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Investigation Of Anticoagulation Properties Of Sulfated Glycosaminoglycan Mimetics, Elsamani I. Abdelfadiel

Theses and Dissertations

Abstract

INVESTEGATION OF ANTICOAGULATION PROPERTIES OF SULFATED

GLYCOSAMINOGLYCAN MIMETICS

By Elsamani Ismail Abdelfadiel, MS

A thesis submitted in partial fulfillment of the requirements for the degree of Master of

Science at Virginia Commonwealth University

Virginia Commonwealth University, 2017.

Supervisor: Umesh R Desai

Professor, Department of Medicinal Chemistry

The existence of thrombosis in numerous pathophysiological situations formed a vast necessity for anticoagulation therapy. Thrombin and factor Xa are the only two factors of the entire coagulation cascade that have been major targets for regulation of clotting via the direct and indirect mechanism of inhibition. Our recent discovery of sulfated non-saccharide glycosaminoglycan …

Mast Cell Activation By Diverse Stimuli Can Be Suppressed By Steroid Therapy And Targeting The Fyn-Stat5b Cascade, Anuya Paranjape

Theses and Dissertations

Mast cells are critical effectors of allergic disease that can be activated by numerous stimuli. We have examined mast cell control by the inflammatory cytokine, IL-33, as well as IgG. In the first study reported here, we found that the synthetic glucocorticoid, dexamethasone, potently and rapidly suppressed IL-33-induced cytokine production from murine bone marrow–derived and peritoneal mast cells, as well as human mast cells. Dexamethasone also antagonized IL-33-mediated enhancement of IgE-induced cytokine production and migration. Although dexamethasone had no effect on IL-33-induced phosphorylation of MAP kinases or NFκB p65 subunit, it antagonized AP-1 and NFκB-mediated transcriptional activity. Finally, intraperitoneal administration …

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 …

Misophonia: An Investigation Of The Lesser-Known Decreased Sound Tolerance Condition, Shannon Cusack

Theses and Dissertations

Misophonia is a decreased sound tolerance condition (DST) that is not yet well-established in the literature. However, the existing research on misophonia shows that it is occurring at substantial levels in the population. The majority of the existing literature has focused on the clinical correlates of misophonia. Although the correlates have been investigated, there is no accepted mechanism behind misophonia etiology or maintenance. The present study examined three hypotheses in order to start to identify potential mechanisms behind misophonia: how emotional predilections are related to the emotional response, how obsessive-compulsive disorder (OCD) symptoms and misophonia are related, and the possibility …

Managing Sociality Of A Captive Female Bornean Orangutan From Breeding To Post-Partum At The Smithsonian's National Zoo, Marie Vergamini

Theses and Dissertations

The Association of Zoos and Aquariums’ Orangutan Species Survival Plan® aims to maintain 100 Bornean orangutans (Pongo pygmaeus) in captivity. Because investment in breeding these lineages is high, properly managing sociality of potential mothers is essential. This study assessed how behaviors of a captive breeding female at the Smithsonian’s National Zoo changed from pre-gestation through the offspring’s sixth month of age to improve breeding recommendations.

The infant Bornean orangutan was born September 2016. Results indicate that during breeding, the mother socialized most with two adult females. During pregnancy, the pregnant female socialized in less energy-consuming ways, i.e. grooming. …

The Status Of Snapping Turtles (Chelydra Serpentina) In Virginia: Population Viability, Demography, Regulatory Analysis, And Conservation, Benjamin C. Colteaux

Theses and Dissertations

Snapping turtles (Chelydra serpentina) are being harvested in unprecedented numbers in the United States (US) to meet the needs of international markets. Over three million live snapping turtles from farm and wild caught stock were exported from the US to Asia in 2012-14 alone. In the Commonwealth of Virginia, records indicate that 29,860 snapping turtles were commercially harvested between 2000 and 2015. Size limits are often used to regulate harvest pressure in snapping turtles and other game species. I analyzed the historic harvest of eleven US states to test the efficacy of minimum-size limit regulations at reducing commercial …

