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The Eagleville Times,Volume 5, Issue 17 (October), Debbie Ryan

Eagleville Times

No abstract provided.

Osteopontin Mediates Obesity-Induced Adipose Tissue Macrophage Infiltration And Insulin Resistance In Mice, Takashi Nomiyama, Diego Perez-Tilve, Daisuke Ogawa, Florence Gizard, Yue Zhao, Elizabeth B. Heywood, Karrie L. Jones, Ryuzo Kawamori, Lisa A. Cassis, Matthias H. Tschöp, Dennis Bruemmer

Internal Medicine Faculty Publications

Obesity is associated with a state of chronic, low-grade inflammation characterized by abnormal cytokine production and macrophage infiltration into adipose tissue, which may contribute to the development of insulin resistance. During immune responses, tissue infiltration by macrophages is dependent on the expression of osteopontin, an extracellular matrix protein and proinflammatory cytokine that promotes monocyte chemotaxis and cell motility. In the present study, we used a murine model of diet-induced obesity to examine the role of osteopontin in the accumulation of adipose tissue macrophages and the development of insulin resistance during obesity. Mice exposed to a high-fat diet exhibited increased plasma …

A Simple Array Platform For Microrna Analysis And Its Application In Mouse Tissues, Xiaoqing Tang, Jozsef Gal, Xun Zhuang, Wang-Xia Wang, Haining Zhu, Guiliang Tang

Plant and Soil Sciences Faculty Publications

MicroRNAs (miRNAs) are a novel class of small noncoding RNAs that regulate gene expression at the post-transcriptional level and play a critical role in many important biological processes. Most miRNAs are conserved between humans and mice, which makes it possible to analyze their expressions with a set of selected array probes. Here, we report a simple array platform that can detect 553 nonredundant miRNAs encompassing the entire set of miRNAs for humans and mice. The platform features carefully selected and designed probes with optimized hybridization parameters. Potential cross-reaction between mature miRNAs and their precursors was investigated. The array platform was …

Mutations In The Cofilin Partner Aip1/Wdr1 Cause Autoinflammatory Disease And Macrothrombocytopenia, Benjamin T Kile, Athanasia D Panopoulos, Roslynn A Stirzaker, Douglas F Hacking, Lubna H Tahtamouni, Tracy A Willson, Lisa A Mielke, Katya J Henley, Jian-Guo Zhang, Ian P Wicks, William S Stevenson, Paquita Nurden, Stephanie S Watowich, Monica J Justice

Faculty, Staff and Student Publications

A pivotal mediator of actin dynamics is the protein cofilin, which promotes filament severing and depolymerization, facilitating the breakdown of existing filaments, and the enhancement of filament growth from newly created barbed ends. It does so in concert with actin interacting protein 1 (Aip1), which serves to accelerate cofilin's activity. While progress has been made in understanding its biochemical functions, the physiologic processes the cofilin/Aip1 complex regulates, particularly in higher organisms, are yet to be determined. We have generated an allelic series for WD40 repeat protein 1 (Wdr1), the mammalian homolog of Aip1, and report that reductions in Wdr1 function …

Downregulation Of Rap1gap Contributes To Ras Transformation, Oxana Tsygankova, Gregory V. Prendergast, Kanchan Puttaswamy, Yan Wang, Michael D. Feldman, Hongbin Wang, Marcia S. Brose, Judy L. Meinkoth

Faculty, Staff and Student Publications

Although abundant in well-differentiated rat thyroid cells, Rap1GAP expression was extinguished in a subset of human thyroid tumor-derived cell lines. Intriguingly, Rap1GAP was downregulated selectively in tumor cell lines that had acquired a mesenchymal morphology. Restoring Rap1GAP expression to these cells inhibited cell migration and invasion, effects that were correlated with the inhibition of Rap1 and Rac1 activity. The reexpression of Rap1GAP also inhibited DNA synthesis and anchorage-independent proliferation. Conversely, eliminating Rap1GAP expression in rat thyroid cells induced a transient increase in cell number. Strikingly, Rap1GAP expression was abolished by Ras transformation. The downregulation of Rap1GAP by Ras required the …

