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Commonwealth Times 2012-02-23

Commonwealth Times, 1969-

No abstract provided.

Commonwealth Times 2012-02-20

Commonwealth Times, 1969-

No abstract provided.

Dynamics Of Substrate Interactions In Trna (M1g37) Methyltransferase: Implications For Drug Discovery, Maria Kiouppis Palesis

Theses and Dissertations

The bacterial enzyme t-RNA (m1G37) methyltransferase (TrmD) is an ideal anti-microbial drug target since it is found in all eubacteria, serves an essential role during protein synthesis, and shares very little sequence or structural homology with its eukaryotic counterpart, Trm5. TrmD, a homodimeric protein, methylates the G37 nucleotide of tRNA using S-adenosyl-L-methionine (SAM) as the methyl donor and thus enables proper codon-anticodon alignment during translation. The two deeply buried binding sites for SAM seen in X-ray crystallography suggest that significant conformational changes must occur for substrate binding and catalytic turnover. Results from molecular dynamics simulations implicate a flexible loop region …

Commonwealth Times 2012-02-06

Commonwealth Times, 1969-

No abstract provided.

Spatial Distribution And Modulation Of Nitric Oxide Synthase In A Hypertensive Rat Model, Andrew Yannaccone

Theses and Dissertations

There are gaps in the fundamental understanding of the expression of nitric oxide synthases (NOS) in the microvasculature. We examined co-localization of NOS1 (nNOS), NOS2 (iNOS) and NOS3 (eNOS) in the spinotrapezius muscle of young adult male Wistar-Kyoto (WKY) and Spontaneously Hypertensive (SHR) rats according to fiber type using immunohistochemistry and brightfield microscopy. Data regarding fiber distribution, population and morphology data were collected. Alkaline phosphatase staining was used to determine capillary density and average number of capillaries around a fiber. Gel electrophoresis and Western blot techniques were used to compare myosin heavy chain (MHC) protein expression with fiber type population …

Commonwealth Times 2012-01-30

Commonwealth Times, 1969-

No abstract provided.

Commonwealth Times 2012-01-23

Commonwealth Times, 1969-

No abstract provided.

Epigenetic Regulation Of Genes Involved In Vascular Dysfunction In Preeclamptic Women, Ahmad Mousa

Theses and Dissertations

DNA methylation is the most recognizable epigenetic mechanism. In general, DNA hypomethylation is associated with increased gene expression whereas DNA hypermethylation is associated with decreased gene expression. To date, little is known about the role of DNA methylation in the pathophysiology of preeclampsia. In this study, we examined the differences in DNA methylation in omental arteries of normal pregnant and preeclamptic women using the high throughput Illumina HumanMethylation27 BeadChip assay. We found 1,685 genes with a significant difference in DNA methylation at a false discovery rate of < 10% with many inflammatory genes having reduced methylation. The thromboxane synthase gene was the most hypomethylated gene in preeclamptic women as compared to normal pregnant women. When we examined the expression of thromboxane synthase in omental arteries of normal pregnant and preeclamptic women we found it to be significantly increased in preeclamptic women. The increased expression was observed in vascular smooth muscle cells, endothelial cells and infiltrating neutrophils. Experimentally induced DNA hypomethylation increased the expression of thromboxane synthase in the neutrophil-like HL-60 cell line, whereas tumor necrosis factor α (TNFα), a neutrophil product, increased its expression in cultured human vascular smooth muscle cells (VSMC). These finding suggest that DNA methylation and release of TNFα by infiltrating neutrophils could contribute to the increased expression of thromboxane synthase in systemic blood vessels of preeclamptic women, contributing to the hypertension and coagulation abnormalities. We also explored the possible contribution of DNA methylation to the altered expression of genes involved in collagen metabolism in preeclampsia. Several matrix metalloproteinase (MMP) genes, including MMP1 and MMP8, were significantly less methylated in preeclamptic women, whereas TIMP and COL genes were either significantly more methylated or had no significant change in their DNA methylation status. Experimentally induced DNA hypomethylation increased the expression of MMP-1, but not TIMP-1 or COL1A1, in cultured VSMCs and increased the expression of MMP-1 and MMP-8 in HL-60 cells. These findings suggest that DNA methylation contributes to the imbalance in genes involved in collagen metabolism in blood vessels of preeclamptic women.

