Nanomedicine Drug Delivery Across Mucous Membranes, Michael G. Lancina Iii

Theses and Dissertations

NANOMEDECINE DRUG DELIVERY ACROSS MUCOUS MEMBRANES

By Michael G. Lancina III

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

Virginia Commonwealth Univeristy, 2017.

Major Director: Dr. Hu Yang, Associate Professor, Chemical and Life Science Engineering

Control over the distribution of therapeutic compounds is a complex and somewhat overlooked field of pharmaceutical research. When swallowing a pill or receiving an injection, it is commonly assumed that drug will spread throughout the body in a more or less uniform concentration and find its way to wherever it is needed. In …

A Comparison Of Computational Methods For Estimating Estuarine Production And Respiration From Diel Open Water Dissolved Oxygen Measurements, Spencer Tassone

Theses and Dissertations

Diel dissolved oxygen (DO) data were used to characterize seasonal, inter-annual, and longitudinal variation in production and respiration for the James River Estuary. Two computational methods (Bayesian and bookkeeping) were applied to these data to determine whether inferences regarding DO metabolism are sensitive to methodology. Net metabolism was sensitive to methodology as Bayesian results indicated net heterotrophy (production < respiration) while bookkeeping results indicated net autotrophy (production > respiration). Differences in net metabolism among the methods was due to low seasonal variation in respiration using the Bayesian method, whereas bookkeeping results showed a strong correlation between production and respiration. Bayesian results suggest a dependence on allochthonous organic matter (OM) whereas …

Effects Of Cumulative Risk On Asthma Outcomes In Urban Children And Adolescents, Samantha A. Miadich

Theses and Dissertations

Pediatric asthma disproportionately affects racial/ethnic minority children and children living in low-income, urban areas. Many families living in low-income, urban areas experience a number of stressors that can place children/adolescents at risk for worse asthma outcomes. This study examined the impact of a cumulative risk model of stressors (e.g., ED visits, quick-relief medication use, lung function, asthma control, QOL) in urban children (7-12 years) with persistent asthma. This study further aimed to examine both the original cumulative risk model and an adolescent-specific cumulative risk model as predictors of asthma outcomes in a sample of 60 adolescents (13-17 years). Asthma-related caregiver …

Investigation On Genetic Modifiers Of Age At Onset Of Major Depressive Disorder, Huseyin Gedik

Theses and Dissertations

Major Depressive Disorder (MDD) is a complex multifactorial disorder, which would lead to disability. Environmental and genetic factors are involved in MDD etiology. The aim of this project was to identify loci modifying age at onset (AAO) of MDD using survival models after adjusting for Childhood Sexual Abuse (CSA). To achieve this aim, a dataset was made available by the China Oxford and VCU Experimental Research on Genetic Epidemiology (CONVERGE) consortium. The study population had 5,220 controls and 5,282 cases with MDD. We performed two univariate association analyses using Cox Proportional Hazard (Cox PH) models. These two are Full Sample …

Fabrication Of Flexible, Biofunctional Architectures From Silk Proteins, Ramendra K. Pal

Theses and Dissertations

Advances in the biomedical field require functional materials and processes that can lead to devices that are biocompatible, and biodegradable while maintaining high performance and mechanical conformability. In this context, a current shift in focus is towards natural polymers as not only the structural but also functional components of such devices. This poses material-specific functionalization and fabrication related questions in the design and fabrication of such systems. Silk protein biopolymers from the silkworm show tremendous promise in this regard due to intrinsic properties: mechanical performance, optical transparency, biocompatibility, biodegradability, processability, and the ability to entrap and stabilize biomolecules. The unique …

N-Alkyl 4-Methylamphetamine Enantiomers And The Implication For Potential Modulation Of Abuse Liability And Enhancement Of Psychoactive Drug Targeting., Ramsey Sitta

Theses and Dissertations

Drugs of abuse have a long history in humanity. Currently however, a subject of great interest is the phenylalkylamine family of drugs. Not only is the abuse liability of interest but also the potential therapeutic expansion of the capabilities of this family of drugs by utilizing the unique stereospecific effects of the newly discovered hybrid compounds. Based upon prior data of N-Alkyl 4-MA the enantiomers of N-Methyl, N-Ethyl, and N-Propyl were analyzed in hDAT, hNET, and hSERT. It was found that there was a negative correlation between chain length and potency and dopaminergic component. In agreement with the currently established …

Reversal Of The Npc Phenotype By Start Domain Proteins, Tavis H. Sparrer

Theses and Dissertations

Niemann Pick Type C (NPC) disease is a fatal childhood neurological disease caused by mutations in the NPC-1 protein, resulting in cholesterol buildup in the late endosomes. StarD4 and StarD5 are cholesterol binding proteins that play a role in the intracellular cholesterol transport. In this study we overexpress StarD4 and StarD5 in in vitro and in vivo models, and find evidence of amelioration of the NPC phenotype. This study demonstrates that the overexpression of these proteins has the potential to be a therapeutic treatment for NPC disease.

