VictorJuiz/thesis huggingface dataset:
Overlapping Roles of Iroquois Homeobox Genes 3 and 4 in the Compaction of the Ventricular Myocardium

Left ventricular noncompaction (LVNC) is a primary congenital cardiomyopathy characterized by prominent trabeculation and intra-trabecular recesses in the ventricular wall. Its genetic basis and pathologic mechanism remain largely unknown. Here it is shown that Irx3;Irx4 double knockout (DKO) mouse mutants represent a novel model of LVNC. Irx3 and Irx4 belong to the family of Iroquois homeobox (Irx) genes, encoding transcription factors important for cardiac function. Mice lacking either Irx3 or Irx4 do not have gross cardiac malformations. In contrast, Irx3;Irx4DKO mice exhibit postnatal lethality and thinner ventricular walls as early as E14.5. By P14, DKO mice have prominent noncompacted trabeculation and abnormal muscular growth that resemble human LVNC. Furthermore, Irx3;Irx4DKO hearts exhibit increased expression of heart failure marker genes, elevated Bmp10 pathway activity, and altered pattern of cardiomyocyte proliferation, each of which are implicated in the pathogenesis of LVNC. Taken together, these studies suggest that Irx3 and Irx4 possess overlapping functions, which are essential to myocardial compaction.

Keywords: Cardiac development
Iroquois
LVNC
Advisor: Hui, Chi-chung
Developing an Auditory Hybrid Brain-computer Interface Based on Near-infrared Spectroscopy and Electroencephalography

Auditory brain-computer interfaces (BCIs) serve as an access pathway for individuals who present as locked-in and have concomitant visual impairments, but they do not perform as well as visual BCIs. Since hybrid BCIs that combine electroencephalography (EEG) and near-infrared spectroscopy (NIRS) outperform unimodal BCIs in motor imagery tasks, we hypothesized that such a hybrid BCI would outperform a unimodal BCI in an auditory oddball task. Eleven non-disabled adults (aged 25.6 Âą 3.3) participated in two offline sessions and eight returned for a third online session. While combined EEG-NIRS classification did not outperform EEG-exclusive classification, combined classification does show modest gains in 2 participants when using all the NIRS data but constraining the EEG data to only a single oddball. In conclusion, NIRS offers limited benefits in terms of classification in a prolonged auditory task paradigm, but future research should focus on optimizing task duration for EEG and NIRS classification.

Keywords: alternative communication
auditory
brain-computer interface
electroencephalography
hybrid
near-infrared spectroscopy
Advisor: Chau, Tom
Identifying Novel Mechanisms of Genome Maintenance in Saccharomyces cerevisiae using the DNA Damage-inducibility of Ribonucleotide Reductase

The identification of genome maintenance genes in Saccharomyces cerevisiae has been limited to loss-of-function screens that ignore the consequences of gene overexpression. Here, I assay expression of the DNA damage-inducible gene, RNR3, using reporter synthetic genetic array (R-SGA) methodology to identify genes that result in genome instability when overexpressed. I find 41 of ~5100 genes screened result in increased RNR3 expression, including known DNA repair genes, transcriptional regulators of RNR3, and a subset of genes exhibiting elevated levels of spontaneous DNA damage as determined by the presence of Rad52 foci. 61% of genes identified had no reported connection to genome stability when compared to previous overexpression studies, leaving 25 novel putative genome maintenance genes for follow-up. Finally, I show that induction of RNR3 in known genome instability mutants is not always dependent on the upstream checkpoint kinase Dun1, suggesting a non-canonical Dun1-independent pathway for RNR3 up-regulation following checkpoint activation.

Advisor: Brown, Grant W
Galectin-9 inhibits B cell receptor (BCR) signaling by regulating BCR organization and mobility

B cells are part of the adaptive immune system and secrete antibodies targeting foreign pathogen (referred to as antigen). B cells are activated by binding of antigen to the antigen-specific B cell receptor (BCR), which initiates downstream signaling cascades necessary for the production of antibodies. Recent data from our lab identified that the glycan-binding lectin known as galectin-9 (Gal-9) binds to IgM-BCR and inhibits B cell activation. However, the molecular mechanism for Gal-9 mediated inhibition B cell activation is still unknown. In this study, we showed that exogenous Gal-9 reorganizes IgM-BCR into larger clusters within the Gal-9 lattice, and concomitantly immobilizes IgM. We also demonstrated that Gal-9 increases the density of inhibitory molecules including CD45 and CD22 together with IgM-BCR in the Gal-9 lattice, consistent with the inhibitory effect of Gal-9 on B cell activation. These findings elucidate a novel extracellular mechanism to regulate signal transduction through BCR.