Statistical Methods For Normalization And Analysis Of High-Throughput Genomic Data, Tobias Guennel

Theses and Dissertations

High-throughput genomic datasets obtained from microarray or sequencing studies have revolutionized the field of molecular biology over the last decade. The complexity of these new technologies also poses new challenges to statisticians to separate biological relevant information from technical noise. Two methods are introduced that address important issues with normalization of array comparative genomic hybridization (aCGH) microarrays and the analysis of RNA sequencing (RNA-Seq) studies. Many studies investigating copy number aberrations at the DNA level for cancer and genetic studies use comparative genomic hybridization (CGH) on oligo arrays. However, aCGH data often suffer from low signal to noise ratios resulting …

Commonwealth Times 2012-01-19

Commonwealth Times, 1969-

No abstract provided.

Identification And Quantification Of Protein Carbonylation By Mass Spectrometry, Qingyuan Liu

Theses and Dissertations

Accumulated evidence indicates oxidative stress plays important roles in disease and aging. Under oxidative stress, lipid peroxidation (LPO) leads to reactive carbonyl species (RCS) that can modify a wide range of biomolecules including protein, DNA and carbohydrate. In this dissertation, we investigate the modification of two model proteins, human serum albumin (HSA) and aconitase (ACO), by the LPO-relevant a, b-unsaturated aldehydes, acrolein (ACR) and 4-hydroxy-2-nonenal (HNE). The investigation is focused on the characterization and quantification ACR and HNE addition to the model proteins. A correlation between HNE modification and ACO activity is also determined. These results provide insights into the …

Quantitative Genetic Methods To Dissect Heterogeneity In Complex Traits, T. Bernard Bigdeli

Theses and Dissertations

Etiological models of complex disease are elusive[46, 33, 9], as are consistently replicable findings for major genetic susceptibility loci[54, 14, 15, 24]. Commonly-cited explanations invoke low-frequency genomic variation[41], allelic heterogeneity at susceptibility loci[33, 30], variable etiological trajectories[18, 17], and epistatic effects between multiple loci; these represent among the most methodologically-challenging issues in molecular genetic studies of complex traits. The response has been con- sistently reactionary—hypotheses regarding the relative contributions of known func- tional elements, or emphasizing a greater role of rare variation[46, 33] have undergone periodic revision, driving increasingly collaborative efforts to ascertain greater numbers of participants and which assay …

Resemblance Of Symptoms For Major Depression Assessed At Interview Versus From Hospital Record Review, Ying Chen, Haimin Li, Yihan Li, Dong Xie, Zhiyang Wang, Fuzhong Wang, Yuan Shen, Sulin Ni, Yan Wei, Yanhua Liu, Lanfen Liu, Chengge Gao, Jun Liu, Lijuan Yan, Gang Wang, Keqing Li, Qiang He, Tiehang Liu, Jinbei Zhang, Yan Ren, Qunli Du, Jing Tian, Honghui Chen, Yanfang Luo, Fengzhi Zhang, Guangwei Sun, Chunjie Shan, Xueyi Wang, Yutang Zhang, Xiaoqin Weng, Yunchun Chen, Zhen Kang, Jing Guan, Yiping Chen, Shenxun Shi, Kenneth S. Kendler, Jonathan Flint, Hong Deng

Psychiatry Publications

Background

Diagnostic information for psychiatric research often depends on both clinical interviews and medical records. Although discrepancies between these two sources are well known, there have been few studies into the degree and origins of inconsistencies.

