Digital Commons Network^™

Epigenetic Regulation Of Drug Metabolizing Enzymes In Normal Aging, Mohamad M. Kronfol

Theses and Dissertations

Geriatric populations are at a higher risk for adverse drug reactions (ADRs). This may be partly due to changes in drug metabolism in old age, but the underlying mechanisms are poorly understood. Prior research in humans and mice has shown age-associated changes to the expression of several genes involved in drug metabolism. Furthermore, studies of human blood showed that epigenetic regulation of genes encoding drug metabolizing enzymes change with age. However, it is unknown if genes in the liver are similarly affected. Therefore, we hypothesize that genes encoding drug metabolizing enzymes may show differential epigenetic regulation in the liver with …

Probing Vibrational Wave Packets In Organophoshorous Molecules Using Femtosecond Time-Resolved Mass Spectrometry (Ftrms), Derrick Ampadu Boateng

Theses and Dissertations

The study of organophosphorus and nitroaromatic compounds is essential due to their suitability as models for understanding the dynamics of radiation induce damage to DNA sugar-phosphate backbone, and the detection of chemical warfare agents as well as nitroaromatic explosives (such as TNT). The ultrafast dynamics of these polyatomic radicals were studied using femtosecond time-resolved mass spectrometry (FTRMS), a versatile method that is capable of monitoring the ultrafast dynamics of rapid dissociation in the gas phase after the removal of an electron. The method uses a technique called pump-probe, which makes use of two time-delayed laser pulses. In this work, the …

3-D Homology Modeling Of Organic Anion Transporters (Oats): Defining The Biochemical Basis For Oat-Substrate Interactions, Christopher Jay

Theses and Dissertations

A goal in the drug development process, as indicated by the FDA, is to evaluate a drug’s ADME profile, as potential drug interactions could exist, leading to adverse drug reactions or loss of efficacy. Transport proteins, specifically organic anion transporters (OATs) are involved in the absorption, distribution, and elimination of small, negatively charged compounds. Although there is an exhaustive list of structurally diverse organic anions which interact with OATs, interactions at a molecular level are still shrouded in mystery particularly due to the lack of a solved crystal structure. Therefore, in silico homology models (hOAT1, 2, 3) were generated using …

Invariance And Invertibility In Deep Neural Networks, Han Zhang

Theses and Dissertations

Machine learning is concerned with computer systems that learn from data instead of being explicitly programmed to solve a particular task. One of the main approaches behind recent advances in machine learning involves neural networks with a large number of layers, often referred to as deep learning. In this dissertation, we study how to equip deep neural networks with two useful properties: invariance and invertibility. The first part of our work is focused on constructing neural networks that are invariant to certain transformations in the input, that is, some outputs of the network stay the same even if the input …

Signaling Mechanism Responsible For 5-Ht2a Receptor Tolerance To Psychedelic Induced Head-Twitch Behavior In Mice, Audrey R. Mcmurtrie

Theses and Dissertations

In recent years, there has been a growing interest in psychedelic compounds stemming from their promising use as therapeutic agents and research tools that can be used to treat and study several neuropsychiatric disorders. Psychedelics have proven useful in a broad range of these diseases - they serve as models for psychosis in schizophrenia but have also had promising results in treating major depressive disorder, anxiety, and other common disorders. Decreased stigmatization surrounding psychedelics has further increased their use in research and clinical settings. In light of these trends and the promising nature of their use, a thorough understanding of …

Role Of Clic4 And The Synaptic Transcriptome In The Behavioral And Molecular Neurobiology Of Ethanol, Rory M. Weston

Theses and Dissertations

Alcohol use disorder (AUD) is a prevalent neuropsychiatric disease with profound health, social, and economic consequences. With an estimated 50% heritability, identifying genes that engender risk and contribute to the underlying neurobiological mechanisms represents an important first step in developing effective treatments. Gene expression studies are an important source of candidate genes for studying AUD, providing windows into the molecular machinery engaged by the brain in response to ethanol. Published studies have identified chloride intracellular channel 4 (Clic4) as an ethanol-regulated gene in brain capable of modulating sensitivity to sedation in multiple species. The functions of Clic4 are …

Robert Cowley: Living Free During Slavery In Eighteenth-Century Richmond, Virginia, Ana F. Edwards

