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Item The relationship between physiological stress response and variation in omics data(Montana State University - Bozeman, College of Letters & Science, 2021) Steward, Katherine Fay; Chairperson, Graduate Committee: Brian Bothner; This is a manuscript style paper that includes co-authored chapters.Omics analysis is the cornerstone of systems biology. It offers comprehensive assessments of stress, interaction networks and connections to phenotype. Defining a stressed phenotype can be challenging, however, as stress response mechanisms can arise from a range of environmental conditions and experimental perturbations. Previous work from our lab noted the possibility of a relationship between stress in omics data and the variation of that data. This connection has yet to be clearly defined, and the cellular mechanisms responsible for the canalization of omics data remain a mystery. In this work I have taken advantage of the sensitivity of metabolomics and proteomics to detect cellular stress and characterize its relationship to variation. By utilizing coefficient of variation (CV) as a statistic of merit, the depth of the relationship between stress and variation can be uncovered. Once the model was clearly defined, a proteomics dataset with a large proportion of protein coverage was utilized to investigate what pathways might be responsible for the metabolite and protein canalization.Item Redox homeostasis and stress in mouse livers lacking the NADPH-dependent disulfide reductase systems(Montana State University - Bozeman, College of Letters & Science, 2019) Miller, Colin Gregory; Chairperson, Graduate Committee: Mary J. Cloninger; Edward E. Schmidt (co-chair); Arne Holmgren, Elias S.J. Arner and Edward E. Schmidt were co-authors of the article, 'Introduction --NADPH dependent and --independent disulfide reductase systems' in the journal 'Free radical biology and medicine' which is contained within this thesis.; Edward E. Schmidt was a co-author of the article, 'Disulfide reductase systems in the liver' in the journal 'British journal of pharmacology' which is contained within this thesis.; Jean A. Kundert, Justin R. Prigge, Julie Amato, Allison E. Perez and Edward E. Schmidt were co-authors of the article, 'Supplemental ascorbate compromises hepatocyte survival and increases risk of acute liver failure during severe oxidative stress' submitted to the journal 'Antioxidant' which is contained within this thesis.; Dissertation contains two articles of which Colin Gregory Miller is not the main author.This thesis includes two reviews that cover the background of cellular disulfide reduction, from its earliest form in hydrothermal vents and its evolution to the current, multifaceted systems that maintain cellular redox homeostasis, to the roles of the disulfide reductase systems in different subcellular compartments, as well as provide a current status for many of the unkown roles disulfide reductase enzymes play. Furthermore, this thesis includes two published research articles, both relating changes in the NADPH-dependent disulfide reductase systems to altered physiology and the possible impacts of these changes to human health (ie cancer, acetaminophen overdose or toxic arsenic exposure.) A third research paper is also included in this thesis, which demonstrates the pro-oxidant effects of administration of the antioxidant ascorbate to TrxR1/Gsr-null livers. This paper is potentially valuable both in a clinical aspect, where ascorbate might be prescribed to counter the effects of excess oxidants, but also to the general public, as ascorbate is one of the most commonly taken over-the-counter supplements. The final chapter of this thesis is fundamental groundwork for future projects aimed at identifying how cells manage accumulation of oxidants/compromised disulfide reductase systems. The two isotopically labled amino acids, L-(^34 S)Met and L-(^34 S)cystine, are valuable tools to monitor S-metabolism, both in the TrxR1/Gsr-null livers but also in other disease states, such as those mentioned above. L-(^34 S)cystine is of particular interest to one of our collaborators, Dr. Gina DeNicola, who plans to use L-(^34 S)cystine to monitor S-metabolism in pancreatic organoids to study pancreatic adenocarcinoma.Item Multivalently presented carbohydrates can be used as drug delivery vehicles and to study protein carbohydrate interactions(Montana State University - Bozeman, College of Letters & Science, 2018) VanKoten, Harrison Wesley; Chairperson, Graduate Committee: Mary J. Cloninger; Wendy M. Dlakic, Robert Engel and Mary J. Cloninger were co-authors of the article, 'Synthesis and biological activity of highly cationic dendrimer antibiotics' in the journal 'Molecular pharmaceutics' which is contained within this thesis.; Rebecca Moore, Coleen Murphy and Mary J. Cloninger were co-authors of the article, 'Probing the LEC-1 and LEC-10 oxidative stress pathway in Caenorhabditis elegans using GALBeta1-4FUC dendrimers' which is contained within this thesis.Dendrimers in general excel as drug delivery vehicles since there are many different ways they can be assembled and different ways to tailor them to the system being studied. Glycodendrimers are generally nontoxic and can be further developed to meet the needs of what is being studied. For instance, in the studies below, a quaternity ammonium compound (QAC) has been attached to a glycodendrimer to determine the antimicrobial activity of a multivalently presented QAC in studies of minimum inhibitory concentration (MIC), biofilm prevention, and bacterial resistance. Results include comparable MICs to those of established antibiotics, prevention of biofilm formation but not disruption of an established biofilm, and establishment of multivalency as a strategy to counteract bacterial resistance. Another heterogeneously functionalized dendrimer was synthesized to study drug release characteristics of a prodrug attached to a cleavable substrate. In these studies, the upregulation of several proteins during cancer progression was taken advantage of including; MMP-2, -7, -9, and galectin-3. Glycodendrimers are tools used to study protein carbohydrate interactions. Study of galectins and their corresponding Beta-galactosides have illuminated their role in several essential biological processes. Multivalency plays a crucial role in many protein-carbohydrate interactions. Galectins are known to interact multivalently with various ligands. Although the role of galectins in this process is not yet fully understood, galectins have been proposed to serve as protective proteins during periods of high oxidative stress. We describe the synthesis of GalBeta1-4Fuc functionalized poly(amidoamine) (PAMAM) dendrimers in order to test C. elegans' response to high oxidative stress. In order to test the function of GalBeta1-4Fuc in vivo, C. elegans were treated with RNAi to knockdown lec-1 or lec-10, and then treated with glycodendrimer and exposed to oxidative stress. C. elegans that were pre-treated with the glycodendrimers were less susceptible to oxidative stress than untreated controls. The glycodendrimers mainly appeared within the digestive tract of the worms, and uptake into the vulva and proximal gonads could also be observed in some instances. This study indicates that multivalently presented GalBeta1-4Fuc can protect C. elegans from oxidative stress by binding to galectins.