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Mef2-Bound Genes May Influence Ethanol Sedation In Drosophila Melanogaster, Katlyn M. Myers

Theses and Dissertations

Alcohol Use Disorder (AUD) is a global health issue that affects millions of people every year. This disorder has serious negative mental and physical consequences. Currently, treatment options for this disorder are largely limited to psychological therapy, with very few medications available to treat it. Being able to identify the environmental and genetic components that influence AUD can help improve diagnosis and treatment options. Previous studies in humans have shown a link between initial sensitivity and risk for alcohol abuse. Our laboratory uses Drosophila melanogaster as a model to study the genetic and environmental components of alcohol-related behaviors. Previous lab …

An Identification Of Tgf-B'S Role In Ischemic Cholangiopathy, Courtney Chmielewski

Theses and Dissertations

Organ transplants are a necessary intervention for many diseases that result in end stage organ failure. The donation pool cannot match the demands of the transplant list, so expanding the pool to include donation after cardiac death (DCD) is desired. However, there are increased odds of graft failure and ischemic cholangiopathy leading to inferior outcomes when DCD livers are used. Ischemic cholangiopathy consists of multiple diffuse strictures and fibrosis of the bile ducts leading to a loss of epithelialization and fibrosis. The cellular mechanism is proposed to be epithelial-to-mesenchymal transition (EMT). TGF-�� is seen as a key initiator of EMT, …

Modeling Gardnerella Host-Pathogen Interaction: Characterization Of Vaginolysin And The Opacity Phenotype, Erin M. Garcia

Theses and Dissertations

Bacterial vaginosis (BV) describes a dysbiotic state of the vaginal mucosa, during which the dominance by beneficial lactobacilli species is lost, the vaginal pH increases, and the flora comprising the vaginal microbiome becomes more diverse. Bacterial taxa associated with this dysbiotic state interact to form a dense polymicrobial biofilm on the surface of the vaginal epithelium. This shift in the vaginal microflora is clinically important, even when symptoms are not noted, as women with BV are at increased risk for acquisition of other sexually transmitted infections, including HIV, and are more than two times as likely to experience preterm birth. …

Towards A Greener Route To Blockbuster Statin Drugs: Harnessing The Power Of Biocatalysis And Integrating Cross-Coupling Catalysis In The Synthesis Of Rosuvastatin, Chanaka M. Amarasekarage

Theses and Dissertations

As global and political awareness about green and sustainable practices sharpens in the face of dramatic climate change and environmentally detrimental practices, one attractive approach is to harness the catalytic potential of enzymes. Thus influenced, our efforts focused on the development of an innovative chemoenzymatic route to widely prescribed Blockbuster statin drugs, specifically rosuvastatin. In this work, we engineered novel deoxyribose phosphate aldolase (DERA) variants via rationally designed site-directed mutagenesis to accept non-natural, less polar substrate, acrolein, along with acetaldehyde. Several of new mutants displayed elevated tolerance towards aldehydes and showed effective incorporation of acrolein into the unprecedented enzymatically-derived chiral …

New Persistent And Chronic Opioid Use In Cancer Survivors After Curative Intent Radiation, Elena V. Fernández

Theses and Dissertations

Background: Emerging evidence suggests that as more patients are surviving cancer, new persistent opioid use (no prior exposure to opioids before cancer therapy but requiring opioid prescriptions after curative intent treatment; NPOU) is of greater concern. In patients receiving curative intent radiation (definitive radiation therapy and as treatment for cure; CIR), the extent to which patients develop NPOU or continue opioid use (COU) following CIR is not known. Neither are factors associated with NPOU or COU, opioid doses, or time to discontinuation (TTD) of opioids in 5CS known. Objectives: Describe longitudinal trends opioid use in cancer survivors who received CIR, …

Ceramide Synthase 2 Interacts With Ceramide Synthases 5 And 6 At The Mrna And Protein Levels, Dorothy Yen

Theses and Dissertations

Ceramides and sphingolipids make up major portions of the plasma membrane and therefore are crucial for cell proliferation, survival, and death. With dysregulation comes numerous pathophysiological conditions, such as Alzheimer's, Huntington's Disease, Creutzfeldt-Jakob, cardiovascular disease, and many cancers. However, the regulation of the enzymes responsible for catalyzing the formation of ceramides is still not well understood. In this experiment, three isoforms were of focus: CerS2, CerS5, and CerS6. Through mRNA, protein, and immunofluorescence analysis, it can be concluded that these isoforms do indeed interact within the human cell in order to upregulate their activity. It was also found that cells …

