Life Sciences Commons^™

Evolution Of Antagonistic Relationships In Proteins: A Case Study Of Radialis- And Diviricata-Like Genes, Ao Gao

Theses and Dissertations

The antagonistic relationship of proteins describes the opponent interactions that result in one protein suppressing the function of another. Developmental genetic studies of Antirrhinum majus demonstrated that two transcription factors from the MYB gene family, RAD and DIV, interact through antagonism to regulate floral dorsoventral asymmetry. Interestingly, similar antagonistic interactions were found among proteins of FSM1 (RAD-like), MYBI (DIV-like), and DRIF in Solanum lycopersicum, which is involved in fruit development. Here, we report on the homology of these antagonistic MYB proteins based on reconstruction of the phylogeny of I-box-like and R-R-type clades, where RAD- and DIV-like belong, …

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 …

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 …

Taf2: A Potential Oncogene For Hepatocellular Carcinoma, Saranya Chidambaranathan Reghupaty

Theses and Dissertations

Astrocyte Elevated Gene 1 (AEG1) is an oncogene for hepatocellular carcinoma (HCC). Its role in HCC pathogenesis has been well studied. A pan cancer analysis of gene expression in multiple databases identified TATA-box binding protein associated factor 2 (TAF2) as the gene that is most frequently co-expressed with AEG1. TAF2 is a protein that is involved in transcription of genes by RNA polymerase II. It is a factor that is dispensable for basal transcription but, required for activated transcription. It has also been shown to be involved in regulating cyclin levels and hence cell cycle progression. Bioinformatic analysis on data …

A Systems Biology Approach For Predicting Essential Genes And Deciphering Their Dynamics Under Stress In Streptococcus Sanguinis, Fadi El-Rami

Theses and Dissertations

Infectious diseases are the top leading cause of death worldwide. Identifying essential genes, genes indispensable for survival, has been proven indispensable in defining new therapeutic targets against pathogens, major elements of the minimal set genome to be harnessed in synthetic biology, and determinants of evolutionary relationships of phylogenetically distant species. Thus, essentiality studies promise valuable revenues that can decipher much of biological complexities.

Taking advantage of the available microbial sequences and the essentiality studies conducted in various microbial models, we proposed a framework for the prediction of essential genes based on our experimentally verified knowledge of the pathways involved in …

Structural And Functional Alterations In Neocortical Circuits After Mild Traumatic Brain Injury, Michal Vascak

Theses and Dissertations

National concern over traumatic brain injury (TBI) is growing rapidly. Recent focus is on mild TBI (mTBI), which is the most prevalent injury level in both civilian and military demographics. A preeminent sequelae of mTBI is cognitive network disruption. Advanced neuroimaging of mTBI victims supports this premise, revealing alterations in activation and structure-function of excitatory and inhibitory neuronal systems, which are essential for network processing. However, clinical neuroimaging cannot resolve the cellular and molecular substrates underlying such changes. Therefore, to understand the full scope of mTBI-induced alterations it is necessary to study cortical networks on the microscopic level, where neurons …

Relb Acts As A Molecular Switch To Drive Chronic Inflammation In Glioblastoma Multiforme (Gbm)., Michael R. Waters

Theses and Dissertations

Inflammation is a homeostatic response to tissue injury or infection, which is normally short- lived and quickly resolves to limit tissue damage. In contrast, chronic inflammation has been linked to a variety of human diseases, including cancers such as glioblastoma multiforme (GBM). GBMs are very aggressive tumors with very low patient survival rates, which have not improved in several decades. GBM tumors are characterized by necrosis and profound inflammation; with cytokines secreted by both GBM cells and the tumor microenvironment. The mechanisms by which chronic inflammation develops and persists in GBM regardless of multiple anti-inflammatory feedback loops remain elusive. This …

Expression Of Matrix Metalloproteinases In Naegleria Fowleri And Their Role In Degradation Of The Extracellular Matrix, Charlton Lam

Theses and Dissertations

Naegleria fowleri is a free-living amoeba found in freshwater lakes and ponds that is the causative agent of Primary Amoebic Meningoencephalitis (PAM). Matrix metalloproteinases (MMPs) have been described in protozoa, such as Plasmodium falciparum, Trypanosoma brucei, and Balamuthia mandrillaris, and have been linked to their increased motility and invasive capability by degrading components of the extracellular matrix (ECM). In addition, MMPs are often upregulated in tumorigenic cells and have been attributed as responsible for the metastasis of certain cancers. In the present study, in vitro experiments indicated that MMPs are linked functionally to the ECM degradation process. …

Moderate Severity Disturbance Has Similar Effects On The Production Of Three Forests Nested Within The Upper Great Lakes Landscape, Benjamin Tai Sagara

Theses and Dissertations

Moderate severity disturbances, which only kill a subset of canopy trees (e.g., via insects, pathogens, and windthrow), are increasingly widespread, and can alter forest structure and production. Whether moderate severity disturbance similarly affects the net primary production (NPP) of different forest stands within inherently heterogeneous landscapes, however, is unknown. We experimentally disturbed three, 2-ha stands varying in forest structure and primary production, reducing stand basal area 38 to 66 % by stem girdling all mature early successional aspen (Populus) and birch (Betula). For nearly a decade, we examined how the forest stands restructured and recovered, and linked post-recovery physical and …