Keywords: B cell
BCR
galectin 9
Advisor: TREANOR, BEBHINN
The Role of RGMa/Neogenin Signaling in Experimental Autoimmune Encephalomyelitis

Repulsive Guidance Molecule A (RGMa) and its receptor, Neogenin, have been reported to play an important role in the developing chick visual system. More recently, RGMa have been implicated in playing a crucial role in the development of Experimental Autoimmune Encephalomyelitis. Here, we show that by blocking the RGMa/Neogenin interaction using a small blocking peptide, we are able to ameliorate the clinical severity of the disease in mice receiving this treatment. Furthermore, we show that this treatment helped maintain blood brain barrier (BBB) integrity. Given its effects on the BBB, we then investigated whether RGMa and Neogenin played a role in modulating the immune system. In an overnight LPS stimulation assay, we report promising data showing a decrease in secretions of IFNď § and TNFÎą. All in all, the data presented here suggests that RGMa/Neogenin presents a novel and untapped therapeutic target, with very promising potential in context of MS treatment.

Advisor: Monnier, Philippe P
On the Competing Roles of Attractiveness and Group Membership in Person Evaluations

Individual preferences notwithstanding, studies on physical attractiveness have suggested that people largely agree about others’ attractiveness and favor attractive individuals. Though this attractiveness halo represents one of the strongest influences over social behavior, psychological literature has documented other robust biases as well. For instance, favoritism towards members of one’s own group guide much of a person’s thoughts and actions. Here, I investigated what happens when these two biases collide by examining how attractiveness affects implicit and explicit evaluations of ingroup and outgroup members. I hypothesized that group membership biases would cede to attractiveness biases; participants would prefer attractive individuals irrespective of group membership. However, whereas the results of Implicit Association Tests showed that participants’ evaluations of ingroup and outgroup targets differed more by group membership, semantic differential scales showed that explicit evaluations differed more by attractiveness levels. A person’s attractiveness and group membership therefore seem to separately affect others’ evaluations.

Keywords: Attractiveness
Group membership
Impression formation
Person perception
Advisor: Rule, Nicholas O
The Anticonvulsant Effects of 5a-dihydroprogesterone in the Rat Amygdala-Kindled Model

The present study investigated the anti-seizure effects of 5-dihydroprogesterone (5-DHP) in an animal model of human drug-resistant complex partial seizures - the rat amygdala-kindling model - using different routes of administration and solvents. 5-DHP in -cyclodextrin administered via the subcutaneous (SQ) route was weakly effective (Rmax=30%). 5-DHP via the intraperitoneal (IP) route in the "benzyl" vehicle, however, suppressed both generalized and focal seizures with ataxia shortly after injection; and generalized seizures around 130 minutes post-injection. The "benzyl" vehicle itself, however, was active at the earlier time, and benzyl alcohol was found to be anticonvulsant. 5-DHP in -cyclodextrin via the intravenous (IV) route suppressed both generalized seizures and focal seizures, with ataxia. A time-response IV study at 5mg/kg showed immediate onset of anticonvulsant action that lasted for about 60 minutes post-injection. In conclusion, 5-DHP demonstrated efficacy in the present study, and 5-DHP analogs might be developed as a new anti-seizure therapy.

Keywords: 5a-dihydroprogesterone
amygdala-kindling
DHP
epilepsy
Advisor: Burnham, Willets M
Mother to fetus transfer of probiotic lactobacilli in mice

Research suggests that the fetal environment is not sterile. The objectives of this study were to demonstrate the presence of bacteria in fetal tissues, including fetal intestine, and to characterize the transfer of probiotic bacteria (Lacidofil速: L. rhamnosus R0011 (95%) and L. helveticus R0052 (5%)) from mother to offspring during pregnancy in CD-1 and C57BL/6 mice. Total bacteria were quantified in the placenta, umbilical cord, and small and large intestine of fetuses derived from both strains of mice, with lactobacilli found to predominate. L. rhamnosus R0011 was quantified in 50% of large intestine and 33% of placenta samples of fetuses derived from CD-1 probiotic treated dams, but not in any fetal tissues derived from CD-1 control or C57BL/6 dams. These findings suggest that fetal tissues are not sterile and contain an abundance of lactobacilli, and that vertical transfer of microorganisms occur during gestation.