Epigenetic Editing To Validate Findings From Methylome-Wide Association Studies Of Neuropsychiatric Disorders, Robin F. Chan

Theses and Dissertations

DNA methylation is necessary for learning, memory consolidation and has been implicated in a number of neuropsychiatric disorders. Obtaining high quality and comprehensive data for the three common forms of methylation in brain is challenging for methylome-wide association studies (MWAS). To address this we optimized a panel of enrichment methods for screening the brain methylome. Results show that these enrichment techniques approach the coverage and fidelity of the current gold standard bisulfite based techniques. Our MBD-based method can also be used with low amounts of genomic material from limited human biomaterials. Psychiatric disorders have high prevalence and are often chronic …

Knockout Of Sphingosine Kinase 1 Attenuates Renal Interstitial Fibrosis In Unilateral Ureteral Obstruction (Uuo) Model, Xiwen Zhang

Theses and Dissertations

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite and an important signaling molecule that plays a significant role in fibrosis. S1P synthesis is catalyzed by sphingosine kinases (SphKs), which phosphorylate sphingosine into S1P. The present study tested the hypothesis that SphK1-S1P signaling pathway participates in the kidney damage in unilateral ureteral obstruction (UUO) model. Wild type and SphK1 knockout mice were subjected to UUO for 7 days or 14 days and then four groups of kidneys were collected: wild type control group (WT-C), wild type UUO group (WT-UUO), SphK1-/- control group (KO-C) and SphK1-/- UUO group (KO-UUO). The mRNA level of …

Role Of Translation Initiation In Regulation Of Epithelial Junctions And Cell Motility, Fahda Fawaz Alsharief

Theses and Dissertations

The integrity and barrier properties of intestinal epithelium are determined by specialized adhesive structures known as intercellular junctions; composed of adherens junctions (AJs), tight junctions (TJs) and focal adhesions that mediate cell-cell and cell matrix interactions, respectively. These two types of epithelial cell adhesions regulate each other during disruption and restitution of the epithelial barrier. Inflammatory cytokines such as interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) are elevated during intestinal inflammation. The most notable effects of IFNγ and TNFα on intestinal epithelial homeostasis involve disruption of apical junctions and attenuation of cell migration. Although molecular mechanisms underlying these …

Discovery Of Mor Selective, Reversible Opioid Antagonist For Potential Use In Treatment Of Drug Dependence, Abdulmajeed Jali

Theses and Dissertations

Abstract

DISCOVERY OF MOR SELECTIVE, REVERSIBLE OPIOID ANTAGONIST FOR POTENTIAL USE IN TREATMENT OF DRUG DEPENDENCE

Abdulmajeed M. Jali, M.S.

A thesis submitted in partial fulfillment of the requirements of Master of Science at Virginia Commonwealth University.

Virginia Commonwealth University, 2017

Director: Dana E. Selley, Ph. D., Department of Pharmacology and Toxicology

Opioid dependence/addiction is a major public health problem that is associated with multiple health and social costs. Pharmacotherapeutic treatment has been relatively effective, but the risk of relapse after treatment remains high. Naltrexone, an opioid antagonist, is FDA-approved for long-term maintenance therapy to reduce relapse risk. However, naltrexone …

The Characterization Of Chimeric Chaperone Flagrp170 As A Novel Radioprotectant, Tyler L. Nguyen

Theses and Dissertations

Abstract

THE CHARACTERIZATION OF CHIMERIC CHAPERONE FLAGRP170 AS A NOVEL RADIOPROTECTANT

By Tyler Nguyen, M.S.

