Medicine and Health Sciences Commons^™

The Β3-Adrenergic Receptor Agonist Mirabegron Improves Glucose Homeostasis In Obese Humans, Brian S. Finlin, Hasiyet Memetimin, Beibei Zhu, Amy L. Confides, Hemendra J. Vekaria, Riham H. El Khouli, Zachary R. Johnson, Philip M. Westgate, Jianzhong Chen, Andrew J. Morris, Patrick G. Sullivan, Esther E. Dupont-Versteegden, Philip A. Kern

Internal Medicine Faculty Publications

BACKGROUND. Beige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains β3-adrenergic receptors (β3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the β3-AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle and improve metabolic homeostasis.

METHODS. Before and after β3-AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemical analysis and gene expression profiling were performed on fat and muscle biopsies. PET-CT scans quantified brown adipose tissue volume and …

An Integrative Cross-Omics Analysis Of Dna Methylation Sites Of Glucose And Insulin Homeostasis, Jun Liu, Elena Carnero-Montoro, Jenny Van Dongen, Samantha Lent, Ivana Nedeljkovic, Symen Ligthart, Pei-Chien Tsai, Tiphaine C. Martin, Pooja R. Mandaviya, Rick Jansen, Marjolein J. Peters, Liesbeth Duijts, Vincent W. V. Jaddoe, Henning Tiemeier, Janine F. Felix, Gonneke Willemsen, Eco J. C. De Geus, Audrey Y. Chu, Daniel Levy, Shih-Jen Hwang, Jan Bressler, Rahul Gondalia, Elias L. Salfati, Christian Herder, Bertha A. Hidalgo, Toshiko Tanaka, Ann Zenobia Moore, Rozenn N. Lemaitre, Min A. Jhun, Jennifer A. Smith, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation …

Incorporating Pathway Information Into Feature Selection Towards Better Performed Gene Signatures, Suyan Tian, Chi Wang, Bing Wang

Biostatistics Faculty Publications

To analyze gene expression data with sophisticated grouping structures and to extract hidden patterns from such data, feature selection is of critical importance. It is well known that genes do not function in isolation but rather work together within various metabolic, regulatory, and signaling pathways. If the biological knowledge contained within these pathways is taken into account, the resulting method is a pathway-based algorithm. Studies have demonstrated that a pathway-based method usually outperforms its gene-based counterpart in which no biological knowledge is considered. In this article, a pathway-based feature selection is firstly divided into three major categories, namely, pathway-level selection, …

Targeting The Brd4/Foxo3a/Cdk6 Axis Sensitizes Akt Inhibition In Luminal Breast Cancer, Jingyi Liu, Weijie Guo, Zhibing Duan, Lei Zeng, Yadi Wu, Yule Chen, Fang Tai, Yifan Wang, Yiwei Lin, Qiang Zhang, Yanling He, Jiong Deng, Rachel L. Stewart, Chi Wang, Pengnian Charles Lin, Saghi Ghaffari, B. Mark Evers, Suling Liu, Ming-Ming Zhou, Binhua P. Zhou, Jian Shi

Molecular and Cellular Biochemistry Faculty Publications

BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or …

Neurotensin Receptor 3/Sortilin Contributes To Tumorigenesis Of Neuroendocrine Tumors Through Augmentation Of Cell Adhesion And Migration, Ji Tae Kim, Dana L. Napier, Heidi L. Weiss, Eun Y. Lee, Courtney M. Townsend, B. Mark Evers

Markey Cancer Center Faculty Publications

Neurotensin (NTS), a 13–amino acid peptide which is distributed predominantly along gastrointestinal tract, has multiple physiologic and pathologic functions, and its effects are mediated by three distinct NTS receptors (NTSRs). Overexpression and activation of NTS signaling components, especially NTS and/or NTSR1, are closely linked with cancer progression and metastasis in various types of cancers including neuroendocrine tumors (NETs). Although deregulation of NTSR3/sortilin has been implicated in a variety of human diseases, the expression and role of NTSR3/sortilin in NETs have not been elucidated. In this study, we investigated the expression and oncogenic effect of NTSR3/sortilin in NETs. Increased protein levels …

