VictorJuiz/thesis huggingface dataset:
The Role of KATP-channels in the Maintenance of Ventricular Fibrillation in Cardiomyopathic Human Hearts

Background: Modulation of ischemia-dependent pathways alters electrophysiological evolution of ventricular fibrillation(VF). Hypothesis: 1)There is regional disease-related expression of KATP-channels in human cardiomyopathic hearts. 2)KATP-channel blockade promotes spontaneous VF termination by attenuating spatiotemporal dispersion of refractoriness(ΔERP). Methods and Results: Electric mapping of control(n=6) and treatment(n=9) (10 μmol/L glibenclamide) isolated human cardiomyopathic hearts was performed. Spontaneous defibrillation and KATP-subunit gene expression were studied. Spontaneous VF termination occurred in 1/6 control and 7/8 treated hearts (P=0.026). After 180 seconds of ischemia, LV transmural dispersion in VF cycle length was observed(p=0.001), which was attenuated by glibenclamide. There was greater gene expression of all KATP-subunit on the endocardium compared with the epicardium(P<0.02). In ischemic rat heart model, ΔERP was verified with pacing protocols (36±5ms vs 4.9±4ms, p=0.019). Conclusions: KATP channel subunit gene expression is heterogeneously altered in the cardiomyopathic human heart. Blockade of KATP channels promotes spontaneous defibrillation by attenuating ischemia-dependent ΔERP during VF.

Keywords: Ventricular Fibrillation
K-ATP Channels
Arrhythmia
Glibenclamide
Advisor: Nanthakumar, Kumaraswamy
Dorian, Paul
V-ATPase a3-d2 and a3-B2 Subunit Interaction in Osteoclasts are Viable Targets for Anti-resorptive Therapeutics

For bone resorption, vacuolar-type H+-ATPases (V-ATPases) on the plasma membranes of osteoclasts acidifies the extracellular millieu adjacent to the bone surface. The V-ATPase a3 and d2 subunits are enriched in osteoclasts. B2 subunit is also expressed on the osteoclast plasma membrane. Disruption of genes encoding subunits a3 and d2 impairs bone resorption. In this study, we have shown an interaction between the a3-B2 and a3-d2 subunits. Luteolin and KM91104 were found to be effective inhibitors of the a3-d2 and a3-B2 interactions respectively. Secondary assays revealed luteolin and KM91104 were not toxic to cells, did not affect osteoclastogenesis yet inhibited bone resorption. Furthermore luteolin did not affect V-ATPase subunit formation or assembly. Inhibitors of osteoclast resorption that do not affect osteoclast viability, preserve osteoclast–osteoblast signalling are desirable than existing anti-resorptives. Therefore, V-ATPase a3–d2 and a3-B2 interactions are viable targets for anti-resorptive therapeutics for osteoporosis.

Keywords: Bone
V-ATPase
osteoclast
drug development
Luteolin
Advisor: Manolson, Morris Frank
Parallels between Gambling and Amphetamine Reinforcement in Pathological Gamblers and Healthy Controls and the Role of Sensitization

Pathological gambling is a serious disorder with lifetime prevalence between 1.1-3.5%. Evidence suggests commonalities in the neurochemical basis of pathological gambling and psychostimulant addiction. However, parallel effects of gambling and a stimulant drug have not been assessed in the same subjects. This study employed a cross-priming strategy in which 12 male pathological gamblers and 11 male controls were exposed to a 15-minute slot machine game and d-amphetamine (0.4 mg/kg). Subjective, cognitive, electrophysiological, and physiological responses were assessed. Gamblers reported greater desire to gamble after both reinforcers, when baseline motivation was controlled. Conversely, gamblers exhibited diminished cardiovascular response to amphetamine. Gamblers also exhibited decreased pre-pulse inhibition (impaired sensorimotor gating), and deficits on this index predicted greater post-amphetamine desire to gamble and decreased heart rate response to the dose. Results are consistent with possible dopaminergic sensitization in pathological gamblers, but also suggest that central noradrenergic receptor deficits contribute importantly to these effects.