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

Virginia Commonwealth University, 2017

Major Director: Dr. Xiang-Yang (Shawn) Wang, Ph.D., Professor, Department of Human and Molecular Genetics

Radiation therapy (RT) is restricted by toxic effects on adjacent normal tissue, which limits RT efficacy in cancer treatment. Damage to normal tissue, such as radiosensitive intestine and bone marrow compartments, results in acute radiation damage. To reduce normal tissue injury in the setting of RT, we …

Depressive Symptoms Among College Students: An Exploration Of Fundamental Cause Theory, Peter A. Carrico

Theses and Dissertations

Fundamental Cause Theory suggests that socioeconomic and demographic factors are causal to various illnesses, including depression. However, no known previously existing research has used Fundamental Cause Theory to create a model of depression among college students. To do this, the present study conducted a stepwise binomial logistic regression to examine how socioeconomic status and the sociodemographic variables of Gender, Race, and Sexual Orientation, and others predict depressive symptoms in a large sample of undergraduates when controlling for stressful life events and social support (N = 2,915). Results support the hypothesis that socioeconomic disparities in depressive symptoms are the result …

Analyzing The Phenotypic Effect Of Three Candidate Genes Associated With Nonsyndromic Craniosynostosis Using A Zebrafish Model, Megan A. Hept

Theses and Dissertations

In normal cranial suture development, the cranial sutures close at predetermined periods of development to allow the brain the capability to grow in a malleable environment. However, in craniosynostosis, cranial sutures prematurely fuse before birth which can lead to a wide range of developmental issues and complications. Craniosynostosis can be categorized as nonsyndromic which involves the sole fusion of one or more of the cranial sutures, or syndromic in which cranial sutures fuse as well as other abnormalities associated with a genetic disorder. Past research has identified three candidate genes that could be possible disease causing mutations in nonsyndromic sagittal …

Expanding Monoamine Transporters Pharmacology Using Calcium Channels, Iwona Ruchala

Theses and Dissertations

Research in drug development meets many challenges including lengthy, complex and costly procedures to identify novel pharmacotherapies. In our lab, we developed a method for fast screening of small molecules that interact with monoamine transports – dopamine and serotonin (DAT, SERT). These membrane proteins play important roles in brain neurotransmission responsible for cognition, motion and pleasure. Dysfunction in dopaminergic and serotonergic systems result in neurological disorders such as depression, Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia and addiction.

DAT and SERT are responsible for uptake of dopamine (DA) or serotonin (5HT) into the synapse and they limit neurotransmitter signaling. Drugs that …

Effect Of Temperature And Genetic Structure On Adaptive Evolution At A Dynamic Range Edge In The North American Gypsy Moth (Lymantria Dispar L.), Trevor M. Faske

Theses and Dissertations

The study of biological invasions is not only essential to regulate their vast potential for ecological and economical harm, they offer a unique opportunity to study adaptive evolution in the context of recent range expansions into novel environments. The North American invasion of the gypsy moth, Lymantria dispar L., since its introduction in 1869 to Massachusetts, has expanded westward to Minnesota, northward to Canada, and southward to North Carolina. Fluctuating range dynamics at the southern invasive edge are heavily influenced by heat exposure over their optimal (supraoptimal) during the larval stage of development. We coupled genomic sequencing with reciprocal …

Contribution Of Asc-Inflammasome To Vascular Endothelial Dysfunction: Role Of Rna Receptor Rig-I, Ashley Pitzer

Theses and Dissertations

Retinoic acid-inducible gene-I (RIG-I) is a putative RNA helicase and recently identified as a cytosolic RNA receptor in mammalian cells. The role of RIG-I in the regulation of vascular function under physiological and pathological conditions is unknown. Recent studies have shown that the inflammasome serves as a crucial initiator of cytokine-mediated inflammation mediating the pathogenesis of cardiovascular disease. The present study tested whether RIG-I activation triggers inflammasome formation and subsequent cytokine-mediated inflammation in the endothelium of mice coronary arteries. Using both genetic and pharmacological interventions of the RIG-I inflammasome, we first characterized whether specific activation of RIG-I via 3pRNA transfection …

Drinking Motives Underlying Internalizing And Externalizing Pathways To Alcohol Misuse In College Students, Jeanne Savage

Theses and Dissertations

Alcohol misuse, including heavy episodic use and negative consequences, is a major public health concern and a particular problem among college students. The etiology of alcohol misuse is not well resolved, with multiple and often contradictory factors implicated in its development. Genetic factors influence alcohol misuse but few specific genes have been identified. A potential reason for these challenges is that alcohol misuse is phenotypically and genetically heterogeneous; that is, there are multiple causal pathways underlying its development. Previous typologies have suggested that distinct internalizing and externalizing pathways are involved, with corresponding differences in profiles of personality, temperament, and comorbid …

