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Acquired immune deficiency syndrome (AIDS) was first discovered in the 1980s, since then, human immunodeficiency virus (HIV) infection and AIDS have become global health, social, and economic concerns. HIV was identified as the cause of AIDS in 1985, and this launched a wide-reaching effort to understand its biology. The knowledge acquired from these vast research efforts contributed to the development of modern therapeutic and preventative treatment strategies. According to recent data from the United Nations Program on HIV/AIDS (UNAIDS), the ratio of infected people to AIDS- related deaths has decreased because of the expanding access to antiretroviral drugs (ARVs). The application of ARVs to HIV+ patients increases patients’ lifespans and improves the quality of life. Remaining as an incurable disease, expanding access to antiretroviral drugs and using prevention strategies are the best options to control the HIV pandemic for now. Treatment strategies with ARVs, however, are not sufficient to adequately address the HIV pandemic. Traditional combinational antiretroviral therapies (cART) for HIV treatment are limited by multiple drawbacks such as possible toxicity, limited drug concentrations, drug resistance, and viral rebound. Additionally, inadequate physicochemical properties of ARVs, such as poor solubility, permeability, and bioavailability, lead to limited absorption and biodistribution, resulting in poor clinical outcomes. Patient compliance and suboptimal efficacy lead to the development of resistant viruses and viral reservoirs. The presence of HIV reservoirs would cause viral rebound two to four weeks after terminating treatments. The complexity of reservoir structure, prolonged cell half-life, and the latent HIV viruses complicate HIV treatments iii targeting viral reservoirs. cART exhibits insufficient efficacy towards reservoir sites because of biological barriers and poor physicochemical properties. These problems highlight an urgent need for novel treatment strategies that are safe and effective to address HIV reservoirs. Innovative and improved delivery systems have been proposed over the years, especially lipid-formulations. Lipid formulations have emerged as promising vehicles owing to their ability to encapsulate molecules with poor solubility and bioavailability, improve active targeting, prolong circulation time, and sustain drug release. Cell-mediated delivery strategy have posed the obstacles of insufficient drug transport and safety. Macrophages, the very same cells that carry the HIV virus, could reach tissues that would otherwise have little or no drug penetration. Macrophages can protect drugs from metabolic degradation with large quantities of drugs for delivery. Activated macrophages express the folate receptor, a potential targeting moiety. In this study, I intended to develop a novel folate-decorated nanoemulsion (FA- NE) for the delivery of ARVs to HIV infected macrophages. To reach the goal, I focused on two goals: (1) construction of a nanocarrier capable of encapsulating ARV drugs with physiological properties suitable for use in drug delivery and (2) enhancement of delivery to HIV infected macrophages. In Chapter 2, I discuss the rationale for nanoART for HIV treatments. I introduce current HIV treatments and their drawbacks, notably the viral rebound due to limited drug concentration in viral reservoirs. Then I explain why nanotechnology would be a promising strategy for HIV treatment and provide examples of nanomedicine. In all iv cases, however, cell uptake and drug release were limited or complicated by toxicity, which is a significant issue for a validated delivery system that are safe and effective. In chapter 3, I introduce the design and development of the FA-NE. This system includes (1) an oil core to encapsulate antiretroviral drugs that are highly hydrophobic, (2) a lipid monolayer to protect the oil core and to form nanoemulsion (3) folate for target. The system was prepared using the emulsification solvent evaporation method, developed and optimized based on physical properties, including size, PDI, zeta potential, and other in vitro characterizations, such as encapsulation efficacy, drug loading, stability, and drug release. Chapter 4 is a continuation of the work done in Chapter 3 and focuses on the enhancement of cellular uptake with folate overexpression cell models. A lipopolysaccharide (LPS) activated macrophages was built and utilized for intracellular drug release and retention evaluations. In Chapter 5, cytotoxicity and antiretroviral efficacy studies are described. With the conclusion drawn in Chapter 4, I was curious if the enhanced cellular uptake can be translated into improved efficacy. As a result, collaborated with Dr. Kamel Khalili, School of Medicine, Temple University, we evaluated antiretroviral efficacy with an HIV indicator cell and monocyte-derived-macrophages from human donors. Furthermore, I performed cytotoxicity assay to evaluate this nanoemulsion system safety profile. Chapter 6 summarizes the highlights and conclusions of this project and provides suggestions for the future. / Pharmaceutical Sciences

