Master of Science, The Ohio State University, 2023, Comparative Biomedical Sciences

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic human retrovirus which causes a lifelong infection. An estimated 5-10 million persons are infected worldwide. However, the true amount of global HTLV-1 carriers is likely much higher given recent reports from newly endemic areas. HTLV-1 is the causative infectious agent of adult T-cell leukemia/lymphoma (ATL), an aggressive and fatal CD4+ T-cell malignancy. The projected lifetime risk of developing ATL is ~5% in HTLV-1-infected individuals and 25% in perinatal HTLV-1 carriers. Despite the exceptional oncogenicity of this virus, no preventative vaccine has been tested in clinical trials to date. However, several vaccine studies have shown protection against HTLV-1 challenge in animals, demonstrating that developing vaccine is feasible. The COVID-19 pandemic and the success of SARS-Cov-2 spike protein mRNA vaccines spurred the popularity of the mRNA vaccine platform. Immunization with encapsulated mRNA offers numerous benefits over conventional vaccines, including improved safety through the delivery of a non-infectious agent and ability to regulate in vivo half-life, as well as enhanced efficacy through modulation of stability and translation. The use for mRNA vaccines in HTLV-1 research warrants investigation. In this study, we developed an mRNA lipid nanoparticle (mRNA-LNP) vaccine encoding for a codon optimized HTLV-1 envelope (Env) and evaluated its efficacy as a vaccine candidate in New Zealand white rabbits. Rabbits (n=6) were vaccinated with two doses of either Env mRNA-LNP or control GFP mRNA-LNP, then challenged with lethally irradiated HTLV-1-infected cells. All rabbits were rechallenged fifteen weeks later to evaluate the durability of vaccine-induced immune responses in protected rabbits. Anti-Env antibody responses were detected by western blot and quantitatively measured using infected cell binding assays in all Env mRNA-LNP vaccinated rabbits after two doses. Three (out of six) Env mRNA-LN (open full item for complete abstract)

Committee: Amanda Panfil (Advisor); Kai Xu (Committee Member); Stefan Niewiesk (Committee Member) Subjects: Biology; Biomedical Research; Immunology

Doctor of Philosophy, University of Akron, 2022, Integrated Bioscience

Opioids have become one of the most misused classes of prescribed medication. Synthetic opioids (e.g., fentanyl) have been responsible for most opioid overdose deaths since 2017. As this epidemic shows no signs of slowing, it is imperative to study the effects of opioids on various aspects of health including bone maintenance. Endogenous opioids (e.g., met-enkephalin) are involved in osteogenesis and bone remodeling. Exogenous opioids can interfere with bone maintenance directly through binding to osteoblasts, limiting bone formation, or indirectly through a cascade of effects limiting sex hormone production. To understand how opioids affect bone microarchitectural and biomechanical properties we first examine bone microstructure throughout the human lifespan to see natural changes occurring without the effects of opioids. Using both Synchrotron Radiation micro-Computed Tomography and confocal laser microscopy, we found bone and lacunar volume fractions to decrease with advancing age while pore diameter increased in the anterior midshaft femur. After finding how bone changes with age under normal circumstances, we sought to examine how prolonged opioid administration affected trabecular microstructure in a model organism (rabbit). We used μCT to examine the proximal tibia by anatomical quadrant (e.g., anterior, posterior). We found that morphine animals had greater bone volume fraction and less trabecular separation than controls. Fentanyl animals had significantly thicker trabeculae and increased trabecular spacing than controls. Detected differences by anatomical region followed the same overall pattern, suggesting biomechanical or anatomical variation rather than due to opioids. We finally examined overall bone strength in a non-weight bearing bone (rib) of the rabbit using uniaxial compression testing to determine how opioids affect overall mechanical competency. We found no difference in mechanical variables between opioid and control groups. Only rib span leng (open full item for complete abstract)

Committee: Brian Bagatto (Advisor); Janna Andronowski (Committee Co-Chair); Henry Astley (Committee Member); David Cooper (Committee Member); Christine Dengler-Crish (Committee Member); Nita Sahai (Committee Member) Subjects: Biology; Biomechanics; Histology; Pharmaceuticals; Physiology

Master of Science, The Ohio State University, 2021, Agricultural and Extension Education