Sound Propagation In Viscous Flows Using Piezoelectric Sensors And Non-Destructive Propagation Techniques And Its Applications, Ahmed M. Abdulkareem

Theses and Dissertations

Structural non-destructive evaluation techniques are applied to viscous flows to detect fluid property changes. The main operating principle consists of an actuator which provides a stimulus, and a sensor to receive a signal traveling to a fluid domain. The main challenge of the operating principle consists of investigating waves traveling in a viscous flow. Traveling waves utilizing a piezoelectric actuator-sensor pair are modeled and the results are validated experimentally. ANSYS models, coupled with a two-way fluid-solid interaction model, are built to investigate how far a signal travels and what frequency ranges are of interest. The numerical model includes modeling three …

Estimating Response Status In Sequential Multiple Assignment (Smar)-Like Trials, Keighly Bradbrook

Theses and Dissertations

Sequential, multiple assignment, randomized trials (SMARTs) allow investigators to develop and compare experimental treatment regimens in which individuals are successively randomized to different treatments based on some set of predetermined rules. The rules used to make decisions on when and how to switch treatments are based on a chosen set of tailoring variables. Although not always true, intermediate response is commonly used as the primary tailoring variable as it is often predictive of future treatment success. As such, successful implementation depends on identifying patients who respond to treatment, though in some situations such mechanisms may not exist. Further, patient-level covariates …

Examining The Role Of Racial Discrimination In Obesity Treatment Disparities Among African American Emerging Adult Women, Kristal Brown

Theses and Dissertations

The overarching goal of the proposed work was to examine how racial discrimination contributes to disparities in adiposity and treatment response between non-Hispanic Black and non-Hispanic White emerging adult women, and to identify potential protective and risk factors that might moderate this association—all in service of improving lifestyle interventions for this high-risk population. Project aims were achieved across three studies. In Study 1, we extracted data for emerging adults (N=261, BMI=33.8+4.9 kg/m², age=21.9+2.1 years) who recently completed a BWL program adapted specifically for emerging adults and compared treatment outcomes for non-Hispanic White and non-Hispanic Black women. In Study …

Beneficiation Of Coal Using Supercritical Water And Carbon Dioxide Extraction, Matthew Decuir Virginia Commonwealth University Cl

Theses and Dissertations

This work explores the use of carbon dioxide, water, and their mixtures as solvent for the pre-combustion beneficiation of raw coal without using any toxic mineral acids in the temperature range of 200-400℃. The fluid polarity, ionic constant, and supercritical point can be adjusted by H₂O/CO₂ ratio and temperature. Adding carbon dioxide to hydrothermal fluid also increases the ionization by forming carbonic acid. Extractions with supercritical fluids have several benefits including enhanced mass transport, ease of separation and recycle, wide range of extractive capability and tunability, better inherent safety, and in the case of carbon dioxide and …

Flexible Methods For Accounting For Distributional Misspecification Of The Response-Adaptive Randomization Ratio In Two-Arm Clinical Trials With Continuous Or Survival Outcomes, Victoria C. Garcia

Theses and Dissertations

Optimal response-adaptive randomization (RAR) is used in clinical trials (CTs) to balance ethics and power by randomizing patients according to the unknown population parameters of an assumed parametric response distribution selected prior to data collection. If the distribution of the observed response data is misspecified, the resulting randomization may produce unanticipated trial characteristics. This dissertation introduces flexible estimators of the optimal RAR ratio that adjust for such misspecification.

When observed response data were continuous in nature, sample moments were estimated from a continuous fit of the empirical CDF. These sample moments then served as the operands for the first flexible …

Data Science Methods For Standardization, Safety, And Quality Assurance In Radiation Oncology, Khajamoinuddin Syed

Theses and Dissertations

Radiation oncology is the field of medicine that deals with treating cancer patients through ionizing radiation. The clinical modality or technique used to treat the cancer patients in the radiation oncology domain is referred to as radiation therapy. Radiation therapy aims to deliver precisely measured dose irradiation to a defined tumor volume (target) with as minimal damage as possible to surrounding healthy tissue (organs-at-risk), resulting in eradication of the tumor, high quality of life, and prolongation of survival. A typical radiotherapy process requires the use of different clinical systems at various stages of the workflow. The data generated in these …

