hospital and physician types involved in generating best-evidence are most successfully implementing it.
Geotechnical Properties of Tailings Effect of Fines Content
Keywords: Critical State Line
Fines Content
Liquefaction
State Parameter
Tailings
Triaxial Test

Liquefaction assessment of mine tailings is currently done using empirical correlations that were developed using data mostly collected in natural soils; their applicability to tailings is yet to be proven. In-situ density represented by the state parameter is the key link between liquefaction susceptibility and the Cone Penetration Test (CPT) measurements that are commonly used to characterize tailings. Quantifying the interdependence of gradation, in-situ state parameter, and CPT measurements is a first step towards developing tailings-specific liquefaction assessment methods. The effect of fines content and gradation on the soil properties and the interpretation of the CPT tip resistance was assessed for Base Metal Tailings. Five gradations with fines contents ranging from 0% to 100% were tested. A series of tests were conducted to evaluate the critical state parameters, shear modulus (G), coefficient of lateral earth pressure at rest (K0), particle shape, and mineralogy.
Transceiver Modelling for High-speed Serial Links
Keywords: Analog-Mixed Signal
CDR
Equalizer
Modelling
Simulation
Transceiver

This thesis deals with evaluating the transceiver circuitry employed in high-speed serial links. Contributions from the thesis can be divided into two segments: object-oriented programming based simulation and step response based modelling for transceiver circuitry. During the object-oriented programming based simulation, each circuit block is treated as a circuit object with the capability to independently simulate its behaviour facilitated through encapsulated properties and methods. The proposed object-oriented scheme incorporates the conventional time-step based analysis into the event-driven simulation in order to support asynchronous circuitry evaluation, while maintaining simulation speed comparable to that of the event-driven scheme. Later, the thesis focuses on step response based on modelling for equalizer and clock and data recovery (CDR) circuit systems to capture their circuit-level nonlinearity during the simulation. It is demonstrated how to generate Spectre-like eye diagrams for equalizers and to describe transistor switching transient and clocking frequency saturation effects for CDR.
Ozone/Peroxide Advanced Oxidation in Combination with Biofiltration for Taste and Odour Control and Organics Removal
Keywords: advanced oxidation process
biofiltration
disinfection by-products
hydrogen peroxide/ozone
Ozone
taste and odour

Ozone (O3) prior to biofiltration can be an effective treatment strategy to achieve multiple drinking water quality goals. These goals include primary disinfection, improved removal of biodegradable organic carbon (generated as a result of ozonation), and oxidation of geosmin and MIB. However, O3 efficiency is dependent on source water characteristics, which impacts performance. This pilot study investigated the effectiveness of advanced oxidation incorporating O3 and hydrogen peroxide/ozone (H2O2/O3) with biofiltration (containing biologically active carbon (BAC) and anthracite) for geosmin and MIB control and disinfection by-product (DBP) precursor reduction. Application of 0.2 H2O2/O3 (mg/mg) prior to BAC resulted in optimal MIB and geosmin removal, especially in cold-water conditions (T = 10°C). In warmer temperatures (22°C), BAC alone was a suitable treatment technology for both geosmin and MIB. In terms of DBP precursor reduction, 0.1 H2O2/O3 (mg/mg) in combination with BAC was found to be the most effective treatment strategy with 37% THM and 10% HAA precursor reductions.
MicroRNA-198: A Novel Tumour Suppressor in Prostate Cancer
Keywords: Epigenetics
microRNA
Prostate Cancer

microRNAs are small non-coding RNA molecules which act as modulators of gene function, and have been identified as playing substantial roles in cancer as both tumor suppressors and oncogenes. This project aims to examine miR-198's role in prostate cancer aggression by analyzing how it influences several hallmarks of cancer. Overexpression of miR-198 diminished proliferation of prostate cancer cell lines and significantly impaired colony formation. Elevated miR-198 abundance was also demonstrated to reduce growth and tumor formation in vivo using LNCaP xenografts. MIB1, an E3 ubiquitin ligase, was a miR-198 target that was reduced with miR-198 overexpression at both the RNA and protein level, and knockdown of MIB1 recapitulated miR-198's effects on proliferation and colony formation. Our evidence supports miR-198 as an important tumor suppressor in prostate cancer, and highlights a potential role as a prostate cancer biomarker, or as a potential target of therapeutics to restore miRNA activity.
Dual-Frequency Ultrasound for Applications in Transcranial Therapy: Simulation and Experimental Results
Keywords: Blood-Brain-Barrier
Cavitation
Dual-Frequency
Focused Ultrasound
Microbubbles
Ultrasound

