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    Computational investigation of enzyme-facilitated cleavage of the phosphodiester bond in nucleic acids
    (Lethbridge, Alta. : University of Lethbridge, Dept. of Chemistry and Biochemistry, 2024-02-05) Kaur, Rajwinder; University of Lethbridge. Faculty of Arts and Science; Wetmore, Stacey D.
    The phosphodiester backbone in nucleic acids is remarkably resistant to degradation. Although high stability is essential for storage of genetic information and proper cell function, some circumstances necessitate the cleavage of the nucleic acid backbone. For example, breaking the DNA backbone is critical to repair damage and maintain genetic integrity, while RNA cleavage is necessary for quality control during protein synthesis. Nucleases are enzymes that facilitate the challenging phosphodiester bond cleavage by accelerating the uncatalyzed reaction. Many nucleases utilize metals to enhance catalysis. Despite several experimental studies on enzymes that cleave phosphodiester bonds in nature, the mechanism for bond cleavage used by many enzymes, including the role and/or number of metal ions involved, is still unclear. Computer modeling is a powerful tool to investigate enzyme-catalyzed reaction mechanisms and discern the roles of the metal/s and amino acids involved in the reaction. This thesis uses computational techniques (i.e., quantum mechanics calculations, molecular dynamics simulations, and quantum mechanics–molecular mechanics calculations) to gain an atomic-level understanding of the phosphodiester bond cleavage reaction catalyzed by nucleases, specifically focusing on APE1, I-PpoI, and EndoV. These enzymes are particularly interesting since they either invoke a single metal ion for catalysis, which conflicts with the two-metal mediated mechanism generally proposed for most nucleases, or the metal-dependence is unknown. The mechanistic details uncovered by this thesis will open the door for new and improved applications of these enzymes in the fields of disease diagnostics, genetic engineering, and therapeutics.
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    Assessment of aryl hydrocarbon receptor mediated toxicity of benzotriazole ultraviolet stabilizers (UV-P, UV-9, UV-090) to fishes
    (Lethbridge, Alta. : University of Lethbridge, Dept. of Biological Sciences, 2024) Johnson, Hunter M.; University of Lethbridge. Faculty of Arts and Science; Wiseman, Steve B.
    Benzotriazole ultraviolet stabilizers (BUVSs) are a class of chemical contaminants used to help counter UV-induced damage to manufactured goods, especially plastics. The broad applicability of BUVSs has resulted in their ubiquitous detection in aquatic ecosystems and biota. Although BUVSs are detected globally in aquatic ecosystems, a limited number of studies have investigated the potential toxic effects of BUVSs to fish. Of the limited toxicity data for BUVSs, studies suggest that certain BUVSs might dysregulate the aryl hydrocarbon receptor (AhR) causing early life-stage toxicity in fishes. Therefore, the objectives of this study were to use in vivo and in vitro approaches to characterize the toxicity of 2-(benzotriazol-2-yl)-4-methylphenol (UV-P), 2-(Benzotriazol-2-yl)-4-methyl-6-prop-2-enyl-phenol (UV-9), and 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl methacrylate (UV-090) as agonists of the AhR across a phylogenetically diverse number of fish species. In vivo toxicity was assessed by exposing zebrafish (Danio rerio) to BUVSs by microinjection and toxicities were assessed by recording embryo mortality and malformations including yolk sac and pericardial edema, and spinal curvature. Each of the tested BUVSs caused dose-dependent increases in embryo mortality following exposure. In vitro activation of the AhR by BUVSs was determined with a luciferase reporter gene (LRG) assay using COS-7 cells transfected with the AhR of zebrafish or eight other species. Results confirm that UV-P and UV-9, cause toxicity via AhR activation whereas, UV-090 lacked the ability to activate the AhR, indicating that its toxicity is independent of the AhR. Furthermore, interspecies differences in sensitivity to AhR activation by BUVSs was observed. Overall, this study fills knowledge gaps regarding the potential toxic effects of BUVSs to fishes and can help guide improved objective assessment of risks posed by BUVS that have AhR agonistic properties for the protection of Canada’s diverse population of fish.