Bee Diversity Of Three Appalachian Shale Barren Sites, Olivia C. Latham

Theses and Dissertations

Insect pollination is vital to ecosystem function. However, climate change, habitat loss, pesticides, and a variety of other anthropogenic sources are contributing to a decline in pollinator diversity. Fragile small ecosystems with a high composition of specialized plant species that rely on specific pollinators such as Appalachian shale barrens, are especially at risk of losing biodiversity. This study combines the use of active sweep net sampling of endemic shale barren forbs and passive trap methods over the course of a bloom season (April-August) in three barren sites to identify bee community populations and visitation relationships between pollinator species and endemic …

Model-Based In-Vitro Pk/Pd Profiling Of Novel Synthetic Allosteric Effectors Of Hemoglobin (Aeh) As Potential Sickle Cell Disease (Scd) Therapeutics, Xiaomeng Xu

Theses and Dissertations

Introduction: Allosteric effectors of hemoglobin (AEH) represent a class of synthetic aromatic aldehydes that transiently form covalent interactions (Schiff-base) with hemoglobin (Hb) to form Hb-AEH adduct, preventing the HbS polymerization and sickling of red blood cells (RBC). The overall objective of this research was to aid in the optimization of novel AEH by understanding their target-site disposition of AEH in relevant biological matrices, e.g., HbA solution, whole blood (WB) and human liver cytosol (HLC), a surrogate of aldehyde dehydrogenase (ALDH)-mediated oxidative metabolism.

Methods: A “universal” HPLC-UV/Vis assay method was developed for the quantitation of HbA-AEH adduct for chemically …

Sphingolipids In Cancer Health Disparities And As Prospective Targets For Cancer Therapy, April E. Boyd

Theses and Dissertations

Lung cancer is the deadliest cancer both in the United States and worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. However, lung cancer disparities are not shared equally across racial groups, with large differences between African American and Caucasian populations. Advances in research have revealed roles of lipid mediators in cancer biology and disease progression, but sphingolipid alterations in tissues should be explored further. To address this, using mass spectrometry (MS), extensive sphingolipidomic characterization of NSCLC tumors and adjacent uninvolved tissues from African American and Caucasian patients were performed. This study revealed that NSCLC …

Recovery From Visual Dysfunction Following Mild Traumatic Brain Injury Is Associated With Adaptive Reorganization Of Retinal Inputs To Lateral Geniculate Nucleus In The Mouse Model Utilizing Central Fluid Percussion Injury., Vishal C. Patel

Theses and Dissertations

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality nationwide. Prevalence of mild TBI (mTBI) vastly outnumbers more severe forms however the associated morbidity has only recently gained public attention. Visual dysfunction is a significant component of mTBI associated morbidity with recovery of function linked with improvement in global outcomes. Examination of sensory and motor pathways in other brain injury paradigms support that recovery is largely dependent on adaptive plasticity of remaining connections. Current examinations of visual function recovery following mTBI is limited to identifying evidence for recovery and objective evidence for adaptive plasticity is limited. Therefore, …

Integration Of Multi-Omic Platforms To Understand The Regulation Of Genes In Human Disease, Eva Lancaster

Theses and Dissertations

Epigenetic mechanisms have been hypothesized to modify gene expression (GE) in response to both genetic variation and environmental exposures, ultimately contributing to the development of complex traits. Epigenome-wide association studies (EWAS) aim to test the theory that marks of DNA methylation (DNAm) have downstream consequences that result in the development of complex diseases. Although these methods have been successful in identifying DNAm patterns in complex traits, specific molecular mechanisms involved in the etiology of complex diseases remain unidentified. This knowledge gap does not originate from a lack of DNAm-trait associations, but rather stems from study design issues that affect the …

Lpa Receptors Modulate Gene Expression During Oligodendrocyte Differentiation, Samantha A. Spencer

Theses and Dissertations

LPA, produced by the lysoPLD activity of ATX, binds its cognate receptors and regulates the development of multiple brain cells, including oligodendrocytes (OLGs). OLGs progress through a lineage from precursor (OPC) to early OLG to immature OLG, until finally the cells mature and enwrap axons to enable saltatory conduction and provide trophic support. The studies in this dissertation characterized the receptors LPA4 and LPA6 as inhibitors of OPC differentiation. Western blot analysis of MS patient lesion tissue found a negative correlation between ATX levels and levels of LPA4 and LPA6. A previously created homology model for LPA4 was used to …

