Digital Commons Network^™

Exploring The Dopamine Transporter Utilizing A Two-Pronged Approach With Novel Cathinone Analogs And Mutant Dopamine Transporters, Charles B. Jones Iii

Theses and Dissertations

The dopamine transporter (DAT) is responsible for the removal of the neurotransmitter from the synaptic gap and a therapeutic target for a multitude of drugs. While the ortholog Drosophila melanogaster dopamine transporter (dDAT) and human serotonin transporter (hSERT) have resolved structures, the human dopamine transporter (hDAT) does not. A 3-D computational homology model of hDAT was constructed for the study of molecular interactions with agents within the central binding site (S1) of the transporter.

Synthetic cathiones are a class of abused stimulant drugs that primarily target DAT. Greater than 150 cathinones have been identified on the clandestine market but there …

Characterization Of Cytochrome P450 3a4 Structure And Ligand Binding Mechanism In Anionic Nanodiscs, David T. Sweeney

Theses and Dissertations

The Cytochromes P450 superfamily are ubiquitous throughout life and are present in some viruses. Humans encode for 57 of these enzymes that are involved in the metabolism of ~90% of all chemicals. These membrane-bound monooxygenase enzymes utilize a heme protoporphyrin at their active site to activate molecular oxygen and oxidize their substrates through an intermediate deemed nature's most powerful oxidizer. They are a powerful system at our disposal yet understanding of their structure and ligand binding mechanisms in the presence of a lipid bilayer remains poorly understood. The focus of this work is on Cytochrome P450 3A4 (CYP3A4). We set …

Development Of Sam-Based Chemical Probes For Methyltransferases, Daniel V. Mongeluzi

Theses and Dissertations

Fig.1. SAM analog for the profiling of MTase activity. A. Chemical structure of probe 1; B. General scheme of the labeling and capture strategy.

A

B

Methylation is a fundamental mechanism used in the biological system to modify the structure and function of biomolecules such as proteins, DNA, RNA, and metabolites.¹ Methyl groups are installed by a large and diverse class of S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTases), which transfer the sulfonium methyl group of SAM to either carbon, nitrogen, oxygen, or other heteroatoms on biomolecules.² Dysregulated MTase activity contributes to numerous diseases, including cancer, metabolic disorders, neurodegenerative diseases. …

Pharmacophoric Evaluation Of 5-Ht2a And 5-Ht2b Serotonin Recpeptors, Prithvi Hemanth

Theses and Dissertations

Serotonin (5-HT) receptors represent a class of receptors involved in a variety of physiological processes including regulation of mood, perception, cognition, appetite, and heart function, and thus serve as drug targets of several drugs such as antipsychotic agents, hallucinogenic drugs, and appetite suppressant drugs. Due to the structural similarity of certain 5-HT receptor subtypes, particularly 5-HT₂ receptors (5-HT_2A, 5-HT_2B receptors) determination and refinement of pharmacophore models of these receptor subtypes can greatly improve the therapeutic efficacy of drugs that target them.

The goals of this study were to define and/or refine existing pharmacophore models for 5-HT …

Therapeutic Modalities For Preventing Osteoarthritis Following Trauma To The Knee, Kayla M. Scott

Theses and Dissertations

Over 32.5 million adults in the United States and 300 million worldwide have osteoarthritis (OA). To date, there are no disease-modifying therapeutics, only strategies to slow OA progression through pain management, regenerative medicine approaches, and ultimately joint replacement.

On a microscale, a phenotypic shift of the normally quiescent articular chondrocytes leads to aberrant expression of pro-inflammatory and catabolic pathways, which are hypothesized to contribute to OA progression. Of note, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and WNT/β-catenin signaling are key players disrupting cartilage homeostasis and driving inflammatory pathway activation. These pathways become dysregulated and form a positive feedback loop, increasing …

Prediction Of Mrna Abundance In Firmicutes: Steps Towards A Universal Model Of Prokaryotic Gene Expression, Jesse J. Raynor

Theses and Dissertations

Measurements of gene expression find use in many areas related to the characterization of prokaryotes. For example, metabolic modeling is commonly employed to assist in the design of engineered microbes by helping to elucidate the organism’s extant metabolic processes. With insights generated from the modeling procedure, targeted genetic modifications can be introduced to the organism to bring about some desired effect. Metabolic models based upon the “flux balance analysis” method (or FBA) can be made more accurate by integrating gene expression data, such as that from RNAseq experiments. For various reasons, gene expression data is not always available for every …