Computational Identification And Functional Validation Of Regulatory Motifs In Cartilage-Expressed Genes, Sherri R Davies, Li-Wei Chang, Debabrata Patra, Xiaoyun Xing, Karen Posey, Jacqueline Hecht, Gary D Stormo, Linda J Sandell

Faculty, Staff and Student Publications

Chondrocyte gene regulation is important for the generation and maintenance of cartilage tissues. Several regulatory factors have been identified that play a role in chondrogenesis, including the positive transacting factors of the SOX family such as SOX9, SOX5, and SOX6, as well as negative transacting factors such as C/EBP and delta EF1. However, a complete understanding of the intricate regulatory network that governs the tissue-specific expression of cartilage genes is not yet available. We have taken a computational approach to identify cis-regulatory, transcription factor (TF) binding motifs in a set of cartilage characteristic genes to better define the transcriptional regulatory …

The Dogs Of Western, Lynn E. Niedermeier

WKU History

Throughout Western's history, dogs belonging to faculty and staff, as well as strays who simply appear and make the Hill their home, have earned the affection of the campus community. A few of their stories are told here.

In Vivo Construction Of Recombinant Molecules Within The Caenorhabditis Elegans Germ Line Using Short Regions Of Terminal Homology, Benedict J. Kemp, Julia Hatzold, Laura A. Sternick, Joshua Cornman-Homonoff, Jessica M. Whitaker, Pamela J. Tieu, Eric J. Lambie

Dartmouth Scholarship

Homologous recombination provides a means for the in vivoconstruction of recombinant DNA molecules that may be problematic to assemble in vitro . We have investigated the efficiency of recombination within the Caenorhabditis elegans germ line as a function of the length of homology between recombining molecules. Our findings indicate that recombination can occur between molecules that share only 10 bp of terminal homology, and that 25 bp is sufficient to mediate relatively high levels of recombination. Recombination occurs with lower efficiency when the location of the homologous segment is subterminal or internal. As in yeast, recombination can also be …

The Eagleville Times,Volume 5, Issue 18, Debbie Ryan

Eagleville Times

No abstract provided.

Western Diet, But Not High Fat Diet, Causes Derangements Of Fatty Acid Metabolism And Contractile Dysfunction In The Heart Of Wistar Rats, Christopher R Wilson, Mai K Tran, Katrina L Salazar, Martin E Young, Heinrich Taegtmeyer

Faculty, Staff and Student Publications

Obesity and diabetes are associated with increased fatty acid availability in excess of muscle fatty acid oxidation capacity. This mismatch is implicated in the pathogenesis of cardiac contractile dysfunction and also in the development of skeletal-muscle insulin resistance. We tested the hypothesis that 'Western' and high fat diets differentially cause maladaptation of cardiac- and skeletal-muscle fatty acid oxidation, resulting in cardiac contractile dysfunction. Wistar rats were fed on low fat, 'Western' or high fat (10, 45 or 60% calories from fat respectively) diet for acute (1 day to 1 week), short (4-8 weeks), intermediate (16-24 weeks) or long (32-48 weeks) …

Characterization Of The Equine 2'-5' Oligoadenylate Synthetase 1 (Oas1) And Ribonuclease L (Rnasel) Innate Immunity Genes, Jonathan J. Rios, Andrey A. Perelygin, Maureen T. Long, Teri L. Lear, Andrey A. Zharkikh, Margo A. Brinton, David L. Adelson

Veterinary Science Faculty Publications

BACKGROUND: The mammalian OAS/RNASEL pathway plays an important role in antiviral host defense. A premature stop-codon within the murine Oas1b gene results in the increased susceptibility of mice to a number of flaviviruses, including West Nile virus (WNV). Mutations in either the OAS1 or RNASEL genes may also modulate the outcome of WNV-induced disease or other viral infections in horses. Polymorphisms in the human OAS gene cluster have been previously utilized for case-control analysis of virus-induced disease in humans. No polymorphisms have yet been identified in either the equine OAS1 or RNASEL genes for use in similar case-control studies.

