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Redox Regulation Of Nlrp3 Inflammasomes: Ros As Trigger Or Effector?, Justine M. Abais, Min Xia, Yang Zhang, Krishna M. Boini, Pin-Lan Li

Pharmacology and Toxicology Publications

Significance: Inflammasomes are multiprotein complexes localized within the cytoplasm of the cell that are responsible for the maturation of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, and the activation of a highly inflammatory form of cell death, pyroptosis. In response to infection or cellular stress, inflammasomes are assembled, activated, and involved in host defense and pathophysiology of diseases. Clarification of the molecular mechanisms leading to the activation of this intracellular inflammatory machinery may provide new insights into the concept of inflammation as the root of and route to human diseases. Recent Advances: The activation of inflammasomes, specifically the most …

Integrating Mrna And Mirna Weighted Gene Co-Expression Networks With Eqtls In The Nucleus Accumbens Of Subjects With Alcohol Dependence, Mohammed Mamdani, Vernell Williamson, Gowon O. Mcmichael, Tana Blevins, Fazil Aliev, Amy Adkins, Laura Hack, Tim Bigdeli, Andrew D. Van Der Vaart, Bradley Todd Webb, Silviu-Alin Bacanu, Gursharan Kalsi, Coga Consortium, Kenneth S. Kendler, Michael F. Miles, Danielle Dick, Brien P. Riley, Catherine Dumur, Vladimir I. Vladimirov

Psychology Publications

Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and …

Genome-Wide Association Data Suggest Abcb1 And Immune-Related Gene Sets May Be Involved In Adult Antisocial Behavior, J E. Salvatore, A. C. Edwards, J. N. Mcclintik, T. B. Bigdeli, A. Adkins, F. Aliev, H. J. Edenburg, T. Foroud, V. Hesselbrock, J. Kramer, J. I. Nurnberger, M. Schuckit, J. A. Tischfield, X. Xuei, D. M. Dick

Psychiatry Publications

Adult antisocial behavior (AAB) is moderately heritable, relatively common and has adverse consequences for individuals and society. We examined the molecular genetic basis of AAB in 1379 participants from a case–control study in which the cases met criteria for alcohol dependence. We also examined whether genes of interest were expressed in human brain. AAB was measured using a count of the number of Antisocial Personality Disorder criteria endorsed under criterion A from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Participants were genotyped on the Illumina Human 1M BeadChip. In total, all single-nucleotide polymorphisms (SNPs) accounted for …

Genome-Wide Association Data Suggest Abcb1 And Immune-Related Gene Sets May Be Involved In Adult Antisocial Behavior, J E. Salvatore, A C. Edwards, J N. Mcclintick, T B. Bidgeli, A Adkins, F Aliev, H J. Edenberg, T Foround, V Hesselbrock, J Kramer, J I. Nurnberger, M Schuckit, J A. Tischfield, X Xuei, D Dick

Psychiatry Publications

Adult antisocial behavior (AAB) is moderately heritable, relatively common and has adverse consequences for individuals and society. We examined the molecular genetic basis of AAB in 1379 participants from a case–control study in which the cases met criteria for alcohol dependence. We also examined whether genes of interest were expressed in human brain. AAB was measured using a count of the number of Antisocial Personality Disorder criteria endorsed under criterion A from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Participants were genotyped on the Illumina Human 1M BeadChip. In total, all single-nucleotide polymorphisms (SNPs) accounted for …

Spag17 Deficiency Results In Skeletal Malformations And Bone Abnormalities, Maria Eugenia Teves, Gobalakrishnan Sundaresan, David J. Cohen, Sharon L. Hyzy, Illya Kajan, Melissa Maczis, Zhibing Zhang, Richard M. Costanzo, Jamal Zweit, Zvi Schwartz, Barbara` D. Boyan, Jerome F. Strauss Iii