Sleep-Related Problems, Sleep-Related Distress, And Sleep-Related Functional Status Among Adult Inpatients Receiving Palliative Care, Lisa C. Sievers

Theses and Dissertations

Palliative care patients may be at a higher risk for sleep-related problems and their negative effects compared to the general population, yet limited sleep research has been done with this population. The purpose of this dissertation was to determine prevalence rates for excessive sleepiness, insomnia, restless legs syndrome (RLS), and high risk for sleep apnea (HRSA); examine relationships between the aforementioned sleep-related problems, sleep-related distress (SD), and sleep-related functional status (SFS); and to determine which sleep-related problem measures along with age and gender predicted SD and SFS among a sample of adult palliative care inpatients. Secondary aims were to understand …

A Deep Learning U-Net For Detecting And Segmenting Liver Tumors, Vidhya Cardozo

Theses and Dissertations

Visualization of liver tumors on simulation CT scans is challenging even with contrast-enhancement, due to the sensitivity of the contrast enhancement to the timing of the CT acquisition. Image registration to magnetic resonance imaging (MRI) can be helpful for delineation, but differences in patient position, liver shape and volume, and the lack of anatomical landmarks between the two image sets makes the task difficult. This study develops a U-Net based neural network for automated liver and tumor segmentation for purposes of radiotherapy treatment planning. Non-contrast simulation based abdominal CT axial scans of 52 patients with primary liver tumors were utilized. …

Development Of Unnatural Amino Acid Mutagenesis Technologies To Control Enzyme Activity And Synthesis Of Chemically Reactive Ubiquitin Probes, Jenny Cheung

Theses and Dissertations

Most of the work vital for the survival of the cell are performed by proteins. The primary sequence of proteins is composed of 20 canonical amino acids. However, these 20 amino acids do not offer the full range of functionalities needed for proteins to do their job. Often times, post-translational modifications (PTM’s) occur to add the required functional group. This interaction between all the different proteins in the proteome in addition to PTM’s create a complex system that scientists are still trying to unravel to this day. Many different tools had been developed for this purpose, and one such tool …

A Spatiotemporal Assessment Of Fish Assemblage Response To Land-Use Change And The Evaluation Of Edna Metabarcoding For Describing Diverse Fish Communities, Timothy M. Owen

Theses and Dissertations

Fish assemblages are often assessed as a biological proxy for environmental health. While humans value healthy environments for the ecosystem services and recreational opportunities they provide, it is increasingly evident that such resources can be paradoxically degraded by anthropogenic activities. In this investigation, we studied the relationship between different intensities of anthropogenic land-use change and habitat-driven fish assemblage response across multiple spatiotemporal scales. Secondarily, we explored the efficacy of eDNA metabarcoding against conventional electrofishing techniques for the purpose of describing complete fish communities. This study was conducted in the Tuckahoe Creek basin near Richmond, Virginia. This James River tributary serves …

The Impact Of Healthcare Professional Students' Racial, Hiv-Related, And Abortion-Related Biases On Recommendations For Prenatal Care, Alison J. Patev

Theses and Dissertations

Black women and HIV-positive women have increased maternal mortality rates and other negative pregnancy outcomes, in part due to disparate prenatal care. Although women who seek abortions do not have the same negative outcomes, abortion stigma exists and is normalized in healthcare. Limited work has examined prenatal care provision for women in these groups, and even less work has explored the prenatal care provision by healthcare trainees (i.e., medical, nurse practitioner, and physician assistant students). Examining the role of bias on the prioritization of prenatal care items by healthcare trainees is imperative. Healthcare education sets the stage for future practice, …

Starting Earnings Of Bachelor’S And Advanced Degree Graduates By Field Of Study: Using Multi-Level Modeling To Estimate The Effects And Early Labor Market Consequences Of Vertical And Horizontal Dimensions Of Higher Education, Qiao Liang

Theses and Dissertations

This study was conducted to better understand early labor market outcomes of higher education and the importance of the vertical and horizontal dimensions of higher education. Using College Scorecard’s institution and field of study levels data and a multilevel modeling approach, it estimated and ranked typical starting earnings associated with a large spectrum of bachelor’s and advanced degree programs, and discussed patterns, variations, and irregularities observed in the ranked earnings. This study also calculated advanced degree effects on the typical starting earnings associated with bachelor’s and advanced degree programs, and set precedence to systematically compare the effects of major, department, …

