Medical Sciences Commons^™

The Adaptor Protein P66shc Governs Central Nervous System Cell Metabolism And Resistance To Aβ Toxicity, Asad Lone

Electronic Thesis and Dissertation Repository

Alzheimer’s disease (AD), a progressive and irreversible neurodegenerative disorder, and is the leading cause of dementia worldwide. It has been posited that AD is caused by the gradual deposition of toxic amyloid-b (Ab) plaques in the brain- that cause oxidative stress and eventually leads to neuronal death and synaptic loss. However, multiple therapies that either interfere with the production, or enhance the removal of Ab from the brain, have ultimately failed to slow or prevent AD. With the ever-increasing burden of AD worldwide, there exists an urgent need for novel therapeutic targets. The adult human brain is an energy demanding …

Sex Differences In Mood And Anxiety-Related Outcomes In Response To Adolescent Nicotine Exposure, Tsun Hay Jason Ng

Electronic Thesis and Dissertation Repository

Nicotine dependence is causally linked to increased risk of mood/anxiety disorders in later life. Females are reported to experience a higher prevalence of anxiety/depressive disorders and challenges in smoking cessation therapies, suggesting a potential sex-specific response to nicotine exposure and mood/anxiety disorder risk. However, pre-clinical evidence of sex-specific responses to adolescent nicotine exposure is unclear. Thus, to determine any sex differences in anxiety/depressive-related outcomes, adolescent male and female Sprague Dawley rats received nicotine (0.4 mg/kg; 3x daily) or saline injections for 10 consecutive days, followed by behavioural testing, in-vivo electrophysiology and Western Blot analyses. Our results revealed that adolescent nicotine …

The Combined Effects Of Physical Exercise And Cognitive Training On Gait Speed And Primary Motor Cortex Metabolism In Individuals With Mild Cognitive Impairment: A 1h-Mrs Analysis, Jack Thomas Emsey Elkas

Electronic Thesis and Dissertation Repository

Mild cognitive impairment (MCI) is a transitional stage before dementia. Altered gait in MCI has been associated with progression to dementia. Using magnetic resonance spectroscopy, a relationship between primary motor cortex (M1) neurochemistry and dual task gait speed has been reported in MCI. Interventional research suggests exercise, cognitive training, and vitamin D supplementation may benefit MCI, yet the combined effect of these treatments on gait speed and M1 metabolism is unknown. Participants with MCI (N=75) were assigned to one of five intervention arms and dual task cost on gait speed and M1 metabolism was assessed before and five months after …

The Sympathetic Neural Control Of The Circulation At Rest And During Exercise: Effects Of Age, Biological Sex, And Sex Hormones, Andrew W. D'Souza

Electronic Thesis and Dissertation Repository

The overall objective of this dissertation was to determine the impact of age, sex, and sex hormones on the discharge behaviours of muscle sympathetic action potentials (APs) as well as the corresponding changes in peripheral vasoconstriction and blood pressure at rest and during exercise. The microneurographic technique was employed to record multi-unit muscle sympathetic nerve activity (MSNA), with a continuous wavelet transform applied post-hoc to evaluate APs within the recorded neurogram. Study One examined the impact of aging on the central and peripheral arcs of the sympathetic baroreflex under resting conditions. This study revealed that middle-aged-to-older adults demonstrated heightened sympathetic …

Shedding Light On Hearing In Coma: Investigating The Applicability Of Functional Near-Infrared Spectroscopy For Assessing Auditory Function And Aiding Prognosis In Patients With Acute Disorders Of Consciousness, Reza Moulavi Ardakani

Electronic Thesis and Dissertation Repository

There is a critical need for a bedside neuroimaging tool to aid in the prediction of functional recovery outcomes for patients with acute disorders of consciousness (DoC) in the early days following severe brain injury. Current neurobehavioral examinations and prognosis tools have limitations in predicting good outcomes, leading to potential mistreatment or premature withdrawal of life support. Functional near-infrared spectroscopy (fNIRS) is a viable candidate for such purposes due to its portability and cost-effectiveness. Auditory processing, viewed as a multi-level and multifaceted brain function, could provide a sensitive and specific marker of residual cognitive function in unresponsive patients. This study …

