Digital Commons Network^™

Xlf-Dependent Nonhomologous End Joining Of Complex Dna Double-Strand Breaks With Proximal Thymine Glycol And Screening For Xrcc4-Xlf Interaction Inhibitors, Mohammed Al Mohaini

Theses and Dissertations

DNA double-strand breaks induced by ionizing radiation are often accompanied by ancillary oxidative base damage that may prevent or delay their repair. In order to better define the features that make some DSBs repair-resistant, XLF-dependent nonhomologous end joining of blunt-ended DSB substrates having the oxidatively modified nonplanar base thymine glycol (Tg) at the first (Tg1) , second (Tg2), third (Tg3) or fifth (Tg5) positions from one 3’ terminus was examined in human whole-cell extracts. Tg at the third position had little effect on end-joining even when present on both ends of the break. However, Tg as the terminal or penultimate …

The Characterization Of A Putative Virulence Factor Expressed By Sneathia Amnii, Amy Sanford

Theses and Dissertations

Preterm birth, defined at birth before 37 weeks gestation, affects millions of newborns worldwide every year. Preterm birth is a leading cause of infant morbidity and mortality. One major cause of preterm birth is preterm premature rupture of membranes (PPROM), which can be triggered by bacterial infection and inflammation. A bacterial species that has been implicated in preterm birth and other obstetric complications is Sneathia amnii. The goals of this study were to observe cytopathogenic effects caused by S. amnii strain Sn35 and identify putative virulence factors causing those effects. Sn35 was able to adhere to, invade, and damage/kill …

Depletion Of The Chromatin Remodeler Chd4 Sensitizes Aml Blasts To Genotoxic Agents And Reduces Tumor Formation, Justin Sperlazza

Theses and Dissertations

Chromodomain Helicase DNA-Binding Protein 4 (CHD4) is an ATPase that alters the phasing of nucleosomes on DNA and has recently been implicated in DNA double stranded break (DSB) repair. Here, we show that depletion of CHD4 in Acute Myeloid Leukemia (AML) blasts induces a global relaxation of chromatin that renders cells more susceptible to DSB formation, while concurrently impeding their repair. Furthermore, CHD4 depletion renders AML blasts more sensitive both in vitro and in vivo to genotoxic agents used in clinical therapy: daunorubicin (DNR) and cytarabine (ara-C). Sensitization to DNR and ara-C is mediated in part by activation of the …

Pemetrexed, A Modulator Of Amp-Activated Kinase Signaling And An Inhibitor Of Wild Type And Mutant P53, Stuti Agarwal

Theses and Dissertations

New drug discoveries and new approaches towards diagnosis and treatment have improved cancer therapeutics remarkably. One of the most influential and effective discoveries in the field of cancer therapeutics was antimetabolites, such as the antifolates. The interest in antifolates increased as some of the antifolates showed responses in cancers, such as mesothelioma, leukemia, and breast cancers. When pemetrexed (PTX) was discovered, our laboratory had established that the primary mechanism of action of pemetrexed is to inhibit thymidylate 22 synthase (TS) (E. Taylor et al., 1992). Preclinical studies have shown that PTX has a broad range of antitumor activity in human …

Investigating The Role Of The Nucleosome Remodeling Factor Nurf As A Regulator Of Gene Expression, Aiman S. Alhazmi

Theses and Dissertations

The nucleosome remodeling factor (NURF) is an evolutionary conserved ATP-dependent chromatin remodeling factor. It was first isolated from Drosophila as a complex with enzymatic activity that once recruited to nucleosome, it slides the nucleosome to provide accessibility for transcription factors. Since then, numerous works from animal models and cell lines show the role of NURF as a regulator of gene expression. NURF interacts with H3K4me3 and sequence specific transcription factors that recruit the complex to promoter regions. Whether this is the only mechanism by which NURF regulates gene expression is not known. However, other ATP-dependent chromatin remodeling complexes are known …

A Novel Antimicrobial Drug Discovery Approach For The Periodontal Pathogen Porphyromonas Gingivalis, Victoria N. Stone

Theses and Dissertations

The human body is colonized by more than 100 trillion microbes which make up an essential part of the body and plays a significant role in health. We now know the over use and misuse of broad-spectrum antibiotics can disrupt this microbiome contributing to the onset of disease and runs the risk of promoting antibiotic resistance. With antibiotic research still on the decline, new strategies are greatly needed to combat emerging pathogens while maintaining a healthy microbiome. We therefore set out to present a novel species-selective antimicrobial drug discovery strategy.