Breaking The Cycle: A Longitudinal Study Of Factors That Disrupt Peer Selection And Influence Processes Among Urban Youth, Kelly E. Oconnor

Theses and Dissertations

Having friends who engage in problem behavior (i.e., aggression, substance use, delinquency) has consistently been linked to adolescents’ own engagement in problem behavior. There are, however, several key gaps in the literature on peer influence. Few studies have considered the influence of friends’ prosocial behavior and there has been limited research to identify promotive factors that influence urban youths’ affiliation with peers who engage in problem and prosocial behavior across early adolescence, a time of heightened susceptibility to peer influence. The purpose of this study was to identify modifiable promotive factors that reduce adolescents’ problem behavior by decreasing exposure to …

Alcohol Use Subgroups Among Rural Middle School Students: The Impact Of Community Violence Exposure, Courtney B. Dunn

Theses and Dissertations

A substantial portion of early adolescents initiate alcohol use. This represents a significant public health concern due to its association with a variety of adverse consequences. Although person-centered analytic approaches such as latent class analysis have been used to describe heterogeneity in adolescents’ alcohol use, most prior studies have focused on high school or older samples. This may obscure patterns of alcohol use that emerge during early adolescence. The current study identified and described subgroups of adolescents based on their alcohol use in a racially diverse sample of rural middle school students. Because research and theory indicate that exposure to …

Identification Of Four Residues Within The Tm4 Of The 5-Ht2a Receptor Necessary For 5-Ht2a·Mglu2 Heteromerization, John Mcginn

Theses and Dissertations

While the etiology is unknown, serotonin and glutamate G protein-coupled receptors (GPCR) neurotransmission dysfunctionality is characteristic of schizophrenia. Previous findings demonstrated that the serotonin 5-hydroxytryptamine 2A (5-HT_2A) receptor and the metabotropic glutamate 2 (mGlu2) receptor assemble into a heteromeric complex; however, little is known of the complete structural interface of the heteromer. Through a mutational-based approach, previous research identified Transmembrane domain 4 (TM4) as being responsible for mediating heteromerization in mGlu2 before determining the particular amino acids responsible for the interface. A similar technique was used in this investigation to determine which component of 5-HT_2A is responsible …

Interclass Gpcr Heteromerization Affects Localization And Trafficking, Rudy Toneatti

Theses and Dissertations

Class A serotonin (5-hydroxytryptamine) 2A (5-HT_2AR) and class C metabotropic glutamate 2 receptors (mGluR2) are seven transmembrane receptors (7TMRs or G protein-coupled receptors – GPCRs) involved in multiple neuropsychiatric disorders including schizophrenia. Previous findings from our laboratory reported that 5-HT_2AR and mGluR2 are dysregulated in the prefrontal cortex of patients suffering from this psychiatric condition, although 5-HT_2AR’s expression was recovered in antipsychotic-medicated patients. Genome-wide association studies on schizophrenia reported that endosomal trafficking that regulates cell surface abundance of another 7TMR implicated in this disease (dopamine D2 receptor) can be altered. Ligand-activated receptors, including the …

The Contribution Of African American Parents’ Stem Racial Socialization And Support To Adolescent Academic Outcomes, Rachel J. Davis

Theses and Dissertations

Historically, African Americans have experienced various inequalities in education that have long contributed to overall educational attainment gaps within the African American community (St. Mary, Calhoun, Tejada, & Jenson, 2018). Thus, African American parents are tasked with instilling messages of racial pride into their children and providing educational support that serve as protective factors against racial discrimination in education (Koch, Lundh, & Harris, 2019). Theoretical frameworks provide a basis of understanding how parent socialization contributes to African American educational outcomes, specifically noting the role of parents’ beliefs and values in dictating mechanisms of value transfer (e.g., buying toys or learning …

The Cb1 Receptor Positive Allosteric Modulator, Zcz011, Attenuates Naloxone-Precipitated Withdrawal Signs In Oxycodone-Dependent Mice And Inhibits Small Intestinal Transit In Mice, Julien Dodu

Theses and Dissertations

The endogenous cannabinoid system tightly regulates a myriad of physiological and pathophysiological functions. Effects of cannabinoids in ameliorating opioid withdrawal signs has been known for decades. Naloxone precipitates several withdrawal signs (e.g., diarrhea, weight loss, jumps, paw flutters, and head shakes) in opioid dependent rodents. ∆⁹-tetrahydrocannabinol (THC) has been shown to ameliorate opioid withdrawal in mice through the activation of cannabinoid type-1 (CB₁) receptors. Inhibition of the endocannabinoid degradative enzymes also attenuates these withdrawal signs (i.e., diarrhea, weight loss, jumps, paw flutters, and head shakes) in opioid-dependent mice. Specifically, inhibition of fatty acid amide hydrolase (FAAH), …