Novel 129xe Magnetic Resonance Imaging And Spectroscopy Measurements Of Pulmonary Gas-Exchange, Alexander M. Matheson

Electronic Thesis and Dissertation Repository

Gas-exchange is the primary function of the lungs and involves removing carbon dioxide from the body and exchanging it within the alveoli for inhaled oxygen. Several different pulmonary, cardiac and cardiovascular abnormalities have negative effects on pulmonary gas-exchange. Unfortunately, clinical tests do not always pinpoint the problem; sensitive and specific measurements are needed to probe the individual components participating in gas-exchange for a better understanding of pathophysiology, disease progression and response to therapy.

In vivo Xenon-129 gas-exchange magnetic resonance imaging (¹²⁹Xe gas-exchange MRI) has the potential to overcome these challenges. When participants inhale hyperpolarized ¹²⁹Xe gas, it …

Transferring Organelles Into Native Neurons: A Disease-Modifying Therapy For Neurodegenerative Disorders, Lohiny Balendran

Electronic Thesis and Dissertation Repository

Currently, there are no disease-modifying therapies to counter the progression of neurodegenerative diseases that are associated with mitochondrial dysfunction in the early stages. In this study, we have used a novel strategy of cell fusion to transfer mitochondria from one cell to another using fusogens (syncytin 1 and syncytin 2). Syncytins are placental proteins encoded by endogenous retroviral envelope genes that promote cellular fusion. In this study, we have proposed that donor cells engineered to stably express syncytin when cocultured with recipient cells will allow fusion and facilitate the transfer of mitochondria into recipient cells. Syncytin-mediated systems revealed about 16.6-18.5% …

Vertebral Endplate Structural Defects: Measurement, Prevalence And Associated Factors, Aliyu Lawan

Electronic Thesis and Dissertation Repository

Objective: To synthesize current knowledge on the association of endplate structural defects (EPSD) with back pain (BP), improve EPSD measurement, and investigate EPSD prevalence, distribution, and association with age and body mass index (BMI).

Methods: In study 1, a systematic review was conducted on five databases for studies reporting on the association between EPSD and BP. Studies 2 and 3 used CTs and mCTs of 19 embalmed cadavers to examine the diagnostic accuracy of common EPSD assessment methods, and to develop and validate a novel method. Study 4 used the novel method on 200 adult males’ MRI to estimate EPSD …

Postexercise Executive Function Benefits And Cerebral Blood Flow: In The Lab And At Home, Benjamin Tari

Electronic Thesis and Dissertation Repository

A single bout of aerobic exercise improves executive function; however, the mechanism, or mechanisms, supporting this improvement remain unclear. One candidate mechanism is an exercise-mediated increase in cerebral blood flow (CBF) that enhances the efficiency of executive-related frontoparietal networks. To evaluate the link between exercise, CBF and executive function, three separate experiments were conducted. In the first study, separate 10-min sessions of moderate-to-heavy-intensity aerobic exercise, and a hypercapnic environment (i.e., 5% CO₂) were implemented. The hypercapnic condition was included because it increases CBF independent of the metabolic demands of exercise. The second study investigated whether exercise intensity-specific changes …

Functional Characterization Of A High-Throughput In Vitro Model To Predict Faecal Microbiota Transplantation (Fmt) Donor Success, Catherine M. Andary

Undergraduate Student Research Internships Conference

Faecal microbiota transplantation (FMT) involves the administration of donor faecal matter to a diseased recipient with the goal of remodeling the host microbiome to provide health benefits. In recent years, FMT has emerged as a potential therapy for a variety of microbiome-associated diseases such as atherosclerosis. Trimethylamine (TMA) is an atherosclerosis-linked metabolite generated by the gut microbiota from dietary precursors which is then oxidized to trimethylamine N-oxide (TMAO) by the liver, contributing to increased gut permeability. It has been shown that FMT may alter or restore the gut microbiome of recipients to reduce plasma TMAO levels. Despite its potential, the …