Systems Biology Approach To Late-Onset Alzheimer's Disease Genome-Wide Association Study Identifies Novel Candidate Genes Validated Using Brain Expression Data And Caenorhabditis Elegans Experiments, Shubhabrata Mukherjee, Joshua C. Russell, Daniel T. Carr, Jeremy D. Burgess, Mariet Allen, Daniel J. Serie, Kevin L. Boehme, John S. K. Kauwe, Adam C. Naj, David W. Fardo, Dennis W. Dickson, Thomas J. Montine, Nilufer Ertekin-Taner, Matt R. Kaeberlein, Paul K. Crane

Biostatistics Faculty Publications

Introduction—We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer's disease (LOAD) loci.

Methods—We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions.

Results—We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aβ …

Increased Birth Weight Is Associated With Altered Gene Expression In Neonatal Foreskin, Leryn J. Reynolds, Rebecca I. Pollack, Richard J. Charnigo, Cetewayo S. Rashid, Arnold J. Stromberg, Shu Shen, John O'Brien, Kevin J. Pearson

Pharmacology and Nutritional Sciences Faculty Publications

Elevated birth weight is linked to glucose intolerance and obesity health-related complications later in life. No studies have examined if infant birth weight is associated with gene expression markers of obesity and inflammation in a tissue that comes directly from the infant following birth. We evaluated the association between birth weight and gene expression on fetal programming of obesity. Foreskin samples were collected following circumcision, and gene expression analyzed comparing the 15% greatest birth weight infants (n = 7) v. the remainder of the cohort (n = 40). Multivariate linear regression models were fit to relate expression levels on differentially …

The Trophic Life Cycle Stage Of The Opportunistic Fungal Pathogen Pneumocystis Murina Hinders The Ability Of Dendritic Cells To Stimulate Cd4+ T Cell Responses, Heather M. Evans, Andrew Simpson, Shu Shen, Arnold J. Stromberg, Carol L. Pickett, Beth A. Garvy

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The life cycle of the opportunistic fungal pathogen Pneumocystis murina consists of a trophic stage and an ascus-like cystic stage. Infection with the cyst stage induces proinflammatory immune responses, while trophic forms suppress the cytokine response to multiple pathogen-associated molecular patterns (PAMPs), including β-glucan. A targeted gene expression assay was used to evaluate the dendritic cell response following stimulation with trophic forms alone, with a normal mixture of trophic forms and cysts, or with β-glucan. We demonstrate that stimulation with trophic forms downregulated the expression of multiple genes normally associated with the response to infection, including genes encoding …

Cib2 Interacts With Tmc1 And Tmc2 And Is Essential For Mechanotransduction In Auditory Hair Cells, Arnaud P. J. Giese, Yi-Quan Tang, Ghanshyam P. Sinha, Michael R. Bowl, Adam C. Goldring, Andrew Parker, Mary J. Freeman, Steve D. M. Brown, Saima Riazuddin, Robert Fettiplace, William R. Schafer, Gregory I. Frolenkov, Zubair M. Ahmed

Physiology Faculty Publications

Inner ear hair cells detect sound through deflection of stereocilia, the microvilli-like projections that are arranged in rows of graded heights. Calcium and integrin-binding protein 2 is essential for hearing and localizes to stereocilia, but its exact function is unknown. Here, we have characterized two mutant mouse lines, one lacking calcium and integrin-binding protein 2 and one carrying a human deafness-related Cib2 mutation, and show that both are deaf and exhibit no mechanotransduction in auditory hair cells, despite the presence of tip links that gate the mechanotransducer channels. In addition, mechanotransducing shorter row stereocilia overgrow in hair cell bundles of …

Micrornas, Heart Failure, And Aging: Potential Interactions With Skeletal Muscle, Kevin A. Murach, John J. Mccarthy

