Veterinary Pathobiology electronic theses and dissertations (MU)
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The items in this collection are the theses and dissertations written by students of the Department of Veterinary Pathobiology. Some items may be viewed only by members of the University of Missouri System and/or University of Missouri-Columbia. Click on one of the browse buttons above for a complete listing of the works.
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Item Functional myology of the primate head and neck with implications for hominin evolution(University of Missouri--Columbia, 2021) McGechie, Faye; Ward, Carol V.[EMBARGOED UNTIL 5/1/2026] The primate nuchal region has been widely cited as reflecting postural and locomotor behaviors. Postural and locomotor reconstructions of fossil primates, particularly fossil hominins, have relied upon untested hypotheses linking nuchal muscle form and function to bony morphologies. This thesis addresses the gap in knowledge of variation in the primate nuchal musculature and its relationship to positional behaviors through the use of gross cadaveric dissections and in silico visualization and quantification of muscle variables. Nuchal muscle mass is best predicted by body size alone across primates. Additionally, in situ attachment sites of the nuchal musculature are similar among closely related taxa rather than among species with similar positional behaviors. Semisuspensory taxa have more dorsoventrally oriented trapezius muscles when compared to closely related but nonsuspensory taxa. Orthograde primates have less powerful longissimus capitis muscles than pronograde primates do. Further, primates that engage in extreme neck rotation demonstrate differentially oriented and more powerful sternocleidomastoid muscles. These combined results, however, do not translate to overall differences in the moment-generating capacity of the nuchal musculature. The main exception is that primates that engage in extreme neck rotation have larger estimates for moments of lateral flexion of the neck when compared to all other taxa. Overall, this study does not support the idea that nuchal muscle function is driven by positional behaviors alone. It further demonstrates the need to consider muscle morphology and function when using a biomechanical framework to interpret the primate fossil record.Item Discovery of novel hepatitis B virus (HBV) antivirals and analysis of mechanisms of action of HBV-targeting agents(University of Missouri--Columbia, 2017) Huber, Andrew Douglas; Sarafianos, Stefan G.[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Chronic hepatitis B virus (HBV) infection leads to liver disease, cirrhosis, and hepatocellular carcinoma. Globally, an estimated 50% of all hepatocellular carcinoma cases are linked to chronic HBV infection. More than 240 million people are chronically infected, and there are 0.5-1 million deaths per year due to HBVrelated liver conditions. HBV treatment options rarely cure infections and are associated with adverse side effects that often outweigh the potential benefits of treatment. New treatments, therefore, are highly desired for HBV therapy. Towards this goal, we have developed novel compounds targeting two viral targets and assessed the mechanisms of action by which these compounds act. We have developed systems for the discovery and evaluation of compounds that inhibit 2 distinct steps in the HBV life cycle. Using these systems, we have developed potent inhibitors of HBV replication that have potential to become clinically used HBV drugs. Furthermore, we have used our methods to evaluate which properties of these compounds are likely to result in better viral inhibition. The work described in this thesis has led to at least 2 new compound groups for potential use as HBV antivirals and provides insight into mechanisms by which potent antivirals can be achieved.Item Biochemical characteristics of different subtypes of human immunodeficiency virus type 1 reverse transcriptase and its interactions with the host factor : apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G(University of Missouri--Columbia, 2017) Kim, Seongmi; Sarafianos, Stefan G.[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Human immunodeficiency virus (HIV) is divided into type 1 (HIV-1) and type 2 (HIV-2). Whereas HIV-2 accounts for 5% of global infections, HIV-1 is responsible for 95% of the global pandemic. HIV-1 is classified into four groups; M, N, O and P. Group M is the most prevalent, including subtypes or clades of A-D, F-H, J, K, over 100 Circulating Recombinant Forms (CRFs), and several Unique Recombinant Forms (URFs). In developed countries (i.e. countries in North America, Western Europe, and Australia), HIV-1B is the most prevalent strain. However, it accounts for only about 12% of worldwide infections. On the other hand, HIV-1C, which is most prevalent in Low- and Middle-Income Countries (LMICs) (e.g. India, Brazil, and many countries in Sub-Saharan Africa), accounts for [about]52% of all HIV infections. Due to its prevalence in developed countries, HIV-1B has been the major target of HIV studies and anti-HIV drug development. However, it has been reported that HIV-1non-B patients have higher rates of treatment failure than HIV-1B patients. To understand the mechanism behind this observation, we applied in vitro biochemical assays, which were performed with four patient-derived reverse transcriptase (RT) proteins isolated from HIV-1B, HIV-1C, CRF01_AE, and CRF02_AG viruses. RT is the HIV enzyme that generates viral DNA from genomic RNA during the early stages of infection, and it is the target for many anti-HIV drugs. RT inhibitors are divided into two types depending on their