Thesis (M.S.)--University of Michigan, 1963. / Includes bibliography: leaves [39]-40.

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<p>Our ability to convert basic knowledge into robust anti-viral therapeutics requires discovery of novel host-virus interactions as well as an informed anti-viral discovery pipeline. We used a genome-scale RNAi-based screen followed by a chemical screen of FDA-approved therapeutics to identify scores of novel dengue virus (DENV) human host dependency factors (HDF) and identified more than 20 potential anti-Zika virus (ZIKV) therapeutics. </p><p>Two genes in particular, TTC35 and TMEM111, strongly inhibited DENV infection and, based on comparisons with published literature, implicated a larger protein, the ER Membrane Protein Complex (EMC), as a pan-flavivirus HDF. The EMC is a poorly characterized multiprotein complex that may function in ER-associated protein biogenesis and/or lipid metabolism. Based on our screen data, we hypothesized that the EMC is an uncharacterized HDF that functions through a common mechanism to promote replication of flaviviruses. We report that DENV, ZIKV, and yellow fever virus (YFV) infections were impressively inhibited, while West Nile Virus (WNV) infection was unchanged, in cell lines engineered to lack EMC subunit 4 (EMC4). Furthermore, targeted depletion of EMC subunits in live mosquitos significantly reduced DENV-2 propagation in vivo. In addition, the accumulation of DENV proteins shortly after infection in EMC4 knockout cells was significantly reduced, suggesting that the EMC promotes viral protein biogenesis. </p><p>We interrogated a library of FDA-approved drugs for their ability to block infection of human HuH-7 cells by a newly isolated ZIKV strain. Selected compounds were further validated for inhibition of ZIKV infection in human cervical, placental, and neural stem cell lines, as well as primary human amnion cells. Established anti-flaviviral drugs (e.g., bortezomib and mycophenolic acid) and others that had no previously known antiviral activity (e.g., daptomycin) were identified as inhibitors of ZIKV infection. Several drugs reduced ZIKV infection across multiple cell types.</p><p>We propose that the EMC may be exploited as a novel therapeutic target for multiple flaviviruses in the future. Also we identified drugs that could be tested in clinical studies of ZIKV infection and provides a resource of small molecules to study ZIKV pathogenesis.</p> / Dissertation

Senescence is an intricate, multifaceted process that can vary among populations, individuals, and traits within individuals. However, the relative importance of factors generating observed differences in senescence patterns remains poorly understood. In particular, there is a lack of studies that quantify both age-dependent and state dependent components of senescence, and do so across different environmental conditions. Also, few studies have explicitly tested cumulative reproductive costs, or how early-life conditions like maternal age and state at offspring birth affect offspring adult phenotypes and senescence trajectories. I use individual-based long-term data from wild yellow-bellied marmots, to quantify chronological (age-dependent) and biological (state-dependent) senescence in female reproductive success and season-specific body mass across two different elevational environments. Since previous reproductive history could influence biological age, I also estimate costs of previous short-term and cumulative long-term reproduction on females' current reproductive success. Finally, I test whether maternal age and state at daughter birth affect daughter reproduction and senescence. I demonstrate complex senescence patterns in body mass and reproductive success. First, senescence in body mass has both age-dependent and state-dependent components, and effects are greater at lower elevation than higher elevation and greater in late summer than in spring. Second, at both elevations, females that reproduced frequently and weaned large litters in previous years have reduced current reproductive probability, while there are no short-term effects of previous reproduction. Finally, higher chronological age and closer proximity to death of the mother have positive environment-dependent effects on daughter reproductive trajectories. Overall, my findings reveal the need to investigate senescence patterns across multiple environments and over long time periods to allow capturing certain intra-individual and inter-generational effects. The persistence of maternal effects into daughters' adult lives highlights the complexity of life-history trade-offs, and calls for more studies that consider such long-term transgenerational effects when studying life-history variation and senescence in wild populations.

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Graduation date: 1993

Caption title: An inaugural dissertation on yellow fever. / Dedicated to Dr. Wright Post, professor of anatomy and surgery in Columbia College, and also to Dr. Isaac Ledyard, health officer, Dr. James Tillary, resident physician, and Dr. Edward Miller, health commissioner.

Thesis (M.S.)--Auburn University, 2007. / Abstract. Vita. Includes bibliographic references.

Thesis (Ph. D.)--University of Adelaide, Dept. of Plant Science, 1998. / Includes bibliographical references (15 leaves ).