2013 UMKC Dissertations - Access Restricted to UMKC
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Item The Role of Host Translation Initiation Factors eIF4H and eIF4A and the Exon Junction Complex in the Control of mRNA turnover and Translation by the Virion Host Shut off Protein of Herpes Simplex Virus(2013) Sadek, Jouliana; Read, George Sullivan, 1948-During lytic infections, the HSV Vhs endonuclease (UL41) degrades many viral and cellular mRNAs. This endonuclease activity is dependent upon the ability of Vhs to bind the host translation initiation factors eIF4AI/II and eIF4H. eIF4AI and 4AII are isoforms of an ATP-dependent RNA helicase that unwinds mRNA secondary structure near the 5’ cap to allow the binding and subsequent scanning of the 40S ribosomal subunit. eIF4H binds and stimulates the helicase activity of eIF4AI/II. Si-RNA mediated knockdown of both eIF4AI/AII isoforms significantly impeded Vhs activity. Furthermore, hippuristanol, a selective eIF4AI/II inhibitor, blocked Vhs-mediated mRNA decay both in vitro and in vivo. In addition, we can restore Vhs activity in cells depleted of their endogenous eIF4H protein levels by transfecting an expression vector that encodes wild-type eIF4H but lacks the sequences recognized by the siRNA. We used this assay to screen a library of mutant eIF4H polypeptides for their ability to participate in Vhs cleavage and assayed their ability to bind eIF4A. These experiments revealed that both binding and stimulating eIF4A helicase activity are required for Vhs activity. In addition, we showed that the splicing history of an mRNA can affect its expression levels and its sensitivity to cleavage by Vhs. In uninfected cells, spliced mRNAs bound by the exon junction complex (EJC) are translated more efficiently than unspliced mRNAs containing an identical primary sequence. Whereas most cellular mRNAs are spliced, most viral mRNAs are not except a few immediate-early and late genes. During HSV-1 infections, spliced mRNAs containing a luciferase reporter were much less sensitive to Vhs-mediated degradation and expressed significantly more RLuc protein per molecule of mRNA, than did the unspliced mRNAs. The intron translational stimulatory effect could be replicated by artificially tethering various EJC components to an intronless RLuc reporter. Furthermore, knocking down the expression of endogenous eIF4AIII, an essential component of the EJC, restores Vhs cutting of spliced transcripts to the same level as unspliced mRNAs. The data suggest that the exon junction complex plays an important role in gene expression during HSV infections and can temporarily protect spliced mRNAs from Vhs endonuclease activity.Item Beneath Mark Twain: Judgments of Justice and Gender in Twain's Early Western Writing, 1861-1873(2013) Roark, Jarrod; Barton, John CyrilBy the time Samuel Clemens began writing journalism and crafting what he called the “sensation hoax” for Virginia City’s Territorial Enterprise in 1862, Americans had been devouring sensational novels and journalism by such American writers as George Lippard, George Thompson, Ned Buntline, Emerson Bennett, and John Rollin Ridge for two decades. These writers, though only a few among many linked to the nineteenth-century Transatlantic genre of sensational fiction, were concerned with social reform in antebellum America, but they gained readership by writing tales about murderers and rapists. These male characters usurp the rights and freedoms of just but powerless men and symbolize the larger cultural anxieties of antebellum Americans living in growing cities. Lippard and Thompson wrote about such crime associated with disparate wealth distribution in the Metropolis, whereas Ridge and Bennett, for example, exposed racial and cultural violence in the American West. Indeed, Clemens, often writing as Mark Twain, combined all of these concerns in his early journalism and sensation hoaxes during the 1860s – state and personal justice, gender, class, race – while exploiting sensational literary depictions of violence that entertained readers but also encouraged readers to critique politics and the ethics of individual actions in the West. The purpose of this dissertation is not to write a history of the American West, nor to write a biography of Mark Twain. Rather, its primary aim is to describe Mark Twain’s sensational journalism and fiction, and his letters to friends and family, that responded to cultural anxieties about crime, punishment, and gender. My goals: to show Twain’s response to violence as a “philosophic observation,” rather than a standard news reporting. Though journalism imparted facts, Twain’s journalism also offered his personal philosophies, his observations, about morality, gender, and justice. With such observations, he became what we might call the “voice of the people.” This study also complicates Twain’s anti-gallows sentiment, for he distrusted capital punishment and yet supported frontier justice. Additionally, Twain developed judgments of subversive women in the West that culminated with a literary verdict in his legal novel The Gilded Age (1873). Before he left the West, however, much of Twain’s discourse about California and Nevada Territory and their spaces – cities and countryside – actually reflected his anxieties about westward expansion and the promise of a utopian West. To borrow Glenn Hendler’s terms, Twain expressed such worries in both his “personal” and “public” sentiments. Finally, this study problemitizes how Twain used his journalism to expose male criminals and to punish them with literary mockery, and yet he also distrusted the female victims who seemed to place themselves in harm’s way and challenged Twain’s assumptions about