Disruption of the homeostasis within the oral cavity can trigger …

Effects Of Hiv-1 Viral Protein Tat On The Viability And Function Of Oligodendroglial Cells, Shiping Zou

Theses and Dissertations

Myelin pallor is frequently reported in HIV patients, and can occur in the CNS prior to other evidence of disease process. Our exploratory studies showed that oligodendrocytes (OLs) are direct targets of HIV-1 Tat (transactivator of transcription). Tat induces a dose-dependent increase of intracellular Ca²⁺ level ([Ca²⁺]_i) in cultured murine OLs, which can be attenuated by ionotropic glutamate receptor (iGluR) antagonists MK801 and CNQX. The Tat-induced [Ca²⁺]_i increase leads to increased death in immature (O4⁺, MBP^-), but not mature (O4⁺, MBP⁺) OLs, over 96 …

Consequences Of Vine Infestation: Linking Abiotic Influences And Biotic Interactions To Successional And Structural Changes In Coastal Communities, Spencer N. Bissett

Theses and Dissertations

Located at the interfaces of terrestrial and marine environments, coastal habitats are inherently vulnerable to the effects of global change. Barrier island systems in particular serve not only as protective buffers against storm events, but also as sentinel ecosystems for observation of the impacts of sea level rise, and of increasing storm frequency and intensity. In the mid-Atlantic region, shrub thickets of Morella species compose the dominant forest community. The often monospecific nature of these plant community assemblages is advantageous to ecological studies and cross-scale applications; the relatively low diversity facilitates transitions between scales. My objective was to investigate the …

Computational Modeling To Assess Surgical Procedures For The Treatment Of Adult Acquired Flatfoot Deformity, Brian A. Smith

Theses and Dissertations

Several surgically corrective procedures are considered to treat Adult Acquired Flatfoot Deformity (AAFD) patients, relieve pain, and restore function. Procedure selection is based on best practices and surgeon preference. Recent research created patient specific models of Adult Acquired Flatfoot Deformity (AAFD) to explore their predictive capabilities and examine effectiveness of the surgical procedure used to treat the deformity. The models’ behavior was governed solely by patient bodyweight, soft tissue constraints, and joint contact without the assumption of idealized joints. The current work expanded those models to determine if an alternate procedure would be more effective for the individual. These procedures …

Effects Of Constant Vs. Fluctuating Temperatures On Performance And Life History Of The Herbivorous Pest Lymantria Dispar (Lepidoptera: Eribidae), Brendan E. Sostak

Theses and Dissertations

The role of temperature variation in organismal performance is understudied, but is critically important for understanding the response of biodiversity to climate change. To address this issue in herbivorous insects, I studied the direct and interactive effects of thermal regime (constant vs. fluctuating temperatures) and nutrition (dietary nitrogen) on gypsy moth (Lymantria dispar) performance under laboratory conditions. Predictions for differences between constant and fluctuating thermal conditions were derived from Jensen’s inequality, and artificial diets of differing nutritional quality were made by modifying nitrogen (casein) content. Larvae were reared in the laboratory under four temperature regimes (22°C constant, 22°C …

Orientia Tsutsugamushi Ankyrin-Repeat Protein Family Targeting Of The Host Endoplasmic Reticulum, Lauren Viebrock

Theses and Dissertations

Abstract

ORIENTIA TSUTSUGAMUSHI ANKYRIN REPEAT-PROTEIN FAMILY TARGETING OF THE HOST ENDOPLASMIC RETICULUM

By Lauren VieBrock, B.S.

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University

Virginia Commonwealth University, 2015

Director: Jason A. Carlyon, Ph.D.

Professor

Microbiology and Immunology

Scrub typhus is an understudied, potentially fatal febrile illness, which poses threat to one billion people annually in the Asia-Pacific region. The host-pathogen interactions that facilitate the intracellular survival of the etiologic agent, Orientia tsutsugamushi, are not well understood. The Orientia tsutsugamushi genome encodes a large number of ankyrin repeat-containing proteins …

Discrete Nonlinear Planar Systems And Applications To Biological Population Models, Shushan Lazaryan, Nika Lazaryan, Nika Lazaryan

Theses and Dissertations

We study planar systems of difference equations and applications to biological models of species populations. Central to the analysis of this study is the idea of folding - the method of transforming systems of difference equations into higher order scalar difference equations. Two classes of second order equations are studied: quadratic fractional and exponential.

