Restricted Theses and Dissertations

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Now showing 1 - 5 of 4386
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    Barriers and Facilitators to the Implementation of a Decolonization Strategy for Staphylococcus aureus prior to Hip and Knee Arthroplasty in Alberta, Canada: A multi-methods study
    (2023-05-16) Whelan, Lindsay Jane; Rennert-May, Elissa; Barkema, Herman; Leal, Jenine; Leslie, Myles
    Alberta recently implemented a decolonization strategy as part of the clinical care pathway prior to hip and knee replacements. The decolonization strategy includes three days of chlorohexidine gluconate (CHG) sponge baths and five days of mupirocin ointment (MO) intranasally twice daily leading up to surgery. Preoperative decolonization prior to hip and knee replacements reduces the incidence of surgical site infections (SSIs), but the effectiveness in Alberta is unknown. For a decolonization strategy to be effective, patients and clinic staff should adhere to the protocol and there should be no negative outcomes. We used multi-methods to assess the barriers and facilitators with a decolonization strategy by assessing patients and clinic staff compliance, and baseline prevalence of antimicrobial resistance (AMR) to topical antibiotics. Using qualitative methods, semi-structured interviews and focus groups were used to understand clinic adherence with decolonization. Knowledge and understanding were central to implementation. When present, knowledge and understanding acted as a facilitator, when absent or inconsistent, it was a barrier to implementation. Using descriptive surveys, we analysed patient compliance with proportions of compliance, differences with compliance in urban versus rural clinics using logistic regression, and reasons for non-compliance with frequency counts. In our analysis, CHG sponges had a greater proportion of compliance compared to MO but not when CHG sponges and MO were used together. Patients in rural clinics had increased odds of compliance with three CHG sponges than urban clinics and males had increased odds of compliance with MO in urban locations. Common reasons for non-compliance included sponges not provided, patient forgot, and surgery date moved. To assess AMR to topical antibiotics, specimens from SSIs following hip or knee arthroplasty were collected (n=81) and 43 specimens were Staphylococcus-positive. Among these specimens, coagulase-negative staphylococci isolates carried resistance genes associated with CHG (n=10) and mupirocin (n=6). Our results indicate that while a decolonization strategy in Alberta has been successfully implemented, it could benefit from improvements with clinic and patient compliance. Furthermore, the prevalence of AMR to topical antibiotics will need to be continuously monitored for changes.
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    Quantum Dot Photoactivation: Mechanisms of Photostability of InP/ZnS Core/Shell Quantum Dots
    (2023-05-08) Sikkema, Toni; Belinda, Heyne; Shi, Yujun; Anikovskiy, Max; Wieser, Michael
    Quantum dots are semiconductor nanocrystals that exhibit unique optical characteristics such as size tunability and broad absorption with applications in biomedical imaging and display technologies. Cadmium-based quantum dots have been widely used as the standard in commercial applications, but their toxic nature poses a significant challenge that needs to be addressed. Of particular interest is the study of indium-based quantum dots, due to their similar optical properties and lower toxicity. Before indium containing quantum dots can be used in optical and biological applications, we need to understand the complicated mechanisms behind their photostability. It has been observed that quantum dots can behave in unpredictable manners in response to light absorption, hindering their development. In this thesis, we add to the body of work surrounding the photostability of indium-based quantum dots, with a focus on their behavior in aqueous environment which is of relevance to their application in biological systems. We studied the photostability of InP/ZnS core/shell quantum dots in organic solvents where they are synthesized and expanded into aqueous environments through modification of the surface chemistry. Our findings show that the behavior of these quantum dots under light exposure depends on the solvent, presence of oxygen, and pH. We have also revealed that consideration of the surface ligand is important in the design of quantum dots. These results suggest that the interaction between quantum dots and light is complex and multi-mechanistic. While this study sheds light on the chemical interactions involved, further research is still necessary.
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    Improving the therapeutic potential of staphylokinase, a potent thrombolytic agent
    (2023-05-26) Baharian, Azin; Vogel, Hans J.; MacDonald, Justin A.; MacCallum, Justin
    Staphylokinase (Sak) is a small bacterial-derived protein (15.5 kDa) that can hydrolyze fibrin-rich blood clots by activating the conversion of plasminogen into plasmin. Several studies have shown the effectiveness of Sak as a thrombolytic agent that could be used to treat stroke or cardiac arrest. However, its short half-life in blood circulation and immunogenicity are the main issues that prevent Sak from clinical applications. Herein, we explore two modifications of Sak to improve its therapeutic potential. Covalently attaching PEG (polyethylene glycol) polymers to therapeutic proteins has been widely applied to improve their pharmacokinetic properties, resulting in several FDA-approved protein-based drugs. Although PEGylation of Sak has previously been investigated, the effects of PEGylation on the 3D structure of Sak have not been studied in detail. In the first part of this research project, site-specific PEGylation of the truncated version of Sak was performed in the immunogenic region of the protein, and three covalent PEGylated derivatives of the protein were prepared. NMR studies showed a slight structural perturbation upon PEGylation, mostly close to the PEGylation site, and a direct relationship between the hydrodynamic radius of the PEGylated protein and the PEG size. Together, the results suggest that PEG and Sak∆10 move relatively independently from each other. As a second approach, we introduce cyclic Sak (cyc-Sak), a novel form of staphylokinase with higher stability and improved plasminogen activation activity. Using an Ssp GyrB split intein, the N- and C-terminal ends of the linear Sak were connected by a peptide bond, rendering the protein into a cyclic form (cyc-Sak). This structural modification was generated at the protein expression level in Escherichia coli, and the cyclic protein could be purified by common chromatography techniques. Successful backbone cyclization was confirmed by NMR spectroscopy of the 13C,15N-labeled cyc-Sak and by chemical cleavage assays. Our studies show that mono-PEGylation and intein-mediated backbone cyclization of Sak are powerful strategies to improve its therapeutic potential. These approaches could be combined to facilitate the design of protein-based medications when the stability of therapeutic proteins is an obstacle to their clinical application.