"C-Terminal Binding Protein 2" An Emerging Oncogene In Colon And Pancreatic Cancers, Ayesha Chawla

Theses and Dissertations

The C terminal binding proteins (CtBP) 1 and 2 are a family of transcriptional co-repressors overexpressed in a variety of cancers, and are frequently associated with poor prognosis and chemoresistance. CtBP has also been characterized in cell culture models as drivers of migration/invasion and epithelial-mesenchymal transition. CtBP mediates its transcriptional corepressor activity via its dehydrogenase domain, and inhibition of this domain interferes with CtBP oncogenic functions. The role of CtBP in APC mutant neoplasia remains obscure even though APC is responsible for degradation of both β-catenin and CtBP in suppressing colorectal tumorigenesis. Our prior work demonstrated that CtBP proteins can …

Electrospraying Extracellular Matrix To Form Nanoparticles, Patrick Link

Theses and Dissertations

Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of death worldwide. Alveolar wall destruction is a significant contributor to COPD. Inflammatory macrophages are a major source of the Extracellular Matrix (ECM) proteolysis. ECM breakdown causes air to get trapped in the alveoli, obstructing airflow. One step in curing COPD may be to convert inflammatory to pro-regenerative macrophages. Recently, decellularized ECM scaffolds have shown the ability to induce a pro-regenerative phenotype.

Yet these scaffolds are incapable for reaching the alveolar region of the lungs. To reach the alveolar region particles need a diameter of 1-5 μm or smaller than 300 …

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 …

The Effect Of Saha On The Expression Of Genes In Wild Type And Hdac2 Knockout Mouse Models And Its Potential Use As Treatment For Schizophrenia, Maryum K. Ijaz

Theses and Dissertations

The symptoms of schizophrenia have been categorized into three subsets including positive, negative, and cognitive symptoms. Although atypical antipsychotic use has shown promising reduction in positive and negative symptoms of schizophrenia, such as hallucination, delusions and flat affect, the cognitive subset of symptoms remains and has an adverse impact on those affected. Chronic treatment with the atypical/secondary antipsychotic clozapine is one example that has ameliorated hallucinations and delusions but results in cognitive memory deficits. When chronically given in conjunction with the HDAC inhibitor, SAHA, the cognitive memory deficits of mouse models decline. HDAC2KO mice were bred and used in chronic …

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 …

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. …

Come Fly With Me: Using Amixicile To Target Periodontal Pathogens And Elucidating The Innate Immune Response In Drosophila Melanogaster, Kathryn Sinclair

Theses and Dissertations

Periodontal diseases (PD) affect 46% of American adults over age 30. These diseases cause symptoms including bleeding and swelling of the gums, bone resorption, and tooth loss, that affect quality of life and have a high economic burden. Periodontal diseases are caused by an imbalance in the oral microbiome, from a healthy state that contains anti-inflammatory commensals like Streptococcus gordonii and mitis, to a diseased state that has pro-inflammatory anaerobic pathogens including Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum, and Tannerella forsythia. The latter initiate disease progression in the oral cavity. However, it’s the host immune …

Big Data Visualization Platform For Mixed Reality, Aliakbar Panahi

Theses and Dissertations

The visualization of data helps to provide faster and deeper insight into the data. In this work, a system for visualizing and analyzing big data in an interactive mixed reality environment is proposed. Such a system can be used for representing different types of data such as temporal, geospatial, network graph, and high dimensional. Also, an implementation of this system for four different data types are created. The data types include network data, volumetric data, high dimensional, and spectral data for different mixed reality devices such as Microsoft HoloLens, Oculus Rift, Samsung Gear VR, and Android ARCore were created. It …