Theses and Dissertations

This thesis examines the life of Robert Cowley, a formerly enslaved man living free during slavery in eighteenth-century Richmond, Virginia. The first chapter examines Cowley’s enslaved life through the records of others. The data collectors and historians of early America did not intend to capture the truth of Black people’s American experiences, except as defined their enslavement--people in service to the wealth-building capacity of the nation. Yet the lives of Black people who lived in proximity to prominent whites can be glimpsed in a variety of records and writings from account books to deeds, from private letters to newspaper advertisements. …

The Impact Of Registered Apprenticeships On The Middle-Skills Gap In Virginia, Yolanda Macklin Crewe

Theses and Dissertations

The skills gap debate has raged among scholars and policymakers for the last few decades. The key questions are whether the gap exists, the extent of the gap and how to minimize the gap. Of particular concern is a skills gap for middle-skills occupations. Since 2014, the federal government has invested over $500 million in registered apprenticeships as a strategy to address the skills gap. Likewise, Virginia has invested over $7.5 million and implemented policies such as VA Executive Order 49 (EO49), to expand registered apprenticeships as a workforce strategy to diminish the skills gap.

The goal of this research …

Language-Supportive Strategies And Their Associations With Child Language Outcomes During Instructional Time, Erin S. Wallace

Theses and Dissertations

In this dissertation, I conducted a correlational study that examined the frequency of educator-delivered language-supportive strategies during instructional time in public Kindergarten classrooms. Additionally, I explored the association between educators’ use of language-supportive strategies and child language outcomes. To index child language, I assessed a sample of 96 children from 10 different classrooms on standardized measures of expressive and receptive language. I recruited 10 educators to participate in the present study and assessed their use of language-supportive strategies during instructional time in the classroom through transcription and coding of audio recordings. The educators completed demographic forms for themselves as well …

Measuring The Impact Of Perceptions Towards Performance-Based Cash Rewards On Performance In Federal Agencies: Testing The Role Of Public Service Motivation As A Causal Chain, Layla F. Alanazi

Theses and Dissertations

Significant research has demonstrated how public service motivation (PSM) predicts individual outcomes, such as job satisfaction, organizational commitment, and choice of employment sector. Other research has demonstrated how PSM serves as an outcome variable. Between these two strands of PSM research, there is a knowledge gap concerning how PSM acts as a mediator. This study contributes to the growing literature on PSM by proposing and testing a causal model that estimates the direct effect of perceptions towards performance-based cash rewards on performance as well as their indirect effect through their influence on PSM, which then influences individual and organizational performance. …

Novel Bayesian Techniques For Dose Response Data, Faten Alamri

Theses and Dissertations

All forms of life are being exposed to different levels of harmful chemicals that can cause various and serious side effects. Toxicological experiments enable researchers to test these chemicals on animal to determine their major effects. Although optimal and acceptable dose levels have been investigated, researchers continue to strive to minimize side effects and the chemical dosages. Dose-response models and other benchmark approaches play a role in determining the acceptable exposure levels of hazardous chemicals. Parametric techniques, used to determine the tolerable dosages, utilizing ANOVA and non-linear regression models are well represented in the literature. We determined the benchmark dose …

Psychological Effects Of Reading: The Role Of Nostalgia In Re-Reading Favorite Books, Margaret A. Kneuer

Theses and Dissertations

There are many positive outcomes from feeling nostalgic, including reductions in loneliness and greater meaning and social connectedness. My primary research goal was to investigate whether I could trigger feelings of nostalgia from re-reading an old favorite book, and whether this elicited nostalgia would increase feelings of connectedness and meaning in life and reduce loneliness. I designed a two-study package (one correlational study and one experiment) to assess re-reading novels. Trait nostalgia was positively associated with enjoyment of re-reading books (Study 1). Re-reading a favorite novel, relative to reading a new novel or a set of newspaper articles, elicited nostalgia. …

Novel Duel Mtor Inhibitors/Ampk Activators Improve Therapeutic Efficacy Of Doxorubicin And Ameliorate Its Associated Cardiotoxicity In Mice, Sahak Eric Hovsepian

Theses and Dissertations

Triple-negative breast cancer (TNBC) is a particularly aggressive subset of breast cancer that has a molecular expression profile which lacks the estrogen receptor (ER), progesterone receptor (ER), and human epidermal growth factor receptor type 2 (HER2). No targeted treatment options currently exist for TNBC, unlike other types of breast cancer, and therefore survival rates are far lower for these patients. The current treatment for TNBC is systemic anthracycline chemotherapy, typically doxorubicin (DOX), which has great clinical efficacy in increasing survival. However, DOX induces a dose-dependent progressive cardiomyopathy, which can present years and up to decades after the last treatment. This …