Center for Muscle Biology Faculty Publications

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by targeting mRNAs for degradation or translational repression. MiRNAs can be expressed tissue specifically and are altered in response to various physiological conditions. It has recently been shown that miRNAs are released into the circulation, potentially for the purpose of communicating with distant tissues. This manuscript discusses miRNA alterations in cardiac muscle and the circulation during heart failure, a prevalent and costly public health issue. A potential mechanism for how skeletal muscle maladaptations during heart failure could be mediated by myocardium-derived miRNAs released to the circulation is presented. An overview …

Association Of Body Mass Index With Dna Methylation And Gene Expression In Blood Cells And Relations To Cardiometabolic Disease: A Mendelian Randomization Approach, Michael M. Mendelson, Riccardo E. Marioni, Roby Joehanes, Chunyu Liu, Åsa K. Hedman, Stella Aslibekyan, Ellen W. Demerath, Weihua Guan, Degui Zhi, Chen Yao, Tianxiao Huan, Christine Willinger, Brian Chen, Paul Courchesne, Michael Multhaup, Marguerite R. Irvin, Ariella Cohain, Eric E. Schadt, Megan L. Grove, Jan Bressler, Kari North, Johan Sundström, Stefan Gustafsson, Sonia Shah, Allan F. Mcrae, Sarah E. Harris, Jude Gibson, Paul Redmond, Janie Corley, Lee Murphy, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Background

The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain.

Methods and Findings

We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs …

Airway Secretory Micrornaome Changes During Rhinovirus Infection In Early Childhood, Maria J. Gutierrez, Jose L. Gomez, Geovanny F. Perez, Krishna Pancham, Stephanie Val, Dinesh K. Pillai, Mamta Giri, Sarah Ferrante, Robert Freishtat, Mary C. Rose, Diego Preciado, Gustavo Nino

Pediatrics Faculty Publications

Background Innate immune responses are fine-tuned by small noncoding RNA molecules termed microRNAs (miRs) that modify gene expression in response to the environment. During acute infections, miRs can be secreted in extracellular vesicles (EV) to facilitate cell-to-cell genetic communication. The purpose of this study was to characterize the baseline population of miRs secreted in EVs in the airways of young children (airway secretory microRNAome) and examine the changes during rhinovirus (RV) infection, the most common cause of asthma exacerbations and the most important early risk factor for the development of asthma beyond childhood.

Methods Nasal airway secretions were obtained from …

Myonuclear Transcription Is Responsive To Mechanical Load And Dna Content But Uncoupled From Cell Size During Hypertrophy, Tyler J. Kirby, Rooshil M. Patel, Timothy S. Mcclintock, Esther E. Dupont-Versteegden, Charlotte A. Peterson, John J. Mccarthy

Physiology Faculty Publications

Myofibers increase size and DNA content in response to a hypertrophic stimulus, thus providing a physiological model with which to study how these factors affect global transcription. Using 5-ethynyl uridine (EU) to metabolically label nascent RNA, we measured a sevenfold increase in myofiber transcription during early hypertrophy before a change in cell size and DNA content. The typical increase in myofiber DNA content observed at the later stage of hypertrophy was associated with a significant decrease in the percentage of EU-positive myonuclei; however, when DNA content was held constant by preventing myonuclear accretion via satellite cell depletion, both the number …

Gap Junction Mediated Mirna Intercellular Transfer And Gene Regulation: A Novel Mechanism For Intercellular Genetic Communication, Liang Zong, Yan Zhu, Ruqiang Liang, Hong-Bo Zhao

Otolaryngology--Head & Neck Surgery Faculty Publications

Intercellular genetic communication is an essential requirement for coordination of cell proliferation and differentiation and has an important role in many cellular processes. Gap junction channels possess large pore allowing passage of ions and small molecules between cells. MicroRNAs (miRNAs) are small regulatory RNAs that can regulate gene expression broadly. Here, we report that miRNAs can pass through gap junction channels in a connexin-dependent manner. Connexin43 (Cx43) had higher permeability, whereas Cx30 showed little permeability to miRNAs. In the tested connexin cell lines, the permeability to miRNAs demonstrated: Cx43 > Cx26/30 > Cx26 > Cx31 > Cx30 = Cx-null. However, consistent with a uniform …

