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Dissecting Bipolar Disorder Heterogeneity Through Familial Aggregation, Symptom Dimensions, and Genetic Risk
No full textBipolar disorder (BD) is a highly heritable but clinically diverse condition, complicating efforts to identify its biological basis. This dissertation investigates familial patterns, symptom dimensions, and genetic risk. A systematic review and meta-analysis identified 14 clinically relevant familial traits, notably age of onset, lithium response, and psychotic features. Principal component analysis in two BD family cohorts revealed consistent latent dimensions, episode frequency and age of onset, that showed greater similarity among relatives, suggesting heritability. Finally, polygenic scores (PGS) were examined in relation to symptom dimensions. While some associations emerged (e.g., PGS for schizophrenia was inversely related to episode frequency), they did not remain significant after correction. Together, these findings support a dimensional, data-driven approach to BD, moving beyond categorical subtypes to capture clinical and genetic complexity. This work contributes to defining biologically meaningful subgroups and informing precision medicine in BD
Synthesis and Characterization of Cationic Polyelectrolytes to Address Changing Source Water Quality
No full textThis research focuses on developing novel cationic flocculants (polyelectrolytes) for drinking water treatment. Cationic flocculants are currently used in many municipal water treatment processes, but are not able to effectively address changing source water quality challenges. These challenges include increased concentration of humic substances and more frequent algae bloom occurrences. Changes in source water quality generally require higher dosing of traditional coagulants and flocculants, which increases treatment cost and sludge production. Hence, this research investigates novel cationic flocculants to determine how comonomer selection and copolymer properties impact treatment performance.
Nine cationic copolymers were synthesized and characterized according to copolymer conversion, molecular weight distribution, zeta potential, and jar testing. Of the materials evaluated, the most promising cationic flocculant was the copolymer of methacrylamide (MAA) and (p-vinylbenzyl)trimethylammonium chloride (VBTMAC), which shows great UV-254 results among other alternative cationic flocculants. These results demonstrate that utilities can adapt to changing source water quality through material innovation, instead of (or alongside) costly process innovation.
Further optimization is still possible through future work, including manipulating the molar ratio of neutral monomer and cationic monomer, improving understanding of intermolecular interactions between target contaminants and promising cationic flocculants, and extending results to bio-derived polymer flocculants. Through an iterative design approach, novel cationic flocculants can be optimized for specific water treatment challenges
Metabolic Regulation Of Transcription Factor Binding To IGHM Enhancer 3 (TFE3) In Obesity And Diabetes-Related Heart Disease
No full textData from the Pulinilkunnil laboratory show that inactivation of TFEB, a MiTF/TFE transcription factor, and lysosomal dysfunction predispose cardiomyocytes to lipid accumulation, mitochondrial defects, and cardiac injury in obesity and diabetes. While TFEB is a key regulator of lysosomal biogenesis and autophagy, transcription factor E3 (TFE3), another MiTF/TFE family member, also regulates lysosome-autophagy genes. TFEB and TFE3 regulate the transcription of genes in the lysosome-autophagy pathway and, in turn, are regulated by the mechanistic target of rapamycin complex 1 (mTORC1)- dependent or independent pathways. However, the role of TFE3 in the heart and its regulation in health and nutrient stress remains unclear. Using rodent and cardiac cell lines models of metabolic maladaptation, this thesis examined the impact of nutrient stress and lipotoxicity on TFE3 protein content and ascertained if the loss of function of TFE3 renders cardiomyocytes susceptible or resistant to mitochondrial dysfunction, insulin resistance, and metabolic maladaptation. Twenty-week high-fat fed C57BL/6J male and female mice showed increased TFE3 protein content, accompanied by a concomitant decline in TFEB, when compared to chow diet-fed animals. Myocardial TFE3 content was also significantly increased in 7-week post Streptozotocin (STZ)-treated type 1 diabetic Wistar rats and in C57BL/6J mice fed a high-fat diet and treated with STZ, mimicking type 2 diabetes. Cardiomyocyte-specific TFEB knockout mice on a high-fat diet showed further upregulation of TFE3, suggesting that nutrient overload augments TFE3 in a TFEB-independent manner. Indeed, saturated fatty acid palmitate treatment ex vivo, increased total TFE3 and either short (TFE3S) of long (TFE3L) isoforms, while reducing TFEB protein in human AC16 cardiomyocyte-like cells, mouse C2C12 myotubes, rat H9c2 cells, and primary neonatal rat (NRCM) and adult rat (ARCM) and mouse (AMCM) cardiomyocytes. Unsaturated fatty