The focus of this research is to develop and extend the application of existing technologies to enhance seismic reservoir characterization. The chapters presented in this dissertation constitute five individual studies consisting of three applications of the Radon transform, one aspect of acoustic wave propagation, and a pilot study of generating a stochastic reservoir model. The first three studies focus on the use of the Radon transform to enhance surface-recorded, controlled-source seismic data. First, the use of this transform was extended to enhance diffraction patterns, which may be indicative of subsurface fractures. The geometry of primary reflections and diffractions on synthetic common-shot-gather data indicate that Radon filters can predict and model primary reflections upon inverse transformation. These modeled primaries can then be adaptively subtracted from the input gather to enhance the diffractions. Second, I examine the amplitude distortions at near and far offsets caused by free-surface multiple removal using Radon filters. These amplitudes are often needlessly reduced due to a truncation effect when the commonly used, unweighted least-squares solution is applied. Synthetic examples indicate that a weighted solution to the transformation minimizes this effect and preserves the reflection amplitudes. Third, a novel processing flow was developed to generate a stacked seismic section using the Radon transform. This procedure has the advantage over traditional summation of normal moveout corrected common midpoint gathers because it circumvents the need to perform manual and interpretive velocity analysis. The fourth study involves the detection of thin layers in periodic layerstacks. Numerical modeling of acoustic wave propagation suggests that the sinusoidal components of an incident signal with a wavelength that corresponds to the periodicity of the material be preferentially reflected. Isolating the different portions of the reflected wavefield and calculating the energy spectra may provide evidence of thin periodic layers which are deterministically unresolvable on their own. Object-based reservoir modeling often incorporates the use of lithology logs, deterministic seismic interpretation, architectural element analysis, geologic intuition, and modern and outcrop analogs. This last project consists of a pilot study where a more quantitative approach to define the statistical parameters currently derived through geologic intuition and analogs was developed. This approach utilizes a simulated annealing optimization technique for inversion and the pilot study shows that it can improve the correlation between synthesized and control logs. / Ph. D.

HEV is an important public health concern due largely to water-borne outbreak. Recent research confirms individual cases of zoonotic transmission due to human exposure to contaminated animal meats. At least four recognized and two putative genotypes of mammalian HEV have been reported: genotypes 1 and 2 are restricted to humans whereas genotypes 3 and 4 are zoonotic. In addition to humans, strains of HEV have been genetically identified from pigs, chickens, rats, mongoose, deer, rabbits and fish. The current experimental vaccines are all based on a single strain of HEV, even though multiple genotypes of HEV are co-circulating in some countries and thus an individual may be exposed to more than one genotype. Therefore, it is important to know if prior infection with a genotype 3 swine HEV will confer protective immunity against subsequent exposure to genotypes 3 and 4 human and swine HEV. In the first study, specific-pathogen-free pigs were divided into 4 groups of 6 each. Pigs in the three treatment groups were each inoculated with a genotype 3 swine HEV, and 12 weeks later, challenged with the same genotype 3 swine HEV, a genotype 3 human HEV, and a genotype 4 human HEV, respectively. Sera from all pigs were tested for HEV RNA and IgG anti-HEV, and fecal samples were also tested for HEV RNA each week. The pigs inoculated with swine HEV became infected as evidenced by fecal virus shedding and viremia, and the majority of pigs also developed IgG anti-HEV prior to challenge at 12 weeks post-inoculation. After challenge, viremia and fecal virus shedding of challenge viruses were not detected, suggesting that prior infection with a genotype 3 swine HEV prevented pigs from developing viremia and fecal virus shedding after challenge with homologous and heterologous genotypes 3 and 4 HEV, respectively. Immunogenic epitopes are located within the open reading frame 2 (ORF 2) capsid protein and recombinant ORF 2 antigens are capable of preventing HEV infection in non-human primates and chickens. In the second study we expressed and purified N-truncated ORF 2 antigens based on swine, rat, and avian HEV strains. Thirty pigs were randomly divided into groups of 6 pigs each and initially vaccinated with 200µg swine ORF 2 antigen, rat ORF 2 antigen, avian ORF 2 antigen, or PBS buffer (positive and negative control groups) and booster with the same vaccine 2 weeks later. At 4 wks, after confirming seroconversion to IgG anti-HEV antibody with ELISA, all groups except the negative control were challenged with swine genotype 3 HEV (administered intravenously). The protective and cross-protective abilities of these antigens were determined following swine genotype 3 challenge by evaluating both serum and fecal samples for HEV RNA using nested RT-PCR and IgG anti-HEV using ELISA. The results from these two studies have important implications for future development of an effective HEV vaccine. As a part of our ongoing efforts to search for potential animal reservoirs for HEV, we tested goats from Virginia for evidence of HEV infection and showed that 16% (13/80) of goat sera from Virginia herds were positive for IgG anti-HEV. Importantly, we demonstrated that selected goat sera were capable of neutralizing HEV in cell culture. Subsequently, in an attempt to genetically identify the HEV-related agent from goats, we conducted a prospective study in a closed goat herd with known anti-HEV seropositivity and monitored a total of 11 kids from the time of birth until 14 weeks of age for evidence of HEV infection. Seroconversion to IgG anti-HEV was detected in 7 out of the 11 kids, although repeated attempts to detect HEV RNA by a broad-spectrum nested RT-PCR from the fecal and serum samples of the goats that had seroconverted were unsuccessful. In addition, we also attempted to experimentally infect laboratory goats with three well-characterized mammalian strains of HEV but with no success. The results indicate that a HEV-related agent is circulating and maintained in the goat population in Virginia and that the goat HEV is likely genetically very divergent from the known HEV strains. / Ph. D.