Keywords: Gambling
Sensitization
Amphetamine
Reinforcement
Prepulse Inhibition
Advisor: Zack, Martin
The Role of Gli3 Transcription Factor in the Developing Mouse Stomach

The Sonic hedgehog (Shh) signaling pathway plays a critical role in murine gastric development. When Shh is knocked out in the mouse embryonic stomach, glandular epithelial hyperplasia occurs. Furthermore, this phenotype was mimicked in Gli3−/−, but not Gli2−/− stomachs. I utilized three additional mouse models that modulate Gli3 activity to better understand the role of Gli3 in the developing stomach - the Gli3Δ699/Δ699 ,Gli3P1−4/P1−4, and Kif7−/− mice. The Gli3P1−4/P1−4 stomach displayed glandular epithelial overgrowth, as did the Kif7−/− stomach to a lesser extent; the Gli3Δ699/Δ699 stomach displayed glandular hypoplasia. Moreover, the Gli3P1−4/P1−4 and Kif7−/− stomachs have a thicker circular smooth muscle, and the Gli3Δ699/Δ699 had a thinner one relative to wild-type. It appears that altering the balance of Gli3 in favour of its activator results in gastric glandular epithelial and circular smooth muscle hyperplasia, and a balance favouring the Gli3 repressor results in hypoplasia.

Keywords: hedgehog pathway
gastric development
Gli3
mouse
Advisor: Kim, Peter
Elucidation of the Protective Mechanism of α Crystallin B in Cardiomyocytes

α-Crystallin B (cryAB) is the most abundant small heat shock protein in cardiomyocytes (CMs), where it has been shown to have potent anti-apoptotic properties. The mechanism by which cryAB prevents apoptosis has not been fully characterized. Therefore, I was interested in elucidating its protective mechanism in CMs. I identified its sub-cellular localization and its binding interactors following H2O2 exposure. I found that cryAB is found in the cytosol under control conditions and that following H2O2 exposure it becomes phosphorylated and translocates to the mitochondria. CryAB silencing resulted in increased apoptosis levels in CMs. Co-immunoprecipitation revealed an apparent increased interaction of cryAB and PcryAB with mitochondrial VDAC, caspase 12 and uncleaved caspase 3 in stressed hearts relative to controls. These results suggest that the cardio-protective effects of cryAB are mediated by its translocation to the mitochondria and its interaction with VDAC, caspase 12 and caspase 3 following exposure to H2O2.

Keywords: crystallin
reactive oxygen species
cardiac cell
protection
mitochondria
heat shock protein
Advisor: Gramolini, Anthony
Characterization of the Hemodynamic Profile of Early Alzheimer's Disease via Arterial Spin Labeling Magnetic Resonance Imaging

Arterial spin labeling is a completely non-invasive method for blood-flow measurement techniques. Alzheimer's disease pathology includes microvascular abnormalities in addition to practically all risk factors having a vascular component that reduces cerebral perfusion. Hemodynamic parameters of cerebral blood flow and arterial transit time were estimated via single-compartment modeling of pseudo continuous arterial spin labeling data and neurocognitive test scores (Alzheimer's disease assessment scale and mini-mental state examination) were compared between a group of healthy (N=20) and early Alzheimer's disease (N=25) subjects before and six months after the Alzheimer's subjects began treatment with cholinesterase inhibitors. The early Alzheimer's group showed improved CBF after 6 months' treatment in every Alzheimer's-prone region except the medial and lateral temporal lobes. No difference in arterial transit time was found between groups, indicating that the pathophysiological process causing hypoperfusion in Alzheimer's disease may differ from vascular dementia.

Keywords: cerebral blood flow
arterial spin labeling
Alzheimer's disease
arterial transit time
Cerebral Hypoperfusion
magnetic resonance imaging
perfusion quantification
Advisor: Stefanovic, Bojana
Mutation and Loss of Heterozygosity in an Individual of the Root-infecting Fungus Armillaria Gallica in a Mixed Hardwood Forest

Long-lived individuals of the opportunistic fungal pathogen Armillaria gallica arise in single mating events, and then grow vegetatively to occupy large territories including multiple woody substrates. In effect, this leaves a spatial record of mutation, the detection of which would allow new inferences about how fungal individuals grow and infect their hosts. In this thesis, I first identified a large individual of A. gallica in eastern Ontario. I then searched for genetic variation within this individual by focusing on the tandemly repeated rRNA gene cluster and four microsatellite markers that are variable in the A. gallica population. I discovered a loss of heterozygosity (LOH) in the rRNA gene-cluster region, forming two genotypes that show significant spatial clustering in a Mantel test. My M.Sc. thesis research serves as a baseline for a genome-wide study of the mutational dynamic within the vegetative growth phase of this large and old Armillaria individual.