A Microlongitudinal Study Of Menopause Symptoms And Problematic Eating In Midlife Women, Dana R. Schreiber

Theses and Dissertations

Women in midlife are at risk for engagement in problematic eating behavior which is associated with negative mental and physical health outcomes. Despite this risk, little is known about precipitating factors that may increase risk in this population. One specific, yet unstudied, factor that may increase risk for problematic eating in midlife women is menopause, which is characterized by distinct symptomatology (e.g., vasomotor symptoms, negative mood, sleep). The purpose of the current study was to investigate the associations among psychological, behavioral, and social symptoms of menopause and problematic eating behavior in midlife women using both retrospective and prospective methodologies. As …

Effects Of Gestational Ozone Exposure On Privileged Placental And Brain Barrier Integrity, Alexander I. Hamm

Theses and Dissertations

Ambient outdoor ozone, a common of component of photochemical smog and urban air pollution, is linked to various neurological and vascular pathologies. Its immediate reaction with lung surfactant after inhalation results in complete reactivity of the gas, with no active ozone passing into circulation. This indicates the presence of secondary and tertiary mediators in ozone-related systemic pathologies after pulmonary insult. In vasculature, ozone exposure is associated with an acute hypertensive phenotype apparent at least 24 hours after dose, such as experienced on a hot summer afternoon in a large metropolitan area like Los Angeles or Mexico City. However, the effects …

An Integrated Exploration Of The Contextual, Relational, And Individual Factors That Impact High School Completion Among African Americans, Lesley B. Winchester

Theses and Dissertations

African American students are consistently reported as having among the lowest high school graduation rates when compared to other races (U.S. Department of Education, 2018). While many studies have sought to explore the potential risks of high school dropout, the intention of this study is to examine the factors that support the exemplary resilience of those students who do complete high school. The present study adopts the framework of García Coll et al.’s, (1996) integrative model of developmental competencies in minority children, as it seeks to identity whether and how contextual (spiritual, educational, cultural); relational (caregiver psychological and physical …

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. …

Evidence Of Local Adaptation To Climate In An Invasive Ectotherm: A Study On The Eurasian Gypsy Moth (Lymantria Dispar) In North America, Phillip M. Gibbs

Theses and Dissertations

Invasive species exist in nearly every ecosystem both terrestrial and aquatic. Improving our understanding of the mechanisms that shape the ability of these organisms to physiologically cope with their surroundings will be crucial to preparing for future impacts of climate change. The Gypsy Moth (Lymantria dispar) has been expanding its range across North America over the last 100+ years since its arrival in Medford, Massachusetts. This study quantifies upper thermal limits (UTL) across 8 different populations of L. dispar in North America and seeks to determine if signals of local adaptation to climate across a latitudinal gradient may …

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, …

Optical Spectroscopy And Theoretical Modelling Of Carrier Dynamics In Group-Iv Alloy Quantum Dots, Rahnuma Rahman

Theses and Dissertations

In recent years, Ge_1−xSn_x alloy quantum dots (QDs) have attracted significant interest due to their potential applications in photodetectors and light emitting devices in visible to mid IR spectral range and compatibility with silicon based platforms. While bulk Ge is an indirect bandgap semiconductor (0.66 eV), direct transitions can be made possible by incorporation of α-Sn at concentrations of ~10%, which however lowers the bandgap. Utilizing quantum confinement by reducing the size to below the Bohr radius also promotes direct transitions and more importantly increases the fundamental transition energies in GeSn alloy QDs, making them suitable for …

Assessing The Feasibility Of Freshwater Mussel Restoration In Urban Streams., John-Reid Ryan

Theses and Dissertations

Abstract

The main objective of this study was to determine whether introduced freshwater mussels (Alewife floater, Utterbackiana implicata) can survive and grow in urban streams in the James River watershed. A secondary objective was to assess differences in U. implicata survival and growth of in the context of differing water quality and food resource conditions among three urban sites and three rural sites. Results from this study show large differences in growth and survivorship of mussels across sites. Higher survivorship was observed among mussels stocked into rural streams (35% and 44%) in comparison to urban streams (3%, 6% and 14%). …

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 …