Obstetrics and Gynecology Publications

Height is the result of many growth and development processes. Most of the genes associated with height are known to play a role in skeletal development. Single-nucleotide polymorphisms in the SPAG17 gene have been associated with human height. However, it is not clear how this gene influences linear growth. Here we show that a targeted mutation in Spag17 leads to skeletal malformations. Hind limb length in mutants was significantly shorter than in wild-type mice. Studies revealed differences in maturation of femur and tibia suggesting alterations in limb patterning. Morphometric studies showed increased bone formation evidenced by increased trabecular bone area …

Sperm Associated Antigen 6 (Spag6) Regulates Fibroblast Cell Growth, Morphology, Migration And Ciliogenesis, Wei Li, Abir Mukherjee, Jinhua Wu, Ling Zhang, Maria E. Teves, Hongfei Li, Shanti Nambiar, Scott C. Henderson, Alan R. Horwitz, Jerome F. Strauss Iii, Xianjun Fang, Zhibing Zhang

Obstetrics and Gynecology Publications

Mammalian Spag6 is the orthologue of Chlamydomonas PF16, which encodes a protein localized in the axoneme central apparatus, and regulates flagella/cilia motility. Most Spag6-deficient mice are smaller in size than their littermates. Because SPAG6 decorates microtubules, we hypothesized that SPAG6 has other roles related to microtubule function besides regulating flagellar/cilia motility. Mouse embryonic fibroblasts (MEFs) were isolated from Spag6-deficient and wild-type embryos for these studies. Both primary and immortalizedSpag6-deficient MEFs proliferated at a much slower rate than the wild-type MEFs, and they had a larger surface area. Re-expression of SPAG6 in the Spag6-deficient MEFs …

Catchment Area Analysis Using Bayesian Regression Modeling, Aobo Wang, David C. Wheeler

Biostatistics Publications

A catchment area (CA) is the geographic area and population from which a cancer center draws patients. Defining a CA allows a cancer center to describe its primary patient population and assess how well it meets the needs of cancer patients within the CA. A CA definition is required for cancer centers applying for National Cancer Institute (NCI)-designated cancer center status. In this research, we constructed both diagnosis and diagnosis/treatment CAs for the Massey Cancer Center (MCC) at Virginia Commonwealth University. We constructed diagnosis CAs for all cancers based on Virginia state cancer registry data and Bayesian hierarchical logistic regression …

Evaluation Of The Performance Of Smoothing Functions In Generalized Additive Models For Spatial Variation In Disease, Umaporn Siangphoe, David C. Wheeler

Biostatistics Publications

Generalized additive models (GAMs) with bivariate smoothing functions have been applied to estimate spatial variation in risk for many types of cancers. Only a handful of studies have evaluated the performance of smoothing functions applied in GAMs with regard to different geographical areas of elevated risk and different risk levels. This study evaluates the ability of different smoothing functions to detect overall spatial variation of risk and elevated risk in diverse geographical areas at various risk levels using a simulation study. We created five scenarios with different true risk area shapes (circle, triangle, linear) in a square study region. We …

Penalized Ordinal Regression Methods For Predicting Stage Of Cancer In High-Dimensional Covariate Spaces, Amanda Elswick Gentry, Colleen K. Jackson-Cook, Debra E. Lyon, Kellie J. Archer

Biostatistics Publications

The pathological description of the stage of a tumor is an important clinical designation and is considered, like many other forms of biomedical data, an ordinal outcome. Currently, statistical methods for predicting an ordinal outcome using clinical, demographic, and high-dimensional correlated features are lacking. In this paper, we propose a method that fits an ordinal response model to predict an ordinal outcome for high-dimensional covariate spaces. Our method penalizes some covariates (high-throughput genomic features) without penalizing others (such as demographic and/or clinical covariates). We demonstrate the application of our method to predict the stage of breast cancer. In our model, …

Generalized Monotone Incremental Forward Stagewise Method For Modeling Count Data: Application Predicting Micronuclei Frequency, Mateusz Makowski, Kellie J. Archer