We investigate the boundedness and persistence of solutions, the global stability of the positive fixed point and the occurrence of periodic solutions of the quadratic rational equations. These results are applied to a class of linear/rational systems that can be transformed into a quadratic fractional equation …

Avatar, Cyborg, Icevorg: Simulacra’S Scion, Guido E. Alvarez

Theses and Dissertations

I propose a theoretical framework that describes how avatars incorporate media as an inherent part of their nature and find a hosting body in cyborgs to navigate and spawn in media. I propose the birth of a new scion that combines avatar, medium and cyborg into a conceptual being that I call “ICEVORG.”

The ICEVORG expands beyond representation into the actual physical world by means of media transgression—more specifically, by the use of the Strange Loop also known as Metalepsis ICEVORG find an effective soil to thrive and interrogate our ideas of reality by means of iteration, expansion, fragmentation and …

Expanding Eco-Visualization: Sculpting Corn Production, Jennifer E. Figg

Theses and Dissertations

This dissertation expands upon the definition of eco-visualization artwork. EV was originally defined in 2006 by Tiffany Holmes as a way to display the real time consumption statistics of key environmental resources for the goal of promoting ecological literacy. I assert that the final forms of EV artworks are not necessarily dependent on technology, and can differ in terms of media used, in that they can be sculptural, video-based, or static two-dimensional forms that communicate interpreted environmental information. There are two main categories of EV: one that is predominantly screen-based and another that employs a variety of modes of representation …

Clinical And Genomic Characterization Of Two Vaginal Megasphaera Species, Abigail L. Glascock

Theses and Dissertations

Two vaginal phylotypes of the genus Megasphaera (phylotype 1 and phylotype 2) were recently associated with bacterial vaginosis (BV), an infection characterized by vaginal dysbiosis. Through an analysis of 16S rRNA profiles of 3,986 women enrolled in the Vaginal Human Microbiome Project, we confirmed that while both phylotypes were associated with BV, Megaspheara phylotype 1 had higher specificity for the condition. Megasphaera phylotype 2 was strongly associated with trichomoniasis. Previous studies have reported that BV-associated organisms are excluded in pregnancy. We observed that Megasphaera phylotype 1, which has been associated with adverse pregnancy outcomes, exhibited a trend of increased prevalence …

The Role Of Α3Β4* Subtype Of Nicotinic Acetylcholine Receptors In Reversing Opioid-Induced Constipation In Mice, Aravind Gade

Theses and Dissertations

Opioids are excellent pain relievers. A major side-effect of chronic opioid treatment is constipation whereas withdrawal following chronic exposure leads to diarrhea and increased gastrointestinal motility. These effects of chronic opioids are mediated by μ-opioid receptors expressed on enteric neurons. Previous studies have shown that chronic opioids enhance sensitivity to nicotine in the gastrointestinal tract. This suggested that prokinetic effects of nicotine mediated through the activation of nicotinic acetylcholine receptors (nAChRs) may be useful in reversing opioid-induced constipation. The goal of this dissertation was to investigate the nAChR subtype expressed on enteric neurons and their role in reversing opioid-induced constipation. …

Meta-Analysis Of Gene Expression Studies, Umaporn Siangphoe

Theses and Dissertations

Combining effect sizes from individual studies using random-effects models are commonly applied in high-dimensional gene expression data. However, unknown study heterogeneity can arise from inconsistency of sample qualities and experimental conditions. High heterogeneity of effect sizes can reduce statistical power of the models. We proposed two new methods for random effects estimation and measurements for model variation and strength of the study heterogeneity. We then developed a statistical technique to test for significance of random effects and identify heterogeneous genes. We also proposed another meta-analytic approach that incorporates informative weights in the random effects meta-analysis models. We compared the proposed …

Using Structural Equation Modeling To Understand The Role Of The Family In Pediatric Asthma Contexts, Nour Al Ghriwati

Theses and Dissertations

Family factors have long been associated with the psychosocial adjustment of children with chronic illnesses, such as asthma (Minuchin, 1975; Rapee, 1997). Research indicates that negative family factors may also contribute to child disease severity, via bio-behavioral mechanisms of effect (Wood et al., 2006); however, these pathways have yet to be examined with a comprehensive focus on more positive family factors. This study sought to examine whether factors such as family cohesion, problem solving abilities, and communication influence asthma symptom severity in children via their effects on child depression and anxiety symptoms. Using structural equation modeling, we identified significant indirect …

Psychoactive Synthetic Cathinones (Or 'Bath Salts'): Investigation Of Mechanisms Of Action, Farhana Sakloth