Stimulated Growth Response To Sand Burial Of A Coastal Shrub, D. Nicole Keller

Theses and Dissertations

Drivers of vegetation zonation on barrier islands are complex and interconnected. Sand burial is a strong driver in dynamic coastal systems, especially in the foredune community. However, it is not well understood how burial impacts the interdunal swales communities and it is especially difficult to separate the effects of burial from salinity. Climate change is altering the frequency of overwash events as well as expanding the range of the native shrub, Morella cerifera, on the Virginia barrier islands. To accurately forecast island response to climate change it is important to understand how the shrub responds to sand burial. Juvenile …

The Impact Of The Fda Warning On Post-Tonsillectomy Opioid Prescribing In Publicly And Privately Insured Children, Dianna J. Soelberg

Theses and Dissertations

Due to reports of significant adverse events, the U.S. FDA placed a Boxed Warning on the opioid codeine in February 2013 – contraindicating its use in pediatric patients undergoing tonsillectomy and/or adenoidectomy. Studies conducted in privately insured children showed a reduction in codeine prescribing and a slight increase in alterative opioid prescribing following the FDA warning, yet the extent to which the FDA warning impacted prescribing in publicly insured children is unknown. Using a quasi-experimental interrupted time series design, this study evaluated codeine and alternative opioid prescribing before and after the FDA warning in both publicly and privately insured children …

State Economic Development: Analyzing The Moderating Effects Of Business Climate On Economic Growth, Sean A. Brazier

Theses and Dissertations

States across the country focus intensely on creating jobs, catalyzing capital investment, and stimulating economic output. They pursue different strategies, mixing and matching a variety of tactics in the pursuit of their economic objectives. While scholars have studied the relationship between economic development tactics and economic growth or business climate and economic growth, none to my knowledge have studied the impact of economic development efforts on economic outcomes while accounting for a state’s business climate.

I found economic development spending to be negatively associated with employment growth (other measures, real gross state product and per capita income growth, were not …

The Impact Of Occupational Therapy Acute Care Services On Readmission Rates For Patients In Medicare’S Hospital Readmission Reduction Program, Jessica M. Edelstein

Theses and Dissertations

The United States (US) health care system is faced with the daunting challenge to make healthcare payments commensurate with quality of care provided. To assess quality, metrics for reimbursement have been established by Medicare. One such quality metric is hospital readmissions (readmissions). Readmissions are associated with poor patient outcomes and costly. Associated poor patient outcomes include higher risk for mortality, deconditioning, nutritional issues and cognitive impairments. As a result, readmissions cost Medicare $26 billion annually. Current strategies for reducing readmissions in the US are fragmented and hospital-specific. While specific strategies may vary, hospitals that have low readmissions rates tend to …

The Effect Of The Senolytic Abt-263 On Androgen Deprivation-Induced Senescent Prostate Tumor Cells, So Min Lee

Theses and Dissertations

Prostate cancer (PCa) is one of the leading causes of cancer-related deaths in men. Although standard treatments such as androgen deprivation therapies (ADT) and antiandrogens have increased survival for many patients, most men placed on these therapies will develop castration-resistant disease (CRPC). Previous studies have shown that these treatments have limited cytotoxicity and instead promote cell growth arrest. Our current work demonstrates that prostate tumor cells grown in the absence of androgens by using charcoal-stripped serum undergo senescence-mediated or senescent-like growth arrest, based on the cellular expression of senescence-associated-beta-galactosidase (SA-β-Gal). Our studies further suggest that this senescence is transient and …

Constraints On Phytoplankton Abundance And Cyanotoxin Production In The Tidal Freshwater James River, Brittany Ann Moretz

Theses and Dissertations

The tidal freshwater James River exceeds chlorophyll-a (CHL-a) water quality standards and the cyanotoxin microcystin is commonly present. Efforts to control harmful algal blooms in the James have brought about significant reductions in nitrogen and phosphorus inputs, but chlorophyll levels have not changed. In order to better understand the factors constraining harmful algal blooms in this system, we performed three factorial mesocosm experiments that tested how light (ambient, enhanced), mixing (weak mixing, well-mixed), and the availability of dissolved inorganic nitrogen (pre/post NH₄⁺ reductions) influence the abundance of phytoplankton (CHLa, particulate organic carbon [POC]) and cyanotoxin production (microcystin, anatoxin) …