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    Niitsitapii heritage education: a poomiikapii approach
    (Lethbridge, Alta. : University of Lethbridge, Dept. of Anthropology, 2023) Weasel Moccasin, Camina N.; University of Lethbridge. Faculty of Arts and Science; Cuellar, Andrea M.
    This is a critical study of the current heritage management practices in southern Alberta, especially as they relate to Niitsitapii (Blackfoot) heritage sites. Two sites in particular, Head-Smashed-In Buffalo Jump and Writing-on-Stone / Aisinai’pi, are used as case studies for this research. Both of these sites have provincial, federal, and global designations resulting in layers of colonial policy focussed on how to best manage the heritage sites. Current heritage management directives and policies are discussed and dissected in order to understand the cultural values they represent and protect. These are compared and contrasted to Niitsitapii cultural values at the core of Niitsitapiiysinni (our way of life). Opinions from the Niitsitapii communities of Kainai and Piikanii were gathered and analyzed. From the responses / engagement received, themes began to emerge highlighting what is of importance, and value, for Niitsitapii people when it comes to managing Niitsitapii heritage. The document ends with discussing and presenting best practices that would benefit and support Indigenous led heritage management policy making.
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    Unsupervised detection of cell ensembles in rats' primary motor cortex during online and offline processing
    (Lethbridge, Alta. : University of Lethbridge, Dept. of Neuroscience, 2023) Nazari Robati, Peyman; University of Lethbridge. Faculty of Arts and Science; Tatsuno, Masami
    Motor actions engage intricate neural processes, spanning active learning phases and crucial offline periods, notably during sleep. Online learning involves diverse neural dynamics, while sleep is known for its role in skill consolidation. While numerous studies have contributed to our understanding of information processing during online and offline learning periods, these investigations have often focused on specific learning phases, leaving the intricate relationships between diverse online learning neural activities and sleep processing relatively unexplored. Here, we embarked on a comprehensive analysis aimed at unraveling the interplay between primary motor cortex (M1) neural activity during reach-to-grasp skill learning and sleep, employing an unsupervised framework. During online training, our findings uncovered four neural dynamics related to the motor execution, with compelling evidence of their replay during post-training sleep, both in Rapid Eye Movement and Slow-Wave Sleep (SWS). Moreover, our data revealed that all cell ensembles, irrespective of their dynamics during the task, exhibited substantial reactivation during spindles coupled with slow-oscillations in SWS. Further exploration on the cortico-hippocampal communication led us to investigate the activation patterns of M1 cell ensembles during hippocampal sharp-wave ripples. Our results demonstrated the dynamic suppression and enhancement modulation of M1 cell ensembles during SWS-ripples across learning days suggesting complex cortico-hippocampal dialogues associated with sensorimotor learning task. We thus contributed to understand the extensive details of neural mechanisms underlying motor learning tasks during online and offline processing periods.
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    Origins of thermalization in quantum cosmology
    (Lethbridge, Alta. : University of Lethbridge, Dept. of Physics and Astronomy, 2023) Osei, Michael Adjei; University of Lethbridge. Faculty of Arts and Science; Dasgupta, Arundhati
    We aim to provide the effect of accelerated frames in cosmology and identify the origins of thermalization in the evolution of the universe. We begin our discussion by discussing general relativity and cosmology, as well as their successes and failures, which leads to the need for quantum cosmology. We then discuss the canonical formulation of general relativity, which is the basis of quantum cosmology, and its issues. We constructed a wavefunction for the universe whose dynamics are governed by the Wheeler-Dewitt equation. Semiclassical approximations simplify assumptions and approximations that bring the equation closer to a form that can be more easily analyzed. The WKB method is used to approximate the wave function. We constructed a transformation that is similar to the Rindler transformation motivated by the Klein-Gordon equation in Minkowski spacetime. We performed the Bogoliubov transformation and obtained a result which suggested thermalization. However, we were not using creation and annihilation operators. To interpret this result, we calculated the density matrix and the square of the density matrix to see if the WKB state is a pure or mixed state. The result from the density matrix calculation suggested that the WKB state is a mixed state, which suggested that the result we obtained from the Bogoliubov transformation can be interpreted as thermalization.