The Role Of Human Msc Derived Exosomes In The Treatment Of Periodontal Diseases, Sonia S. Talegaonkar

Theses and Dissertations

Periodontal disease affects 47% of Americans over 30. Characterized by microbial dysbiosis and unregulated inflammation, severe periodontitis causes degradation of bone and soft tissue around teeth. Current treatments have limited regenerative outcomes and frequent reinfection by harmful bacteria. Human mesenchymal stem cells (hMSCs) have been shown to promote wound healing and tissue regeneration. Many therapeutic benefits of hMSCs are due to their secretome products, like exosomes. Our long-term goal is to develop periodontal therapies with hMSC exosomes. The objectives of this study were to determine the effect of hMSC-derived exosomes on cellular activity of hMSCs and investigate whether hMSC exosome …

Study Of Molecular Interactions Of Glycosaminoglycans And Glycosaminoglycan Mimetics With Their Protein Targets, Daniel K. Afosah

Theses and Dissertations

Glycosaminoglycans (GAGs) are complex linear chain carbohydrate molecules found on virtually all animal cell surfaces. Owing to their negatively charged nature, GAGs interact with a number of different proteins. Thus, although they have great potential as therapeutic agents, their apparent promiscuous interactions increase their side effect risk. GAG mimetics, including GAG oligosaccharides and non-saccharide GAG mimetics (NSGMs) are viable approaches to address this. This work discusses sulfated benzofuran thrombin inhibitors with submaximal protease inhibition, sulfated diflavonoid inhibitors of plasmin and GAG oligosaccharides with selectivity for human neutrophil elastase (HNE).

Anticoagulants are very important for the treatment of thrombotic diseases. The …

The Role Of Klf1 In Regulating Γ-Globin Gene Repressors, Anna P. Kovilakath

Theses and Dissertations

Sickle cell disease and β-thalassemia affect millions of people worldwide. γ-globin is the fetal counterpart to the adult β-globin. Research has shown that affected patients with higher than normal γ-globin show less severe symptoms. Therefore, reversing or preventing the hemoglobin switch from γ- to β- globin is a promising avenue of research for treating these diseases. KLF1 is an erythroid transcription factor involved in hemoglobin switching. Herein, we show that KLF1 directly regulates the γ-globin repressor gene LRF in both the mouse and human systems. KLF1 may also directly activate γ-globin expression by binding the promoter. In human HUDEP-2 cells, …

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 …

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 …

Pnpase In C. Elegans: Mutagenic Analysis To Complement Knockdown Studies, Danielle K. Seibert

Theses and Dissertations

PNPase is a gene implicated as a potential target for cancer therapy; human mutations also present with deafness, myopathies, and neuropathies. In this study, C. elegans was used to investigate the effect of knocking out PNPase in a whole animal. C. elegans knockdown studies have reported an extended lifespan via an increase in ROS production. Further noted are larger mitochondria and an increase in fzo-1 expression. Knockout animals previously constructed using CRISPR/Cas9 were used for this study. We aimed to confirm these findings validating previous studies. It was discovered that PNPase knockout animals demonstrated a similar lifespan extension that was …

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 …

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 …

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). …

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. …

Integrating Genetics And Neuroimaging To Study Subtypes Of Binge Drinkers, Megan E. Cooke

Theses and Dissertations

Risky alcohol use is a major health concern among college students, with 40.1% reporting binge drinking (5 or more drinks in one occasion) and 14.4% reporting heavy drinking (binge drinking on 5 or more occasions) in the past month. Risky alcohol use is thought to be the result of a complex interplay between genes, biological processes, and other phenotypic characteristics. Understanding this complex relationship is further complicated by known phenotypic heterogeneity in the development of alcohol use. Developmental studies have suggested two pathways to risky alcohol use, characterized by externalizing and internalizing characteristics, respectively. However, the underlying biological processes that …

The Effects Of The Hiv-1 Tat Protein And Morphine On The Structure And Function Of The Hippocampal Ca1 Subfield, William D. Marks

Theses and Dissertations

HIV is capable of causing a set of neurological diseases collectively termed the HIV Associated Neurocognitive Disorders (HAND). Worsening pathology is observed in HIV+ individuals who use opioid drugs. Memory problems are often observed in HAND, implicating HIV pathology in the hippocampus, and are also known to be exacerbated by morphine use. HIV-1 Tat was demonstrated to reduce spatial memory performance in multiple tasks, and individual subsets of CA1 interneurons were found to be selectively vulnerable to the effects of Tat, notably nNOS+/NPY- interneurons of the pyramidal layer and stratum radiatum, PV+ neurons of the pyramidal layer, and SST+ neurons …

Modulating The Innate Immune Response To Electrospun Scaffolds And Polymer Degradative Byproducts, Daniel Abebayehu

Theses and Dissertations

Implanted biomaterials often induce inflammation that frequently leads to the foreign body response, fibrosis, and the failure of the implant. Thus, it is important to evaluate how cells interact with materials to promote a more regenerative response. It is critical to determine how to modulate the response of tissue resident innate immune cells, as they are among the first cells to interact with implanted materials. Among tissue resident innate immune cells are mast cells, which are inflammatory sentinels that degranulate and orchestrate the fate of other cell populations, such as monocytes/macrophages and lymphocytes. Mast cells have also been reported to …

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 …

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 …