Local Admixture Of Amplified And Diversified Secreted Pathogenesis Determinants Shapes Mosaic Toxoplasma Gondii Genomes, Hernan Lorenzi, Asis Khan, Michael S. Behnke, Sivaranjani Namasivayam, Lakshmipuram S. Swapna, Michalis Hadjithomas, Svetlana Karamycheva, Deborah Pinney, Brian P. Brunk, James W. Ajioka, Daniel Ajzenberg, John C. Boothroyd, Jon P. Boyle, Marie L. Dardé, Maria A. Diaz-Miranda, Jitender P. Dubey, Heather M. Fritz, Solange M. Gennari, Brian D. Gregory, Kami Kim, Jeroen P. J. Saeij, Chunlei Su, Michael W. White, Xing-Quan Zhu, Daniel K. Howe, Benjamin M. Rosenthal, Michael E. Grigg, John Parkinson, Liang Liu, Jessica C. Kissinger

Veterinary Science Faculty Publications

Toxoplasma gondii is among the most prevalent parasites worldwide, infecting many wild and domestic animals and causing zoonotic infections in humans. T. gondii differs substantially in its broad distribution from closely related parasites that typically have narrow, specialized host ranges. To elucidate the genetic basis for these differences, we compared the genomes of 62 globally distributed T. gondii isolates to several closely related coccidian parasites. Our findings reveal that tandem amplification and diversification of secretory pathogenesis determinants is the primary feature that distinguishes the closely related genomes of these biologically diverse parasites. We further show that the unusual population structure …

Differential Gene Expression Profiles Reflecting Macrophage Polarization In Aging And Periodontitis Gingival Tissues, Octavio A. Gonzalez, Michael John Novak, Sreenatha S. Kirakodu, Arnold J. Stromberg, R. Nagarajan, Chifu B. Huang, K. C. Chen, Luis Orraca, J. Martinez-Gonzalez, Jeffrey L. Ebersole

Center for Oral Health Research Faculty Publications

Recent evidence has determined a phenotypic and functional heterogeneity for macrophage populations. This plasticity of macrophage function has been related to specific properties of subsets (M1 and M2) of these cells in inflammation, adaptive immune responses and resolution of tissue destructive processes. This investigation hypothesized that targeted alterations in the distribution of macrophage phenotypes in aged individuals, and with periodontitis would be skewed towards M1 inflammatory macrophages in gingival tissues. The study used a non-human primate model to evaluate gene expression profiles as footprints of macrophage variation in healthy and periodontitis gingival tissues from animals 3-23 years of age and …

Novel Human Abcc9/Sur2 Brain-Expressed Transcripts And An Eqtl Relevant To Hippocampal Sclerosis Of Aging, Peter T. Nelson, Wang-Xia Wang, Bernard R. Wilfred, Angela Wei, James Dimayuga, Qingwei Huang, Eseosa T. Ighodaro, Sergey C. Artiushin, David W. Fardo

Sanders-Brown Center on Aging Faculty Publications

ABCC9 genetic polymorphisms are associated with increased risk for various human diseases including hippocampal sclerosis of aging. The main goals of this study were 1 > to detect the ABCC9 variants and define the specific 3′ untranslated region (3′UTR) for each variant in human brain, and 2 > to determine whether a polymorphism (rs704180) associated with risk for hippocampal sclerosis of aging pathology is also associated with variation in ABCC9 transcript expression and/or splicing. Rapid amplification of ABCC9 cDNA ends (3′RACE) provided evidence of novel 3′ UTR portions of ABCC9 in human brain. In silico and experimental studies were performed focusing on …

The C-Terminal Domain (Ctd) Of Human Dna Glycosylaseneil1 Is Required For Forming Berosome Repair Complex With Dna Replication Proteins At The Replicating Genome: Dominant Negative Function Of The Ctd, Pavana M. Hegde, Arijit Dutta, Shiladitya Sengupta, Joy Mitra, Sanjay Adhikari, Alan E. Tomkinson, Guo-Min Li, Istvan Boldogh, Tapas K. Hazra, Sankar Mitra, Muralidhar L. Hegde