Constructing An In Vitro 3d Model Of The Human Placenta, Michael Zheng

Undergraduate Student Research Internships Conference

The placenta is critical for nurturing fetal growth and development, with dysregulated placentation associated with adverse pregnancy outcomes. The main fetal and maternal placental components consist of trophoblasts and modified endometrial stromal cells known as decidual cells, respectively. Since investigating in vivo placentas in humans through non-invasive methods is challenging, comprehensive in vitro placental models are needed for in-depth studies. However, in vitro 3D placental models that adequately represent and combine fetal and maternal components have been lacking. In this study, we achieved valuable progress in developing an in vitro 3D placental model inclusive of fetal and maternal constituents. We …

Mistranslating Trnas Alter The Heat Shock Activation By Hsf1, Rebecca Dib

Undergraduate Student Research Internships Conference

Translation, or the production of protein from an mRNA blueprint, is among the most fundamental processes to life as we know it. tRNAs are essential to accurate translation, as they decode the codons of mRNA and recruit corresponding amino acids. Variant tRNAs with anticodon mutations can decrease translational fidelity by recruiting the incorrect amino acid, an aberrant process known as mistranslation. When proteins are produced with incorrect amino acid sequences, they may misfold. The heat shock response functions to alleviate cellular stress caused by misfolded proteins, either by refolding or targeting misfolded proteins for degradation. Hsf1 acts as a transcriptional …

The Effect Of Type 1 Diabetes On The Metabolic Response To Exercise, Theres Tijo

Undergraduate Student Research Internships Conference

Type 1 Diabetes Mellitus (T1DM) is an autoimmune disorder that results in insufficient endogenous insulin production. Regular exercise has numerous health benefits for individuals with T1DM, however, most insulin-dependent diabetics avoid physical activity due to the fear of exercise-induced hypoglycemia (low blood glucose/BG).

The risk of hypoglycemia in this population may be partly due to lower liver glycogen stores which is a major source of blood glucose during exercise. However, the mechanism that leads to lower glycogen stores in T1DM is unknown.

The purpose of this study was to determine the effect of an acute bout of moderate-intensity aerobic exercise …

Examining The Association Between Brain Mri Measures At 7 Tesla And Cognition Following Covid-19 Infection, Helma Heidari

Electronic Thesis and Dissertation Repository

The long-term neuropsychological, cognitive, and neurobiological effects of the severe acute respiratory syndrome (SARS-CoV-2) in survivors with milder symptoms are still poorly understood. In this thesis we evaluated cognitive and psychological changes approximately five weeks after a wide range of symptoms in COVID-19 illness and determined whether advanced diffusion magnetic resonance imaging measures within subcortical brain structures of the limbic system were related to neurological, respiratory, psychiatric, and gastric symptoms experienced during the acute phase of illness. Cognitive and neuropsychological evaluations were performed in 45 participants who experienced neurological symptoms during the acute phase of COVID-19 illness. Participants also underwent …

The Role Of Coagulase-Negative Staphylococcal Secreted Products On Staphylococcus Aureus And Staphylococcus Lugdunensis Infections, Denny Chin

Electronic Thesis and Dissertation Repository

The Staphylococcus genus is comprised of over 40 bacterial species. The most well-studied species in this genus is the notorious human pathogen Staphylococcus aureus, a bacterium that produces coagulase among many other virulence factors. Since S. aureus is a major health burden and causes a plethora of diseases in humans, it has received significant attention and much research has been done to understand its biology to treat diseases caused by this pathogen. However, the coagulase-negative staphylococci (CoNS) make up most of the staphylococcal species and have received less attention since they are thought to have a lesser impact on …

Investigating A Novel Receptor That Mediates Vasoconstriction In Mouse Femoral Arteries, Joselia Carlos