Synergy: Game Design + Qur'an Memorization, Sultana Jesmine Moulana

Theses and Dissertations

The rise of digital technology has transformed nearly every part of our daily lives, including the way we learn and memorize. Such transformations raise interesting questions for one of the most long-standing and demanding memorization tasks in the world: the memorization of the Islamic holy book, The Qur’an. For Muslims, The Qur’an is a timeless, sacred text, cradling within its covers many profound images, stories, and parables. Despite rigorous research in the fields of game design and memorization techniques, very little work has been done in combining these two areas of research to create a game-based memorization experience of The …

Ca2+/Calmodulin-Dependent Protein Kinase Type Ii (Camk-Ii) Is Required For Hematopoietic Stem Cell Specification, Camden E. Kurtz

Theses and Dissertations

Ca2+/Calmodulin-dependent protein kinase type II (CaMK-II) is a Serine/Threonine protein kinase that is activated by Ca2+ and Calmodulin to phosphorylate substrates involved in myriad developmental processes. This project implicates CaMK-II in specification of HSCs, and zebrafish provide an ideal embryonic model to study hematopoiesis. Zebrafish genetic manipulation was achieved through: incubation in chemical inhibitors; injection of notochord-targed WT and DN CaMK-II constructs with Transposase; and injection of camk2g1 translation-blocking morpholino antisense oligonucleotide (MO). Whole-mount in situ hybridization (WISH) and immunolocalization on zebrafish embryos allowed visualization of key HSC markers and pathway components that implicated CaMK-II in the specification of HSCs. …

Role Of Mir-155 And Mir-146a In Mast Cell Function, Amina Abdul Qayum

Theses and Dissertations

Mast cells are resident immune cells abundantly found in the tissue at the host-environment interface, where they play a critical role in inflammatory allergic responses. Mast cell responses may be regulated by the cytokine milieu at the site of inflammation. Recent studies have revealed microRNAs to be important in altering cytokine signaling in immune cells. Here, we demonstrate for the first time that IL-10 and IL-33 induce miR-155 and miR-146a, respectively, to alter mast cell functions. We report that IL-10 enhanced IgE induced activation of mast cells. IL-10 effects are dependent on Stat3 activation, which elicits miR-155 expression, resulting in …

Discovery And Characterization Of Bile Acid And Steroid Metabolism Pathways In Gut-Associated Microbes, Spencer Harris

Theses and Dissertations

The human gut microbiome is a complex microbial ecosystem residing in the lumen of our gastrointestinal tract. The type and amounts of microbes present in this ecosystem varies based on numerous factors, including host genetics, diet, and environmental factors. The human gut microbiome plays an important role in normal host physiological functions, including providing energy to colonocytes in the form of short-chain fatty acids. However, gut microbial metabolites have also been associated with numerous disease states. Current tools for analyzing the gut microbiome, such as high-throughput sequencing techniques, are limited in their predictive ability. Additionally, “-omic” approaches of studying the …

'The Writing Writes Itself': Deleuzian Desire And The Creative Writing Mfa Degree, Ginger Walker

Theses and Dissertations

This post-qualitative inquiry project investigated subjectivity (sense of self) among graduates of creative writing Master of Fine Arts (MFA) programs. The project asked how subjectivity is involved in the creative writing process and how that process fuels further writing after a creative piece (such as the MFA thesis) is completed. A post-qualitative, thinking-with-theory approach was used to explore the role of subjectivity among four anonymous graduates of creative writing MFA programs who provided writing samples describing their creative writing processes. Following the thinking-with-theory approach, the data were analyzed using Deleuze and Guattari’s theory of productive desire. Study findings are presented …

Hub Proteins, Paralogs, And Unknown Proteins In Bacterial Interaction Networks, Neha Sakhawalkar

Theses and Dissertations

Proteins are the functional units of cells. However, a major portion of the proteome does not have a known functional annotation. This dissertation explores protein -protein interactions, involving these uncharacterized or unknown function proteins. Initially, protein – protein interactions were tested and analyzed for paralogous proteins in Escherichia coli. To expand this concept further and to get an overview, protein – protein interactions were analyzed using ‘comparative interactomics’ for four pathogenic bacterial species including Escherichia coli, Yersinia pestis, Vibrio cholerae and Staphylococcus aureus. This approach was used to study unknown function protein pairs as well as to …