structure. First, Nucleoside/nucleotide Reverse Transcriptase Inhibitors (NRTIs), which bind the active site of the RT and act as chain terminators. In addition, a new type of NRTI, called 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), works as a translocation inhibitor. Second, Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) inhibit RT by binding to an allosteric site. Nevirapine (NVP) belongs to the first generation of NNRTIs, however HIV-1 develops resistance mutations frequently during NVP treatment. Rilpivirine (RPV) has been developed to target NVP-resistant viruses but it is not frequently used in LMICs. In this study, we determined the biochemical characteristics of HIV-1 RTs from various subtypes and determined kinetic constants of inhibition by EFdA, NVP, and RPV. The results show that all of the tested HIV-1 RTs incorporate EFdA with better efficiency than their natural cognate substrate, dATP, which suggests that EFdA would be effective against all of the tested HIV-1 subtypes. Furthermore, generally NVP binds RTs with a lower affinity than RPV, implying that NVP would be a less effective inhibitor than RPV. However, in the case of CRF02_AG RT, NVP binds with similar affinity to RPV, suggesting CRF02_AG patients may respond better to NVP than patients infected with other subtypes. HIV-1C has less binding affinity to RPV than other subtypes, which is consistent with clinical reports showing that HIV-1C patients have a higher rate of treatment failure with RPV. Finally, we have studied the effect of a host factor, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G (APOBEC3G), on HIV-1 RT. APOBEC3G (A3G) has been reported to inhibit several retroviral infections. To date, there are two established mechanisms of this inhibition, which are hyper-mutagenesis and roadblock. In this study, we investigated a third mechanism, the direct inhibition of HIV-1 RT, using in vitro RT assays. Our results showed that A3G does inhibit the activity of HIV-1 RT by affecting the catalytic rate of dNTP incorporation (kcat), supporting the direct inhibition mechanism. Interestingly, A3G had similar inhibitory activity against a related viral RT (from Moloney Murine Leukemia Virus), but no activity against DNA polymerase I.Item Transcriptome profiling of rattus norvegicus embryonic stem cells by RNA-sequencing(University of Missouri--Columbia, 2014) Johnson, Nathan Tyler; Bryda, Elizabeth C.Embryonic Stem Cells (ESCs) are a critical tool for producing targeted knockout animals and understanding development. ESCs were successfully isolated from rats in 2008 and have been used in producing several targeted knockout animal models. To date, little characterization of rat ESCs (rESCs) has been done. In order to establish a rESC transcriptome, RNA-Seq was done on mRNA from the rESC cell line DAc8, the first male germline competent rat ESC line to be described and the first to be used to generate a knockout rat model. RNA-Seq was chosen as it is currently the most sensitive transcriptome analysis method. In the studies described here, the genes expressed in rat ESCs were identified, and a subset of the undescribed isoforms and unannotated rat genes revealed by this analysis were confirmed by RT-PCR analysis. Importantly, the rESC data allowed comparison with previously reported data for mouse and human ESCs to begin to understand the similarities and differences of the transcriptomes of ESCs from different mammalian species.Item Dietary nutrients implicated in the etiopathogenesis of human and animal diseases(University of Missouri--Columbia, 2017) Hooper, Sarah E.; Backus, RobertHyperthyroidism is a spontaneous disease that results in an abnormal elevation of circulating concentrations of one or more thyroid hormones. Despite being the most commonly diagnosed endocrine disorder of domestic cats, the etiopathogenesis remains unknown. My dissertation research sought to investigate whether the dietary nutrients selenium, water, and taurine cause an overstimulation of the thyroid gland and alter the function of the hypothalamic-pituitary-thyroid axis. Because feline hyperthyroidism is clinically and pathologically similar to toxic nodular goiter or Plummer's disease, one of the most common types of hyperthyroidism in humans, I sought to determine if cats are a better animal model than rats for studying dietary causes of hyperthyroidism. To my knowledge, this is the first project to conduct simultaneous animal studies where two species are assessed for suitability as animal models for a human disease and concurrently conduct hypothesis-driven research on potential dietary etiologies of a disease that affects both the domestic feline population and humans. This unique experimental design provided strong support that cats are a better animal model of toxic multinodular goiter, because we were able to establish that cats have an individual set-point for thyroid-stimulating hormone (TSH) which similar to humans. Additionally, we showed that there was a positive correlation with taurine consumption and circulating triiodothyronine (T3) in female rats but not male rats. Women are five to eight times more likely to suffer from a thyroid disease. Our findings indicate future research is needed to determine if supplemental taurine and consumption of high taurine diets predisposes women to thyroid gland disorders. Furthermore, in cats, consumption of water significantly altered the production of T3 and caused a 20% increase in activity level. Because consumption of canned cat food has been the only consistently identified risk factor in epidemiological studies, our results indicate future studies should focus on the relationship between water consumption and feline thyroid physiology.