RESULTS: …

The Eagleville Times,Volume 5, Issue 17 (September), Debbie Ryan

Eagleville Times

No abstract provided.

Recent Advances In Cancer Stem/Progenitor Cell Research: Therapeutic Implications For Overcoming Resistance To The Most Aggressive Cancers., M. Mimeault, Ralph Hauke, Parmender P. Mehta, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Overcoming intrinsic and acquired resistance of cancer stem/progenitor cells to current clinical treatments represents a major challenge in treating and curing the most aggressive and metastatic cancers. This review summarizes recent advances in our understanding of the cellular origin and molecular mechanisms at the basis of cancer initiation and progression as well as the heterogeneity of cancers arising from the malignant transformation of adult stem/progenitor cells. We describe the critical functions provided by several growth factor cascades, including epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor (SCF) receptor (KIT), hedgehog and Wnt/beta-catenin signalling pathways that …

14-3-3 Proteins Interact With The Beta-Thymosin Repeat Protein Csp24, Terry Crow, Juan-Juan Xue-Bian, Joseph T Neary

Faculty, Staff and Student Publications

Conditioned stimulus pathway protein 24 (Csp24) is a beta-thymosin-like protein that is homologous to other members of the family of beta-thymosin repeat proteins that contain multiple actin binding domains. Actin co-precipitates with Csp24 and co-localizes with it in the cytosol of type-B photoreceptor cell bodies. Several signal transduction pathways have been shown to regulate the phosphorylation of Csp24 and contribute to cellular plasticity. Here, we report the identification of the adapter protein 14-3-3 in lysates of the Hermissenda circumesophageal nervous system and its interaction with Csp24. Immunoprecipitation experiments using an antibody that is broadly reactive with several isoforms of the …

Phosphorylation-Induced Conformational Switching Of Cpi-17 Produces A Potent Myosin Phosphatase Inhibitor, Masumi Eto, Toshio Kitazawa, Fumiko Matsuzawa, Sei-Ichi Aikawa, Jason A. Kirkbride, Noriyoshi Isozumi, Yumi Nishimura, David L. Brautigan, Shin-Ya Ohki

Department of Molecular Physiology and Biophysics Faculty Papers

Phosphorylation of endogenous inhibitor proteins specific for type-1 Ser/Thr phosphatase (PP1) provides a mechanism for reciprocal coordination of kinase and phosphatase activities. Phosphorylation of Thr38 in the inhibitor protein CPI-17 transduces G-protein-mediated signaling into a > 1000-fold increase of inhibitory potency toward myosin phosphatase. We show here the solution NMR structure of phospho-T38-CPI-17 with r. m. s. d. of 0.36 ± 0.06 Å for the backbone secondary structure, which reveals how phosphorylation triggers a conformational change and exposes the PP1 inhibitory surface. This active conformation is stabilized by the formation of a hydrophobic core of intercalated side-chains, which is not formed …

The Eagleville Times,Volume 5, Issue 16, Debbie Ryan

Eagleville Times

No abstract provided.

All-Trans Retinoic Acid Mediates Enhanced T Reg Cell Growth, Differentiation, And Gut Homing In The Face Of High Levels Of Co-Stimulation, Micah J. Benson, Karina Pino-Lagos, Mario Rosemblatt, Randolph J. Noelle

Dartmouth Scholarship

We demonstrate that all-trans retinoic acid (RA) induces FoxP3(+) adaptive T regulatory cells (A-Tregs) to acquire a gut-homing phenotype (alpha 4 beta 7(+) CC chemokine receptor 9(+)) and the capacity to home to the lamina propria of the small intestine. Under conditions that favor the differentiation of A-Tregs (transforming growth factor-beta1 and interleukin 2) in vitro, the inclusion of RA induces nearly all activated CD4(+) T cells to express FoxP3 and greatly increases the accumulation of these cells. In the absence of RA, A-Treg differentiation is abruptly impaired by proficient antigen presenting cells or through direct co-stimulation. In the presence …

