1,989 research outputs found

    Undergraduate Catalog of Studies, 2023-2024

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    Graduate Catalog of Studies, 2023-2024

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    Undergraduate Catalog of Studies, 2023-2024

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    UMSL Bulletin 2023-2024

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    The 2023-2024 Bulletin and Course Catalog for the University of Missouri St. Louis.https://irl.umsl.edu/bulletin/1088/thumbnail.jp

    Graduate Catalog of Studies, 2023-2024

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    UMSL Bulletin 2022-2023

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    The 2022-2023 Bulletin and Course Catalog for the University of Missouri St. Louis.https://irl.umsl.edu/bulletin/1087/thumbnail.jp

    Understanding Glycans and Glycosidases in Infection and Biofilm Formation as a Route to Novel Antimicrobials

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    Periodontitis is a chronic bacterially induced disease characterized by inflammation of the gingivae and subsequent destruction of the tissues and supporting structures of the periodontium, which can lead to tooth loss. The red complex pathobionts: Porphyromonas gingivalis and Tannerella forsythia are mostly associated with periodontitis and are shown to modulate the host’s innate immune system. These oral pathogens secrete sialidase enzymes that they use to scavenge sialic acids found at the terminus of host glycoprotein chains for nutrition or to evade host immune responses. Activities of these pathogens, therefore, poses a problem to public health as such, necessitates the need to carry out research aimed at understanding this important enzyme as a route for the development of novel inhibitors of periodontitis and other immune-modulatory diseases. Over-expressed P. gingivalis (SiaPG) and T. forsythia (NanH) sialidase enzymes were purified using HisTag low-affinity chromatography, and the sialidase activity was tested using 4-methylumbelliferyl N-acetyl-α-D-neuraminic acid sodium salt (MUNANA), as substrate. Inhibition studies using whole cells and the purified sialidases of T. forsythia (NanH) and P. gingivalis (SiaPg), showed ECG as the best plant-derived inhibitor, while 2e3aDFNeu5Ac9N3 as the most potent of all the screened compounds. Additionally, Palmatine and Berberine chloride synergistically inhibited almost a 100 % NanH sialidase activity, with mechanisms of action (MOA) showing Palmatine, Berberine chloride, and 2e3aDFNeu5Ac9N3, as non-competitive, uncompetitive and competitive inhibitors of NanH sialidase, respectively. Furthermore, sialidase promotes the growth of P. gingivalis and T. forsythia, and supports host-pathogen interactions via adhesion and invasion of oral epithelial cells (H357). In addition, the role of P. gingivalis and T. forsythia sialidases on host innate immune modulation in the presence or absence of 2e3aDFNeu5Ac9N3 was also assessed using flow cytometry. NanH sialidase of T. forsythia appears to upregulate the secretion of pro-inflammatory cytokines such as interleukin-6 (IL-6), IL-8, and IL1-β in the cell supernatants, which was abrogated significantly by 2e3aDFNeu5Ac9N3 with minimal cytotoxic effects on the oral epithelial cells. Also, molecular docking of several inhibitors into the active-site pockets of NanH-apo and SiaPg using AutoDock Vina and PyMol suggested that Oseltamivir, Siastatin B, DANA, and 2e3aDFNeu5Ac9N3 coordinate the arginine triad (Arg423, Arg487, Arg212 and Arg194, Arg213, Arg460), of NanH and SIaPg of T. forsythia and P. gingivalis, respectively. Also, the nucleophilic dyad tyrosine and glutamate interact with the anomeric carbon as well as the acid/base aspartate residue Asp237/Asp280 interacting with the N-acetyl group of respective inhibitors. The superior inhibitory properties of 2e3aDFNeu5Ac9N3 on both the purified and whole cell sialidase activities of P. gingivalis and T. forsythia make it a promising compound, and can further be developed as a novel immunomodulatory agent of periodontitis or other inflammatory diseases

    Undergraduate Catalog of Studies, 2022-2023

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    Flavonol Glucosylation: A Structural Investigation of the Flavonol Specific 3-O Glucosyltransferase Cp3GT

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    Flavonoid glycosyltransferases (GTs), enzymes integral to plant ecological responses and human pharmacology, necessitate rigorous structural elucidation to decipher their mechanistic function and substrate specificity, particularly given their role in the biotransformation of diverse pharmacological agents and natural products. This investigation delved into a comprehensive exploration of the flavonol 3-O GT from Citrus paradisi (Cp3GT), scrutinizing the impact of a c-terminal c-myc/6x histidine tag on its enzymatic activity and substrate specificity, and successfully achieving its purification to apparent homogeneity. This established a strong foundation for potential future crystallographic and other structure/function analyses. Through the strategic implementation of site-directed mutagenesis, a thrombin cleavage site was incorporated proximal to the tag, followed by cloning in Pichia pastoris, methanol-induced expression, and cobalt-affinity chromatography for initial purification stages. Notably, the recombinant tags did not exhibit a discernible influence on Cp3GT kinetics, substrate preference, pH optima, or metal interactions, maintaining its specificity towards flavonols at the 3-OH position and favoring glucosylation of quercetin and kaempferol. Subsequent purification steps, including MonoQ anion exchange and size-exclusion chromatography, yielded Cp3GT with ≥95% homogeneity. In silico molecular models of Cp3GT and its truncated variants, Cp3GTΔ80 and Cp3GTΔ10, were constructed using D-I-TASSER and COFACTOR to assess binding interactions with quercetin and kaempferol. Results indicated minimal interference of c-myc/6x-his tags with the native Cp3GT structure. This study not only lays a foundation for impending crystallographic studies, aiming to solidify the understanding of Cp3GT\u27s stringent 3-O flavonol specificity, but also accentuates the potential of microbial expression platforms and plant metabolic engineering in producing beneficial compounds. To this end, a thorough review of four pivotal classes of plant secondary metabolites, flavonoids, alkaloids, betalains, and glucosinolates, was conducted. This will open avenues for further research and applications in biotechnological, medical, and agricultural domains

    Computational Approaches to Drug Profiling and Drug-Protein Interactions

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    Despite substantial increases in R&D spending within the pharmaceutical industry, denovo drug design has become a time-consuming endeavour. High attrition rates led to a long period of stagnation in drug approvals. Due to the extreme costs associated with introducing a drug to the market, locating and understanding the reasons for clinical failure is key to future productivity. As part of this PhD, three main contributions were made in this respect. First, the web platform, LigNFam enables users to interactively explore similarity relationships between ‘drug like’ molecules and the proteins they bind. Secondly, two deep-learning-based binding site comparison tools were developed, competing with the state-of-the-art over benchmark datasets. The models have the ability to predict offtarget interactions and potential candidates for target-based drug repurposing. Finally, the open-source ScaffoldGraph software was presented for the analysis of hierarchical scaffold relationships and has already been used in multiple projects, including integration into a virtual screening pipeline to increase the tractability of ultra-large screening experiments. Together, and with existing tools, the contributions made will aid in the understanding of drug-protein relationships, particularly in the fields of off-target prediction and drug repurposing, helping to design better drugs faster
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