acid, Oleate treatment had a variable effect on the protein content of total TFE3 or its isoforms in different cell lines. Efficient TFE3 knockdown (>70%) was achieved in AC16, H9c2, C2C12, and NRCMs. TFE3 silencing in AC16 cells increased lipid droplet (LD) accumulation and triglyceride (TAG) content under oleate loading. High-resolution respirometry revealed reduced glucose- and fatty acid-linked oxygen consumption in TFE3-deficient NRCMs, C2C12, and H9c2 cells, despite increased OXPHOS complex proteins indicating flux of lipids away from oxidation towards LD-TAG formation. Additionally, in AC16 and C2C12 cells, TFE3 silencing blunted insulin-induced phosphorylation of p70S6K (Thr389) and Akt (Ser473), a downstream effector of insulin’s metabolic and mitogenic action. Collectively, this thesis examined the previously unexplored role of cardiomyocyte TFE3 and uncovered the critical role of TFE3 in altering lipid handling, mitochondrial respiration, and insulin signaling. This research advances the understanding of nutrient regulation of TFE3 and clarifies the role of TFE3 in cardiac energy metabolism and insulin signalling, plausibly facilitating functional outcomes and therapeutic targeting in obesity and diabetes related heart disease. It remains to be determined whether TFE3 action depends on transcription factor cooperativity with TFEB, governing metabolic adaptation and cardiac function
Effect of Gonadotropin Releasing Hormone (Ovaplant-L) Dose on Induced Spawning of Female Striped Bass (Morone saxatilis)
No full textTo identify the lowest effective dose to achieve spawning in striped bass, three doses of sGnRHa (Ovaplant-L; Syndel) were compared: 10, 30 and 70 µg kg-1, in triplicate. An experimental unit was a 1500 L tank stocked with 1 female and three male striped bass; with nine tanks total. Broodstock were ‘cold-banked’ at 12°C starting 24 May with increase to 18°C over 14 (Trial 1) and six (Trial 2) days. Oocyte maturation was slower than predicted, confounding effect of Ovaplant dose. Ovaplant-L injection resulted in 33.3% (6 of 18) females spawning. Seven required follow-up injection of hCG (350 IU kg-1; hCG). Remaining five failed to oviposite fertile oocytes. Three of four females who received 70 µg kg-1 Ovaplant-L and whose eggs were matured (≤15 Bayless hours) successfully spawned, compared to other treatment groups’ (3 of 5; 10 µg kg-1) (0 of 5; 30 µg kg-1) spawning success
Understanding Experiences of Children with Physical Disabilities Participating in a Novel Pediatric Wheelchair Skills Training Program
No full textBackground. Independent mobility, the ability to move freely in one’s environment without assistance, is essential for children’s development, participation, and belonging. Children with physical disabilities may use manual wheelchairs (MWCs) to support their mobility, but without proper training, they may have difficulty using them effectively and face increased risk of injury. The Wheelchair Skills Training Program (WSTP) is effective for adults, yet its application for children has been limited. As such, a pediatric adaptation is now being tested through a multi-site randomized controlled trial. To support the understanding of the WSTP’s feasibility and effectiveness, it is imperative to explore children’s and families’ experiences. Purpose. This thesis captured the values, preferences, and experiences of children participating in the pediatric WSTP and their caregivers. Methods. A qualitative collective case study was conducted with six children and six caregivers who completed semi-structured interviews. Child interviews included collaboration with caregivers and child-friendly elicitation tools (i.e., vignettes, illustrations). Data were analyzed using reflexive thematic analysis and dyadic analysis within cross-case analysis. Findings. Three themes were identified: (1) Supporting Independence and Mobility, where families described increased independence and reduced caregiver strain; (2) Building Skills & Confidence Through Consistent Challenge, where children reported developing mastery through overcoming challenges; and (3) Empowering Children Through Positive Relationships, which emphasizes the role of supportive relationships in fostering children’s motivation and engagement. Conclusion. Centering participant experiences highlights how the pediatric WSTP can be tailored to children’s needs and inform strategies for broader implementation across settings
Interventions and Implementation Strategies to Mitigate Nursing Burnout in Critical Care Nurses: A Scoping Review
No full textIntroduction: The strain on the nursing workforce presents major challenges for the sustainability of health service delivery. With 75% of nurses in Canada reporting symptoms of burnout, this is influencing nurses leaving. This scoping review aimed to identify what interventions have been utilized to mitigate nursing burnout in critical care nurses since the COVID-19 pandemic.
Methods: This scoping review followed the Joanna Briggs Institute methodology. The databases searched include MEDLINE All (Ovid), Embase (Elsevier Embase. com), CINAHL with Full Text (EBSCOhost), and PsycINFO (EBSCOhost).
