Now showing items 1-20 of 4393

    • Socio-Economic Factors and Cardiovascular Disease Mortality: A County-Level Analysis of Georgia

      Adepu, Sanjana (Augusta University, 2019-10)
      Background: With over 20,000 deaths (~1 in every 3 deaths) per year, Cardiovascular Disease (CVD) is the leading cause of death in Georgia. Studying the overall impact of multiple socioeconomic factors (SES) on CVD could lead to a better understanding of the determinants of public health. The factors examined in this study include physical inactivity, median household income, health insurance, and air quality. While several studies examine the effects of a single SES factor on CVD, this study analyses multiple SES factors on CVD death rates in Georgia. Methods: County-level socioeconomic factors for Georgia were obtained from The Center for Disease Control and Prevention. A multiple regression model was developed to identify the factors that explain CVD death rates in Georgia. Results: In Georgia, the median household income and annual average ambient concentrations of PM2.5 were the most significant factors. Lower levels of median household income were associated with higher CVD death rates; higher concentrations of PM2.5 were associated with higher CVD death rates. Additionally, leisure-time physical inactivity was marginally significant, which indicates higher percentages of physical inactivity led to higher CVD death rates. Conclusion: Policies that increase median household income and lower annual ambient concentrations may also have secondary benefits to public health and, in particular, cardiovascular disease death rates in Georgia. Future studies could expand upon this analysis by studying the effects of SES on the national level.
    • MYCN STIMULATES GLYCINE DECARBOXYLASE (GLDC) IN NEUROBLASTOMA TO PROMOTE TUMORIGENESIS

      Alptekin, Ahmet; Biomedical Sciences (Augusta University, 2019-05)
      Genomic amplification of the oncogene MYCN is a major driver in the development of high-risk neuroblastoma, a pediatric cancer with poor prognosis. Given the challenge in targeting MYCN directly for therapy, we sought to identify MYCN-dependent metabolic vulnerabilities that can be targeted therapeutically. Here, we report that the gene encoding glycine decarboxylase (GLDC), which catalyzes the first and rate-limiting step in glycine breakdown with the production of one-carbon unit 5,10-methylene-tetrahydrofolate, is a direct transcriptional target of MYCN. GLDC expression is markedly elevated in MYCN-amplified neuroblastoma tumors and cell lines. This transcriptional upregulation of GLDC expression is of functional significance, as GLDC depletion by RNA interference inhibits the proliferation and tumorigenicity of MYCN-amplified neuroblastoma cell lines. Metabolomic profiling reveals that GLDC knockdown disrupts purine and central carbon metabolism and reduces citrate production, leading to a decrease in the steady-state levels of cholesterol and fatty acids, which are essential to sustain cell proliferation. In addition, microarray gene expression profiling shows that GLDC silencing downregulates genes involved in regulation of cell proliferation. These findings suggest that GLDC is a key player in MYCN-regulated cancer metabolism and a potential drug target in the treatment of high-risk neuroblastoma.
    • The Antidote: Volume 1

      Wang, Bing; Allen, Griffen; Cardoso, Leticia; Chandra, Upasana; Stephens, Michael; Iyoha, Ehiremen; Juarez, Erick; McKenzie, Savannah; Owen, Jack; Jalla, Rasmita; et al. (Augusta University Libraries, 2019)
    • Terminal competencies of the baccalaureate nursing graduate

      Eberhart, Aeris Dee; School of Nursing (1974-05)
    • Drug-induced myotonia in the rat

      Dondero, Linda C; Department of Anatomy (1968-06)
    • The innervation of human fetal muscle spindles

      Dissin, Jonathen; Department of Anatomy (1973-06)
    • Development of the blood-thymus barrier and the effects of lipid RES blocking agents on the adult barrier

      Davenport, William Daniel; Department of Cell and Molecular Biology (1976-05)
    • Isolation and characterization of a lysogenic strain of nocardia erythropolis

      Crockett, Jennifer K; Department of Cell and Molecular Biology (1972-04)
    • A qualitative study of urinary excretion of carbohydrates by mentally retarded children