Keywords: Armillaria gallica
somatic mutation
Advisor: Anderson, James
Inhibition of Transthyretin Fibrillogenesis Using a Conformation Specific Antibody

Immunoglobulin-mediated inhibition of amyloid fibril formation in vivo is a promising strategy for the treatment of protein misfolding diseases such as the amyloidoses. Here we focus on transthyretin amyloidoses, a group of protein conformation diseases caused by the misfolding of the serum protein transthyretin into fibrillar structures that deposit in specific organs and tissues—often with serious pathological consequences. Using a structure-guided immunological approach, we report a novel antibody that selectively recognizes monomeric, misfolded conformations of transthyretin in vitro. Raised to an epitope normally buried in the native form of transthyretin, this antibody was found to suppress transthyretin fibrillogenesis at substoichiometric concentrations in vitro. Overall, the selectivity and inhibitory nature of the antibody signals the potential use of conformation specific antibodies in the diagnosis and treatment of transthyretin amyloidoses, conditions which remain difficult to treat and are widely under/misdiagnosed at the current time.

Keywords: Transthyretin
Senile Systemic Amyloidosis
Familial Amyloid Polyneuropathy
Familal Amyloid Cardiomyopathy
Antibody Design
Advisor: Chakrabartty, Avijit
Dealloying and Formation of Nanoporosity in Noble-metal Alloys

Nanoporosity formation by selective dissolution of Ag-5 at. pct Au in perchloric acid has been investigated with regards to the mechanism of stress-corrosion cracking (SCC), film-induced cleavage in particular. It has been proven that dealloying of silver-gold systems containing low concentration of gold leads to the formation of a three dimensional nanoporous layer and that it can be carried out in a broad range of potentials and concentrations of a dealloying solution. Therefore, stress-corrosion cracking observed in these alloys may be caused, initiated or at least accompanied by the formation of nanoporosity resulting from dealloying. These results will have impact on the fabrication of cheaper nanomaterials where there is required large surface to volume ratio with gold as the outermost layer. Understanding the role of dealloying will also help us to design new materials of higher resistance against stress-corrosion cracking.

Keywords: Dealloying
Nanoporosity
Advisor: Newman, Roger C.
Oxidative Palladium(II)-catalyzed Arene C-H Bond Functionalization and Progress towards the Total Synthesis of 6-Deoxyerythronolide B

To address the issue of unnecessary functional group transformations in synthesis, the direct functionalization of carbon-hydrogen (C―H) bonds presents itself as an efficient and atom economical process. In particular, palladium(II)-catalyzed oxidative functionalization of arene C–H bonds were investigated to yield intermolecular and intramolecular arylations. Kinetic studies and characterization of bimetallic palladium(II) complexes led to the discovery of two other palladium(II)-catalyzed processes: arene hydroxylation and selective chlorination of anilides. Realizing the potential of biocatalysis and of transition-metal catalysis, we marriaged these two fundamentally different methods to access complex molecules in rapid and step economical ways and chose popular synthetic target, 6-deoxyerythronolide B to showcase the efficiency of these stereoselective reactions. To form the 14-membered lactone, we employed a transition-metal catalyzed ring-closing metathesis. Two different fragments were assembled via traditional and reliable aldols, oxidations and reductions, crotylations and protective group chemistry.

Keywords: oxidative cross coupling
total synthesis
Advisor: Dong, Vy Maria
Evaluating a New Display of Information Generated from LiDAR Point Clouds

The design of a texture display for three-dimensional Light Detection and Ranging (LiDAR) point clouds is investigated. The objective is to present a low fidelity display that is simple to compute in real-time, which utilizes the pattern processing capabilities of a human operator to afford an understanding of the environment. The efficacy of the display is experimentally evaluated by in comparison with a baseline point cloud rendering. Subjects were shown data based on virtual hills, and were asked to plan the least-steep traversal, and identify the hill from a set of distractors. The major conclusions are: comprehension of LiDAR point clouds from the sensor origin is difficult without further processing of the data, a separated vantage point improves understanding of the data, and a simple computation to present local point cloud derivative data significantly improves the understanding of the environment, even when observed from the sensor origin.