Biostatistics Publications

The cytokinesis-block micronucleus (CBMN) assay can be used to quantify micronucleus (MN) formation, the outcome measured being MN frequency. MN frequency has been shown to be both an accurate measure of chromosomal instability/DNA damage and a risk factor for cancer. Similarly, the Agilent 4×44k human oligonucleotide microarray can be used to quantify gene expression changes. Despite the existence of accepted methodologies to quantify both MN frequency and gene expression, very little is known about the association between the two. In modeling our count outcome (MN frequency) using gene expression levels from the high-throughput assay as our predictor variables, there are …

Identifying Molecular Features Associated With Psychoneurological Symptoms In Women With Breast Cancer Using Multivariate Mixed Models, Qing Zhou, Colleen Jackson-Cook, Debra Lyon, Robert Perera, Kellie Archer

Biostatistics Publications

Breast cancer (BC) is the second most common cancer among women. Research shows many women with BC experience anxiety, depression, and stress (ADS). Epigenetics has recently emerged as a potential mechanism for the development of depression.1 Although there are growing numbers of research studies indicating that epigenetic changes are associated with ADS, there is currently no evidence that this association is present in women with BC. The goal of this study was to identify high-throughput methylation sites (CpG sites) that are associated with three psychoneurological symptoms (ADS) in women with BC. Traditionally, univariate models have been used to examine …

Pdgfrα Signaling Drives Adipose Tissue Fibrosis By Targeting Progenitor Cell Plasticity, Tomoaki Iwayama, Cameron Steele, Longbiao Yao, Mikhail G. Dozmorov, Dimitris Karamichos, Jonathan D. Wren, Lorin E. Olson

Biostatistics Publications

Fibrosis is a common disease process in which profibrotic cells disturb organ function by secreting disorganized extracellular matrix (ECM). Adipose tissue fibrosis occurs during obesity and is associated with metabolic dysfunction, but how profibrotic cells originate is still being elucidated. Here, we use a developmental model to investigate perivascular cells in white adipose tissue (WAT) and their potential to cause organ fibrosis. We show that a Nestin-Cre transgene targets perivascular cells (adventitial cells and pericyte-like cells) in WAT, and Nestin-GFP specifically labels pericyte-like cells. Activation of PDGFRα signaling in perivascular cells causes them to transition into ECM-synthesizing profibrotic cells. Before …

B-Cell And Monocyte Contribution To Systemic Lupus Erythematosus Identified By Cell-Type-Specific Differential Expression Analysis In Rna-Seq Data, Mikhail G. Dozmorov, Nicolas Dominguez, Krista Bean, Susan R. Macwana, Virginia Roberts, Edmund Glass, Judith A. James, Joel M. Guthridge

Biostatistics Publications

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by complex interplay among immune cell types. SLE activity is experimentally assessed by several blood tests, including gene expression profiling of heterogeneous populations of cells in peripheral blood. To better understand the contribution of different cell types in SLE pathogenesis, we applied the two methods in cell-type-specific differential expression analysis, csSAM and DSection, to identify cell-type-specific gene expression differences in heterogeneous gene expression measures obtained using RNA-seq technology. We identified B-cell-, monocyte-, and neutrophil-specific gene expression differences. Immunoglobulin-coding gene expression was altered in B-cells, while a ribosomal signature was prominent in …

Assessment Of Weighted Quantile Sum Regression For Modeling Chemical Mixtures And Cancer Risk, Jenna Czarnota, Chris Gennings, David C. Wheeler

Biostatistics Publications

In evaluation of cancer risk related to environmental chemical exposures, the effect of many chemicals on disease is ultimately of interest. However, because of potentially strong correlations among chemicals that occur together, traditional regression methods suffer from collinearity effects, including regression coefficient sign reversal and variance inflation. In addition, penalized regression methods designed to remediate collinearity may have limitations in selecting the truly bad actors among many correlated components. The recently proposed method of weighted quantile sum (WQS) regression attempts to overcome these problems by estimating a body burden index, which identifies important chemicals in a mixture of correlated environmental …

Evaluating Geographically Weighted Regression Models For Environmental Chemical Risk Analysis, Jenna Czarnota, David C. Wheeler, Chris Gennings