Keywords: Bacteria
Microbiology
Microbiota
Nutrition
Pregnancy
Probiotics
Advisor: Comelli, Elena M
A Novel Digital Memory Augmentation Device to Improve Autobiographical Memory in Older Adults

A promising approach to minimize the effects of autobiographical memory (AM) loss in aging is digital memory augmentation (DMA), whereby a device records information in one's day-to-day life for later review. Despite producing benefits to memory recall, current DMA protocols do not incorporate findings from the cognitive neuroscience literature which have been shown to improve memory. In the current study, we developed a novel DMA device which takes into account the neurobiology underlying AM, and various principles from cognitive psychology known to improve learning and memory. Participants used this device to record events and review them back in a speeded and distributed manner throughout the day. We found that using our DMA device specifically improved recall of episodic AM details without affecting recall of non-episodic AM details in older adults. We also found that using our DMA device improved immediate memory recall as measured by the Wechsler Memory Scale: Logical Memory Test (Wechsler, 2008). Furthermore, the benefits in episodic AM details derived from using our DMA device could be predicted by scores on the Montreal Cognitive Assessment (Nasreddine et al., 2005). The results of our study suggest that our novel DMA device can provide a means to improve episodic AM memory in older adults.

Keywords: aging
autobiographical memory
digital memory augmentation
episodic memory
Advisor: Barense, Morgan D
Examining the Impact of Item-Distractor Similarity Using a Validated Circular Shape Space

How does interference impact memory? Previous work on memory for colour suggest that the similarity of distracting information can differentially alter how visual representations are forgotten. In Experiment 1, we describe the creation of the Validated Circular Shape Space (VCS space), a novel â Shape Wheelâ whereby the subjective similarity of 360 shapes varied incrementally around a circular space. Pairwise shape similarity ratings were collected over a series of validation steps and multidimensional scaling was used to iteratively validate the shape space to ensure subjective circularity. In Experiment 2, we then used this set of shapes to assess how shape memory was impacted by distracting information that varied in subjective similarity relative to the study shape. We found that when distractors were similar to the studied shape, a significant benefit to memory accuracy was observed. When distractors were dissimilar to the studied shape, accuracy was significantly reduced. In contrast, no differences in precision was observed in any of the conditions relative to baseline. These results may imply the existence of surround suppression which acts to shield shape memory from the degradation of highly similar distractors. Overall, we have developed a novel circular shape space that is homogenous across individuals and show that memory for shapes can be systematically impacted by the subjective similarity of distractors.

Keywords: Interference
Mixture Model
Shape Wheel
Similarity
Advisor: Barense, Morgan D.
The role of Eph-ephrin signalling in the cell-to-cell spread of Listeria monocytogenes

Listeria monocytogenes is a Gram-positive human pathogen that has emerged as a model organism for studying intracellular parasitism. After cellular invasion, these bacteria escape the phagosome using the pore-forming toxin Listeriolysin O (LLO) and two phospholipases C. Expression of ActA allows Listeria to undergo actin-based motility in the cytosol, leading to formation of cell surface protrusions that can be engulfed by neighbouring cells, allowing cell-to-cell spread. Here, I demonstrate that ephrin-B1 plays an important role in restricting Listeria cell-to-cell spread. Ephrin-B1 restricts Listeria spread by limiting their ability to initiate protrusion formation. The pore-forming toxin LLO is known to promote cell-to-cell spread of Listeria and was found to be required for the increased spread observed in ephrin-B1-deficient cells. This suggests that LLO can promote protrusion formation/stability in the absence of ephrin-B1. Collectively, ephrin-B1 functions as a specific host factor to counteract the function of LLO in promoting efficient Listeria spread.