Electronic Thesis and Dissertation Repository

The synthetic peptide trans-cinnamoyl-leucine-isoleucine-glycine-arginine-leucine-ornithine-amide (tcLIGRLO) causes smooth muscle contraction in mouse femoral arteries. The identity of the receptor that mediates this response is undetermined. We hypothesize that the novel mechanism for tcLIGRLO-induced contractions involves a G-protein coupled receptor (GPCR) and a G_q-Ca²⁺ signalling pathway. Chapter 2 describes experiments using femoral arteries isolated from male and female systemic protease-activated receptor 2 (PAR2KO) mice (n=31; 21 – 39 weeks of age) using tcLIGRLO and the G_q-inhibitor, YM-254890 (YM). Contractions produced by tcLIGRLO did not differ by sex but decreased as age increased. YM inhibited tcLIGRLO-induced contractions. Chapter …

Validation Of Arterial Spin Labeling For Longitudinal Monitoring And Differential Diagnosis Of Frontotemporal Dementia, Tracy Ssali

Electronic Thesis and Dissertation Repository

Frontotemporal dementia (FTD) is a devastating neurodegenerative disease characterized by a rapid decline in behavioural, language, and motor abilities. Advances in the understanding of FTD genetics and pathophysiology, and the subsequent development of novel disease modifying treatments have highlighted the need for tools to assess their efficacy. While structural magnetic resonance imaging (MRI) and functional imaging with ¹⁸F-flurodeoxyglucose (FDG) positron emission tomography (PET) are used for clinical diagnosis, structural changes are subtle at the early stages and PET imaging is expensive and access limited. Given the coupling of cerebral blood flow (CBF) to energy metabolism, an attractive alternative is …

Free Fatty Acid Treatment Alters Autophagy During Mouse Preimplantation Embryo Development, Zuleika C. L. Leung

Electronic Thesis and Dissertation Repository

Obesity-induced hyperlipidemia is one of the main factors for female infertility. Hyperlipidemia, specifically with high levels of palmitic acid (PA) and oleic acid (OA), interferes with preimplantation development. Autophagy is essential in early embryo development but, it is unknown whether hyperlipidemia affects autophagic mechanisms in preimplantation embryos. It was hypothesized that PA will alter autophagy in preimplantation mouse embryos and that the subsequent effects will be reversed by OA. PA impaired blastocyst development by arresting embryos at the 8-cell stage. PA also elevated early embryo autophagy by increasing autophagosome formation, decreasing maturation, and disrupting degradation. Co-treatment with OA showed developmental …

Exogenous Surfactant As A Delivery Vehicle For Intrapulmonary Therapeutics, Brandon J. Baer

Electronic Thesis and Dissertation Repository

As an organ system, the lung has unique advantages and disadvantages for direct drug delivery. Its contact with the external environment allows for the airways to be easily accessible to intrapulmonary delivery. However, its complex structure, which divides into more narrow airways with each branch, can make direct delivery to the remote alveoli challenging. The objective of this thesis was to overcome this issue by using exogenous surfactant, a lipoprotein complex used to treat neonatal respiratory distress syndrome, as a carrier for pulmonary therapeutics. It was hypothesized that therapeutics administered with a surfactant vehicle would display enhanced delivery to the …

Effect Of Carbon Monoxide Releasing Molecule 3 (Corm - 3) On Platelet Adhesion To Human Brain Microvascular Endothelial Cells, Najat S. El-Farra

Undergraduate Student Research Internships Conference

Sepsis is characterized by the widespread inflammation of the body. Systemic inflammation activates and recruits inflammatory cells (e.g., leukocytes) and platelets to the affected organs.

During these inflammatory conditions, human brain microvascular endothelial cells (hBMEC) and platelets both upregulate adhesive molecules rendering platelets to adhere to hBMEC.

Although carbon monoxide is thought of as a toxic molecule to many, previous work shows its anti-inflammatory properties. Evidence has shown carbon monoxide-releasing molecules (e.g., CORM-3; that release small, non-toxic amounts of CO) can combat the effects of severe inflammation in several in vivo animal model.