A Comparison Of Computer- And Interviewer-Administered Measures To Identify Heavy/Problem Alcohol And Other Drug Use In Primary Care Patients, David J. Pomm

Theses and Dissertations

Substance use is a leading cause of morbidity and mortality that is under-identified in primary care settings. Screening for substance use in primary care requires an efficient and accurate approach. Exploring methods to collect sensitive and accurate data about substance use and related problems is important to inform research practice and clinical care. Using RCT data comparing computerized and therapist delivered brief intervention for substance use problems, the present study had a unique opportunity to compare computerized anonymous and confidential surveys to a confidential, interviewer-administered assessment in a sample of N = 540 males and females at risk for heavy/problem …

Black Women And Body Image: Implications Of The Racialized Beauty Aesthetic, Rachel L. Boutte

Theses and Dissertations

Black women have the highest prevalence of overweight and obesity relative to any other demographic group in the United States, however current weight management interventions appear least effective for them. Although several hypotheses have been proposed to explain these outcomes, few studies have collected data to evaluate how well they fit the lived experiences of Black women. In particular, the potential roles of body image and body dissatisfaction in the development and maintenance of overweight and obesity in Black women are not well understood. Extant literature largely reports that Black women are inoculated from body dissatisfaction due to cultural factors, …

Design Hub: Activating Community By Design, Ed Williams

Theses and Dissertations

MOTIVATION

At the turn of the century, Robert Putnam (2000, 27) wrote “...a powerful tide bore Americans into ever deeper engagement in the life of their communities, but a few decades ago that tide reversed and we were overtaken by a treacherous rip current.” Putnam is describing a loss of “social capital” throughout American society. Research suggests that many of our contemporary issues are the result of a decline in “social capital,” or “community.”

This pervasive lack of community is thought to be detrimental to “educational performance, safe neighborhoods, equitable tax collection, democratic responsiveness, everyday honesty, and even our health …

Exosomes As Systemic Mediators Of Nanotube Induced Neurotoxicity, Christopher G. Canal

Theses and Dissertations

Extra-pulmonary effects of nanoparticle inhalation have been well documented; however, mechanisms for conveying peripheral bioactivity remain elusive. Recent studies point to indirect molecular mediators shed into the circulation. Protein and lipid alternatives to cytokines or chemokines have been proposed, yet the diversity among responses suggests a broader assemblage of factors. Recently we have proposed proteolytic fragment peptides as an additional source of bioactivity, which interestingly were significantly associated with exosomal proteins after enrichment analysis. Here we tested whether modeled exposure to multi-walled carbon nanotubes (MWCNT) could alter the composition and bioactivity of circulating exosomes. Male C57BL/6 mice were exposed by …

Adverse Childhood Experiences In Children Presenting To Integrated Pediatric Primary Care, Irene A. Jacobs

Theses and Dissertations

The prevalence of adverse childhood experiences (ACEs) has created a significant public health concern in the United States. A vast body of literature examining adult populations has displayed a dose-response association between cumulative ACEs and chronic illnesses (Chapman et al., 2004; Felitti et al., 1998). ACEs research conducted with children and adolescents has indicated higher ACE scores associated with learning and behavioral problems (Burke et al., 2011), health risk behaviors (Garrido et al., 2018), and mental health challenges (Mackner et al., 1997). However, ACEs research and subsequent interventions have largely relied upon retrospective data retrieved from adults (Felitti et al., …

Competing Models Of Exposure To Community Violence Among Urban Youth: Dimensional Versus Person-Centered Approaches, Sarah K. Pittman

Theses and Dissertations

Exposure to community violence is prevalent among urban youth residing in neighborhoods with high rates of crime and violence. Although there is strong evidence suggesting that community violence exposure is associated with negative consequences on youth development, there are inconsistencies in theories and evidence regarding the nature of these associations. Methodological limitations of dimensional approaches to conceptualizing exposure, including the assumption that adolescents are similar in their frequency and patterns of exposure, likely contribute to the inconsistencies in findings of associations. Recently, person-centered methods have been used to elucidate associations between community violence exposure and consequences on adolescent development. However, …