Since the advent of industrialized animal production, breeds of livestock species have seen a decrease in their population and many face the threat of extinction. These breeds have unique genetic and historical significance. Since the 1970s, research has been done looking at the scientific aspect of conserving these breeds. However, little research has been done on the role of individuals in rare breed conservation, and none has considered the potential part that youth could play in it. This quantitative study explores the trends in rare breed exhibition in Midwest state 4-H shows. In addition, the current knowledge of superintendents, their thoughts on member breed decision influences, and their motivation as it applies to rare breeds was examined. Data collected for this study consists of show data from Midwest state 4-H fair poultry and rabbit shows, and survey data collected from state superintendents. Findings from this study suggest that rare breeds in poultry and rabbits are being shown at state 4-H fairs and superintendents and youth are interested in rare breeds, but lack of knowledge on these breeds or access to breeding stock may impede their growth. Youth based organizations in these species and national organizations need to work together to promote more education on this topic, as well as help connect youth with resources and breeders.

Committee: Emily Buck Dr. (Advisor); Keith Smith Dr. (Committee Member) Subjects: Agricultural Education; Animal Sciences

Doctor of Philosophy (PhD), Ohio University, 2020, Biological Sciences (Arts and Sciences)

Sound localization is the ability to pinpoint sound source direction in three dimensions using auditory cues. Sound localization in the horizontal plane involves two binaural cues (involving two ears), namely, difference in the time of arrival of sounds and difference in the level of sounds between the ears, known as interaural time difference (ITD) and interaural level difference (ILD), respectively. Electrical recordings of neural activity, mostly in awake Dutch-Belted rabbits, have shown that neurons in the auditory nervous system, especially the inferior colliculus, which is an obligatory area along the auditory pathway, use these binaural cues to encode sound source direction (that is, directional information) in their firing rates (that is, the number of times they fire an action potential in a second). However, not much is known about neural encoding of directional information following hearing loss. Studies on human subjects have revealed a deterioration of sound localization ability pointing to a potential degradation of neural encoding of directional information as well. Here, we probe this by measuring directional information in neural firing rates from the inferior colliculi of awake, Dutch-Belted rabbits with severe noise-induced hearing loss. To induce hearing loss, rabbits were overexposed to loud noise. Our overexposure resulted in widespread damage to sensory hair cells within the hearing organ embedded within the ears, called the cochlea, and created a ~50-dB elevation in hearing thresholds (that is, minimum responsive sound levels). Neural measurements showed that neural firing rates, on average, contained less directional information with hearing loss than normal hearing, even when sounds were sufficiently loud to evoke responses from neurons. This was because many sound-driven neurons conveyed directional information via monaural (involving one ear) sound level cues. Remaining sound-driven neurons were purely ILD-sensitive and exhibited a comple (open full item for complete abstract)

Committee: Mitchell Day Dr. (Advisor); Scott Hooper Dr. (Committee Member); Li Xu Dr. (Committee Member); Alexander Neiman Dr. (Committee Member) Subjects: Neurosciences

MS, University of Cincinnati, 2019, Medicine: Biomedical Research Technology

Fluoxetine is a wide spread mood disorder modulator and acts by inhibiting the reuptake of serotonin from the synaptic cleft. However, serotonin, and its main membrane transporter, are involved in multiple processes in mammals, hence raising the question whether these are also affected by modulation. In humans, such known side effect is anorgasmia. Recent work suggests that the mechanism underlying the human female orgasm is a derivative of that triggering ovulation in copulation-induced mammals, such as rabbits. In this study we tested, whether serotonin modulation by fluoxetine in the rabbit's central nervous system (CNS) affects their ovulation rates. To this end, we treated one group of New Zealand White rabbits with a daily dose of either 2 or 4 mg/kg fluoxetine mixed with Critical Care® food supplement, for 14 days. The control group received only the Critical Care. On day 13 of treatment, the control and treated groups were mated to a fertile male and necropsied 24h later to establish the rates of ovulation. We found that copulation-induced ovulation was 25% less effective in inducing ovulation in fluoxetine-treated females than the control group, however the dose of fluoxetine had no effect on response. To test, whether this effect of fluoxetine was due to modulation of serotonin signaling in the CNS rather than peripheral in tissues (where serotonin uses the same transporter), we repeated the experiment by circumventing the involvement of the CNS. Instead of inducing ovulation by copulation, we induced it downstream of CNS, by injection of human chorionic gonadotropin (hCG) (50.I.U.). In this case, we did not observe a significant effect of fluoxetine (4mg/kg) on ovulation when compared to the untreated controls. Consistent with the lack of significant local effect of fluoxetine on ovulation in this treatment, we also found no significant histological changes in ovaries, specifically on numbers of follicles in different developmental stages (primary, sec (open full item for complete abstract)