Recent developments in focused ultrasound (FUS) technologies have shown enormous potential to advance medical efforts in therapy, especially to targets in the central nervous system (CNS). One of the major limitations in treating disease in the CNS is the selective permeability of the blood-brain barrier (BBB); an interface responsible for regulating the transport of molecules between the circulatory system and the brain extracellular milieu. Recent work has uncovered the potential of FUS+microbubbles (MBs) to temporarily create localized BBB opening and permit the movement of target therapeutics into the CNS. However, FUS therapies are highly dependent on ultrasound frequency, particularly for transcranial targets where the incident FUS wave must pass through the highly attenuating and reflective skull bone. This thesis provides simulation and benchtop evidence that simultaneous, phase-controlled sonications of both high and low-frequency FUS can enhance or suppress MB activity at frequencies and pressures relevant to transcranial MB-mediated FUS therapy.
FIRST PRINCIPLES STUDY OF STRUCTURAL-MECHANICAL PROPERTY RELATIONSHIP OF TWO-DIMENSIONAL TRANSITION METAL DICHALCOGENIDES AND PHOSPHORENE ALLOTROPES
Keywords: Bond rotation
Density functional theory
Mechanics
Non linear elastic constants
Phosphorene
Transition metal dichalcogenides

The structural and mechanical properties of four Transition metal dichalcogenides (TMDs): Rhenium disulfide (ReS2), Rhenium diselenide (ReSe2), Niobium disulfide (NbS2), Niobium diselenide (NbSe2) and nine phosphorene allotropes under large strains were investigated using first-principles density functional theory (DFT) calculations. A complete set of nonlinear elastic constants upto the fifth order were determined for four TMDs. NbSe2 was found to withstand highest failure strain of 38% among four TMDs under uniaxial tension in armchair direction. The energy required to rotate a bond in NbSe2 was found to be significantly smaller than bond stretching. Alpha phosphorene could sustain tensile strain upto 31% and 24% under uniaxial tension in armchair and zigzag directions, respectively. This enormous strain limit of alpha phosphorene resulted from its unique puckered structure. The tensile strain applied in x direction stretched the pucker of phosphorene, rather than significantly extending the P-P bond lengths.
Multifactorial Immune Cell-Based Development of Heart Failure
Keywords: Adaptive Immunity
Cardiovascular Disease
Dendritic Cell
Heart Failure
Macrophage
Viral Myocarditis

The development of heart failure is a complex and multifactorial process. Risk factors such as prior viral cardiac infection and hypertension identify individuals at risk of developing heart failure, and the current literature has conflicting evidence about the role of individual cardiac immune cell subsets in these pathologies. Some of the contradictory results stem from the fact that immune cells within the myocardium have been characterized only superficially. In addition, the interaction between different risk factors, while clinically important, has been ignored at the basic science level. In this thesis, we first specifically define an important, yet uninvestigated cardiac immune subset â the dendritic cell (DC). We show the myocardium contains two specific conventional DC lineages (CD103+ and CD11b+), that possess unique, tissue-specific and lineage-specific mechanisms that regulate their life cycle and tissue residency. We identified cardiac CD103+ DCs as critical in inducing antigen-specific CD8+ T cell responses following subclinical viral myocarditis, and preventing the development of heart failure. In addition, chronic hypertension also predisposes mice to develop heart failure following subclinical viral myocarditis, highlighting that only by combining two risk factors, does heart failure develop.
Serial Sectioning for 3D Imaging under Scanning Electron Microscopy
Keywords: SBFSEM
Ultramicrotome

Serial block face scanning electron microscopy (SBFSEM) is a powerful method that can create 3D reconstructions of large volumes for morphology studies in micro or nano biological or materials science compared to conventional ultramicrotomy. It allows visualization of long, dense networked structures with nanoscopic resolutions. Despite its utility, the adoption rate is low because installing state-of-the-art systems require extensive modifications to the SEM chamber due to their large size. This thesis presents a prototype for a plug-and-play SBFSEM system using specially designed compact micro and nanopositioners that can be placed inside the SEM with no modifications to the SEM. Through iterations of empirical calculations, computer simulations, and prototyping, an ultramicrotome capable of cutting thin, uniform sections was designed. The function of the system was validated by sectioning and reconstructing a copper TEM grid of known dimensions. The reconstruction was accurate to within 1% of original dimensions.
Developing Gene Therapy Methods to Inhibit a BAG Family Co-chaperone Protein in Rat Substantia Nigra
Keywords: Adeno-associated virus
Gene therapy
Parkinson's disease
Short hairpin RNA
Substantia nigra

Parkinsonâ s disease (PD) is a progressive neurodegenerative disorder affecting dopaminergic neurons in the substantia nigra (SN). Bcl2-associated athanogene 5 (BAG5) is a co-chaperone that promotes dopaminergic cell death in animal models of PD and dopaminergic degeneration. BAG5 also inhibits Hsp70 and parkin, which are protective in animal models of PD, and interacts with several other proteins implicated in PD pathogenesis. Thus, BAG5 represents a promising therapeutic target for PD. This thesis describes the development of a viral vector that can deliver shRNA against BAG5 to rat SN. We identified shRNAs that efficiently knocked down BAG5 in two cell lines and packaged them into lentivirus (LV) and adeno-associated virus (AAV) 1/2 vectors. AAV-shBAG5 demonstrated superior expression in SN compared to LV. In rat SN, AAV-shBAG5 produced significant BAG5 knockdown and protected neurons from axotomy injury. This work provides the foundation for future studies of BAG5 knockdown in rat models of PD.
Development and Psychometric Evaluation of the Muscular Dystrophy Child Health Index of Life with Disabilities (MDCHILD) Questionnaire in Children with Duchenne Muscular Dystrophy
Keywords: Duchenne muscular dystrophy
Evaluation
Outcomes research
Paediatric
Patient priorities
Psychometrics