      Cravey, Eurgene C; Department of Cell and Molecular Biology (1964-08)
    • Ultrastructure of the crown cells of stingrays (Genus Dasyatis)

      Crandall, Wilson T; Department of Anatomy (1970-05)
    • The effects of glucocorticoid administration on collagen metabolism in skin

      Counts, David F; Department of Cell and Molecular Biology (1974-12)
    • solation and partial characterization of gamma-glutamyl transpeptidase from rat kidney

      Counts, David F; Department of Cell and Molecular Biology (1973-04)
    • Phosphorylation of EPS8 Mediates Its Downstream Signaling and Biological Functions

      Shahoumi, Linah Abdalla; Biomedical Sciences (Augusta University, 2019-05)
      Epidermal growth factor receptor pathway substrate 8 (EPS8) is a scaffolding protein involved in regulating cell proliferation, actin dynamics and receptor trafficking in human cells. EPS8 expression is increased in a range of human cancers including head and neck squamous cell carcinoma (HNSCC). Previous studies have indicated that overexpression of EPS8 enhances mitogenesis and migration of tumor cells and is sufficient to convert non-tumorigenic cells to a tumorigenic phenotype. The non-receptor tyrosine kinase Src is reported to phosphorylate EPS8 at four tyrosine residues, although the impact of this on EPS8 function is unknown. The purpose of this study was to investigate the role of tyrosine phosphorylation of EPS8 at Src target sites in modulating biochemical functions, cell growth, motility, actin dynamics and tumorigenesis in HNSCC. Expression plasmids encoding EPS8 with amino acid substitutions to phenylalanine (F) at the four putative Src phosphorylation sites (Y485F, Y525F, Y602F, Y774F), and all four combined (FFFF), were prepared by site-directed mutagenesis. To evaluate the effect of unphosphorylated EPS8 on downstream signals and biological behavior, mutants were transfected into a model cell line, HN4, which expresses a low endogenous level of EPS8 similar to normal keratinocytes. Additionally, cells were treated with dasatinib, a Src inhibitor, to block phosphorylation of Src substrates. Expression of downstream targets of EPS8 was evaluated by western blotting. Wound closure, proliferation, immunofluorescence and tumorgenicity assays were used to investigate the impact of phenylalanine mutations on the biological functions of EPS8. Forkhead box (FOX) M1 transcription factor (FOXM1), aurora kinase A (AURKA) and aurora kinase B (AURKB) levels were decreased in cells expressing the non-phosphorylatable FFFF- and Y602F-EPS8 mutants, while cells harboring the Y485F-, Y525F- and Y774F-EPS8 mutants showed no differences in the expression of these proteins compared to controls. Consistent with this, dasatinib treatment resulted in a significant decrease in the expression of EPS8 downstream targets. In addition, both Y602F- and FFFF-EPS8 mutants elicited a significant reduction in tumor cell proliferation, motility and actin remodeling. However, blocking Src-mediated EPS8 phosphorylation showed increased tumorigenicity in vivo compared with non-transfected control. Conversely, blocking all putative Src phosphorylation sites except Y602 revealed an increase in the cell cycle mediators, tumor cell proliferation, motility, and a more prominent cortical actin cytoskeleton. These data suggest a crucial role for phosphorylation of EPS8 at Y602 in mediating pro-tumorigenic signal.
    • FLAGELLAR CHAPERONES AND CONTROL OF CAMPYLOBACTER JEJUNI MOTILITY