Committee: Louis Muglia M.D. (Committee Chair); Mihaela Pavlicev Ph.D. (Committee Member); Kaushik Roychoudhury Ph.D. (Committee Member) Subjects: Developmental Biology

MFA, Kent State University, 2018, College of the Arts / School of Art

Spreading prolifically and harmfully, invasive species overpower the areas they inhabit. This body of work contextualizes the concept of invasive species into five main parts. Each element, ivy vines, honeysuckle plants, rabbits, black beetles and cicadas, are classified as invasive for their destructive tendencies. In addition to this, each serves as a metaphor for different aspects and characteristics of myself and life. Whether they be representative of a moment from childhood or of a trial of adulthood. "Invasive" presents a series of 23 suspended fabric panels and 3 crafted benches that come together to create a large scale three-dimensional sculpture to capture the essence of my concept.

Committee: Janice Lessman-Moss (Advisor); Taryn McMahon (Committee Member); John-Michael Warner (Committee Member); Andrew Kuebeck (Committee Member) Subjects: Fine Arts; Folklore; Interior Design; Textile Research

Master of Science, The Ohio State University, 2015, Comparative and Veterinary Medicine

Radiation therapy is widely used in the management of patients with soft tissue sarcoma, genitourinary and gastrointestinal tumors, head and neck tumors, or secondary bone metastasis. Bystander injury to bone in the course of external beam radiation therapy is a prevalent problem associated with considerable morbidity, including the development of osteoradionecrosis and pathologic fractures. Morbidity is high in patients incurring fractures secondary to radiation therapy. Post-radiation fractures have high non-union rates or prolonged healing times. There is a clear and pressing need for a reliable and clinically relevant animal model in which it will be possible to perform new and advanced surgical strategies to repair radiation induced fractures. Rabbits have been used in previous studies on radiation injury to bone with work focusing on the jaw or craniofacial skeleton. The current study was designed to develop a model of radiation injury to long bones in the rabbit. Using a 4 x 9 Gy radiation protocol over four consecutive days, we were able to establish late radiation injury to bone. With this protocol we were able to create significant changes in cortical and trabecular bone microstructure, and mechanical properties as determined by reference point indentation. This model of radiation-induced bone injury should allow for preclinical development of new surgical, pharmaceutical, or regenerative medicine approaches to alleviating the adverse effects of radiation therapy on bone and fracture healing.

Committee: Eric Green (Advisor); Matthew Allen (Committee Member); Thomas Scharschmidt (Committee Member) Subjects: Radiation

Bachelor of Science, Ashland University, 2014, Biology/Toxicology

Animals that are kept in captivity need enrichment activities to live better lives. There are many types of enrichment such as cognitive, auditory, and visual. This study focuses on olfactory enrichment, which was chosen because cats use their olfactory sense in communication and in hunting. This means that olfactory enrichment has a profound effect upon them. This study was done to look at olfactory enrichment for cats that were housed communally in a rescue shelter. This experiment was novel because it looked at cats that were not housed individually as was done in previous studies. The study looked at four scents: lavender, rabbit, catnip, and silver vine. The cats were housed communally, which allowed them to constantly interact with the stimulus and each other. Another novelty of this experiment was the use of silver vine as an enrichment scent, which had been used previously with big cats but not with domestic felines. The experiment measured the behavior of the cats to look at the enriching effects of the scents. The cats were videotaped while they interacted with the cloth. The frequencies of behaviors were then quantified and analyzed. It was found that lavender had a significant effect on the frequency of sitting behavior, rabbit, and catnip had no significant effects on behavior, and silver vine had a significant effect on the frequency of sitting and playing. The results of the study show that it is possible to use enrichment for cats that are housed communally in a shelter and that silver vine is an effective enrichment scent because it increased play behavior. Future studies should focus on the other benefits of silver vine and other scents that could be beneficial for cats living in a communally housed shelter.