Validation Study Of The Science Literacy Assessment: A Measure To Assess Middle School Students' Attitudes Toward Science And Ability To Think Scientifically, Tammy Mckeown

Theses and Dissertations

This study investigated validity evidence for the Science Literacy Assessment, an instrument designed to assess middle school students’ ability to think scientifically as well as their motivation and beliefs about science (Fives, Huebner, Birnbaum, & Nicolich, 2014). Specifically, three sources of evidence were considered; internal structure, concurrent criterion-related, and predictive criterion-related. Exploratory factor analysis was utilized to examine the underlying factor structure of each of the instrument’s two components, motivation and beliefs related to science and demonstrated scientific literacy. Pearson product-moment correlations were calculated to determine the relationship between scores on the motivation and belief component of the Science Literacy …

Longitudinal Bidirectional Relations Between Subtypes Of Anxiety And Callous-Unemotional Traits In Early- To Mid-Adolescence, Stephanie A. Hitti

Theses and Dissertations

Callous-Unemotional (CU) traits are characterized by limited empathy, lack of guilt or remorse, and callous use of others. They are a risk factor for adult psychopathy, especially when comorbid with conduct problems. Thus, efforts to identify risk factors and consequences of CU traits have been prominent. One construct that may act as both a risk factor for and consequence of CU traits among youth is anxiety. While the most consistent finding is in this literature is a negative relation between CU traits and anxiety, findings have been mixed. The present study examined bidirectional relations between three subtypes of anxiety (i.e. …

Developmental Trajectories Of Alcohol Use And Alcohol Use Disorder, Elizabeth C. Long

Theses and Dissertations

Alcohol use (AU) and alcohol use disorder (AUD) are leading causes of morbidity, premature death, and economic burden. They are also associated with high levels of disability and many other negative outcomes. Twin and family studies have consistently shown that AU and AUD are complex traits influenced by both genetic and environmental factors. Although much has been learned about the genetic and environmental etiology of AU and AUD, significant gaps remain. These include the need for a more comprehensive understanding of the roles of risk and protective factors, and the nature of developmental trajectories underpinning the progression from AU to …

The Role Of Afrocentric Features In Mental Healthcare Utilization And Counselor Preferences In Black College Students, Randl B. Dent

Theses and Dissertations

Though mental health issues are prevalent in Black young adults, they underutilize mental healthcare services. This research examined the role of feature-based discrimination in mental healthcare (under)utilization. Study 1, a secondary analysis of the National Longitudinal Study of Adolescent to Adult Health, provided no evidence supporting a link between skin tone and mental healthcare utilization, when controlling for depression diagnosis. However, when controlling for depression symptoms, there was a trend such that Black young adults with darker, as opposed to lighter, skin tone utilized healthcare less. Study 2, an experimental study with 33 Black college students, showed 73% of the …

Understanding Over-The-Counter Medication Use And Decision-Making Among Community-Dwelling Us Older Adults: A Mixed-Methods Approach, Yoshita Paliwal

Theses and Dissertations

Introduction

Older adults are regular consumers of over-the-counter (OTC) medications. OTC medications are generally considered safe, and convenient to use without requiring a prescription. However, the safety of an OTC medication and the final health outcome depends in part upon consumers’ perceptions, beliefs, and their decision-making about OTC medication use. The main objectives of this study were: 1) to examine the prevalence and characteristics of OTC medication use among community-dwelling US older adults (65 years and older), 2) to explore older adults’ knowledge, attitudes, beliefs and experiences about OTC medications, and 3) to elicit the OTC medication decision-making process in …

Heme Oxygenase 1 Expression After Traumatic Brain Injury And Effect Of Pharmacological Manipulation On Functional Recovery., Nicholas H. Russell

Theses and Dissertations

Traumatic Brain Injury (TBI) is an increasingly diagnosed constellation of injuries derived from acute mechanical trauma to the brain. With the rise of advanced neuroimaging techniques recent focus has oriented primarily towards the mild-moderate range of TBI which previously was missed diagnostically. Characteristically, these advances have shown increasing areas of micro-hemorrhage in susceptible areas of the brain and to date there are no treatment modalities targeting micro-hemorrhages or their sequelae. This dissertation explores the effects of the resulting heme processing response in the days following injury with a particular focus on inducing early heme clearance from the parenchyma using a …