Objective: To adapt the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) to develop an outcome measure that reflects the health-related priorities of the DMD population and to test the psychometric properties of the resulting outcome measure. Method: Interviews with children with DMD and their primary caregivers followed by surveys with healthcare professionals informed the adaptation of the CPCHILD and sensibility evaluation of the new measure, the Muscular Dystrophy Child Health Index of Life with Disabilities (MDCHILD). Internal consistency, test-retest reliability, and construct validity of the MDCHILD were evaluated. Results: Instructions, scales and items were modified due to the input of stakeholders. The MDCHILD consists of 47 items over 7 domains. The MDCHILD demonstrated good internal consistency, excellent test-retest reliability, and strong evidence of construct validity. Conclusion: The MDCHILD is a promising outcome measure of health-related priorities for children with DMD.
The Role of Temperature, Nutrient Availability and Organo-mineral Interactions in Altering Soil Organic Matter Degradation
Keywords: Climate Change
Gas chromatography-mass spectrometry
Nuclear Magnetic Resonance spectroscopy
Organo-Mineral Interactions
Soil Warming

Increases in temperature and nutrient availability may accelerate soil organic matter (SOM) decomposition while organo-mineral interactions may potentially stabilize SOM components. After 32 years of warming, nitrogen and phosphorus (N+P) fertilization, and the combined treatment, SOM degradation was not significantly enhanced in Arctic soils. Considerable variability in the biomarker data may be attributable to spatial heterogeneity among the blocks. In the second project, biomarker investigations indicated that mineral interactions likely protect lignin from extraction. Suberin and cutin protection of lignin was not observed until after clay mineral dissolution by hydrofluoric acid (HF). This suggests that clay mineral interactions may play a more dominant role in the protection of lignin than interactions with suberin and cutin. Overall, this thesis demonstrates that biomarker methods can show how the distribution of SOM may be reflective of topographical patterns and can provide further evidence that mineral protection mechanisms help stabilize SOM components.
Role of Tankyrase Inhibitors in the Generation of NKX6-1+ Endoderm
Keywords: Beta cells
Diabetes
NKX6-1
Pancreas
Stem cells
Tankyrase

Despite continuous research efforts, there is still no cure for type 1 diabetes (T1D). Generating human β-cells from human pluripotent stem cells holds an unprecedented potential in treating T1D, as this approach could provide an infinite supply of physiologically suitable insulin-producing cells. However, emphasis must be directed towards an optimization of current differentiation approaches, which draw from recapitulating the developmental process of pancreas organogenesis. For β-cell differentiation, several key stages demand further investigation, such as driving the expression of NKX6-1, a transcription factor necessary for β-cell development. Our lab has performed a small molecule screen that has identified a class of small molecules capable of inducing an NKX6-1+/PDX1+ population in vitro, called tankyrase inhibitors. We have performed in vitro differentiation and transplantation into immunocompromised mice to confirm tankyrase inhibitor-treated populations generate β-like cells in vitro and in vivo. We describe a novel approach to generate pancreatic progenitor cells from hESCs.
Molecular Mechanism and Effects of Furan Fatty Acid Metabolite CMPF on Adipocytes
Keywords: Adipose tissue/adipocytes
CMPF
Diabetes
Fatty acid Metabolism
Hypothalamic NPY/AgRP neurons
Hypothalamic POMC neurons

In rodents, increased plasma level of CMPF caused preferential fatty acid utilization over glucose in the pancreatic Î˛ cells. Here, we aimed to investigate whether CMPF directly alters adiposity in adipocytes. Compared to CON-HFD, CMPF-HFD mice, which are administered with CMPF for one week prior to four-week HFD feeding, exhibited less adiposity in mice. However, in vitro and ex vivo fat models showed 1) absence of transporters of CMPF, 2) no CMPF accumulation, and 3) no change in fatty acid metabolism with CMPF treatment. Utilizing transfection studies, we showed that CMPF does not activate FFAR1 and FFAR4, however, it increased Ca+2i when transported through OATs. CMPF also did not activate hypothalamic NPY/AgRP and POMC neurons despite their expression of OAT(s). These studies identified the novel action of CMPF in increasing Ca+2i while allowing us to eliminate adipocyte and hypothalamic NPY/AgRP and POMC neurons as direct targets of CMPF.