Committee: Mason Posner PhD (Advisor); Richard Stoffer PhD (Other) Subjects: Behavioral Sciences; Biology

PhD, University of Cincinnati, 2005, Engineering : Biomedical Engineering

The objective of this study was to test the governing hypothesis that implanting mesenchymal stem cell (MSC)-seeded collagen gel and collagen sponge scaffolds into surgically induced rabbit patellar tendon (PT) defects will improve the repair tissues'structural and material properties as well as histological appearance. We evaluated the effects of MSC-construct seeding concentration and collagen concentration on the in vivo repair quality after defect injury to the rabbit patellar tendon.In addition, we investigated the effects of adding a collagen sponge scaffold andmechanical stimulation using a silicone dish system on the in vivo repair of the rabbit patellar tendon. The effects of those treatments were assessed using biomechanical and immunohistochemical assays at 12 weeks post surgery. No significant differences were found in the biomechanical properties of the cellgel repairs with different MCS and collagen concentrations. The maximum force and linear stiffness for these repairs was 30% of normal central PT and no ectopic bone was found in any repair site. In a subsequent study, different collagen scaffolds (fibers, films,and sponges) were evaluated in vitro. We found that constructs prepared with cells,collagen gel and collagen sponge exhibited the greatest cell viability, penetration and mechanical integrity after 14 days in culture. In an attempt to increase the stiffness of the repairs, a type I collagen sponge was incorporated into the cell-gel constructs. The cell gel-sponge repairs averaged 75% of the normal tendon linear stiffness and 60% of the normal tendon maximum force. In the next study, cell-gel-sponge constructs were mechanically stimulated and used for rabbit PT repair. Linear stiffness and linear modulus for the stimulated repairs averaged 80% and 40% of normal PT values, respectively. In the last study, cell-sponge constructs (using a different collagen sponge)were mechanically stimulated and used for rabbit PT repair. Linear stiffness and li (open full item for complete abstract)

Committee: Dr. David Butler (Advisor) Subjects: Engineering, Biomedical

MS, University of Cincinnati, 2002, Engineering : Aerospace Engineering

Previous work performed in Noyes-Giannetras Laboratory has shown that mechanical alignment of undifferentiated mesenchymal stem cells about a suture causes alignment of cells and contraction of constructs in culture in a form that is suitable for implantation for tendon repair. With preliminary proof of concept, it is now our goal to fine-tune this procedure to determine the various factors that will lead to the highest quality tissue from a biomechanical standpoint and the fastest cell proliferation rates in culture. The basis for this step assumes that natural in-vivo conditions are optimal for in-vitro culture and that if we can simulate in-vivo forces or strains for a variety of activities we can precondition the implant and cells to the signals they will receive after surgery. However, these in-vivo force patterns are generally not known for a tissue for different activities and likely vary from tendon to tendon. Knowing tendon and ligament forces during normal activities is important in order to understand the levels of in-vivo forces the constructs will be expected to bear once implanted. While researchers have to date failed to develop tissue-engineered replacements that match the ultimate mechanical properties of normal tissues, it is conceivable that less stringent design requirements based on normal activity forces (rather than ultimate or failure properties) may be sufficient for functional efficacy. The purpose of this research study was to determine the in-vivo force-time patterns acting on the rabbit patellar tendon and Achilles tendon models for two speeds of activity and for two inclinations of activity. In addition, we sought to determine the failure properties of these tissues so as to compute safety factors (i.e. ratios of failure tissue force to in-vivo operating force). This data will provide design parameters for preparing tissue engineered implants containing mesenchymal stem cells (MSCs) that will more effectively repair surgical defects in (open full item for complete abstract)

Committee: Dr. David L. Butler (Advisor) Subjects:

Master of Fine Arts, The Ohio State University, 2012, Industrial, Interior Visual Communication Design

Oral traditions and expressions in African cultures include a variety of forms: short stories, tales, riddles, proverbs, legends, myths, traditional songs and poems, prayers, theatrical performances and many more. African cultures use these avenues to pass on the knowledge of their society, values and the collective history of their tribes, which keeps their cultural identity alive. This study explores how oral culture can be leveraged in the digital environment. To do this, all the forms mentioned above will be assessed on how they translate into the digital realm. Almost all the methods above involve some form of interaction, whether it is touch, question and answers, dances, acting or just clapping. There is also the important area of sound inflection, with which a good storyteller can bring the story to life in the minds of the listeners. The challenge that I anticipate and will try to resolve is how these delivery methods that rely on the surroundings and settings can be simulated in the digital environment. This project is based on the hypothesis that the interactive environment will be more favorable for storytelling over the traditional book among the Diaspora communities. I will be testing a sample digital book created using the Apple iBooks Author software on the iPad environment to gather data to prove or disprove my hypothesis. I will then use the data to inform a future version of the digital book that will be used as a self-standing educational tool on any mobile device. I hope that this approach could be used as a template for documenting appropriate cultural heritages around the world. I strongly believe that the more cultures are documented, the more we can all gain an understanding of one another which could lead to better communication and fewer wars and conflicts. I see this project as a step in that direction.