Theses and Dissertations

Synthetic cathinones represent threatening and high abuse-potential designer drugs. These are analogs of cathinone (the b-keto analog of amphetamine (AMPH)) a naturally occurring stimulant found in the plant Catha Edulis. Methcathinone (MCAT) was the first synthetic analog of cathinone to be identified in 1987 by Glennon and co-workers and it exerted its action primarily through the dopamine transporter (DAT). Most central stimulants exert their action via monomaine transporters by causing either the release (e.g. cathinone analogs such as MCAT) or by preventing the reuptake (e.g. cocaine) of the neurotransmitter dopamine (DA) thus increasing the extracellular synaptosomal concentration of this …

Interaction Between Atm Kinase And P53 In Determining Glioma Radiosensitivity, Syed F. Ahmad

Theses and Dissertations

Glioblastoma multiforme (GBM) is the most common primary brain tumor. Studies have shown that targeting the DNA damage response can sensitize cancer cells to DNA damaging agents. Ataxia telangiectasia mutated (ATM) is involved in signaling DNA double strand breaks. Our group has previously shown that ATM inhibitors (ATMi) sensitize GBM cells and tumors to ionizing radiation. This effect is greater when the tumor suppressor p53 is mutated.

The goals of this work include validation of a new ATM inhibitor, AZ32, and elucidation of how ATMi and p53 status interact to promote cell death after radiation. We propose that ATMi and …

Factors That Influence Breast Cancer Diagnoses In Virginia Women 40-64 Years Old Who Utlized The Every Woman’S Life Program 1998-2012, Melanie C. Dempsey

Theses and Dissertations

This dissertation examines sociodemographic determinants and preventive health behaviors among women 40-64 years of age who participated in the Virginia Department of Health’s Every Woman’s Life breast cancer screening program. Utilizing secondary data, this research sought to explore patterns of breast cancer incidence, mammography screening utilization and sources of health information among low-income women.

The Virginia Department of Health provided a large sample size (N=34,942) on which to perform binary logistic regression analyses. Sociodemographic determinants and preventive health behaviors were analyzed as potential influencing factors in the diagnosis of breast cancer, the stage at the time of diagnosis and source …

Normalizing Tumor Vasculature Using Sepiapterin To Increase Radiosensitivity, Ninu Bruno

Theses and Dissertations

Our studies examine the role of nitric oxide synthase (NOS) in tumor vasculature. NOS is “uncoupled” in tumor cells, resulting in peroxynitrite (ONOO^-) formation in lieu of nitric oxide (NO). NO signaling is critical for vascular function, thus uncoupling of eNOS in endothelial cells may partly explain the poor vasculature found within tumors. NOS can be “recoupled” through Sepiapterin (SP) treatment of tumor cells. We examined whether SP could normalize tumor vasculature, promoting radiosensitivity. Optoacoustic tomography of flank xenografts and spontaneous tumor models demonstrate that SP significantly enhances percent oxyhemoglobin in tumors. Immunohistochemical analysis of SP-treated tumors showed …

The Role Of Psychology In Integrated Primary Care For Complex Patients: Effects On Mental Health, Utilization Of Medical Services, And Physiological Markers Of Health, Danielle C. Worthington

Theses and Dissertations

This study served as an initial evaluation of integrated psychology services within a clinic designed to serve uninsured patients with complex medical concerns and high utilization histories at the Medical College of Virginia in Richmond, Virginia. The current study evaluates patient outcomes, and more specifically, it further quantifies and describes the role that psychologists play in the primary care setting and their impact on utilization of medical care and in improved health outcomes. Additionally, the study evaluates psychologists’ success at treating mental and behavioral health conditions within the primary care model. The present study demonstrates that patients with complex medical …

Nitric Oxide Synthase Activity And Its Modulation In The Treatment Of Colorectal Cancer, Asim Alam

Theses and Dissertations

The American Cancer Society estimates more than 141,000 new cases of and about 50,000 deaths from colorectal cancer every year. Treatment options include surgery, radiation therapy and targeted therapies such as anti-angiogenics. However, no therapies address the key driving factor of colorectal cancer: inflammation. It is well known that chronic inflammatory conditions such as Crohn’s Disease, ulcerative colitis, diabetes, obesity and cigarette smoking all elevate the risk of developing colorectal cancer. One of the hallmarks of chronic inflammation is the elevated levels of reactive oxygen/nitrogen species (ROS/RNS). A primary source of these ROS/RNS is uncoupled Nitric Oxide Synthase (NOS). Under …