Principal findings

We compared data from structured interviews and medical records on 1,970 Han Chinese women with recurrent DSM-IV major depression (MD). Correlations were high for age at onset of MD (0.93) and number of episodes (0.70), intermediate for family history (+0.62) and duration of longest episode (+0.43) and variable but generally more modest for individual depressive symptoms (mean kappa = 0.32). Four factors …

Comparison Of Statistical Tests For Association Between Rare Variants And Binary Traits, Silviu-Alin Bacanu, Matthew R. Nelson, John C. Whittaker

Psychiatry Publications

Genome-wide association studies have found thousands of common genetic variants associated with a wide variety of diseases and other complex traits. However, a large portion of the predicted genetic contribution to many traits remains unknown. One plausible explanation is that some of the missing variation is due to the effects of rare variants. Nonetheless, the statistical analysis of rare variants is challenging. A commonly used method is to contrast, within the same region (gene), the frequency of minor alleles at rare variants between cases and controls. However, this strategy is most useful under the assumption that the tested variants have …

Network-Assisted Investigation Of Combined Causal Signals From Genome-Wide Association Studies In Schizophrenia, Peilin Jia, Lily Wang, Ayman H. Fanous, Carlos N. Pato, Todd L. Edwards, Zhongming Zhao

Psychiatry Publications

With the recent success of genome-wide association studies (GWAS), a wealth of association data has been accomplished for more than 200 complex diseases/traits, proposing a strong demand for data integration and interpretation. A combinatory analysis of multiple GWAS datasets, or an integrative analysis of GWAS data and other high-throughput data, has been particularly promising. In this study, we proposed an integrative analysis framework of multiple GWAS datasets by overlaying association signals onto the protein-protein interaction network, and demonstrated it using schizophrenia datasets. Building on a dense module search algorithm, we first searched for significantly enriched subnetworks for schizophrenia in each …

Low Dose Nicotine And Antagonism Of Β2 Subunit Containing Nicotinic Acetylcholine Receptors Have Similar Effects On Affective Behavior In Mice, Shawn M. Anderson, Darlene H. Brunzell

Pharmacology and Toxicology Publications

Nicotine leads to both activation and desensitization (inactivation) of nicotinic acetylcholine receptors (nAChRs). This study tested the hypothesis that nicotine and a selective antagonist of β2*nAChRs would have similar effects on affective behavior. Adult C57BL/6J male mice were tested in a conditioned emotional response (CER) assay which evaluates the ability of an aversive stimulus to inhibit goal-directed behavior. Mice lever-pressed for a saccharin reinforcer according to a variable schedule of reinforcement during sessions in which two presentations of a compound light/tone conditioned stimulus (CS) co-terminated with a 0.1 or 0.3 mA, 0.5 s footshock unconditioned stimulus (US). During testing in …

Preclinical Determinants Of Drug Choice Under Concurrent Schedules Of Drug Self-Administration, Matthew L. Banks, S. Stevens Negus

Pharmacology and Toxicology Publications

Drug self-administration procedures have played a critical role in the experimental analysis of psychoactive compounds, such as cocaine, for over 50 years. While there are numerous permutations of this procedure, this paper will specifically focus on choice procedures using concurrent schedules of intravenous drug self-administration. The aims of this paper are to first highlight the evolution of drug choice procedures and then review the subsequent preclinical body of literature utilizing these choice procedures to understand the environmental, pharmacological, and biological determinants of the reinforcing stimulus effects of drugs. A main rationale for this paper is our proposition that choice schedules …

Processing Of Damaged Dna Ends For Double-Strand Break Repair In Mammalian Cells, Lawrence F. Povirk

Pharmacology and Toxicology Publications

Most DNA double-strand breaks (DSBs) formed in a natural environment have chemical modifications at or near the ends that preclude direct religation and require removal or other processing so that rejoining can proceed. Free radical-mediated DSBs typically bear unligatable 3′-phosphate or 3′-phosphoglycolate termini and often have oxidized bases and/or abasic sites near the break. Topoisomerase-mediated DSBs are blocked by covalently bound peptide fragments of the topoisomerase. Enzymes capable of resolving damaged ends include polynucleotide kinase/phosphatase, which restores missing 5′-phosphates and removes 3′-phosphates; tyrosyl-DNA phosphodiesterases I and II (TDP1 and TDP2), which remove peptide fragments of topoisomerases I and II, respectively; …

Mice Deficient In Gem Gtpase Show Abnormal Glucose Homeostasis Due To Defects In Beta-Cell Calcium Handling, Jenny E. Gunton, Mary Sisavanh, Rebecca A. Stokes, Jon Satin, Leslie S. Satin, Min Zhang, Sue M. Liu, Weikang Cai, Kim Cheng, Gregory J. Cooney, D. Ross Laybutt, Trina So, Juan-Carlos Molero, Shane T. Grey, Douglas A. Andres, Michael S. Rolph, Charles R. Mackay

Pharmacology and Toxicology Publications

Aims and Hypothesis

Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo.