Molecular Determinants Of Mg2+ And Ca2+ Permeability And Ph Sensitivity In Trpm6 And Trpm7*S, Mingjiang Li, Jianyang Du, Jianmin Jiang, William J. Ratzan, Li-Ting Su, Loren W. Runnels, Lixia Yue

UCHC Articles - Research

The channel kinases TRPM6 and TRPM7 have recently been discovered to play important roles in Mg²⁺ and Ca²⁺ homeostasis, which is critical to both human health and cell viability. However, the molecular basis underlying these channels’ unique Mg²⁺ and Ca²⁺ permeability and pH sensitivity remains unknown. Here we have created a series of amino acid substitutions in the putative pore of TRPM7 to evaluate the origin of the permeability of the channel and its regulation by pH. Two mutants of TRPM7, E1047Q and E1052Q, produced dramatic changes in channel properties. The I–V relations of E1052Q and …

The Failed Regulatory System For Animal Imports Into The United States – And How To Fix It, Peter Jenkins

Managing Vertebrate Invasive Species

This paper provides a synopsis of the Defenders of Wildlife report entitled Broken Screens: The Regulation of Live Animal Imports in the United States, released in August 2007. That report assessed the complex federal system for regulating live wild animal imports as applied to the 2,241 non-native species that were identified in United States Fish and Wildlife Service records as being imported between 2000 and 2004, inclusive. The report describes the “coarse risk screening” conducted for those species by searching the scientific literature and United States and international databases. If one or more reliable sources indicated a species was …

The Eagleville Times,Volume 5, Issue 15, Debbie Ryan

Eagleville Times

No abstract provided.

Chronic Administration Of R-Flurbiprofen Attenuates Learning Impairments In Transgenic Amyloid Precursor Protein Mice, Thomas Kukar, Sonya Prescott, Jason L. Eriksen, Vallie Holloway, M. Paul Murphy, Edward H. Koo, Todd E. Golde, Michelle M. Nicolle

Molecular and Cellular Biochemistry Faculty Publications

BACKGROUND: Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). We and others have shown that certain NSAIDs reduce secretion of Abeta42 in cell culture and animal models, and that the effect of NSAIDs on Abeta42 is independent of the inhibition of cyclooxygenase by these compounds. Since Abeta42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Abeta42 selectively may be associated with their protective effect. We have previously identified R-flurbiprofen (tarenflurbil) as a selective Abeta42 lowering agent with greatly reduced cyclooxygenase activity that …

The Eagleville Times,Volume 5, Issue 14, Debbie Ryan

Eagleville Times

No abstract provided.

Phenotypic Alterations In Type Ii Alveolar Epithelial Cells In Cd4+ T Cell Mediated Lung Inflammation, Marcus Gereke, Lothar Gröbe, Silvia Prettin, Michael Kasper, Stefanie Deppenmeier, Achim D. Gruber, Richard I. Enelow, Jan Buer, Dunja Bruder

Dartmouth Scholarship

Although the contribution of alveolar type II epithelial cell (AEC II) activities in various aspects of respiratory immune regulation has become increasingly appreciated, our understanding of the contribution of AEC II transcriptosome in immunopathologic lung injury remains poorly understood. We have previously established a mouse model for chronic T cell-mediated pulmonary inflammation in which influenza hemagglutinin (HA) is expressed as a transgene in AEC II, in mice expressing a transgenic T cell receptor specific for a class II-restricted epitope of HA. Pulmonary inflammation in these mice occurs as a result of CD4+ T cell recognition of alveolar antigen. This model …

Regulation Of Meiotic Cohesion And Chromosome Core Morphogenesis During Pachytene In Drosophila Oocytes, Radhika S. Khetani, Sharon E. Bickel

Dartmouth Scholarship

During meiosis, cohesion between sister chromatids is required for normal levels of homologous recombination, maintenance of chiasmata and accurate chromosome segregation during both divisions. In Drosophila, null mutations in the ord gene abolish meiotic cohesion, although how ORD protein promotes cohesion has remained elusive. We show that SMC subunits of the cohesin complex colocalize with ORD at centromeres of ovarian germ-line cells. In addition, cohesin SMCs and ORD are visible along the length of meiotic chromosomes during pachytene and remain associated with chromosome cores following DNase I digestion. In flies lacking ORD activity, cohesin SMCs fail to accumulate at oocyte …