Biostatistics Publications

In the evaluation of cancer risk related to environmental chemical exposures, the effect of many correlated chemicals on disease is often of interest. The relationship between correlated environmental chemicals and health effects is not always constant across a study area, as exposure levels may change spatially due to various environmental factors. Geographically weighted regression (GWR) has been proposed to model spatially varying effects. However, concerns about collinearity effects, including regression coefficient sign reversal (ie, reversal paradox), may limit the applicability of GWR for environmental chemical risk analysis. A penalized version of GWR, the geographically weighted lasso, has been proposed to …

Virginia Dental Journal (Vol. 92, No. 3, 2015)

Virginia Dental Journal

No abstract provided.

Adipose-Derived Mesenchymal Stem Cells Improve Glucose Homeostasis In High-Fat Diet-Induced Obese Mice, Mingjun Cao, Qingjie Pan, Huanshen Dong, Xinxu Yuan, Yang Li, Zhen Sun, Xiao Dong, Hongjun Wang

Pharmacology and Toxicology Publications

Introduction

Effective therapies for obesity and diabetes are still lacking. The aim of this study was to evaluate whether a single intravenous infusion of syngeneic adipose-derived mesenchymal stem cells (ASCs) can reduce obesity, lower insulin resistance, and improve glucose homeostasis in a high-fat diet-induced obese (DIO) mouse model.

Methods

Seven-week-old C57BL/6 mice were fed a high-fat diet for 20 weeks to generate the DIO mouse model. Mice were given a single intravenous infusion of ex vivo expanded syngeneic ASCs at 2 × 10 ⁶ cells per mouse. DIO or CHOW mice injected with saline were used as controls. Body weights, …

Effects Of Menthol On Nicotine Pharmacokinetic, Pharmacology And Dependence In Mice, Sharki D. Alsharari, Justin R. King, Jacob C. Nordman, Pretal P. Muldoon, Asti Jackson, Andy Z. X. Zhu, Rachel F. Tyndale, Nadine Kabbani, M. Imad Damaj

Pharmacology and Toxicology Publications

Although menthol, a common flavoring additive to cigarettes, has been found to impact the addictive properties of nicotine cigarettes in smokers little is known about its pharmacological and molecular actions in the brain. Studies were undertaken to examine whether the systemic administration of menthol would modulate nicotine pharmacokinetics, acute pharmacological effects (antinociception and hypothermia) and withdrawal in male ICR mice. In addition, we examined changes in the brain levels of nicotinic receptors of rodents exposed to nicotine and menthol. Administration of i.p. menthol significantly decreased nicotine’s clearance (2-fold decrease) and increased its AUC compared to i.p. vehicle treatment. In addition, …

Contribution Of Nrf2 To Atherogenic Phenotype Switching Of Coronary Arterial Smooth Muscle Cells Lacking Cd38 Gene, Ming Xu, Xiao-Xue Li, Lei Wang, Mi Wang, Yang Zhang, Pin-Lan Li

Pharmacology and Toxicology Publications

Background/Aims: Recent studies have indicated that CD38 gene deficiency results in dedifferentiation or transdifferentiation of arterial smooth muscle cells upon atherogenic stimulations. However, the molecular mechanisms mediating this vascular smooth muscle (SMC) phenotypic switching remain unknown. Methods & Results: In the present study, we first characterized the phenotypic change in the primary cultures of coronary arterial myocytes (CAMs) from CD38-/- mice. It was shown that CD38 deficiency decreased the expression of contractile marker calponin, SM22α and α-SMA but increased the expression of SMC dedifferentiation marker, vimentin, which was accompanied by enhanced cell proliferation. This phenotypic change in CD38-/- CAMs was …

Concentration-Dependent Diversification Effects Of Free Cholesterol Loading On Macrophage Viability And Polarization, Xiaoyang Xu, Aolin Zhang, Ningjun Li, Pin-Lan Li, Fan Zhang