In this current study, we are looking …

Cerebrovascular Compliance In Humans, Marcy Erin Moir

Electronic Thesis and Dissertation Repository

Pulsatile blood flow consists of two components: steady flow and oscillatory flow. Steady blood flow is primarily regulated by vascular resistance while vascular compliance represents a key mediator of oscillatory blood flow. However, most studies investigating the regulation of cerebral blood flow in humans have focused on vascular resistance. Recently, emerging evidence has implicated vascular compliance as an important contributor to the regulation of cerebral perfusion. Therefore, the research contained herein aimed to i) quantify cerebrovascular compliance responses to blood pressure alterations and ii) explore mechanisms regulating cerebrovascular compliance in humans. The studies employed a Windkessel modelling approach to calculate …

Maternal Lifelong Western Diet Consumption Impacts Placental And Brain Development In The Term Guinea Pig Fetus, Carlene H. Cihosky

Electronic Thesis and Dissertation Repository

Both metabolic and cognitive dysfunction can originate from fetal reprogramming precipitating from adverse conditions experienced in utero. Of note is the western diet (WD), which is associated with maternal energy imbalances that may hinder fetal development through altered placental function. Brain-derived neurotrophic factor (BDNF), a growth factor that supports the placenta and developing brain, is responsive to such energy imbalances. This study sought to investigate the impact of lifelong maternal WD consumption on fetoplacental development, focusing on relations between placental changes, and fetal growth and neurodevelopment in a guinea pig model. Maternal WD consumption resulting in a lean metabolically …

Rapid Microscopic Fractional Anisotropy Imaging Via An Optimized Linear Regression Formulation., N J J Arezza, D H Y Tse, C A Baron

Medical Biophysics Publications

Water diffusion anisotropy in the human brain is affected by disease, trauma, and development. Microscopic fractional anisotropy (μFA) is a diffusion MRI (dMRI) metric that can quantify water diffusion anisotropy independent of neuron fiber orientation dispersion. However, there are several different techniques to estimate μFA and few have demonstrated full brain imaging capabilities within clinically viable scan times and resolutions. Here, we present an optimized spherical tensor encoding (STE) technique to acquire μFA directly from the 2nd order cumulant expansion of the powder averaged dMRI signal obtained from direct linear regression (i.e. diffusion kurtosis) which requires fewer powder-averaged signals than …

Differential Effects Of Kim-1 In Subcutaneous And Orthotopic Renca Models Of Kidney Cancer, Demitra M. Yotis Dy

Electronic Thesis and Dissertation Repository

Renal Cell Carcinoma (RCC) is the most common and fatal type of kidney cancer. Over 30% of patients that are diagnosed with RCC exhibit metastases. Almost 88% of patients with distant metastases succumb to the disease within 5 years of diagnosis. Kidney Injury Molecule-1 (KIM-1) is a cell surface glycoprotein that is not expressed in a healthy kidney but becomes highly expressed on proximal tubular epithelial cells (PTECs) following injury. Data from the Cancer Genome Atlas (TCGA) reveals that >90% of RCC tumours express KIM-1 mRNA and that higher expression levels correlate with increased overall survival rates of patients. The …

Protein Misfolding Toxicity And Inclusion Formation In Cellular Models Of Neurodegeneration, Sonja E. Di Gregorio

Electronic Thesis and Dissertation Repository

Protein misfolding characterizes most neurodegenerative diseases. Protein misfolding is the conversion of specific proteins from their normal, often soluble, and native three-dimensional conformation into an aberrant, often insoluble, non-functional conformation. Protein inclusions and aggregates are among the major pathological hallmarks of protein misfolding associated with many neurodegenerative diseases. Yet, the role of aggregates and inclusions is not clearly defined and heavily debated. This study utilizes powerful genetic approaches in yeast and verification in mammalian neuronal cell lines to address the misfolding and toxicity of three proteins, the Rho Guanine Nucleotide Exchange Factor (RGNEF), Matrin3, which are involved in amyotrophic lateral …