Integrated Nanoscale Imaging And Spatial Recognition Of Biomolecules On Surfaces, Congzhou Wang

Theses and Dissertations

Biomolecules on cell surfaces play critical roles in diverse biological and physiological processes. However, conventional bulk scale techniques are unable to clarify the density and distribution of specific biomolecules in situ on single, living cell surfaces at the micro or nanoscale. In this work, a single cell analysis technique based on Atomic Force Microscopy (AFM) is developed to spatially identify biomolecules and characterize nanomechanical properties on single cell surfaces. The unique advantage of these AFM-based techniques lies in the ability to operate in situ (in a non-destructive fashion) and in real time, under physiological conditions or controlled micro-environments.

First, AFM-based …

Physicochemical And Structural Analysis Of Polymers As Putative Drugs, Meghan L. Thompson

Theses and Dissertations

Sulfated low molecular weight lignins (LMWLs) have shown good activity as anticoagulants by allosterically inhibiting thrombin, as well as promising agents for treating emphysema through inhibition of elastolysis, oxidation, and inflammation. Sulfated LMWLs are chemo-enzymatically synthesized from starting monomers caffeic, ferulic, and sinapic acid into sulfated dehydropolymers known as CDS, FDS, and SDS. To further the LMWLs’ development as drugs, their structural composition and physicochemical characteristics were defined in this work. The molecular weight distribution profile of the sulfated LMWLs from size exclusion chromatography performed on a high pressure liquid chromatography system (SEC-HPLC) changed from bimodal when no surfactant is …

Measuring The Impact Of Recognized Patient-Centered Medical Homes (Pcmh), Rick Moore

Theses and Dissertations

This dissertation proposal seeks to understand if the increasingnumbers (density) of recognized PCMH practices incommunities affect avoidable hospitalizations related toambulatory care sensitive conditions (ACSC), as measured bythe AHRQ Composite Prevention Quality Indicators (PQI). Theresearch has two purposes: 1. Establish constructs and hypotheses to measurethe effect of the increasing numbers of NCQA-Recognized PCMH practices in communities(counties). 2. Using an outcomes-based measurement approach,investigate the relationship between growingdensities of NCQA-Recognized PCMH practicedoctors among all primary care doctors (PCD) ina community and the associated impact on theutilization of inpatient care, specifically related toACSCs, as measured by the AHRQ CompositePQIs.

The research is quasi-experimental in …

Examination Of Basal Neuroendocrine Levels In Oif/Oef/Ond Veterans, Sage E. Hawn

Theses and Dissertations

Abstract

EXAMINATION OF BASAL NEUROENDOCRINE LEVELS IN OIF/OEF/OND VETERANS

By Sage E. Hawn, B.S.

A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University.

Virginia Commonwealth University, 2015.

Major Director: Ananda B. Amstadter, PhD.

Associate Professor

Departments of Psychiatry, Psychology, & Human and Molecular Genetics

High rates of combat exposure exist among veterans of the recent conflicts, and are associated with debilitating mental health conditions, including posttraumatic stress disorder (PTSD). Numerous psychosocial and biologic factors are associated with PTSD, including the HPA-axis. The present study aimed to compare baseline neuroendocrine …

Conduction States Of The Human Dopamine Transporter, Krasnodara Cameron

Theses and Dissertations

Dysregulation of dopaminergic homeostasis has been established as the primary source of numerous neurological disorders including Parkinson’s and drug addiction. A tonic increase of dopamine (DA) in the nucleus accumbens is required for associating everyday events and behaviors with rewards. Yet many addictive exogenous compounds such as amphetamine (AMPH) and cocaine (COC) produce a much greater augmentation of synaptic DA levels that are linked to euphoria and a shift in behavior towards drug seeking. The protein responsible for maintaining extracellular levels of DA is the dopamine transporter (DAT). It is primarily located in the perisynaptic area at terminals of pre-synaptic …

Exploring Dimensions Of Well-Being Among Spouses Of Active-Duty Service Members, Lisa A. Gray

Theses and Dissertations

During an era when the United States has been engaged in the longest waging wars in U.S. history, military families have been exposed to extraordinary amounts of stress and have had to learn to adapt in a culture where repeated deployments, recurrent family separations, and frequent relocations have become the norm. A surge in research in recent years on the families of Service members has brought increased attention to the unique challenges and demands of spouses, raising concerns about how to best meet their needs. Despite the increased attention, few studies have focused on spousal well-being. Acknowledging this lack of …