Toxicology and Cancer Biology Faculty Publications

The human DNA glycosylase NEIL1 was recently demonstrated to initiate prereplicative base excision repair (BER) of oxidized bases in the replicating genome, thus preventing mutagenic replication. A significant fraction of NEIL1 in cells is present in large cellular complexes containing DNA replication and other repair proteins, as shown by gel filtration. However, how the interaction of NEIL1 affects its recruitment to the replication site for prereplicative repair was not investigated. Here, we show that NEIL1 binarily interacts with the proliferating cell nuclear antigen clamp loader replication factor C, DNA polymerase δ, and DNA ligase I in the absence of DNA …

Ferritin Levels In The Cerebrospinal Fluid Predict Alzheimer's Disease Outcomes And Are Regulated By Apoe, Scott Ayton, Noel G. Faux, Ashley I. Bush, Charles D. Smith, Greg A. Jicha, Peter A. Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Alzheimer's Disease Neuroimaging Initiative

Neurology Faculty Publications

Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. …

Chaperone Hsp47 Drives Malignant Growth And Invasion By Modulating An Ecm Gene Network, Jieqing Zhu, Gaofeng Xiong, Hanjiang Fu, B. Mark Evers, Binhua P. Zhou, Ren Xu

Markey Cancer Center Faculty Publications

The extracellular matrix (ECM) is a determining factor in the tumor microenvironment that restrains or promotes malignant growth. In this report, we show how the molecular chaperone protein Hsp47 functions as a nodal hub in regulating an ECM gene transcription network. A transcription network analysis showed that Hsp47 expression was activated during breast cancer development and progression. Hsp47 silencing reprogrammed human breast cancer cells to form growth-arrested and/or noninvasive structures in 3D cultures, and to limit tumor growth in xenograft assays by reducing deposition of collagen and fibronectin. Coexpression network analysis also showed that levels of microRNA(miR)-29b and -29c were …

Apparent Role For Borrelia Burgdorferi Luxs During Mammalian Infection, William K. Arnold, Christina R. Savage, Alyssa D. Antonicello, Brian Stevenson

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The Lyme disease spirochete, Borrelia burgdorferi, controls protein expression patterns during its tick-mammal infection cycle. Earlier studies demonstrated that B. burgdorferi synthesizes 4,5-dihydroxy-2,3-pentanedione (autoinducer-2 [AI-2]) and responds to AI-2 by measurably changing production of several infection-associated proteins. luxS mutants, which are unable to produce AI-2, exhibit altered production of several proteins. B. burgdorferi cannot utilize the other product of LuxS, homocysteine, indicating that phenotypes of luxS mutants are not due to the absence of that molecule. Although a previous study found that a luxS mutant was capable of infecting mice, a critical caveat to those results is that bacterial …

G9a Is Essential For Emt-Mediated Metastasis And Maintenance Of Cancer Stem Cell-Like Characters In Head And Neck Squamous Cell Carcinoma, Shuli Liu, Dongxia Ye, Wenzheng Guo, Wenwen Yu, Yue He, Jingzhou Hu, Yanan Wang, Ling Zhang, Yueling Liao, Hongyong Song, Shuangshuang Zhong, Dongliang Xu, Huijing Yin, Beibei Sun, Xiaofei Wang, Jingyi Liu, Yadi Wu, Binhua P. Zhou, Zhiyuan Zhang, Jiong Deng

Markey Cancer Center Faculty Publications

Head and neck squamous cell carcinoma (HNSCC) is a particularly aggressive cancer with poor prognosis, largely due to lymph node metastasis and local recurrence. Emerging evidence suggests that epithelial-to-mesenchymal transition (EMT) is important for cancer metastasis, and correlated with increased cancer stem cells (CSCs) characteristics. However, the mechanisms underlying metastasis to lymph nodes in HNSCC is poorly defined. In this study, we show that E-cadherin repression correlates with cancer metastasis and poor prognosis in HNSCC. We found that G9a, a histone methyltransferase, interacts with Snail and mediates Snail-induced transcriptional repression of E-cadherin and EMT, through methylation of histone H3 lysine-9 …