Keywords: LiDAR
teleoperation
point clouds
interface
Advisor: Milgram, Paul
Regulating BCA2: An Investigation into E3 Ligase Activity

The BCA2 E3 ligase is expressed in a majority of invasive breast cancers. BCA2 has inherent autoubiquitination activity which contributes to cell migration and proliferation processes. Here, ten novel BCA2 binding proteins were found using yeast and bacterial screening. Two of which were human homolog of Rad23 variant A (hHR23a) and 14-3-3σ. In vivo and in vitro assays confirmed that both hHR23a and 14-3-3σ bound BCA2 and were co-expressed with BCA2 in breast cancer cells. Interaction of BCA2 with hHR23a and 14-3-3σ affect the autoubiquitination and auto-degradation activity of BCA2. Multi-ubiquitination of hHR23a-bound BCA2 was dramatically lower than that of free BCA2, this corresponded to increased BCA2 expression and half-life. Furthermore, phosphorylated BCA2 protein was stabilized by interaction with 14-3-3σ, via substrate inhibition of BCA2 autoubiquitination. High expression of BCA2 is correlated with grade in breast cancer and regulation of this E3 ligase’s activity may be important to cancer progression.

Keywords: E3 Ligase
BCA2
breast cancer
Advisor: Seth, Arun
Signal-dependent Translation of the Platelet Transcriptome: The Roles of αIIbβ3 Integrin, Fibrinogen and Fibronectin in Platelet de novo Protein Synthesis

Although platelets are anucleate, they do inherit 1500-3000 mRNA transcripts from their megakaryocyte progenitors, in addition to all the machinery essential for protein synthesis; however, there is little understanding why platelets initiate de novo synthesis of these transcripts. Our group demonstrated that fibrinogen (Fg), a ligand of platelet Glycoprotein (GP)IIb-IIIa (αIIbβ3 integrin), is required for platelet P-selectin expression and that engagement of Fg with GPIIb-IIIa is essential for this process. The present study shows that murine platelets incubated with Fg synthesize P-selectin de novo, and this synthesis is blocked by puromycin. A similar effect is also observed when platelets are incubated with fibronectin, another ligand of GPIIb-IIIa. Furthermore, platelets from both ligand- (Fg−/−, von Willebrand factor−/−, apolipoprotein A-IV−/−) and GPIIb-IIIa-deficient mice have altered proteomes. These data suggest an intricate mechanism by which engagement of platelets with their environment triggers signal-dependent translation of the platelet transcriptome, consequently altering the platelet proteome.

Keywords: protein synthesis
fibrinogen
fibronectin
P-selectin
αIIbβ3 integrin
GPIIb-IIIa
Advisor: Ni, Heyu
Leytin, Valery
Possible Role of Osteoblasts in Regulating the Initiation of Endochondral Repair Process during Fracture Healing

Fracture repair is a regenerative event that involves the precise coordination of a variety of cells for successful healing process. Within the microstructure hierarchy of bone repair, the predominant cells involved include the chondrocytes, osteocytes, osteoblasts, and osteoclasts. Although the role of osteoblasts during fracture healing has been previously shown, their role during the initiation phase of endochondral fracture repair remains unclear. In order to study the role of osteoblasts during fracture repair, we used a transgenic mouse model expressing the herpes simplex virus thymidine kinase gene in early differentiating osteoblasts, which allows conditional ablation of cells in osteoblastic lineage upon treatment with the Gancicolvir drug. Results from this study suggest that not only are osteoblasts required in later stages of fracture repair as the medium for bone synthesis, and osteoclast activation during bone remodelling, but could also be required for the initiation and advancement of the endochondral ossification process.

Keywords: Fracture repair
Endochondral Ossification
Osteoblast
Osteoclast
Chondrocyte
Herpes simplex virus thymidine kinase
Gacnciclovir
Advisor: Alman, Benjamin
Miller, Freda
Diagnostic Accuracy of MRI for Assessment of T-category, Lymph Node Metastases, and Circumferential Resection Margin Involvement in Patients with Rectal Cancer: A Systematic Review and Meta-analysis

BACKGROUND: MRI is increasingly being used for rectal cancer staging. The purpose of this study was to summarize published evidence to determine the accuracy of MRI for T-category, lymph node (LN) metastases, and circumferential resection margin (CRM) involvement in rectal cancer. METHODS: Sensitivity, specificity, and diagnostic odds ratios (DOR) were estimated using hierarchical summary receiver operating characteristics modeling and bivariate random effects modeling. RESULTS: MRI was more specific for CRM (94%, 95%CI 88-97) than for T-category (75%, 95%CI 68-80) and LN’s (71%, 95%CI 59-81) but was more sensitive for T-category (87%, 95%CI 81-92) than for CRM (77%, 95%CI 57-90) and LN’s (77%, 95%CI 69-84). DOR was higher for CRM (56.1, 95%CI 15.3-205.8) than for LN’s (8.3, 95%CI 4.6-14.7) and T-category (20.4, 95%CI 11.1-37.3). CONCLUSIONS: MRI has good accuracy for both CRM and T-category and should be considered for preoperative rectal cancer staging. In contrast, LN assessment is poor on MRI.

