Chemicals and Drugs Commons^™

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 Role Of Reactive Oxygen Species In The Accumulation Of Driver Mutations In B Cell Acute Lymphoblastic Leukemia, Mia P. Sams

Electronic Thesis and Dissertation Repository

B cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with recurrent mutations and high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine was tested for its ability to prolong lifespan of a mouse model of B-ALL and reduce frequency of mutations. Mice treated with 1g/L of N-acetylcysteine in drinking water were found to have delayed onset of B-ALL at 11 weeks of age and changes in gene expression relating to B cell development, calcium-apoptosis signaling, and pathways in cancer, although no differences in lifespan were observed. Tumours from treated …

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 …

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 …

21°C Is The Emerging Ideal Temperature For Kidney Preservation In The Presence Of Hydrogen Sulfide, Smriti Juriasingani

Electronic Thesis and Dissertation Repository

Kidney transplantation is the treatment of choice for patients with end-stage kidney disease. However, the shortage of transplantable kidneys has led to ever-increasing waiting lists. As a result, kidneys obtained via donation after cardiac death (DCD) are being used more frequently for transplantation. However, they exhibit poorer outcomes due to ischemia-reperfusion injury (IRI) and cold preservation methods, such as static cold storage (SCS). Supplementing cold preservation solutions with hydrogen sulfide donors, such as AP39, has been shown to improve renal IRI and graft outcomes, but the injury associated with cold preservation remains. This thesis evaluates the effect of subnormothermic kidney …

“One Of The Most Elaborate Doping Ploys In Sports History”: The Impact Of The 2016 Russian Doping Scandal On Anti-Doping, Wada And Athletes’ Rights, Mikael J. Gonsalves

Electronic Thesis and Dissertation Repository

This dissertation analyzes the impacts of the 2016 Russian doping scandal from a philosophical and historical perspective. This dissertation’s second chapter, the article entitled (1) “The Brave New World of Athletes’ Rights: A Canadian Perspective on Significant Shifts for the World Anti- Doping Agency” in time for the World Anti-Doping Agency’s (WADA) 20 th anniversary, puts into words the new investigative reality of contemporary anti-doping. It explains a new attitude of anti-doping authorities in response to the ‘game-changing’ Russian manipulation of samples, what has been described as “one of the most elaborate doping ploys in sports history” 1 (Icarus, 2016) …

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 …

The Effects Of Maternal Delta-9-Tetrahydrocannabinol And Cannabidiol Exposure On Fetal Heart Development In Mice, Gregory Robinson

Electronic Thesis and Dissertation Repository

Up to 22.6% of pregnant women consume cannabis during pregnancy despite the uncertainty of teratogenicity of the main ingredients in cannabis, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). This study tested the hypothesis that gestational THC and CBD exposure leads to heart abnormalities. Daily, oral THC exposure induced heart abnormalities in 68% of offspring with three main phenotypes including thickened semilunar valves, ventricular myocardial hypertrophy and hypoplastic coronary arteries in fetuses, and postnatal cardiac dysfunction. Altered gene expression of key cardiogenic regulators, increased proliferation, and reduced epicardial epithelial-to-mesenchymal-transition were demonstrated implicating potential mechanisms responsible for these abnormalities. Also, maternal CBD exposure resulted …

Deciphering The Ck2-Dependent Phosphoproteome And Its Integration With Regulatory Ptm Networks, Teresa Nunez De Villavicencio Diaz

Electronic Thesis and Dissertation Repository

Protein functions are regulated by the post-translational addition of covalent modifications on certain amino acids. Depending on their distance within the 3-dimensional structure, addition/removal of individual post translational modifications (PTMs) can be impacted by others. This PTM interplay constitutes an essential regulatory mechanism that interconnects the molecular networks in the cell. Protein CK2, a clinically relevant acidophilic Ser/Thr kinase, may be responsible for 10-20% of the human phosphoproteome. Such estimates agree with the number of known substrates, which continues to expand. Furthermore, the demonstration that CK2 participates in hierarchical phosphorylation and has similar sequence determinants to caspases suggest extensive PTM …

Maternal Nicotine Exposure Induces Congenital Heart Defects In The Offspring Of Mice, Elizabeth Greco

Electronic Thesis and Dissertation Repository

Congenital heart defects are the most prevalent birth defect, and maternal cigarette smoking is a known risk factor. Nicotine replacement therapies are recommended to pregnant women who smoke to aid in smoking cessation, as this alternative is thought to be much safer compared to cigarette smoking. However, these products contain nicotine, and the safety of nicotine on the developing heart is not well known. In this thesis, a mouse model was used to test the hypothesis that maternal nicotine exposure (MNE) during pregnancy leads to congenital heart defects and coronary artery defects in the offspring of mice. MNE resulted in …

The Mitochondrial Calcium Uniporter Regulator 1 (Mcur1) Matrix Domain Is A Self-Associated Multimer Sensitive To Divalent Cations, Naveed Siddiqui

Electronic Thesis and Dissertation Repository

Mitochondria are primarily appreciated for the generation of adenosine triphosphate (ATP), a chemical store of energy required by all cells. These organelles, however, also play key roles in apoptosis, autophagy and shaping cytosolic calcium (Ca²⁺) signaling via Ca²⁺ uptake into the mitochondrial matrix. This Ca²⁺ uptake is mediated chiefly via the mitochondrial Ca²⁺ uniporter (MCU), an inner mitochondrial membrane protein that oligomerizes to form a Ca²⁺ selective pore. MCU is regulated by several protein binding partners, including the recently identified MCU regulator-1 (MCUR1). MCUR1 stabilizes a higher order MCU heterocomplex through interactions with MCU …