Designer Receptors Enhance Memory In A Mouse Model Of Down Syndrome, Ashley M. Fortress, Eric D. Hamlett, Elena M. Vazey, Gary Aston-Jones, Wayne A. Cass, Heather A. Boger, Ann-Charlotte E. Granholm

Neuroscience Faculty Publications

Designer receptors exclusively activated by designer drugs (DREADDs) are novel and powerful tools to investigate discrete neuronal populations in the brain. We have used DREADDs to stimulate degenerating neurons in a Down syndrome (DS) model, Ts65Dn mice. Individuals with DS develop Alzheimer's disease (AD) neuropathology and have elevated risk for dementia starting in their 30s and 40s. Individuals with DS often exhibit working memory deficits coupled with degeneration of the locus coeruleus (LC) norepinephrine (NE) neurons. It is thought that LC degeneration precedes other AD-related neuronal loss, and LC noradrenergic integrity is important for executive function, working memory, and attention. …

Visualization-Aided Classification Ensembles Discriminate Lung Adenocarcinoma And Squamous Cell Carcinoma Samples Using Their Gene Expression Profiles, Ao Zhang, Chi Wang, Shiji Wang, Liang Li, Zhongmin Liu, Suyan Tian

Markey Cancer Center Faculty Publications

INTRODUCTION: The widespread application of microarray experiments to cancer research is astounding including lung cancer, one of the most common fatal human tumors. Among non-small cell lung carcinoma (NSCLC), there are two major histological types of NSCLC, adenocarcinoma (AC) and squamous cell carcinoma (SCC).

RESULTS: In this paper, we proposed to integrate a visualization method called Radial Coordinate Visualization (Radviz) with a suitable classifier, aiming at discriminating two NSCLC subtypes using patients' gene expression profiles. Our analyses on simulated data and a real microarray dataset show that combining with a classification method, Radviz may play a role in …

The P38alpha Mitogen-Activated Protein Kinase Limits The Cns Proinflammatory Cytokine Response To Systemic Lipopolysaccharide, Potentially Through An Il-10 Dependent Mechanism, Adam D. Bachstetter, Bin Xing, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: The p38α mitogen-activated protein kinase (MAPK) is a well-characterized intracellular kinase involved in the overproduction of proinflammatory cytokines from glia. As such, p38α appears to be a promising therapeutic target for neurodegenerative diseases associated with neuroinflammation. However, the in vivo role of p38α in cytokine production in the CNS is poorly defined, and prior work suggests that p38α may be affecting a yet to be identified negative feedback mechanism that limits the acute, injury-induced proinflammatory cytokine surge in the CNS.

METHODS: To attempt to define this negative feedback mechanism, we used two in vitro and two in vivo models …

Cyclic Di-Gmp-Dependent Signaling Pathways In The Pathogenic Firmicute Listeria Monocytogenes, Li-Hong Chen, Volkan K. Köseoğlu, Zehra T. Güvener, Tanya Myers-Morales, Joseph M. Reed, Sarah E. F. D'Orazio, Kurt W. Miller, Mark Gomelsky

Microbiology, Immunology, and Molecular Genetics Faculty Publications

We characterized key components and major targets of the c-di-GMP signaling pathways in the foodborne pathogen Listeria monocytogenes, identified a new c-di-GMP-inducible exopolysaccharide responsible for motility inhibition, cell aggregation, and enhanced tolerance to disinfectants and desiccation, and provided first insights into the role of c-di-GMP signaling in listerial virulence. Genome-wide genetic and biochemical analyses of c-di-GMP signaling pathways revealed that L. monocytogenes has three GGDEF domain proteins, DgcA (Lmo1911), DgcB (Lmo1912) and DgcC (Lmo2174), that possess diguanylate cyclase activity, and three EAL domain proteins, PdeB (Lmo0131), PdeC (Lmo1914) and PdeD (Lmo0111), that possess c-di-GMP phosphodiesterase activity. Deletion of all …

Rorα Binds To E2f1 To Inhibit Cell Proliferation And Regulate Mammary Gland Branching Morphogenesis, Gaofeng Xiong, Ren Xu