Keywords: Rectal cancer
Magnetic resonance imaging
Diagnostic accuracy
Staging
Meta-analysis
Advisor: Kennedy, Erin
Immigration Status and Mental Health: Invisible Lives and Hidden Realities of Undocumented Youth: A Pilot Study

Individuals with no immigration status are one of the fastest growing migrant populations in Canada, totaling over half a million. Yet, there has been little empirical research on the developmental impacts of living without formal immigration status. In the present study, 47 non-status adolescents were interviewed about their general experiences of growing up in Canada without status, to examine the mental health and developmental impacts particular to this population. Results from the study indicated that lack of immigration status is implicated in significant developmental impairments. Lack of immigration status is associated with difficulties with identity formation and consolidation, compromised self-efficacy, acculturative stress and compromised peer relations, which in turn results in poorer developmental and mental health outcomes. Findings are discussed in terms of both theoretical and practical implications, and directions for future research are outlined.

Keywords: Nonstatus
Development
Advisor: Peterson-Badali, Michele
Adolescent Social Perspective Taking in Contexts of Social Justice: Examining Perceptions of Social Group Differences

The present mixed-methods study examined adolescents’ social perspective taking in contexts of social justice as demonstrated by their awareness and interpretations of hypothetical peer interactions depicting racism and sexism. Fifty adolescents in Grades 9 and 12 participated in a semi-structured interview in which they were presented with two scenarios, involving adolescents in conflicts portraying racism and sexism. They were asked a series of questions designed to elicit their awareness and understanding of social group differences. Qualitative analyses revealed three categories of adolescents’ responses, reflecting distinct interpretations of social group differences. On average, adolescents assumed a perspective that was naïve to the disparities existing between vulnerable and less vulnerable social groups. Furthermore, it was shown that older adolescents had significantly more sophisticated social justice understandings than younger adolescents. These findings highlight the need to educate adolescents about issues of social justice and facilitate an appreciation of social group differences.

Keywords: social perspective taking
social justice
adolescent development
social cognition
Advisor: Arnold, Mary Louise
The Relationship between Reading Comprehension and Adolescents with and without ADHD

This study examined reading comprehension in adolescents with and without attention deficit hyperactivity disorder (ADHD). Forty-five youth with ADHD (26 males, 19 females) and 42 adolescents without ADHD (20 males, 22 females) between the ages of 13 and 18 completed standardized tests of achievement. The results of multiple regression analyses indicated that orthographic and semantic abilities were related to reading comprehension. Both the orthographic (i.e., spelling) measure and the semantic (i.e., oral vocabulary) measure explained unique amounts of variance on the reading comprehension measure. Next, it was found that adolescents with ADHD were significantly more likely to have a Specific Reading Comprehension Disability (S-RCD) than adolescents without ADHD. Last, it was found that adolescents with ADHD and an S-RCD demonstrated poorer performance on academic measures that depend in part on comprehension (e.g., math problem solving) than adolescents with ADHD without an S-RCD.

Keywords: ADHD
comprehension
Advisor: Martinussen, Rhonda
Lecithin-linker Microemulsion-based gels for Drug Delivery

Microemulsions have gained interest from the pharmaceutical industry due to their ability to co-solubilize hydrophilic and lipophilic drugs, and to provide enhanced drug penetration. In this work, thermosensitive gelatin- and poloxamer 407-stabilized microemulsion-based gels (MBGs) were formulated using alcohol-free, low toxicity and low viscosity lecithin-based linker microemulsions. The addition of gelatin to water-rich bicontinuous microemulsions induced the formation of clear viscoelastic gels containing an oil-rich microemulsion as the gelatin seemed to dehydrate the original microemulsion. The addition of poloxamer 407 to water-continuous microemulsions produced MBGs with different gelation temperatures. High concentrations of lipophilic components in the microemulsion, particularly the oil, reduced sol-gel transition temperature, while hydrophilic components increased sol-gel transition temperature. Gelatin and poloxamer MBGs provided desirable viscoelastic properties for ophthalmic and transdermal applications with minimal impact on the transport properties of the original microemulsions.

Keywords: lecithin microemulsion
microemulsion-based gel
transdermal drug delivery
ophthalmic drug delivery
Advisor: Acosta, Edgar