The Falling Creek Reservoir (FCR) in Roanoke is monitored for water quality and other key measurements to distribute clean and safe water to the community. Forecasting these measurements is critical for management of the FCR. However, current techniques are limited by inherent Gaussian linearity assumptions. Since the dynamics of the ecosystem may be non-linear, we propose neural network-based schemes for forecasting. We create the LatentGAN architecture by extending the recurrent neural network-based ProbCast and autoencoder forecasting architectures to produce multiple forecasts for a single time series. Suites of forecasts allow for calculation of confidence intervals for long-term prediction. This work analyzes and compares LatentGAN's accuracy for two case studies with state-of-the-art neural network forecasting methods. LatentGAN performs similarly with these methods and exhibits promising recursive results. / Master of Science / The Falling Creek Reservoir (FCR) is monitored for water quality and other key measurements to ensure distribution of clean and safe water to the community. Forecasting these measurements is critical for management of the FCR and can serve as indicators of significant ecological events that can greatly reduce water quality. Current predictive techniques are limited due to inherent linear assumptions. Thus, this work introduces LatentGAN, a data-driven, generative, predictive neural network. For a particular sequence of data, LatentGAN is able to generate a suite of possible predictions at the next time step. This work compares LatentGAN's predictive capabilities with existing neural network predictive models. LatentGAN performs similarly with these methods and exhibits promising recursive results.

Gizzard shad were illegally introduced to Claytor Lake in the late 1980s and soon established a thriving population. This study assessed 1) the degree to which gizzard shad were utilized by piscivores (pelagic - striped bass Morone saxatilis, hybrid striped bass M. chrysops x M. saxatilis, and walleye Stizostedion vitreum, and three littoral black basses Micropterus spp.), 2) the availability of gizzard shad as potential prey as determined from age and growth analysis, and 3) the performance (growth rates, relative weight, and relative abundance) of piscivores before versus after gizzard shad establishment. Gizzard shad were more highly utilized by pelagic predators (especially striped bass and their hybrids) than black basses. Rapid growth of gizzard shad (mean back-calculated length at age-1 = 155 mm TL) meant that almost all morphologically available shad were age-0. The reliance on one edible age class of gizzard shad resulted in an unstable food supply as evidenced by much greater striped bass shad consumption in Summer 1998 (63 % by weight) when age-0 shad were more abundant than in Summer 1997 (7 % by weight). Striped bass was the only species to exhibit faster growth rates and mean relative weight (Wr) values in the 1990s versus pre-shad years. Walleye (except age-1) and black bass growth rates declined, and mean Wr values either remained consistent or declined. Largemouth bass and walleye were the only sportfish to show increases in relative abundance. Benefits of gizzard shad as a forage fish appear to be limited to striped bass and its hybrid species. It is possible that gizzard shad have had, directly or indirectly, an adverse impact on the black basses of Claytor Lake, but explanatory analysis of these relationships was beyond the scope of this study. / Master of Science

The CE-QUAL-W2 model has been selected as a tool for use in water quality management studies of the Occoquan Reservoir. In order for the model to achieve its best possible predictive capability, additional quantitative information on denitrification rates in the reservoir was required. A microcosm operating protocol was developed to obtain such information and also to enhance the understanding of complex nitrate-sediment-phosphorus interactions. The microcosm system developed was a biphasic system, consisting of a single continuous stirred tank reactor (CSTR), or a series of CSTRs containing representative sediment and water samples from the reservoir. The system was configured to simulate the bottom waters in the upper reaches of the reservoir during anoxic conditions. Nitrate concentrations in the microcosm system were monitored, and first-order denitrification-rate constants calculated to be used as an input to the reservoir water quality model CE-QUAL-W2. Other water chemistries were also monitored to investigate the nitrate effects on water quality. From the investigation results, it appears that the first-order denitrification-rate constant of the model should be set at 0.22 day-1 instead of the model default value. Nitrate was also observed to be removed by chemical and/or biologically mediated reduction by reduced forms of manganese. Once the nitrate was depleted, soluble manganese was released from the sediment first, followed by soluble iron. The release of phosphorus was not observed in this study after the depletion of nitrate, but nevertheless, was believed to occur. The absence of the release was attributed to phosphorus adsorption to the Plexiglas reactor walls. / Master of Science