Methods

Gem-deficient mice were generated and their metabolic phenotype characterised by …

On The Specificity Of Heparin/Heparan Sulfate Binding To Proteins. Anion-Binding Sites On Antithrombin And Thrombin Are Fundamentally Different, Philip D. Mosier, Chandravel Krishnasamy, Glen E. Kellogg, Umesh R. Desai

Medicinal Chemistry Publications

Background

The antithrombin–heparin/heparan sulfate (H/HS) and thrombin–H/HS interactions are recognized as prototypic specific and non-specific glycosaminoglycan (GAG)–protein interactions, respectively. The fundamental structural basis for the origin of specificity, or lack thereof, in these interactions remains unclear. The availability of multiple co-crystal structures facilitates a structural analysis that challenges the long-held belief that the GAG binding sites in antithrombin and thrombin are essentially similar with high solvent exposure and shallow surface characteristics.

Methodology

Analyses of solvent accessibility and exposed surface areas, gyrational mobility, symmetry, cavity shape/size, conserved water molecules and crystallographic parameters were performed for 12 X-ray structures, which include 12 …

Pyridoxal 5′-Phosphate Is A Slow Tight Binding Inhibitor Of E. Coli Pyridoxal Kinase, Mohini S. Ghatge, Roberto Contestabile, Martino L. Di Salvo, Jigar V. Desai, Amit Gandhi, Christina M. Camara, Rita Florio, Isabel N. Gonzalez, Alessia Parroni, Verne Schirch, Martin A. Safo

Medicinal Chemistry Publications

Pyridoxal 5′-phosphate (PLP) is a cofactor for dozens of B6 requiring enzymes. PLP reacts with apo-B6 enzymes by forming an aldimine linkage with the ε-amino group of an active site lysine residue, thus yielding the catalytically active holo-B6 enzyme. During protein turnover, the PLP is salvaged by first converting it to pyridoxal by a phosphatase and then back to PLP by pyridoxal kinase. Nonetheless, PLP poses a potential toxicity problem for the cell since its reactive 4′-aldehyde moiety forms covalent adducts with other compounds and non-B6 proteins containing thiol or amino groups. The regulation of PLP homeostasis in the cell …

Design, Synthesis, And In Vitro And In Vivo Biological Studies Of A 3′-Deoxythymidine Conjugate That Potentially Kills Cancer Cells Selectively, Qiong Wei, Dejun Zhang, Anna Yao, Liyi Mai, Zhiwei Zhang, Qibing Zhou

Medicinal Chemistry Publications

Thymidine kinases (TKs) have been considered one of the potential targets for anticancer therapeutic because of their elevated expressions in cancer cells. However, nucleobase analogs targeting TKs have shown poor selective cytotoxicity in cancer cells despite effective antiviral activity. 3′-Deoxythymidine phenylquinoxaline conjugate (dT-QX) was designed as a novel nucleobase analog to target TKs in cancer cells and block cell replication via conjugated DNA intercalating quinoxaline moiety. In vitro cell screening showed that dT-QX selectively kills a variety of cancer cells including liver carcinoma, breast adenocarcinoma and brain glioma cells; whereas it had a low cytotoxicity in normal cells such as …

Virginia Commonwealth University Graduate And Professional Programs Bulletin [2012], Virginia Commonwealth University

VCU Bulletins

Graduate and professional programs bulletin for Virginia Commonwealth University for the academic year 2012-2013. It includes information on academic regulations, degree requirements, course offerings, faculty, academic calendar, and tuition and expenses for graduate programs.

The Removal Of Pluto From The Class Of Planets And Homosexuality From The Class Of Psychiatric Disorders: A Comparison, Peter Zachar, Kenneth S. Kendler

Psychiatry Publications

We compare astronomers' removal of Pluto from the listing of planets and psychiatrists' removal of homosexuality from the listing of mental disorders. Although the political maneuverings that emerged in both controversies are less than scientifically ideal, we argue that competition for "scientific authority" among competing groups is a normal part of scientific progress. In both cases, a complicated relationship between abstract constructs and evidence made the classification problem thorny.

