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- ItemPrefrontal regulation of exploratory behavior: complementary functions of medial prefrontal and orbitofrontal cortices in a competitive choice task(Lethbridge, Alta. : University of Lethbridge, Dept. of Neuroscience, 2025) Livingstone, Benjamin A. S.; University of Lethbridge. Faculty of Arts and Science; Gruber, Aaron J.; McDonald, Robert J.Adaptive decision-making requires balancing exploration of uncertain options with exploitation of known rewards. This thesis investigates how the rat medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) contribute to this trade-off during a competitive binary choice task (BCT), where stereotyped responses are punished and stochastic responding is rewarded. Male Long-Evans rats received excitotoxic lesions to the mPFC, OFC, or sham surgery, then performed the BCT across stable and volatile conditions. Behavior was analyzed using generalized linear mixed models to assess trial-level changes in extraneous feeder sampling (EFS), a non-rewarded exploratory action. Lesions did not impair overall task engagement. However, OFC lesions caused a persistent elevation in EFS during the first post-operative session, consistent with impaired suppression of valueless behavior. In contrast, mPFC lesions led to an accelerated within-session decline in EFS, suggesting a deficit in sustaining exploratory strategies over time. Under environmental uncertainty, when the physical configuration of the task changed mid-session, both lesion groups showed a blunted increase in EFS and failed to reduce exploration across days. These findings reveal a dissociation in stable environments: the OFC is critical for value-based suppression of exploration, while the mPFC supports its flexible maintenance. Under uncertainty, both regions are necessary for adaptive exploration, suggesting that they converge within a broader prefrontal network recruited during volatile conditions. This work clarifies the distinct and overlapping roles of the mPFC and OFC in regulating exploration and offers insight into prefrontal contributions to flexible decision-making.
- ItemSulfur diimides and their tin(IV) complexes, and contributions to improved models for X-ray crystal structures(Lethbridge, Alta. : University of Lethbridge, Dept. of Chemistry and Biochemistry, 2025) Hill, Nathan D. D.; University of Lethbridge. Faculty of Arts and Science; Boeré, René T.; Dibble, Peter W.Modernization of X-ray crystallographic structure model refinement using NoSpherA2 and an extensive investigation of the chemical and electrochemical properties of sulfur diimides (SDIs) and their tin(IV) chloride complexes are described. NoSpherA2, an X-ray model refinement tool recently integrated into the free-to-use Olex2 program, is shown by thorough comparative analysis to significantly outperform conventional Independent Atom Model (IAM) methods. Consistent improvements in hydrogen atom placement and non-H bond precisions demonstrate the benefits of incorporating NoSpherA2 into routine processing of crystallographic data. The synthesis of a systematic series of SDIs is presented alongside a comprehensive study of their fundamental properties, both on their own and as ligands in tin(IV) complexes. Their voltammetric behaviour is meticulously documented and suggests the SDIs are acting as redox-active ligands. This foundational work positions SDIs as promising candidates in this very active field of research, and provides warrant and clear direction for future endeavours therein.
- ItemInvestigation of dengue virus RNA terminal region interactions with human host proteins(Lethbridge, Alta. : University of Lethbridge, Dept. of Chemistry and Biochemistry, 2025) Demeler, Aysha K.; University of Lethbridge. Faculty of Arts and Science; Patel, Trushar R.Dengue virus (DENV) is a globally important arthropod-borne pathogen responsible for dengue fever, which can range from mild fever to severe hemorrhagic fever and shock syndrome. With no specific antiviral treatments available, understanding the molecular mechanisms of DENV replication and its interactions with host proteins is essential. This study focuses on two interconnected projects that use advanced biophysical techniques to address these challenges. The first project assesses biophysical methods for studying protein-protein interactions (PPIs) in solution, using the sfGFP-anti-GFP nanobody system as a model. Techniques such as microscale thermophoresis, fluorescence correlation spectroscopy, analytical ultracentrifugation, isothermal titration calorimetry, and size exclusion chromatography coupled with multi-angle light scattering were systematically compared. This analysis creates a reliable framework for studying PPIs, which can be applied to protein-RNA and RNA-RNA interactions. The second project examines the interaction between DENV serotype 2 (DENV-2) and the human DEAD-Box Helicase 6 protein (DDX6), a host factor involved in viral replication and assembly. By exploring the molecular interactions between the terminal regions of DENV-2 RNA and DDX6, this work aims to provide mechanistic insights into how DENV hijacks host proteins. To support these studies, DDX6 was expressed recombinantly with a superfolder green fluorescent protein (sfGFP) tag, which facilitates detection in fluorescence-based assays and improves protein yield. Collectively, these findings establish that DDX6 recognizes each structural domain of the DENV-2 3′ UTR independently. Through a robust biophysical framework, we demonstrated this interaction using multiple complementary techniques, extending detailed characterization to a domain that has not been previously studied in depth.