Pp2cdelta (Ppm1d, Wip1), An Endogenous Inhibitor Of P38 Mapk, Is Regulated Along With Trp53 And Cdkn2a Following P38 Mapk Inhibition During Mouse Preimplantation Development., Jenny A Hickson, Barry Fong, Patricia H Watson, Andrew J Watson

Obstetrics & Gynaecology Publications

Preimplantation embryos utilize mitogen-activated protein kinase signaling (MAPK) pathways to relay signals from the external environment to prepare appropriate responses and adaptations to a changing milieu. It is therefore important to investigate how MAPK pathways are regulated during preimplantation development. This study was conducted to investigate whether PP2Cdelta (Ppm1d, WIP1) is expressed during mouse preimplantation development and to determine the influences of p38 MAPK inhibition on expression of Trp53 (p53), Ppm1d, (WIP1), and Cdkn2a (p16) during mouse preimplantation development. Our results indicate that Trp53, Ppm1d, and Cdkn2a mRNAs and TRP53 and PP2Cdelta proteins are expressed throughout mouse preimplantation development. Treatment …

Energizing Mirna Research: A Review Of The Role Of Mirnas In Lipid Metabolism, With A Prediction That Mir-103/107 Regulates Human Metabolic Pathways, Bernard R. Wilfred, Wang-Xia Wang, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

MicroRNAs (miRNAs) are powerful regulators of gene expression. Although first discovered in worm larvae, miRNAs play fundamental biological roles-including in humans-well beyond development. MiRNAs participate in the regulation of metabolism (including lipid metabolism) for all animal species studied. A review of the fascinating and fast-growing literature on miRNA regulation of metabolism can be parsed into three main categories: (1) adipocyte biochemistry and cell fate determination; (2) regulation of metabolic biochemistry in invertebrates; and (3) regulation of metabolic biochemistry in mammals. Most research into the 'function' of a given miRNA in metabolic pathways has concentrated on a given miRNA acting upon …

The Eagleville Times,Volume 5, Issue 13, Debbie Ryan

Eagleville Times

No abstract provided.

Neural Reprogramming In Retinal Degeneration, Robert E Marc, Bryan W Jones, James R Anderson, Krista Kinard, David W Marshak, John H Wilson, Theodore Wensel, Robert J Lucas

Faculty, Staff and Student Publications

PURPOSE: Early visual defects in degenerative diseases such as retinitis pigmentosa (RP) may arise from phased remodeling of the neural retina. The authors sought to explore the functional expression of ionotropic (iGluR) and group 3, type 6 metabotropic (mGluR6) glutamate receptors in late-stage photoreceptor degeneration.

METHODS: Excitation mapping with organic cations and computational molecular phenotyping were used to determine whether retinal neurons displayed functional glutamate receptor signaling in rodent models of retinal degeneration and a sample of human RP.

RESULTS: After photoreceptor loss in rodent models of RP, bipolar cells lose mGluR6 and iGluR glutamate-activated currents, whereas amacrine and ganglion …

The Eagleville Times,Volume 5, Issue 12, Debbie Ryan

Eagleville Times

No abstract provided.

Meeting Report: The Role Of Environmental Lighting And Circadian Disruption In Cancer And Other Diseases, Richard G. Stevens, David E. Blask, George C. Brainard, Johnni Hansen, Steven W. Lockley, Ignacio Provencio, Mark S. Rea, Leslie Reinlib

Department of Neurology Faculty Papers

Light, including artificial light, has a range of effects on human physiology and behavior and can therefore alter human physiology when inappropriately timed. One example of potential light-induced disruption is the effect of light on circadian organization, including the production of several hormone rhythms. Changes in light-dark exposure (e.g., by nonday occupation or transmeridian travel) shift the timing of the circadian system such that internal rhythms can become desynchronized from both the external environment and internally with each other, impairing our ability to sleep and wake at the appropriate times and compromising physiologic and metabolic processes. Light can also have …