Pharmacology and Toxicology Publications

Background/Aims: The accumulation of free cholesterol in atherosclerotic lesions has been well documented in both animals and humans. In studying the relevance of free cholesterol buildup in atherosclerosis, contradictory results have been generated, indicating that free cholesterol produces both pro- and anti-atherosclerosis effects in macrophages. This inconsistency might stem from the examination of only select concentrations of free cholesterol. In the present study, we sought to investigate the implication of excess free cholesterol loading in the pathophysiology of atherosclerosis across a broad concentration range from (in µg/ml) 0 to 60. Methods:Macrophage viability was determined by measuring formazan formation and …

Pursuing Cardioprotective Health Through Research, Sterling Giles

AUCTUS: The Journal of Undergraduate Research and Creative Scholarship

Recent VCU Chemistry graduate Salma Omer and her team of fellow researchers discovered that the supplement Viagra, intended for treating erectile dysfunction, may protect the heart from diabetic damage and damage from excessive alcohol consumption.

Osseointegration Of Wrapped Dental Implants In Rabbits, Alex Whitehead

AUCTUS: The Journal of Undergraduate Research and Creative Scholarship

Edentulous patients (those lacking teeth) require one of two approaches to augmentation: inserting a vertical bone graft, or subperiosteally anchoring a device on which an implant can be attached. Bone grafts have had unpredictable results and can undergo resorption over time, compromising implant stability and success. As of the subperiosteal approach, current materials have not proven to directly integrate with the bone, in a process termed osseointegration. Therefore, we used additive manufacturing to create a Ti6Al4V alloy surface with a specific roughness to determine if it would be osseoinductive in a challenging rabbit model over six weeks.

Neuronal Migration: How Do You Build A Brain?, Sravya Uppalapati

AUCTUS: The Journal of Undergraduate Research and Creative Scholarship

Senior biology major Alex Burkard is working in the Walsh Neurodevelopment Laboratory at VCU to help answer the question, ‘How do you build a brain?’ Burkard is researching neuronal migration in Zebrafish and how cellular polarity affects hindbrain development.

Immortal Mortals, Sterling Giles

AUCTUS: The Journal of Undergraduate Research and Creative Scholarship

Junior Information Systems and Bioinformatics major Michael Kiflezghi focuses his research interests on an organism’s lifespan and gut microbial communities.

Endogenous Bdnf Augments Nmda Receptor Phosphorylation In The Spinal Cord Via Plcγ, Pkc, And Pi3k/Akt Pathways During Colitis, Miao Liu, Jarren C. Kay, Shanwei Shen, Li-Ya Qiao

Physiology and Biophysics Publications and Presentations

Background

Spinal central sensitization is an important process in the generation and maintenance of visceral hypersensitivity. The release of brain-derived neurotrophic factor (BDNF) from the primary afferent neurons to the spinal cord contributes to spinal neuronal plasticity and increases neuronal activity and synaptic efficacy. The N-Methyl-D-aspartic acid (NMDA) receptor possesses ion channel properties, and its activity is modulated by phosphorylation of its subunits including the NMDA receptor 1 (NR1).

Methods

Colonic inflammation was induced by a single dose of intracolonic instillation of tri-nitrobenzene sulfonic acid (TNBS). NR1 phosphorylation by BDNF in vivo and in culture was examined by western …

Molecular Overlap In The Regulation Of Sk Channels By Small Molecules And Phosphoinositides, Miao Zhang, Xuan-Yu Meng, Ji-Fang Zhang, Meng Cui, Diomedes E. Logothetis

Physiology and Biophysics Publications and Presentations

Phosphatidylinositol 4,5-bisphosphate (PIP2) directly interacts with the small-conductance Ca2+-activated K+2-a (SK2-a) channel/calmodulin complex, serving as a critical element in the regulation of channel activity. We report that changes of protein conformation in close proximity to the PIP2 binding site induced by a small-molecule SK channel modulator, NS309, can effectively enhance the interaction between the protein and PIP2 to potentiate channel activity. This novel modulation of PIP2 sensitivity by small-molecule drugs is likely not to be limited in its application to SK channels, representing an intriguing strategy to develop drugs controlling the activity of the large number of PIP2-dependent proteins.