Keywords: EFNB1
Eph
ephrin
Listeria monocytogenes
listeria spread
Advisor: Brumell, John H
Validation and Mechanistic Studies of Gluconeogenesis Regulators Identified from Zebrafish Chemical Genetic Screens

Phosphoenolypyruvate carboxykinase (PEPCK) is the rate limiting enzyme in hepatic gluconeogenesis, which produces glucose from pyruvate to maintain circulating glucose level according to the bodyâ s needs. Cytosolic PEPCK (pck1) is widely studied for its crucial role in hepatic gluconeogenesis. High levels of pck1 are associated with the development of type 2 diabetes; conversely, improved insulin sensitivity is observed in mice with decreased pck1 level. Ten potential lead compounds from previous screening of 727 FDA-approved compounds were examined using pck1 zebrafish reporter lines, Tg(pck1:luc2) and Tg(pck1:Venus). Compounds were tested in larval zebrafish and ranked based on their ability to regulate pck1 expression and glucose levels. Subsequently, a diabetic mouse model was used to further validate the potential anti-hyperglycemic effects of the selected compound (Esomeprazole, Eso). Eso treatment improved glucose homeostasis in diabetic mice as determined by pyruvate tolerance tests. Here we describe a possible mechanism of action of Eso, which involves regulation of hepatic gluconeogenesis through insulin-dependent down-regulation of pck1.

Keywords: Diabetes
Drug repurposing
Gluconeogenesis
Pck1
Pyruvate tolerance test
Zebrafish
Advisor: Wen, Xiao-Yan
Microfluidics for Measuring Solubility and Diffusion Coefficient of Solvent in Bitumen

In this thesis, a microfluidic approach is developed to determine both the solubility and diffusivity of propane in the Athabasca bitumen at a range of reservoir-relevant pressures and temperatures. The presented microfluidic approach offers advantages over the conventional methods including fast quantification, small volume requirement, and ease of operation at high temperatures and pressures. The fabricated glass-silicon microfluidic chip contains a Pressure â Volume â Temperature (PVT) microchannel with full temperature and pressure control, connected to both solvent and bitumen supply. The cross-sectional area of the bitumen supply channel was only 2.5% that of the cell, approximating a closed PVT system. One-dimensional oil swelling due to solvent diffusion was captured consecutively using fluorescence microscopy and the solvent solubility and diffusion coefficient were then determined through image analysis and established mathematical models. The final results are in strong agreement with the available published data obtained by conventional methods.

Keywords: Bitumen
Diffusion coefficient
Hydrocarbon solvent
Microfluidic
Solubility
Advisor: Sinton, David
Patterns of Methadone Use and Perinatal Outcomes Among Pregnant Women in Ontario

Methadone maintenance therapy (MMT) is the standard treatment for opioids use disorder during pregnancy as it minimizes opioid cravings and withdrawal symptoms without causing sedation or euphoria. We conducted a population-based cohort study among Ontario public drug beneficiaries who used MMT during pregnancy to determine their timing of initiation, number of gaps in therapy during pregnancy, maternal characteristics, and rates of perinatal outcomes. Among 1,842 women, the median age was 27 years, 71.2% (N=1,311) were multiparous, 87.6% (N=1,614) initiated MMT before conception, and 61.7% (N=1,137) of women had zero gaps in MMT during pregnancy. 22.2% of infants were small for gestational age, 17.5% were preterm, and 5.9% had a congenital anomaly. These outcomes generally did not differ based on number of gaps or timing of initiation. However, the cohort's outcome rates were higher compared to general populations, suggesting that this is an at-risk population in need of increased clinical support.

Keywords: Addiction
Methadone
Opioids
Pregnancy
Advisor: Gomes, Tara
Sproule, Beth
Advanced Multifunctional Micro-Textured Thermoplastic Elastomeric Fiber Composites

Micro-Textured Composite surfaces are becoming increasingly useful in several applications such as friction, hydrophobicity and abrasion resistance. This work focuses on development of a novel surface texturing approach using fiber de-bonding and pull-out method that would not require any additional post texturing process. First, several different types of fibers are studied with two different thermoplastic matrices (Thermoplastic polyurethane and Styrene-Butadiene-Styrene). Their friction properties on wet ice as well as their hydrophobic behaviors are studied. This is followed by conducting an abrasion study of these composite surfaces to determine the abrasion resistance of these textured surfaces and relate to their microtextured surface properties. After development and characterization of these textured composite surfaces, a more faster approach of fabricating aligned fiber composites using fused deposition modelling is developed. To verify fiber alignment with the new developed rapid prototyping methodology, the new fabricated composite surfaces are textured and their surface properties are characterized.