Hiv-1 Drug Resistance To Integrase Strand Transfer Inhibitors In Hiv-1 Non-B Subtypes, Emmanuel Ndashimye

Electronic Thesis and Dissertation Repository

Human immunodeficiency syndrome (HIV-1) has infected over 75 million people and over 35 million have succumbed to virus related illnesses. Despite access to a variety of antiretroviral therapy (ART) options, ART programs have been disproportionally spread in the world with low-and middle-income countries (LMICs) facing challenges to access the most potent ART options. With less potent ART remaining in use in LMICs, HIV-1 drug resistance (HIVDR) presents a growing challenge in LMICs. Since approval of the first-generation integrase strand transfer inhibitor (INSTIs), Raltegravir (RAL) in 2007, INSTIs remain the best choice as a backbone of ART. Access to second generation …

Functional Role Of Dream And Dyrk1a In High-Grade Serous Ovarian Cancer Cell Dormancy, Pirunthan Perampalam

Electronic Thesis and Dissertation Repository

High-grade serous ovarian cancer (HGSOC) is the most common form of ovarian cancer. The majority of women are disproportionately diagnosed at an advanced stage (stage III-IV) of the disease when tumours have progressed beyond the ovaries or fallopian tubes and into the peritoneal cavity. Survival rates at late-stage are as low as 25% and chemoresistant disease recurrence is common, affecting up to 90% of patients. Multicellular clusters called spheroids contribute to dormancy, chemoresistance, and metastases and are a major challenge to treatment of HGSOC. Spheroid cells undergo reversible quiescence to evade chemotherapy in a process mediated by the mammalian DREAM …

Evaluating Anesthetic Protocols For Non-Human Primate Functional Neuroimaging, Megha Verma

Electronic Thesis and Dissertation Repository

Functional magnetic resonance imaging (fMRI) is a non-invasive technique that can be used to measure a proxy of neural activity in vivo with high spatial specificity. One subject can be followed for a long period of time to assess changes in functional brain organization. However, fMRI is extremely sensitive to motion. The challenges of training non-human primates to reduce motion in an MRI scanner motivate the study of anesthesia which is commonly used to substitute for this training. In this thesis, I compare three different commonly used anesthetic protocols: isoflurane, propofol-fentanyl in combination, and fentanyl alone, to test which of …

Pathway‐Extended Gene Expression Signatures Integrate Novel Biomarkers That Improve Predictions Of Patient Responses To Kinase Inhibitors, Ashis Bagchee‐Clark, Eliseos J. Mucaki, Tyson Whitehead, Peter Rogan

Biochemistry Publications

Cancer chemotherapy responses have been related to multiple pharmacogenetic biomarkers, often for the same drug. This study utilizes machine learning to derive multi‐gene expression signatures that predict individual patient responses to specific tyrosine kinase inhibitors, including erlotinib, gefitinib, sorafenib, sunitinib, lapatinib and imatinib. Support vector machine (SVM) learning was used to train mathematical models that distinguished sensitivity from resistance to these drugs using a novel systems biology‐based approach. This began with expression of genes previously implicated in specific drug responses, then expanded to evaluate genes whose products were related through biochemical pathways and interactions. Optimal pathway‐extended SVMs predicted responses in …

Targeting Cd5 To Enhance Immune T Cell Activation And Function In Treatment Of Solid Tumours, Faizah Alotaibi

Electronic Thesis and Dissertation Repository

CD5 is a member of scavenger receptor cysteine-rich superfamily that is expressed primarily on T cells. It can attenuate T-cell receptor signaling and impair cytotoxic T lymphocyte (CTL) activation and is a therapeutic targetable tumour antigen expressed on leukemic T and B cells. However, the potential therapeutic effect of functionally blocking CD5 to increase T cell anti-tumour activity against tumours (including solid tumours) has not been explored. CD5^- solid tumours in CD5 knockout mice display increased in anti-tumour immunity. Hence, blocking CD5 function may have a potential therapeutic effect by enhancing CTL function. Here, I assessed CD5 levels in …