Results: These interventions were mapped using the Behavior Change Wheel and the Implementation in Context Frameworks. Interventions summarized in this review were diverse, with mindfulness-based interventions emerging as the most common approach.
Conclusion: While most interventions focused on individuals, interventions that target multiple tiers of the healthcare system appear to offer the greatest potential for sustainable change
PEROXISOME-METABOLISM IN THE REGULATION OF IMD (TNF) PATHWAY
No full textThe aim of this thesis is to further explore the potential immunomodulatory role of peroxisomes in regulating the IMD pathway in Drosophila, and specifically how peroxisome metabolism could regulate the assembly of Imd oligomerization through the production of distinct lipids for the activation of immune and inflammatory pathways. This study could reveal a mechanism of regulation of innate and inflammatory pathway such as the oligomerization of adaptor proteins in the TNF pathway. potentially paving the way for insights into human immune disorders linked to hyperactivation of inflammatory signaling such as the TNF pathway.Aberrant NF-κB signaling drives chronic inflammation. Using Drosophila melanogaster, I investigated the Immune Deficiency (IMD) pathway, analogous to mammalian TNF signaling, which activates NF-κB against Gram-negative bacteria. My research identified peroxisomes as novel regulators of this pathway. Peroxisome-derived diacylglycerol (DAG) promotes the formation of Imd amyloid-like structures in macrophages, a critical step for NF-κB activation. Immunofluorescence and qPCR revealed that amyloid formation strongly correlates with transcription of antimicrobial genes, whereas peroxisome-deficient cells failed to form amyloids and mounted poor immune responses. Overall, my Ph.D. research uncovers a conserved immuno-metabolic circuit in which peroxisomes control TNF-NF-κB activation, providing insights into host defence and potential therapies for TNF-mediated immune disorders in humans
WHEN CHATBOTS MEET EMOJI: THE EFFECTS ON CONTINUED USAGE INTENTION
No full textChatbots are increasingly adopted in customer service to offer convenient and timely assistance. However, the effect of adding emojis on user experience remains underexplored. This thesis seeks to fill this gap by investigating how emoji usage influences users’ continuance use intention in different service situations, while also exploring the underlying mechanisms. Results from two experiments indicate that emojis in customer service chatbots positively affect users perceived social presence and attitudes toward the chatbot, which in turn increase their intention to continue using the service. Moreover, the outcome of the service (successful vs. unsuccessful) plays a moderating role. This thesis applies the Computers Are Social Actors (CASA) theory and Language Expectancy Theory (LET) to explore how emoji usage influences user expectations based on service outcomes. Additionally, the findings provide valuable insights for managers and chatbot designers, offering practical guidance on how to improve chatbot services and enhance user satisfaction
EXPLORING PHARMACOLOGICAL CHOLINERGIC MODULATION AND ITS MECHANISMS AS A THERAPEUTIC APPROACH IN AMYOTROPHIC LATERAL SCLEROSIS
No full textAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapeutic options. This work investigates the potential of targeting cholinergic signalling as a treatment avenue using the mSOD1G93A mouse model of ALS. Building upon prior findings that genetically silencing spinal C-boutons combined with swimming improves disease outcomes, we tested whether chronic administration of pharmacological antagonists could produce similar benefits. Initial experiments with atropine, a non-selective cholinergic antagonist, improved motor function and extended humane endpoint in both swimming and non-swimming ALS mice, suggesting a central role for cholinergic modulation beyond physical activity. Subsequent studies with methoctramine, an M2-selective cholinergic antagonist, showed even greater efficacy, particularly when administered early and independent of exercise. However, methoctramine was ineffective when administered at symptomatic stages, suggesting a critical window of administration for its beneficial effects. Notably, methoctramine was undetectable in cerebrospinal fluid after its administration, pointing to peripheral mechanisms of action. EMG recordings and electrophysiological analyses revealed enhanced neuromuscular transmission following methoctramine treatment, likely due to increased acetylcholine release at the neuromuscular junction. The improvements seen in mSOD1G93A mice following chronic administration of methoctramine may also involve Schwann cell proliferation and enhanced repair via antagonism of the M2 receptor. Since methoctramine was ineffective when administered at symptomatic stages, this suggests limited regenerative potential once denervation and Schwann cell senescence are established. Overall, our work shows methoctramine’s capabilities in slowing ALS disease progression, as well as shedding some light on some of the potential mechanisms behind these effects. We hope that these findings will advance future research efforts and guide the development of therapeutic strategies targeting the mechanisms examined in this thesis, in the context of ALS and other motor neuron disorders