Impact Of V-Ets Erythroblastosis Virus E26 Oncogene Homolog 1 Gene Polymorphisms Upon Susceptibility To Autoimmune Diseases, Ye Zhou, Miao Liu, Jun Li, Fiza Hashmi, Zhi Mao, Ning Zhang, Liang Zhou, Weiran Lv, Jingwei Zheng, Xiaoli Nie, Changzheng Li

Physiology and Biophysics Publications and Presentations

V-ets erythroblastosis virus E26 oncogene homolog 1 (ETS1) is recognized as a gene of risk to autoimmune diseases (ADs). Two single nucleotide polymorphisms (SNPs) in ETS1 (rs1128334 G>A and rs10893872 T>C) were considered associated with ADs risk. However, the results remain conflicting.

We performed a meta-analysis to evaluate more precise estimations of any relationship. We searched PubMed, OvidSP, and Chinese National Knowledge Infrastructure databases (papers published prior to September 12, 2014) and extracted data from eligible studies. Meta-analysis was performed using the STATA 12.0 software. Random effect model or fixed effect model were chosen according to …

A Rapid In Vivo Screen For Pancreatic Ductal Adenocarcinoma Therapeutics, Ozhan Ocal, Victor Pashkov, Rahul K. Kollipara, Yalda Zolghadri, Victoria H. Cruz, Michael A. Hale, Blake R. Heath, Alex B. Artyukhin, Alana L. Christie, Pantelis Tsoulfas, James B. Lorens, Galvin H. Swift, Rolf A. Brekken, Thomas M. Wilkie

Physiology and Biophysics Publications and Presentations

Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related deaths in the United States, and is projected to be second by 2025. It has the worst survival rate among all major cancers. Two pressing needs for extending life expectancy of affected individuals are the development of new approaches to identify improved therapeutics, addressed herein, and the identification of early markers. PDA advances through a complex series of intercellular and physiological interactions that drive cancer progression in response to organ stress, organ failure, malnutrition, and infiltrating immune and stromal cells. Candidate drugs identified in organ culture or cell-based screens …

Nicotinic Acetylcholine Receptor (Nachr) Dependent Chorda Tympani Taste Nerve Responses To Nicotine, Ethanol And Acetylcholine, Zuo Jun Ren, Shobha Mummalaneni, Jie Qian, Clive M. Baumgarten, John A. Desimone, Vijay Lyall

Physiology and Biophysics Publications and Presentations

Nicotine elicits bitter taste by activating TRPM5-dependent and TRPM5-independent but neuronal nAChR-dependent pathways. The nAChRs represent common targets at which acetylcholine, nicotine and ethanol functionally interact in the central nervous system. Here, we investigated if the nAChRs also represent a common pathway through which the bitter taste of nicotine, ethanol and acetylcholine is transduced. To this end, chorda tympani (CT) taste nerve responses were monitored in rats, wild-type mice and TRPM5 knockout (KO) mice following lingual stimulation with nicotine free base, ethanol, and acetylcholine, in the absence and presence of nAChR agonists and antagonists. The nAChR modulators: mecamylamine, dihydro-β-erythroidine, and …

Starvation-Induced Collective Behavior In C. Elegans, Alexander B. Artyukhin, Virginia Commonwealth University J. Yim, Mi Cheong Cheong, Leon Avery

Physiology and Biophysics Publications and Presentations

We describe a new type of collective behavior in C. elegans nematodes, aggregation of starved L1 larvae. Shortly after hatching in the absence of food, L1 larvae arrest their development and disperse in search for food. In contrast, after two or more days without food, the worms change their behavior—they start to aggregate. The aggregation requires a small amount of ethanol or acetate in the environment. In the case of ethanol, it has to be metabolized, which requires functional alcohol dehydrogenase sodh-1. The resulting acetate is used in de novo fatty acid synthesis, and some of the newly made fatty …