- ItemUnderstanding PTPLP specificity: from atomic resolution to rational mutagenesis(Lethbridge, Alta. : University of Lethbridge, Dept. of Chemistry and Biochemistry, 2025) Cleland, Colyn P.; University of Lethbridge. Faculty of Arts and Science; Mosimann, Steven C.; Girodat, DylanTo understand substrate specificity of protein tyrosine phosphatase-like myo-inositol phosphatases (PTPLPs), I determined the X-ray crystallographic structures of two divergent PTPLP’s (30% sequence identity), PhyAdm from Solidesulfovibrio magneticus and PhyAlp from Legionella pneumophila str. Paris, in complex with InsP6. Both enzymes feature a CRGG phosphate-binding loop (P-loop) sequence, a shared InsP6 dephosphorylation pathway and a novel InsP6 binding mode. Comparison with the previously solved PhyAsr structure in complex with InsP6, which features a CEAG P-loop sequence, revealed that conformational differences in InsP6 binding were linked to the identity of the x2 residue in the P-loop. This finding prompted the investigation of additional novel PTPLPs containing similar and divergent naturally occurring x1x2 P-loop variants. The results established a relationship between InsP6 dephosphorylation pathways and P-loop x1x2 residues, identifying the P-loop as a primary determinant of PTPLP specificity. To demonstrate an understanding of PTPLP specificity, I rationally engineered P-loop mutants of PhyAdm and PhyAsr that swapped their x1x2 residues. Each mutant exhibited the InsP6 dephosphorylation pathway characteristic of the other enzyme. Structural analysis of the PhyAsr P-loop mutant in complex with its new dephosphorylation products confirmed that the x1x2 residue pairing influences substrate binding modes within the active site. These findings significantly advance our understanding of PTPLP substrate specificity and suggest a variety of novel research directions to further expand upon the structure-function relationship of these enzymes.
- ItemGenetic population structure of the least flycatcher (Empidonax minimus): implications for evaluating migratory connectivity(Lethbridge, Alta. : University of Lethbridge, Dept. of Biological Sciences, 2025) Castro García, Sara; University of Lethbridge. Faculty of Arts and Science; Burg, Theresa M.Over the last six decades, avian aerial insectivores in North America have experienced an overall decline of ~60% in their population across their breeding ranges. Understanding their population genetic structure and spatial connections across the annual cycle is critical to determining potential factors driving these trends; however, this information is limited for many species. This study uses RADseq data to examine population structure and connectivity in least flycatchers (Empidonax minimus) across North America. Supported by field and museum sampling, blood, feather, and/or tissue samples were collected from 14 sites throughout the breeding range as well as during migration in Canada and the USA, and on the non-breeding grounds in Mexico. The results from principal components analysis (PCA), pairwise FST, STRUCTURE, and least-cost corridor analyses indicate high levels of gene flow among breeding populations, with weak genetic structure observed between two groups that exhibit an east-west split, which is enhanced using outlier loci. A genetic stock identification analysis was conducted to determine the breeding origin of the non-breeding samples, utilizing outlier loci. Twelve out of 29 non-breeding samples were successfully assigned to a breeding population. In two of the three non-breeding locations, individuals of mixed origin were observed, indicating weak migratory connectivity. The results indicate that the weak migratory connectivity and young age of the species might contribute to the low levels of population structure observed. This study allowed to increase the comprehension of the genetic structure and migratory connectivity of the least flycatcher.