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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 …

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 …

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 …

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 …

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 …

Multi-Label Classification Models For Heterogeneous Data: An Ensemble-Based Approach., Jose Maria Moyano Murillo

Theses and Dissertations

In recent years, the multi-label classification gained attention of the scientific community given its ability to solve real-world problems where each instance of the dataset may be associated with several class labels simultaneously, such as multimedia categorization or medical problems.

The first objective of this dissertation is to perform a thorough review of the state-of-the-art ensembles of multi-label classifiers (EMLCs). Its aim is twofold: 1) study state-of-the-art ensembles of multi-label classifiers and categorize them proposing a novel taxonomy; and 2) perform an experimental study to give some tips and guidelines to select the method that perform the best according to …

Reducing Material Attractiveness Utilizing Pu-238 And U-232, Cody Lloyd

Theses and Dissertations

Decreasing the material attractiveness of uranium and plutonium materials is crucial to nuclear nonproliferation. The International Atomic Energy Agency (IAEA) implements safeguards across the world on a limited budget. Not only does decreasing material attractiveness reduce the possibility of proliferation, but also may lighten the financial burden on the IAEA if safeguards can be reduced. Two particular isotopes that have negative material attractiveness traits are ²³⁸Pu and ²³²U. Without isotopic separation technology, these isotopes cannot be removed from plutonium and uranium materials respectively. Both ²³⁸Pu and ²³²U produce large quantities of heat by alpha decay. High …

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 …

The Analysis Of Neural Heterogeneity Through Mathematical And Statistical Methods, Kyle Wendling

Theses and Dissertations

Diversity of intrinsic neural attributes and network connections is known to exist in many areas of the brain and is thought to significantly affect neural coding. Recent theoretical and experimental work has argued that in uncoupled networks, coding is most accurate at intermediate levels of heterogeneity. I explore this phenomenon through two distinct approaches: a theoretical mathematical modeling approach and a data-driven statistical modeling approach.

Through the mathematical approach, I examine firing rate heterogeneity in a feedforward network of stochastic neural oscillators utilizing a high-dimensional model. The firing rate heterogeneity stems from two sources: intrinsic (different individual cells) and network …

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 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 …

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, …

Investigation Of Molecular Mechanisms Of Liver Preservation Injury: A Complication Preceding Organ Transplantation, Ria C. Fyffe-Freil

Theses and Dissertations

Of the over 108,000 American awaiting a life-saving organ transplant today, over 12,000 (11%) of those need a new liver (OPTN, 2020). Last year, only 35% of patients on the waiting list for an organ were transplanted. Improving the quality of marginal organs by preventing or reversing preservation injury could vastly increase the number of transplants performed. Washout of circulating blood during liver procurement with cold University of Wisconsin solution flushes out any endogenous pro-survival signaling molecules. We investigated lysophospholipid (LPL) surface receptors (G-protein coupled receptors for lysophosphatidic acid (LPA) and sphingosine- 1-phosphate (S1P)) and their role in protecting hepatocytes …

Separate And Unequal: Latinx Access, Enrollment And Completion Of Ap Coursework In The State Of Virginia, Virginia Elizabeth Palencia

Theses and Dissertations

In response to the national problem of overrepresentation of Latinx students in general education classes, this study addresses Latinx access to Advanced Placement (AP) coursework, enrollment, and completion patterns in Virginia, a growing destination state for many Latinx families and students. Through a secondary data analysis of both the Civil Rights Data Collection (2015-6) and College Board data (2016), this quantitative study mapped patterns of disproportionality in AP access, enrollment, and completion for Latinx students, who comprise 13% of enrollment in Virginia public high schools. In addition, a case study of two diverse school districts provides evidence of segregation and …