Committee: Paul Nini Prof. (Advisor); Noel Mayo Dr. (Committee Member); Brian Stone Prof. (Committee Member) Subjects: African History; African Literature; African Studies; Black History; Design; Fine Arts; Folklore; Minority and Ethnic Groups

Doctor of Philosophy, The Ohio State University, 2012, Comparative and Veterinary Medicine

The complex retrovirus Human T-lymphotropic virus type-1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma and other lymphocyte-mediated inflammatory disorders. In endemic regions, HTLV-1 is primarily spread from mother to child through infected breast milk. The establishment of persistent HTLV-1 infection following the ingestion of infected lymphocytes is determined by the delicate balance between viral spread and the host immune response. The immunopathogenesis of these early events is not completely understood, and advances in this area have been hindered by the lack of an appropriate animal model. This thesis describes a novel rabbit model of HTLV-1 milk-borne infections, and provides data to understand the early immunological and virological events following oral mucosal exposure to HTLV-1. Herein, we performed an extensive examination of the rabbit gut-associated lymphoid tissue. Using two quantitative methods to exam lymphocyte subsets within the major inductive sites our data revealed similarities between rabbits and humans. This information validates this species as a model for mucosal immunology studies following oral exposure to HTLV-1 and establishes reference ranges for future studies. Our data provides important knowledge of the immune response against HTLV-1 infection following oral exposure to infected lymphocytes. We established a protocol for infection via the oral mucosal route using a method that mimics infant exposure to repeated doses of comparable numbers of infected lymphocytes. We further characterized this model of infection through evaluation of humoral and cellular immune responses and viral parameters. We determined that rabbits exposed orally to HTLV-1 infected lymphocytes develop a persistent infection characterized by a delayed and variable humoral immune response similar to infected infants. Rabbits exposed by this route also displayed a variable, decreased and delayed peripheral cellular immune response with lower (open full item for complete abstract)

Committee: Stefan Neiweisk DVM/PhD (Advisor); Michael Lairmore DVM/PhD (Committee Member); Burkhard Mary Jo DVM/PhD (Committee Member); Wellman Maxey DVM/PhD (Committee Member) Subjects: Immunology; Virology

Master of Science, The Ohio State University, 2010, Veterinary Clinical Sciences

Purpose. To evaluate efficacy, biocompatibility and stability of a surgically implanted telemetric scleral sensor (TSS). To obtain an intraocular pressure (IOP) measurement without the need for topical anesthesia, patient compliance or corneal contact as is necessary with conventional applanation or rebound tonometry. Methods. A TSS was surgically implanted subconjunctivally and sutured to the sclera of the right eye of 10 juvenile female NZW rabbits. IOP was monitored using the TSS and a Tono-Vet twice daily for two weeks, then twice weekly until sacrifice. Ophthalmic examination was performed weekly and the eyes were graded according to the modified Hackett-MacDonald scheme. Two rabbits were sacrificed at 2, 4, 8, 12 and 16 weeks. Manometric IOP values were also recorded in 5mmHg intervals up to 70mmHg and compared to TSS. Eyes were submitted for histopathology. Results. Fibrosis and inflammation between the sclera and implant were graded on a scale of 0-4 for extent and severity, respectively. The grade of fibrosis and inflammatory response ranged from 1-4 (mean 2.5) and 0-2.3 (mean 1.2), respectively and was not associated with time. The predominant cell types recorded were the granulocyte and lymphocyte. Scleral thinning was observed at the site of TSS contact. Initial readings showed good correlation between the TSS and Tono-Vet, but premature dislocation of the TSS in 6 rabbits limited collection of manometric data. Conclusions. Although initial readings showed good correlation between the TSS and Tono-Vet, the overall size and design of the TSS contributed to fibrosis and premature dislocation of the sensor.