The Effects Of Disturbance And Species Specific Interactions On Diversity In An Agent Based Forest Simulation, Matthew E. Mills

Theses and Dissertations

In ecology literature, there is much data which suggests that conspecific negative density dependence (CNDD) and abiotic disturbances increase biodiversity in forests. This thesis elucidates the notion that not only do these two forces increase diversity, but they may also interact with one another in order to achieve higher levels of biodiversity. Abiotic disturbances, like fires and hurricanes, can indirectly impact conspecific effects because when these forces remove individuals from the landscape, the role of the conspecific effects will change. The interaction of these two factors in biodiversity are explored in an agent based forest simulation through a resource surface. …

Characterization Of Staphylococcal Nuclease And Tudor Domain Containing Protein 1 (Snd1) As A Molecular Target In Hepatocellular Carcinoma And Non-Alcoholic Steatohepatitis, Nidhi H. Jariwala

Theses and Dissertations

CHARACTERIZATION OF STAPHYLOCOCCAL NUCLEASE AND TUDOR DOMAIN CONTAINING PROTEIN 1 (SND1) AS A MOLECULAR TARGET IN HEPATOCELLULAR CARCINOMA AND NON-ALCOHOLIC STEATOHEPATITIS

Nidhi Jariwala, PhD

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Integrative Life Sciences

Virginia Commonwealth University, 2017

Devanand Sarkar, M.B.B.S., PhD.

Associate Professor, Department of Human and Molecular Genetics

Virginia Commonwealth University

Richmond, Virginia

SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). Oncoprotein SND1 regulates gene expression at a post-transcriptional level in multiple cancers including hepatocellular carcinoma (HCC). …

The Effect Of Combined Sewer Overflows On The Abundance Of Antibiotic Resistance Genes And Bacteria In The James River, Enjolie Levengood

Theses and Dissertations

Antibiotic resistance is a major threat to human health. Clinical situations are the main focus for antibiotic resistance research, but understanding the spread of resistance in the environment is also vital. A major contributor to this spread is wastewater from combined sewer overflow (CSO) events. The effect of CSO events on antibiotic resistance in the James River near Richmond, Virginia was studied using genomic and microbiological approaches. The abundance of genes associated with resistance to quinolones (qnrA) and tetracycline (tetW) was strongly correlated with the presence of fecal indicator bacteria (E. coli abundance) as well …

Skinface, Islam Shehab

Theses and Dissertations

Throughout history, skin manipulation was primarily practiced for cultural, tribal, or religious purposes. In the contemporary landscape, skin manipulation has been objectified and commercialized. This is exemplified through bio-upholstery, foreign materials under our skin and changing the skin structure.

This thesis investigates skin manipulation, with the intent to focus experimentation on the skin’s lines of cleavage, a topographical map drawn on our skin and used to define the direction where skin has the most and least flexibility. The aim is to connect and explore materials that can be used as a second skin, while at the same time examining and …

Comparing The Structural Components Variance Estimator And U-Statistics Variance Estimator When Assessing The Difference Between Correlated Aucs With Finite Samples, Anna L. Bosse

Theses and Dissertations

Introduction: The structural components variance estimator proposed by DeLong et al. (1988) is a popular approach used when comparing two correlated AUCs. However, this variance estimator is biased and could be problematic with small sample sizes.

Methods: A U-statistics based variance estimator approach is presented and compared with the structural components variance estimator through a large-scale simulation study under different finite-sample size configurations.

Results: The U-statistics variance estimator was unbiased for the true variance of the difference between correlated AUCs regardless of the sample size and had lower RMSE than the structural components variance estimator, providing better type 1 error …

Towards A Model Of Internal/External Motivation To Respond Without Prejudice: An Examination Of White Racial Identity And Affect, Christina Barnett

Theses and Dissertations

The current study explored how White racial identity influences the relationship between affective reactions to racism and one’s internal or external motivation to respond without prejudice. The first aim was to examine the bivariate relationships between White racial identity ego schemas and affective reactions to racism. The second aim examined the bivariate relationships between affective reactions to racism and an internal/external motivation to respond without prejudice. The third aim explored whether Phase I or Phase II White racial identity ego schemas explained the relation of affective reactions to racism and internal/external motivation to respond without prejudice. PROCESS mediation models were …