Keywords: 3D Printing
Abrasion
Fiber Composites
Friction
Hydrophobicity
Advisor: Naguib, Hani E
Dynamic Mechanical Properties of Short Fiber Reinforced Polymers

Recently there has been a drive to replace traditional engineering materials with polymeric solutions. Fiber reinforced polymers offer combine the inherent benefits of polymers such as light weight and anti-corrosion with high strength and stiffness to weight ratios. Polymers are highly viscoelastic meaning they have both elastic, solid, and viscous, fluid like behavior and their mechanical properties are time dependent. Dynamic mechanical analysis is a useful tool in measuring the viscoelastic behavior of materials, and glass transition in response to cyclic loading cycles. Each chapter in this work studies the dynamic mechanical behavior of a different class of polymer, from polyurethane thermosetting rubber, to polyester based thermoplastic elastomer, to high performance polyamide thermoplastic. In each case, novel composite materials have been developed and characterized by reinforcement with selective fibers which was found to significantly enhance the mechanical and thermal properties of the pure polymer.

Keywords: Composites
Mechanical Properties
Polymer
Viscoelasticity
Advisor: Naguib, Hani E
Synthesis of Isocyanates from CO2 and Amines under Mild Conditions

A mild and metal-free synthesis of unsymmetrical ureas and carbamates from amine and atmospheric carbon dioxide has been developed. The carbamic acid intermediates derived from aryl amines and CO2 in the presence of DBU were subjected to the dehydrating action of activated sulfonium reagents commonly used in Swern oxidations. The resulting isocyanate was detected by in-situ React IR before being quenched with amines and alcohols to afford ureas and carbamates. Diisocyanates relevant to the polyurethane industry, such as 4,4'-methylene diphenyl diisocyanate (MDI) and toluene-2,4-diisocyanate (TDI), have also been synthesized in good yields through the mild dehydration of the corresponding dicarbamic acids. The present thesis also describes the preliminary application of this mild dehydration in synthesizing hydantoin derivatives from amino amides and CO2.

Keywords: aryl amine
carbon dioxide
isocyanate
Advisor: Rousseaux, Sophie
Yudin, Andrei
Assembly of the Human R2TP Chaperone Complex

The Human R2TP complex is composed of hRvb1, hRvb2, RPAP3 and hPih1, and it is required for snoRNP biogenesis, PIKK signaling and RNA polymerase II assembly. Despite its important functions, much information on the structure of the human R2TP complex is still not available. In order to build up a foundation for the structural and functional studies of the human R2TP complex, I endeavored to reconstitute the complex in vitro. I successfully purified the human R2TP proteins, studied the interactions amongst these proteins, and attempted the complex reconstitution using different methods. Amongst the R2TP proteins, hRvb1 and hRvb2 could oligomerize together to form the hRvb1/hRvb2 complex, and RPAP3 and hPih1 could also interact to form the RPAP3/hPih1 complex. However, the interaction across the two sub-complexes of R2TP seemed to be rather weak, suggesting the successful formation of the complete R2TP complex might require help from extra assembly factors.

Keywords: Pih1
PIH1D1
R2TP
RPAP3
RUVBL
Rvb
Advisor: Houry, Walid A.
Williams, David B.
Cbl-b deficient CD4+ T cells mediate resistance against regulatory T cells through IL-2 overproduction

Regulatory T cells play crucial roles in health and diseases through their immunosuppressive properties. In particular, Treg cells in the tumor microenvironment are known to restrict anti-tumor immune response and therefore understanding mechanisms of resistance to Treg-mediated immunosuppression serves as an attractive therapeutic avenue. E3 ubiquitin ligase Cbl-b is a regulator of multiple TCR signaling pathways, and has demonstrated its potential in rendering T cells impartial to the suppressive signals of Treg cells through regulating cytokines. This study specifically explored cellular mechanisms associated with Cbl-b KO CD4+Foxp3- effector T cell resistance against Treg cells. Cbl-b KO CD4+Foxp3 T cells hyper-produced IL-2 and together with IL-2RÎą upregulation served as an important mechanism to escape suppression by Treg cells. Overall, the study offers insights into the potential development of CD4+ T cells resistant to suppression by regulatory T cells.

Keywords: cytokine
immunity
immunosuppression
inflammation
T cell
Treg
Advisor: Ohashi, Pamela S