Committee: David Wilkie DVM (Advisor); Anne Gemensky-Metzler DVM (Committee Member); Steven Weisbrode VMD (Committee Member); Paul Weber MD (Committee Member) Subjects: Ophthalmology; Veterinary Services

Doctor of Philosophy, The Ohio State University, 2010, Biophysics

It is well known that the rate of intracellular calcium ([Ca2+]i) decline is an important factor governing relaxation in unloaded myocardium. However, it remains unclear to what extent, under near physiological conditions, the intracellular calcium transient amplitude and kinetics contribute to the length dependent increase in force and increase in duration of relaxation. We hypothesize that myofilament properties, rather than calcium transient decline, primarily determines the duration of relaxation in adult mammalian myocardium. To test this hypothesis, first, we simultaneously measured force of contraction and calibrated [Ca2+]i transients in isolated, thin rabbit trabeculae, at various lengths at 37 °C. Time from peak tension to 50% relaxation (RT50) increased significantly with length, while time from peak calcium to 50% decline (CD50) was not prolonged. At optimal length, increasing the extracellular calcium concentration increased both developed force and calcium transient amplitude, but RT50 remained unchanged, while intracellular calcium decline actually accelerated. Thus, an increase in muscle length will result in an increase in both force and duration of relaxation, while the latter is not governed primarily by the rate of [Ca2+]i decline. Next, in order to elucidate additional determinants of relaxation other than the sarcoplasmic reticulum (SR) at various frequencies within the in vivo range, we altered the calcium handling in rat and rabbit by inhibiting the sarcoplasmic reticulum. We chose rat and rabbit for this study because of how their sources for activator calcium differ. Trabeculae, iontophoretically loaded with bis-fura-2, were subjected to ryanodine and cyclopiazonic acid to inhibit SR function. Simultaneous force and [Ca2+]i measurements were obtained at 1-4 Hz in rabbit and at 4-8 Hz in rat before and after SR inhibition. Inhibition of the SR resulted in increased diastolic and peak calcium levels as well as decreased developed force in b (open full item for complete abstract)

Committee: Paul Janssen Ph.D. (Advisor); Jonathan Davis Ph.D. (Committee Member); Peter Reiser Ph.D. (Committee Member); Mark Ziolo Ph.D. (Committee Member) Subjects: Biophysics

Doctor of Philosophy, The Ohio State University, 2008, Molecular, Cellular, and Developmental Biology

Human T-cell leukemia virus type 1 (HTLV-1) is a pathogenic retrovirus that has the capacity to transform primary human T-lymphocytes in culture and infected individuals. After nearly 30 years of research, the exact mechanism by which HTLV-1 induces cellular transformation and ultimately disease still remains elusive. Tax has been identified as the major viral determinant and is essential to the HTLV-1-mediated T-cell transformation process. The HTLV-1 accessory proteins p12, p13, and p30 are dispensable in culture, but are required for the maintenance of viral loads in vivo. In this dissertation, we sought to broaden our knowledge of HTLV-1 using in vitro culture assays and two animal model approaches focusing our efforts on understanding the contribution of a novel antisense encoded gene, the HTLV-1 basic leucine zipper factor (Hbz), in virus biology. Chapter 1 reviewed important aspects of HTLV-1 pathobiology and highlighted insightful comparative studies between HTLV-1 and HTLV-2. Our work in Chapter 2 determined that the HBZ protein is dispensable for immortalization/transformation of T-lymphocytes in culture, but is required for efficient infectivity and persistence in inoculated rabbits. In Chapter 3, utilizing Hbz-specific short hairpin RNA lentiviral vectors, we showed that Hbz significantly contributed to tumor formation and neoplastic cell spread in the NOG mouse transplant model. Chapter 4 expanded on Chapter 3 to show that Hbz functions in two molecular forms, mRNA and protein, to synergistically increase cell proliferation in vitro. Collectively our results indicate that the Hbz gene negativly regulates Tax-mediated viral gene expression and dysrupts the cellular microenviroment to ultimately support virus survival. The data in this dissertation have allowed us to better understand the contribution of Hbz to HTLV-1 infection, and its involvement in the development of disease.