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    Aqueous Chemical Solution Deposition of Epitaxial Lead-Free Ferroelectric Sodium Potassium Niobate (KNN) thin films
    (2023-05-12) Mohammed, Ahmed Zaher; Dolgos, Michelle; Birss, Viola Ingrid; Shi, Yujun; Roberts, Edward; Shimizu, George
    Potassium Sodium Niobate (KxNa1-xNbO3, KNN) thin films were fabricated on SrTiO3 (STO) substrates using an environmentally friendly aqueous Chemical Solution Deposition (CSD) approach, employing water-soluble Na, K, and Nb polyoxometalate precursors. This green route for KNN thin film fabrication offers reduced environmental impact and potential industrial scalability. The annealing recipe was optimized through a detailed investigation, finding that a one-minute annealing at 700°C after each deposition yielded the best structural properties. The impact of varying the K+/Na+ stoichiometry on the films' structural properties was systematically examined. The investigation demonstrated a trend between the K+/Na+ molar ratio in the precursor solution and the strain-state and lattice parameters of the resulting films, suggesting adding 50% excess potassium in the precursor solution is promising for optimal ferroelectric performance. Leveraging the versatility of the aqueous synthesis, lithium was incorporated as a dopant in the precursor solution. Different Li concentrations were investigated, and it was determined that a 6% Li concentration improved the films' structure compared to undoped samples. This demonstrates the potential of aqueous deposition for incorporating dopants to enhance material properties. The study further highlighted the potential for strain engineering and additional dopant incorporation using the aqueous CSD method, opening up avenues for further exploration and optimization of KNN thin films' properties.
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    Investigating the Mediating Fusion Machinery and Biological Role of a Novel Late-Stage Phagocytic Event
    (2023-05-16) Nguyen, Jenny Ai; Yates, Robin; Canton, Johnathan; Frank, Jirik; Humberto, Jijon
    This dissertation investigates eructophagy, a newly discovered process in which macrophages release soluble contents of the phagolysosome (PL) through fusion with the plasma membrane (PM). This study aims to determine the molecular machinery involved in membrane fusion during eructophagy and its role in antigen presentation. Macrophages play a crucial role in combating infections and maintaining homeostasis by phagocytosing invading pathogens and cellular debris into the phagolysosome (PL). It was believed that the contents of the PL that were not employed for antigen presentation were completely digested and recycled as primary building blocks, while indigestible material were stored in lysosomes. Therefore, how macrophages make immunostimulatory molecules, such as nucleic acids, polysaccharides, or lipids, available for immune detection is not well understood. Recently, eructophagy emerged as a novel process that allows macrophages to expel soluble components of the PL into the external environment, potentially serving as a form of intercellular communication to disseminates otherwise unavailable bioactive molecules during inflammation. The molecular machinery underlying membrane fusion during eructophagy has not been elucidated. To address this, we used a lentiviral short hairpin RNA knockdown library of conditionally immortalized monocytes to target genes involved in fusion, fission, and trafficking events to examine their potential role in eructophagy. A novel microscopy-based assay that reports eructophagy events as flashes of fluorescence was used, and it was found that eructophagy is dependent on genes involved in degradative and secretory autophagy. This led to further exploration of the role of autophagosomes in eructophagy. Vesicular blebs protruding from PLs were observed before eructophagy and vanished after resolution. Interfering with autophagosome-PL or autophagosome-PM fusion modulated the incidences of PL-associated blebs, thereby suggesting that these structures are autophagosomes. Immunofluorescence demonstrated that blebs colocalize with markers of the mature autophagosome ATG5 and LC3B. Furthermore, using supernatant transfer and triple cell coculture experiments, we demonstrate that eructophagy is used by macrophages to transfer antigens to vicinal APCs to enhance antigen presentation to T cells. Collectively, this dissertation reveals a novel mechanism of macrophage-mediated antigen transfer and suggests a putative model in which blebs are mature autophagosomes bridging the PL to the PM to facilitate eructophagy.