Detection Of Horizontal Transfer Of Individual Genes By Anomalous Oligomer Frequencies, Jeff Elhai, Hailan Liu, Arnaud Taton

Study of Biological Complexity Publications

Background

Understanding the history of life requires that we understand the transfer of genetic material across phylogenetic boundaries. Detecting genes that were acquired by means other than vertical descent is a basic step in that process. Detection by discordant phylogenies is computationally expensive and not always definitive. Many have used easily computed compositional features as an alternative procedure. However, different compositional methods produce different predictions, and the effectiveness of any method is not well established.

Results

The ability of octamer frequency comparisons to detect genes artificially seeded in cyanobacterial genomes was markedly increased by using as a training set those …

Optimizing Read Mapping To Reference Genomes To Determine Composition And Species Prevalence In Microbial Communities, John Martin, Sean Sykes, Sarah Young, Karthik Kota, Riva Sanka, Nihar U. Sheth, Joshua Orvis, Erica Sodergren, Zhengyuan Wang, George M. Weinstock, Makedonka Mitreva

Study of Biological Complexity Publications

The Human Microbiome Project (HMP) aims to characterize the microbial communities of 18 body sites from healthy individuals. To accomplish this, the HMP generated two types of shotgun data: reference shotgun sequences isolated from different anatomical sites on the human body and shotgun metagenomic sequences from the microbial communities of each site. The alignment strategy for characterizing these metagenomic communities using available reference sequence is important to the success of HMP data analysis. Six next-generation aligners were used to align a community of known composition against a database comprising reference organisms known to be present in that community. All aligners …

Shared Resistance To Aging And Als In Neuromuscular Junctions Of Specific Muscles, Gregorio Valdez, Juan C. Tapia, Jeff W. Lichtman, Michael A. Fox, Joshua R. Sanes

Anatomy and Neurobiology Publications

Normal aging and neurodegenerative diseases both lead to structural and functional alterations in synapses. Comparison of synapses that are generally similar but respond differently to insults could provide the basis for discovering mechanisms that underlie susceptibility or resistance to damage. Here, we analyzed skeletal neuromuscular junctions (NMJs) in 16 mouse muscles to seek such differences. We find that muscles respond in one of three ways to aging. In some, including most limb and trunk muscles, age-related alterations to NMJs are progressive and extensive during the second postnatal year. NMJs in other muscles, such as extraocular muscles, are strikingly resistant to …

Menorah Review (No. 76, Winter/Spring, 2012)

Menorah Review

A Neo-Zionist Vison -- An Idiosyncratic Journey to God -- An Open Letter to Tarek Fatah -- Books in Brief: New and Notable -- Changing the Course of a River -- Leaves without Trees -- Moreshet: From the Classics - The Ethical Will of Eleazar of Mayence -- Zachor: John Locke's Letter Concerning Toleration

Spxa1 Involved In Hydrogen Peroxide Production, Stress Tolerance And Endocarditis Virulence In Streptococcus Sanguinis, Lei Chen, Xiuchun Ge, Xiaojing Wang, Jenishkumar R. Patel, Ping Xu

Philips Institute for Oral Health Research Publications

Streptococcus sanguinis is one of the most common agents of infective endocarditis. Spx proteins are a group of global regulators that negatively or positively control global transcription initiation. In this study, we characterized the spxA1 gene in S. sanguinis SK36. The spxA1 null mutant displayed opaque colony morphology, reduced hydrogen peroxide (H2O2) production, and reduced antagonistic activity against Streptococcus mutans UA159 relative to the wild type strain. The ΔspxA1 mutant also demonstrated decreased tolerance to high temperature, acidic and oxidative stresses. Further analysis revealed that ΔspxA1 also exhibited a ~5-fold reduction in competitiveness in an animal model of …

Virginia Commonwealth University Fall Commencement Program [2012], Virginia Commonwealth University

VCU Commencement Programs

No abstract provided.