Markey Cancer Center Faculty Publications

Retinoic acid receptor-related orphan nuclear receptor alpha (RORα) is a potent tumor suppressor that reduces cell proliferation and inhibits tumor growth. However, the molecular mechanism by which it inhibits cell proliferation remains unknown. We demonstrate a noncanonical nuclear receptor pathway in which RORα binds to E2F1 to inhibit cell cycle progression. We showed that RORα bound to the heptad repeat and marked box region of E2F1 and suppressed E2F1-regulated transcription in epithelial cells. Binding of RORα inhibited E2F1 acetylation and its DNA-binding activity by recruiting histone deacetylase 1 (HDAC1) to the protein complexes. Knockdown of HDAC1 or inhibition of HDAC …

Vcam-1/Α4Β1 Integrin Interaction Is Crucial For Prompt Recruitment Of Immune T Cells Into The Brain During The Early Stage Of Reactivation Of Chronic Infection With Toxoplasma Gondii To Prevent Toxoplasmic Encephalitis, Qila Sa, Eri Ochiai, Tomoko Sengoku, Melinda E. Wilson, Morgan Brogli, Stephen Crutcher, Sara A. Michie, Baohui Xu, Laura Payne, Xisheng Wang, Yasuhiro Suzuki

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Reactivation of chronic infection with Toxoplasma gondii can cause life-threatening toxoplasmic encephalitis in immunocompromised individuals. We examined the role of VCAM-1/α4β1 integrin interaction in T cell recruitment to prevent reactivation of the infection in the brain. SCID mice were infected and treated with sulfadiazine to establish a chronic infection. VCAM-1 and ICAM-1 were the endothelial adhesion molecules detected on cerebral vessels of the infected SCID and wild-type animals. Immune T cells from infected wild-type mice were treated with anti-α4 integrin or control antibodies and transferred into infected SCID or nude mice, and the animals received the same antibody every other …

Psmb9 Codon 60 Polymorphisms Have No Impact On The Activity Of The Immunoproteasome Catalytic Subunit B1i Expressed In Multiple Types Of Solid Cancer, Ji Eun Park, Lin Ao, Zachary Miller, Kyungbo Kim, Ying Wu, Eun Ryoung Jang, Eun Young Lee, Kyung Bo Kim, Wooin Lee

Pharmaceutical Sciences Faculty Publications

The proteasome is a key regulator of cellular protein homeostasis and is a clinically validated anticancer target. The immunoproteasome, a subtype of proteasome expressed mainly in hematopoietic cells, was initially recognized for its role in antigen presentation during the immune response. Recently, the immunoproteasome has been implicated in several disease conditions including cancer and autoimmune disorders, but many of the factors contributing to these pathological processes remain unknown. In particular, the codon 60 polymorphism of the PSMB9 gene encoding the β1i immunoproteasome catalytic subunit has been investigated in the context of a variety of diseases. Despite this, previous studies have …

Withaferin A Effectively Targets Soluble Vimentin In The Glaucoma Filtration Surgical Model Of Fibrosis, Paola Bargagna-Mohan, Sunil P. Deokule, Kyle G. Thompson, John Wizeman, Cidambi Srinivasan, Sunil Vooturi, Uday B. Kompella, Royce Mohan

Ophthalmology and Visual Science Faculty Publications

Withaferin A (WFA) is a natural product that binds to soluble forms of the type III intermediate filament (IF) vimentin. Currently, it is unknown under what pathophysiological contexts vimentin is druggable, as cytoskeltal vimentin-IFs are abundantly expressed. To investigate druggability of vimentin, we exploited rabbit Tenon's capsule fibroblast (RbTCF) cell cultures and the rabbit glaucoma filtration surgical (GFS) model of fibrosis. WFA potently caused G₀/G₁ cell cycle inhibition (IC₅₀ 25 nM) in RbTCFs, downregulating ubiquitin E3 ligase skp2 and inducing p27(Kip1) expression. Transforming growth factor (TGF)-ß-induced myofibroblast transformation caused development of cell spheroids with numerous elongated invadopodia, which WFA blocked …