Committee: Patrick Green PhD (Advisor); Michael Lairmore PhD (Committee Member); Marshall Williams PhD (Committee Member); Kathleen Boris-Lawrie PhD (Committee Member) Subjects: Molecular Biology

Doctor of Philosophy, The Ohio State University, 2007, Veterinary Biosciences

Torsades de pointes (TdP) is a polymorphic ventricular tachycardia characterized by a distinctive pattern of undulating QRS complexes that twist around the isoelectric line. TdP has been associated with QT interval prolongation of the electrocardiogram; therefore, the QT interval has come to be recognized as a surrogate marker for the risk of TdP. Currently preclinical in vitro and in vivo methods as well as biomarkers for proarrhythmias have been imperfect in predicting drug-induced TdP in humans. The goal of the present dissertation is to create rabbit with myocardial failing heart as an in vivo animal model to predict TdP in humans and to determine mechanism(s) underlying TdP in this model. Electrocardiograms were recorded from bipolar transthoracic leads in conscious healthy rabbits, and the algorithm for removing effect of heart rate on QT is QTc=QT/(RR)0.72. The rabbit with myocardial failure was created by coronary ligation and validated with drugs known to be torsadogenic or non-torsadogenic in humans. A greater percentage of rabbits with failing hearts developed TdP following intravenous infusion of known torsadogens than did normal rabbits exposed to the same drug protocol. None of the rabbits in either group developed TdP when exposed to known non-torsadogens. These results suggested that a rabbit with myocardial failure possesses specificity and sensitivity to assess drugs that tend to induce TdP when given to humans. The results from isolated myocytes of myocardial failure suggested that (1) the re-entrant circuits emanating from action potential durations of different duration, (2) triggered activity in the form of EADs, and (3) increased dispersion of repolarization are responsible for genesis of the TdP in the failing rabbit heart. The torsadogenic-modifying effects of verapamil, ryanodine, KB-R7943, W-7, KN-93, and H-8 on ventricular premature depolarizations (VPDs) and TdP were then evaluated in the conscious failing rabbit heart. Verapamil, ryanod (open full item for complete abstract)

Committee: Robert Hamlin (Advisor) Subjects: Biology, Veterinary Science

Doctor of Philosophy, The Ohio State University, 2005, Veterinary Biosciences

Human T-cell leukemia virus type 1 (HTVL-1) is the first identified human retrovirus. In addition to gag, pol, and env genes, HTLV-1 contains four open reading frames (ORF) within its pX region. ORF II encodes p30II and p13II. Herein, we determine the in vivo significance of p30II by inoculating rabbits with cell lines expressing either a wild-type clone of HTLV-1 (ACH.1) or a p30II mutant clone (ACH.30.1). Compared to ACH.1 rabbits, ACH.30.1 rabbits had lower antibody titers, a smaller percentage of seropositive animals, a smaller percentage of animals with provirus in peripheral blood mononuclear cells (PBMC), and lower proviral loads. Sequencing revealed that provirus in ACH.30.1 provirus positive rabbits had reverted to wild-type sequence. We conclude that there is strong selective pressure for expression of p30II in vivo. We next sought to determine if p30II modulates cellular apoptosis. A greater percentage of ACH.30.1 cells were induced into apoptosis compared to ACH.1 cells following treatment with camptothecin (specific for S-phase of cell cycle). There was no difference in apoptosis induction between ACH.30.1 and ACH.1 cells following treatment with etoposide (intrinsic pathway) or TRAIL (extrinsic pathway). p30II did not modulate susceptibility to apoptosis when expressed in 293T cells or in Jurkat T cells. Expression of p30II in Jurkat T cells reduced cell proliferation by delaying onset of division. Although p30II does not modulate susceptibility to apoptosis, it does reduce cell proliferation. HTLV-1 Env Ser75Ile, Asn95Asp, and Asn195Asp mutants are able to immortalize lymphocytes in vitro. Herein, we examine the effects of these mutations in rabbits via inoculations with ACH.75, ACH.95, ACH.195, and ACH.1 cell lines. All mutations were maintained in vivo. ACH.75 and ACH.95 rabbits had decreased antibody responses to Gag and Env. One ACH.195 rabbit had an antibody response to HTLV-1 proteins and HTLV-2 Env. Another ACH.195 rabbit had provirus in PBMC b (open full item for complete abstract)