Sickle Cell Disease Associated Lipid Changes And Their Relevance Towards The Disease Pathogenesis And Lipid Biomarkers And Embryo Quality In In Vitro Fertilization; Pregnancy Success Differentially Expressed By Body Weight, Suad Alshammari

Theses and Dissertations

Abstract

Sickle cell disease (SCD) is a group of genetic disorder that occurs due to genetic mutation of a beta-globin gene that lead to production of pathogenic hemoglobin S (HB S). Genotypes of SCD include Hb SS (sickle cell anemia) which is the most common and severe form of SCD affects about 20 to 25 million people worldwide, HbSC, Hb Sβ+- thalassemia, and Hb Sβ0-thalassemia. SCD is characterized by multiorgan complications that, in turn, affect lipids composition. During hypoxia a sequence of changes will take place such as HbS polymerization, erythrocyte rigidity and stickiness, and oxidative stress. The combination of …

Behavioral And Quantitative Electroencephalogram Alterations During The Whisker Nuisance Task Following Mild Traumatic Brain Injury In Mice, David Wildman

Theses and Dissertations

Mild traumatic brain injury (mild TBI) has been shown to cause an array of symptoms in individuals lasting up to several years. Several publications have lead researchers to believe that parvalbumin axotomy and its associated changes with gamma oscillations may be the driving force for these symptoms. Several publications have demonstrated alterations in both resting gamma and evoked gamma by way of parvalbumin dysfunction. Our research analyzed resting and evoked gamma obtained by electroencephalograms (EEG) in nine mild TBI mice and six SHAM mice by utilizing a behavioral test known as the Whisker Nuisance Task (WNT). The central fluid percussion …

The Importance Of Connection: Contributions Of Relationships With Fathers And Connections To School To Delinquent Behavior And Positive Youth Development, Colleen S. Walsh

Theses and Dissertations

Risk-taking and boundary pushing are hallmarks of adolescent behavior, making the identification of promotive and protective factors related to both delinquent behavior and positive adolescent functioning essential. Previous studies have provided compelling evidence that suggests aspects of familial relationships may successfully attenuate delinquent behavior and support positive functioning outcomes. Despite these findings, the father-adolescent relationship is understudied in association with these outcomes. The current study examined relations between adolescents’ perception of school connectedness and father-adolescent relationship quality and delinquent behavior and positive adolescent functioning outcomes. This study used data collected when youth were nine and fifteen years old from the …

Associations Between Social Determinants Of Health And Chlamydia Infections Among Georgia Counties, Bre'auna K. Beasley

Theses and Dissertations

Chlamydia is a growing public health concern that disproportionately impacts southern states. While social determinants of health are not direct causes of chlamydia infections, studies have found that these determinants do influence infections by creating environments that promote or hinder health seeking behaviors, as well as exposure to risk factors. Guided by the Social Ecological Model of Public Health and the Healthy People 2030 Social Determinants of Health Conceptual Framework, this dissertation study aimed to examine the associations between social determinants of health and chlamydia infections among Georgia counties. This study employed a correlational research design. Aggregate-level secondary data for …

Deep Learning Assisted Intelligent Visual And Vehicle Tracking Systems, Liang Xu

Theses and Dissertations

Sensor fusion and tracking is the ability to bring together measurements from multiple sensors of the current and past time to estimate the current state of a system. The resulting state estimate is more accurate compared with the direct sensor measurement because it balances between the state prediction based on the assumed motion model and the noisy sensor measurement. Systems can then use the information provided by the sensor fusion and tracking process to support more-intelligent actions and achieve autonomy in a system like an autonomous vehicle. In the past, widely used sensor data are structured, which can be directly …

Development And Evaluation Of A Combinatorial Rt-Qpcr Multiplex For Forensic Body Fluid Identification, Carolyn A. Lewis

Theses and Dissertations

Body fluid identification is essential in the forensic biology workflow that assists DNA analysts in determining where to collect DNA evidence. Current presumptive tests lack the sensitivity and specificity molecular techniques can achieve; therefore, molecular methods, such as microRNA and microbial signatures, have been extensively researched in the forensic community. Limitations of each method suggest combining molecular markers to increase discrimination efficiency of multiple body fluids from a single assay. While microbial signatures have been successful in identifying fluids with high bacterial abundances, microRNAs have shown promise in fluids with low microbial abundance. A disadvantage of RNA analysis in forensic …