Good As We Know It: Goodness In Design Discourse Since 1870, Garreth C. Blackwell

Theses and Dissertations

This dissertation examines the ways in which design and design practitioners have defined value in the design discourse through the vocabulary and concept of goodness since 1870. These definitions of value have been central to design discourse both past and present and deal with the impact and purpose of design work as well as its role in the creation of the approaching future. Since before the coalescence of graphic design as a separate field of design, these questions have been tied to the form, function or social impact of the objects created by designers. Despite the prevalence of this line …

Tumor-Intrinsic Inflammatory Pathways Associated With Tumor Dormancy And Recurrence, Savannah E. Butler

Theses and Dissertations

The successful treatment of breast cancer is limited due to a fraction of tumor cells escaping drug-treatment by entering a dormant state, only to relapse years or decades later at distant sites. Host-driven chronic inflammatory cells such as M2 macrophages play an important role in tumorigenesis, but the role of tumor-intrinsic inflammatory signaling involved in tumor dormancy and recurrence is unknown. We sought to determine the role of tumor-intrinsic inflammatory pathways in mouse mammary carcinoma cells (MMC) treated with Adriamycin (ADR), a clinically relevant chemotherapeutic drug. We found that ADR-induced dormant tumor cells autonomously produced pro-inflammatory cytokines, in vitro. …

The Influence Of Genetic And Environmental Factors On Quit Attempt In Adolescent And Young Adult Twins, Gladys Langi

Theses and Dissertations

The purpose of this study was to examine the genetic and environmental influences on lifetime quit attempt in three US adolescent and young adult twin samples (N total = 6,322). The study utilized a common-contingent-causal (CCC) model to estimate these factors for lifetime quit attempts, after accounting for the factors for lifetime cigarette use and cigarettes per day. The study also examined age and sex differences, as well as the degree of relationship between these smoking phenotypes. The results demonstrated significant genetic influences for lifetime quit attempts in adolescents and young adults. No sex differences were observed for the contributions …

Profiling Precursor Lipids For Specialized Pro-Resolution Molecules In Platelet-Rich Fibrin Following Fish Oil And Aspirin Intake, Danielle M. Mccormack

Theses and Dissertations

Background: Current research has demonstrated that aspirin and fish oil (EFA) increase plasma levels of specialized pro-resolution molecules (SPMs). This study investigates their effects on SPM precursor pools in platelet rich fibrin (PRF). Methods: Twenty healthy volunteers were randomly assigned to take aspirin; EFA or aspirin and EFA. Four hours later, SPM precursor levels were quantified using combined Liquid Chromatography tandem mass spectrometry. The differences between the groups: Aspirin (yes or no), EFA (yes or no), were analyzed by ANCOVA, testing for group differences after covarying out the baseline value. Results: There were 4 significant interactions, 1 with an aspirin …

Profiling Precursor Lipids For Specialized Pro-Resolution Molecules In Platelet-Rich Plasma Following Fish Oil And Aspirin Intake, Lisa A. Turner

Theses and Dissertations

Background: Unfavorable outcomes following periodontal surgeries can be attributed to impaired resolution mechanisms likely due to decreased levels of specialized pro-resolution molecules (SPM). The current study investigates if SPM substrate pools in platelet-rich plasma preparations (PRP) can be increased by essential fatty acid (EFA) and / or aspirin supplementation. Methods: Nineteen healthy volunteers were randomly assigned to take i) aspirin; ii) EFA; iii) aspirin and EFA. Four hours after intake, the lipid precursor pools in PRP were quantified using combined Liquid Chromatography tandem mass spectrometry (LC-MS/MS) and the data statistically analyzed using ANCOVA. Results: Of the 77 metabolites screened, only …