      Fiedler, Jarred; Department of Biochemistry and Molecular Biology (2018-11)
      Campylobacter jejuni is a leading cause of bacterial gastroenteritis, with an annual incidence of 140 million cases globally and 1.3 million cases in the United States. Approximately 1/1000 of C. jejuni infections lead to the onset of Guillain-Barré Syndrome, the world’s leading cause of acute paralysis. While the pathogenic mechanisms of C. jejuni are incompletely understood, it is known that flagellar motility is a primary virulence factor. Flagella are involved in host cell adherence and invasion, biofilm formation, and chick colonization. Flagellar assembly is dependent on the coordinated regulation of flagellar subunit synthesis via transcriptional and post-transcriptional regulators, as well as flagellar chaperones which maintain flagellar subunits in an unfolded state. In C. jejuni, the post-transcriptional regulator CsrA regulates flagellar biogenesis in C. jejuni by binding to the mRNA for flaA, repressing FlaA synthesis. CsrA regulatory activity on flagellar and non-flagellar targets is predicted to be modulated by protein-protein interactions with the flagellar chaperone FliW. Both FliW and a second flagellar chaperone FliS are predicted to participate in flagellar assembly by binding to FlaA. Therefore, we investigated the roles of FliW and FliS in CsrA regulation and flagellar biogenesis by constructing and characterizing a fliS mutant of C. jejuni strain 81-176, and by testing for the presence of protein-protein interaction(s) among CsrA, flagellin, and flagellar chaperones. We created an in-frame deletion mutant of fliS, and determined that the deletion of fliS resulted in a loss of motility and reduced the capacity of C. jejuni to autoagglutinate and form biofilm. We also used a bacterial two-hybrid system to study possible binding among the flagellarrelated proteins FlaA, FliS, FliW, and CsrA. Additionally, we performed deletion analysis of fliW in pT25, with the goal of identifying the region of FliW that mediates binding to CsrA. CsrA bound to full-length FliW, but no other protein-protein interactions were evident using the two-hybrid system. Surprisingly, CsrA did not interact with fragments of FliW, suggesting that the CsrA-binding site of FliW may be complex. These results show that flagellar biogenesis is accomplished by interactions of flagellar chaperones that link motility with the regulation of Campylobacter pathogenesis-related properties.
    • SF3B1 mutation promotes c-MYC protein stability and modulation of SF3B1 constitutes an effective therapeutic strategy in chronic lymphocytic leukemia.

      Han, Qimei; Biomedical Sciences (Augusta University, 2019-10)
      The splicing factor, SF3B1, is frequently mutated and causes shorter disease progression free survival and inferior overall survival in chronic lymphocytic leukemia (CLL). However, how mutant SF3B1-induced alternative splicing events contribute to inferior prognosis remains elusive. In this study, we demonstrated that SF3B1 mutation causes aberrant splicing of PPP2R5A mRNA by the usage of a cryptic 3’ splice site. Consequently, a frameshift is induced during translation and multiple pre-mature stop codons are created, leading to its degradation through a process known as nonsense-mediated decay (NMD). The aberrant splicing and downregulation of PPP2R5A at both mRNA and protein levels were confirmed in primary CLL samples and exogenous mutant SF3B1 overexpression models. Furthermore, the decreased expression of PPP2R5A preserves c-MYC serine62 phosphorylation and increases c-MYC protein abundance by promoting its protein stability. Knocking down of PPP2R5A in CLL cells retains the phosphorylation of c-MYC at serine62 and increases c-MYC level, which further confirms its essential role in increased c-MYC stability. SF3B1 has been suggested as a potential therapeutic target in multiple malignancies. We demonstrated that SF3B1 modulator sudemycin D6 (SD6) effectively suppresses CLL cell growth and induces apoptosis both in vitro and in vivo. RNA sequencing analysis revealed a significant increase in global intron retention (IR) in SD6-treated CLL cells. Pathway analysis of the genes associated with increased IR suggested that B-cell receptor (BCR) and PI3K signaling pathways were among the most important pathways being deregulated by SD6. The increase in IR was inversely correlated with a decrease in mRNA and protein levels of a number of key molecules in the BCR/PI3K pathways. SD6 also induced a time-dependent exon-skipping event in anti-apoptotic MCL1 mRNA and resulted in significant down-regulation of another anti-apoptotic gene TRAF1, thus collectively contributing to the SD6-induced apoptosis. Furthermore, SD6 overcame the pro-survival and pro-growth signals and synergized with established CLL therapies, such as ibrutinib, idelalisib, and venetoclax, to induce apoptosis in primary CLL cells, particularly when co-cultured with bone marrow stromal cells and T-cell-derived cytokines. Collectively, these results provide a strong rationale for future clinical development of spliceosome modulators and potential combination therapies for the treatment of CLL.
    • Radiation adaptation in the rat

      Corrill, Lydia S.; Department Of Biology (1968-09)