Functional Limitations And Well-Being Throughout The Adult Lifespan: The Moderating Role Of Sleep, Claire M. Williams

Theses and Dissertations

Functional limitations represent individuals’ difficulty with completing essential activities of daily living, such as sitting, stooping, and walking. Though functional limitations have been linked to lower well-being outcomes, less is known about potential protective factors for well-being in the experience of functional limitations. The present study used archival data from the MIDUS Refresher study to evaluate how sleep and salient aspects of identity may alter the association between the experience of functional limitations and well-being. In particular, this study had two central aims: to examine the associations between functional limitations, life satisfaction, and affect and detect how aspects of identity …

Microrna In The Mammalian Growth Plate: Matrix Vesicles And 1Α,25-Dihydroxyvitamin D3, Niels C. Asmussen

Theses and Dissertations

Growth plate chondrocytes are the driving force of long bone elongation and they accomplish this vital task, in part, by producing, remodeling, and finally mineralizing the cartilage tissue that makes up the growth plate. This mineralized tissue is turned over again as bone forming cells invade and began the process of turning mineralized cartilage into bone. Chondrocytes undergo a distinct series of observable phases as they move through this process transitioning from a stage of proliferation to one of hypertrophy and finally capillary invasion. Chondrocytes produce matrix vesicles (MVs) that they release into the growth plate and that attach to …

Live Cell Biomass Tracking For Basic, Translational, And Clinical Research, Graeme Murray

Theses and Dissertations

Single cell mass is tightly regulated throughout generations and the cell cycle, making it an important marker of cell health. Abnormal changes in cell size can be the first indication of dysfunction in response to environmental stimuli such as cytotoxic drugs. Described here is the further development of high-speed live cell interferometry (HSLCI) to concurrently measure the changes in single cell mass of thousands of cells over time. Critically, the high-throughput nature of HSLCI provides realistic pictures of tumor heterogeneity. This throughput enabled HSLCI to correctly predict in vivo carboplatin sensitivity of three triple negative breast cancer patient derived xenografts, …

Prolactin Drives A Dynamic Stat5a/Hdac6/Hmgn2 Cis-Regulatory Landscape Exploitable In Er+ Breast Cancer, Justin M. Craig

Theses and Dissertations

The hormone prolactin has been implicated in breast cancer pathogenesis and regulates chromatin engagement by the transcription factor, STAT5A. STAT5A is known to inducibly bind promoters and cis-regulatory elements genome-wide, though the mechanisms by which it exerts specificity and regulation of target gene expression remain enigmatic. We previously identified HDAC6 and HMGN2 as cofactors that facilitate prolactin induced, STAT5A mediated gene expression. Here, multi-condition STAT5A, HDAC6, and HMGN2 ChIP-seq with parallel condition RNA-seq are utilized to reveal the cis-regulatory landscape and cofactor dynamics underlying prolactin stimulated gene expression in breast cancer. We find that prolactin regulated genes are …

Bayesian Experimental Design For Bayesian Hierarchical Models With Differential Equations For Ecological Applications, Rebecca Atanga

Theses and Dissertations

Ecologists are interested in the composition of species in various ecosystems. Studying population dynamics can assist environmental managers in making better decisions for the environment. Traditionally, the sampling of species has been recorded on a regular time frequency. However, sampling can be an expensive process due to financial and physical constraints. In some cases the environments are threatening, and ecologists prefer to limit their time collecting data in the field. Rather than convenience sampling, a statistical approach is introduced to improve data collection methods for ecologists by studying the dynamics associated with populations of interest. Population models including the logistic …

First-Year Retention At Virginia Commonwealth University: Understanding Student Departure And The Potential Impact Of Academic Advising, Ben Plache

Theses and Dissertations

This dissertation examines first-year enrollment at Virginia Commonwealth University to determine what factors are associated with an increased likelihood of a student not being retained, and for which of these factors there is evidence that academic advising is an effective intervention. A survey of common retention models identified six factors associated with retention likelihood: student background prior to enrollment (“pre-enrollment factors”), financial support, institutional support, institutional performance, institutional engagement, and student intention. Prior research has shown that academic advising is an effective intervention for two of these factors: institutional performance and institutional support.

The significance of these factors was tested …