The Role Of The Nucleosome Remodeling Factor Nurf In Inhibiting T And Natural Killer Cell Mediated Antitumor Immunity By Suppressing Tumor Antigenicity And Natural Cytotoxicity Receptor Co-Ligands, Kimberly Mayes

Theses and Dissertations

Tumor immunoediting is a dynamic process in which the immune response attacks tumor cells by detecting danger signals and tumor antigens. In order to survive, tumor cells develop mechanisms to avoid detection or destruction by the immune system. To counteract this, several strategies are being developed to enhance the antitumor immune response, including the depletion of immunosuppressive cells, enhancing the activation of antitumor immune cells and increasing tumor cell immunogenicity. These therapies have seen limited success individually, however, and it is likely that combination therapy with novel targets will be necessary to see reproducible beneficial responses. Epigenetic modifications are attractive …

Design, Synthesis, And Biological Screening Of Selective Mu Opioid Receptor Ligands As Potential Treatments For Opioid Addiction, Samuel Obeng

Theses and Dissertations

Today, more Americans die each year because of drug overdoses than are killed in motor vehicle accidents. In fact, in 2015, more than 33,000 individuals died due to an overdose of heroin or prescription opioids. Sadly, 40-60 % of patients on current opioid addiction treatment medications relapse. Studies have shown that the addiction/abuse liability of opioids are abolished in mu opioid receptor (MOR) knock-out mice; this indicates that the addiction and abuse liability of opioids are mainly mediated through MOR. Utilizing the “message-address concept”, the our laboratory reported a novel non-peptide, reversible MOR selective ligand 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α (isoquinoline-3-carboxamido)morphinan (NAQ). Molecular modeling …

Diabetes-Induced Expression And Regulation Of Glp-1 Levels By Bile Acid Receptors (Tgr5 & Fxr), Joseph R. Spengler

Theses and Dissertations

Diabetes Mellitus has continued to drastically affect the health of the world and many complications can prove fatal. As long as this metabolic disease persist, research discoveries will need to continue to be made so that patient outcomes and healthcare are dramatically enhanced. In recent years, GLP-1 has been the topic of conversation for diabetes research, due to its promising effects in promoting insulin sensitivity. Furthermore, bile acids and their receptors (TGR5 & FXR) have shown promise in their actions in the regulation of GLP-1, and thus glucose homeostasis. Here we have shown the detection and increased expression of TGR5 …

Walking In Beauty: Responsive And Responsible Health And Healing Among Virginia American Indian People, Amy J. Prorock-Ernest

Theses and Dissertations

Little is systematically known about the collective health and well-being of Virginia American Indian people. This study sought to explore the meaning of health and healing among Virginia American Indian people in the context of a reservation-based, non-federally funded health clinic. Using an emergent approach to qualitative research grounded in a constructivist inquiry paradigm and guided by Indigenous research principles, a total of 24 in-depth, semi-structured interviews were conducted with 17 American Indian service-users of the Clinic. Through an inductive thematic analysis of participant stories, a framework for understanding responsive and responsible health and healing was derived. The framework includes …

Alpha6 Beta2 Subunit Containing Nicotinic Acetylcholine Receptor Contributions To Abuse-Related Effects Of Nicotine And Alcohol, Alexandra M. Stafford

Theses and Dissertations

Pharmacotherapies for tobacco and alcohol cessation are only modestly successful, so it is important to better understand mechanisms underlying their use and abuse. The overarching goal of this research is to assess a6b2 subunit containing nicotinic acetylcholine receptor (a6b2*nAChR; *denotes possible assembly with other subunits) contributions to abuse-related effects of nicotine and alcohol. In the absence of a6b2*nAChR-selective agonists, a6b2*nAChR gain-of-function (a6L9’S) mice provide a tool for selective activation of a6b2*nAChRs. Using the a6L9’S mice together with nicotine doses sub-threshold for stimulation of native nAChRs, these studies tested the hypothesis that activation of a6b2*nAChRs is sufficient to promote neurochemical and …