Effects Of G Protein Signalling Modulator 3 On Cellular Signalling, Aneta A. Surmanski

Electronic Thesis and Dissertation Repository

G protein coupled receptors (GPCRs) promote G protein heterotrimer (Gα·GDP/Gbg) activation.GPCRsignalling is limited via G protein GTPase activity and b-arrestin-receptor interactions. G Protein Signalling Modulators (GPSMs) are proteins that may influence receptor signalling through G protein activity. GPSM3 modulates their activity by binding to Ga_i-GDP, limiting nucleotide exchange and preventing its re-association to Gbg. The impact of GPSM3 on signalling is unknown.We hypothesize that GPSM3 will decrease Ga_i-dependent signalling while promoting Gbg-dependent signalling in G_i-coupled GPCRs.

GPSM3 significantly inhibited b-arrestin recruitment to α_2A-adrenergic and m-opioid receptors via a Gbg-dependent mechanism, …

Producing A Subunit Vaccine For Porcine Epidemic Diarrhea Virus, Zayn Khamis

Electronic Thesis and Dissertation Repository

Porcine epidemic diarrhea virus (PEDv) causes disease and mortality to piglets worldwide. Most vaccines used to combat the disease have been ineffective live attenuated virus vaccines. The goal of this project was to produce a plant-made subunit vaccine based off the membrane protein of the virus. This is the first time this protein has been produced in plants. An elastin-like polypeptide fusion membrane protein accumulated up to 0.8 mg/g of fresh leaf weight when transiently expressed in Nicotiana benthamiana. Virus-like particles were also produced for the first time for PEDv, and were able to form with just the membrane …

Genomic Predictors Of Drug Response To The Alpha-Specific Phosphoinositol 3-Kinase (Pi3ka-Alpha) Inhibitor Byl719 In Head And Neck Cancers, Giananthony T. Rizzo

Electronic Thesis and Dissertation Repository

PIK3CA is the only frequently mutated, druggable oncogene in head and neck squamous cell cancer (HNSCC), with PIK3CA point mutations and gene amplification rates of 17.5% and 40% respectively, with higher rates in HPV-positive disease. The objective of this research was to determine the effects of BYL719, an α-specific PI3K inhibitor in HNSCC cell lines.

All cell lines with PIK3CA hotspot point mutations or gene amplifications will be sensitive to BYL719.

Twenty-eight HNSCC cell lines were subjected to increasing concentrations of BYL719 and cell viability was measured over time. Cell lines were screened for activating PIK3CA hotspot mutations and amplifications …

The Effects Of Ocean Acidification And Eutrophication On The Growth, Lipid Composition And Toxicity Of The Marine Raphidophyte Heterosigma Akashiwo., Julia Rose Matheson

Electronic Thesis and Dissertation Repository

Anthropogenic forcing, such as ocean acidification caused by rising carbon dioxide emissions, and eutrophication due to increased nutrient loadings in run-off, are causing major changes to the biogeochemistry of the oceans. As a consequence, coastal phytoplankton are susceptible to altered biogeochemical environments. This study examined the effect of a lower pH and increased levels of nutrients on the common coastal harmful alga, Heterosigma akashiwo. Growth rates, maximal cell yields, neutral lipid accumulation and toxicity of cells grown under various pH and nutrients regimes were measured. H. akashiwo growth was near maximal when grown at lower pH levels. There was …

Development Of Non-Covalent Functionalization Of Carbon Nanotubes For Sirna Delivery, King Sun Siu

Electronic Thesis and Dissertation Repository

RNA interference (RNAi) therapy is promising for treating various diseases but the delivery of small interfering RNA (siRNA) is difficult. To overcome the technical difficulties of siRNA delivery, an efficient and targeted delivery of siRNA is required for efficient RNAi therapy. Single-walled carbon nanotubes (CNT) has been used for nucleic acid delivery such as siRNA delivery. It has been found that CNT can gain entry into the cells by a diffusion-like mechanism which was called “nano-needle”. However, the solubility of CNT is low in most of the solvents including water. Functionalization of CNT can be carried out to enhance the …

Nrf2 Activation By Dimercaptopropanol Attenuates Mutant Huntingtin Toxicity, Kyle M. Dailey

Electronic Thesis and Dissertation Repository

Huntington’s disease (HD) is a fatal neurodegenerative disorder resulting from the expansion of a trinucleotide repeat within the HD gene. At the cellular level mutant HTT (mHTT) aggregates perturb cellular metabolism, intracellular trafficking and mitochondrial function, resulting in the increased production of reactive oxygen species (ROS) an event closely linked with nerve cell death. Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-sensitive transcription factor responsible for transcribing neuroprotective genes under the control of the antioxidant response element (ARE), which work to counteract high intracellular ROS levels. I have identified significant increases in cell viability, NRF2 nuclear localization, and …

Metastatic Disease: Interactions Between Tumor Cells And Host Environment During Cancer Cell Spread, Jennifer M. Maclean

Electronic Thesis and Dissertation Repository

Tumor and metastasis formation are not cell autonomous phenomena, but rather an evolution of disease within and responding to the host environment. Metastatic spread from a primary tumor occurs as a result of a complex interplay between tumor cells and the host, wherein tumor cells must escape the primary tumor, enter the host vasculature, travel to and arrest in a distant tissue and survive and grow in that new organ. It is known that cells that progress through these stages must both escape and exploit host systems, yet the mechanisms used are not fully understood. Therefore, the goal of this …