gender and chastity.Item The Cellular and Molecular Mechanisms of Prostaglandin E₂ in Myogenesis(2013) Mo, Chenglin; Igwe, Orisa JohnProstaglandin E₂ (PGE₂), the most abundant prostaglandin (PG) in our body, has multiple biological functions related to physiological activities and the development of diseases. Emerging evidence has shown that PGE2 plays an important role in regulating the survival and proliferation of hematopoietic stem cells, suggesting that PGE₂ signaling could be essential for tissue development and regeneration. Previous results have also indicated that inhibition of PGE₂ synthesis through the cycoloxygenase-2 (COX-2) pathway at an early stage of muscle recovery from damage attenuated skeletal muscle regeneration. However, the exact mechanisms by which PGE₂ regulates skeletal muscle development and regeneration are elusive. In this project, the central hypothesis is that PGE₂ signaling through its G protein-coupled E prostanoid (EP) receptors is essential for skeletal muscle development or regeneration. Murine skeletal muscle cell line C2C12 was used as a model to test this hypothesis. The first part of the project is concerned with the role of PGE₂ in myogenic differentiation. Activation of PGE₂ signaling promoted C2C12 myogenic differentiation, which resulted from the upregulation of genes related to myogenic differentiation, calcium signaling and other pathways. Two EP receptors, EP1 and EP4, were identified as the major isoforms in C2C12 cells. Blockage of either receptor significantly inhibited C2C12 myogenesis. Our results indicated that EP1 signaling is involved in regulating myogenin expression, while activation of EP4 receptor is important for fusion. In addition, the effect of PGE₂ on myoblast proliferation was also determined. Although treatment with PGE₂ or EP1/4 agonist did not alter C2C12 proliferation, inhibition of either EP1 or EP4 receptor caused G0/G1 phase arrest, which subsequently inhibited C2C12 proliferation. Furthermore, COX-1 was shown to be the major COX isoform expressed in C2C12. Inhibition of COX-1, but not COX-2, negatively regulated C2C12 myogenic differentiation. In conclusion, our data have demonstrated that PGE₂ plays a multifaceted role in regulating C2C12 proliferation and myogenic differentiation through EP1 and EP4 receptors. Our results also provide new insights for the function of COX-1–derived PGE₂ during differentiation from myoblasts to myotubes.Item The function of Drosophila Integrin-Dim7-Elmo-Mbc→Rac signaling pathway in the muscle attachment formation and maintenance(2013) Liu, Ze; Geisbrecht, Erika R.The Engulfment and Cell Motility (Elmo)-(Myoblast city) Mbc→Rac signaling pathway is evolutionarily conserved from C. elegans to vertebrates and is essential for many developmental processes, including phagocytosis and cell migration. Flies that possess mutations in the elmo locus are lethal and exhibit defects in myoblast fusion, thorax closure, and border cell migration. Herein, using mass spectrometry approaches to identify new players in the Elmo signaling pathway, we uncovered Drosophila Importin-7 (Dim7), encoded by moleskin (msk), as a potential Elmo-interacting protein. In msk mutants, which exhibit muscle detachment phenotypes, the tendon cell differentiation factors Stripe or activated Mitogen-activated kinase (pMAPK) are missing from the tendon cells. Our data shows that Msk signals from the muscle cell via the secreted Epidermal growth factor receptor (Egfr) ligand Vein to regulate tendon cell maturation. In the muscle, Dim7 acts upstream to recruit the Elmo-Mbc signaling module to the ends of muscles for stable muscle attachments. Both Dim7 and Elmo are localized to the muscle attachment sites (MASs) during myogenesis, and phenotypic analysis of elmo mutants show muscle attachment defects as that of previously described in msk. The muscle detachment phenotype in msk mutants can be rescued by components in the Elmo-signaling pathway, including the Elmo-Mbc complex, an activated Elmo variant, or constitutively active Rac. In actively contracting larval muscles, integrins function as upstream signals to mediate Dim7-Elmo enrichment to the MASs. We postulate that the regulation of Rac activity at the ends of muscles locally modulates the internal actin cytoskeleton to maintain stable muscle attachments during muscle growth or in response to changes in force transmission in active muscle contraction.Item Development Theory and the Cold War: A Historical Analysis of Latin American Structuralism from 1930 to 1970(2013) Bracarense, Natália; Forstater, Mathew, 1961-Latin America has experimented with two different development strategies over the last two centuries. First, and currently, an “outward-oriented” program based on exports of primary commodities. Alternatively, for a few years following World War II, a domestic industrialization from within strategy received support. A consensus that both models failed to achieve sustainable development in Latin America opened space for rethinking development theory and policy in the beginning of the twenty-first century. This dissertation uses an historical approach to analyze the post-WWII development theories in order to inform the new development debate. What motivated alternative theories and how were they conditioned by historical contexts? What were the consequences of accepting the policies prescription originated from these theories in Latin America? Why were alternative models and policies so short-lived? According to this dissertation the demise of development economics was due to both theoretical deficiencies and politics. To become resilient, development theory needs to build its core on historically grounded principles.