Committee: Michael Lairmore (Advisor) Subjects: Biology, Molecular

Doctor of Philosophy, Miami University, 2011, English

In this dissertation I show how the conservative movement lured the white working class out of the Democratic New Deal Coalition and into the Republican Majority. I argue that this political transformation was accomplished in part by what I call the "invention" of Middle America. Using such cultural representations as mainstream print media, literature, and film, conservatives successfully exploited what came to be known as the Social Issue and constructed "Liberalism" as effeminate, impractical, and elitist. Chapter One charts the rise of conservative populism and Middle America against the backdrop of 1960s social upheaval. I stress the importance of backlash and resentment to Richard Nixon's ascendancy to the Presidency, describe strategies employed by the conservative movement to win majority status for the GOP, and explore the conflict between this goal and the will to ideological purity. In Chapter Two I read Rabbit Redux as John Updike's attempt to model the racial education of a conservative Middle American, Harry "Rabbit" Angstrom, in "teach-in" scenes that reflect the conflict between the social conservative and Eastern Liberal within the author's psyche. I conclude that this conflict undermines the project and, despite laudable intentions, Updike perpetuates caricatures of the Left and hastens Middle America's rejection of Liberalism. Chapter Three illustrates how conservative rhetoric and much of popular culture had merged into a unified message of conservative populism. I argue that the first two Dirty Harry movies and the novel and film adaptation of Death Wish dramatize the Right's talking points on crime and the judiciary, and I describe how they reinforce the conservative movement's construction of Liberalism as effete and out of touch. In Chapter Four I detail the Hardhat Riots of May 1970 to establish the context for my reading of the film Joe, which depicts the resentment-based alliance between white collar economic conservatives and blue coll (open full item for complete abstract)

Committee: Timothy Melley PhD (Committee Chair); C. Barry Chabot PhD (Committee Member); Whitney Womack Smith PhD (Committee Member); Marguerite S. Shaffer PhD (Committee Member) Subjects: American Literature; Film Studies; Literature; Motion Pictures

Master of Arts, Miami University, 2009, Psychology

The hippocampus and cerebellum are critically involved in trace eyeblink classical conditioning (EBCC). The mechanisms underlying the hippocampal-cerebellar interaction during this task are not well understood, although hippocampal theta (3-7 Hz) oscillations are known to reflect a favorable state for EBCC. Two groups of rabbits received trace EBCC in which a brain-computer interface administered trials in either the explicit presence or absence of naturally occurring hippocampal theta. A high percentage of robust theta led to a striking enhancement of learning accompanied by rhythmic theta-band (6-7 Hz) oscillations in the interpositus nucleus (IPN) and cerebellar cortex that were time-locked both to hippocampal rhythms and sensory stimuli during training. Rhythmic activity was absent in the cerebellum of the non-theta group. These data strongly suggest a beneficial impact of theta-based coordination of hippocampus and cerebellum and, importantly, demonstrate that hippocampal theta oscillations can be used to regulate the functional properties of the cerebellum.

Committee: Stephen Berry PhD (Advisor); Jennifer Quinn PhD (Committee Member); Dragana Ivkovich Claflin PhD (Committee Member) Subjects: Psychobiology

Doctor of Philosophy, Miami University, 2008, Psychology

Rabbit eyeblink classical conditioning (EBCC) is a task widely used to understand the neurobiological correlates of associative learning and memory. The hippocampus has proven to be an important structure in acquiring the association between the conditioning stimuli and the development of conditioned responses. This study used a brain-computer interface to trigger conditioning trials in the presence (T+) or absence (T-) of a frequency component of the hippocampal field potential historically related to sensory processing and attention, termed theta. The presence of theta has been shown to facilitate learning in this task as well as accelerate learning related unit responses in the hippocampus, but the precise nature of its beneficial effect in hippocampal neurophysiology has yet to be determined. In this study, tetrodes were lowered into the dorsal hippocampus of four groups of rabbits including those who received paired or unpaired conditioning stimuli in both T+ and T- theta conditions. Specialized signal processing software compared the extracted data streams from each wire of the tetrode to separate the waveforms into single neuron responses. Each sorted neuron was then categorized according to its firing properties as pyramidal cells or one of the known types of interneurons that exist in the hippocampus. The individual units were analyzed for their relation to the pretrial period as well as for how they responded to the conditioning stimuli. Interneurons were highly correlated with hippocampal state used to trigger the trials, supporting the existence of interneurons that systematically vary with the ongoing theta activity. Interneuron responses to the conditioning stimuli were generally dependent on hippocampal state, demonstrating excitatory responses in T+ groups and suppression in T- groups. Pyramidal cells that demonstrated suppression to the conditioning stimuli were also more common in T- groups, while excitatory pyramidal cells were more related to ass (open full item for complete abstract)

Committee: Stephen Berry PhD (Advisor); Allan Pantle PhD (Committee Member); Dragana Ivkovich Claflin PhD (Committee Member); Kathleen Killian PhD (Committee Member) Subjects: Behaviorial Sciences; Physiological Psychology; Psychobiology; Psychology