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Sample records for biology ccr national

  1. CEPPAD, CAMMICE, and RAPID (CCR) Data from Los Alamos National Laboratory (LANL)

    DOE Data Explorer

    The Comprehensive Energetic Particle and Pitch Angle Distribution (CEPPAD) Experiment, the Charge and Mass Magnetospheric Ion Composition Experiment (CAMMICE), and the experiment for Research with Adaptive Particle Imaging Detectors (RAPID) refer to specific instruments mounted on the Polar satellite launched by NASA in February of 1996 and the Cluster II spacecraft launched in 2000 under the auspices of the European Space Operations Centre (ESOC), Germany. All three instruments are participating in the International Solar Terrestrial Physics Program (ISTP), to which the Global Geospace Science Program (GGSP) is the U.S. contribution. The CCR Science Team is composed of members of three instrument teams on the ISTP satellites POLAR and CLUSTER. DOE's Los Alamos National Laboratory is part of that team, and the CCR website is maintained at LANL. CCR Summary Data Plots are available from the LANL website through either the specialized browser or as digitized data from an anonymous FTP. ISTP data of various kinds can be obtained from NASA at http://pwg.gsfc.nasa.gov/istp/

  2. Design, Synthesis and Biological Evaluation of Novel Piperazine Derivatives as CCR5 Antagonists

    PubMed Central

    Liu, Tao; Weng, Zhiyong; Dong, Xiaowu; Chen, Linjie; Ma, Ling; Cen, Shan; Zhou, Naiming; Hu, Yongzhou

    2013-01-01

    By using a fragment-assembly strategy and bioisosteric-replacement principle, a series of novel piperazine derivatives were designed, synthesized, and evaluated for their cellular target-effector fusion activities and in vitro antiviral activities against HIV-1. Preliminary structure-activity relationships (SARs) of target compounds were concluded in this study, and five compounds were found to exhibited medium to potent CCR5 fusion activities with IC50 values in low micromolar level. Among evaluated compounds, 23 h was found to be a CCR5 antagonist with an IC50 value of 6.29 µM and an anti-HIV-1 inhibitor with an IC50 value of 0.44 µM. PMID:23308267

  3. CCR1 and CCR5 promote hepatic fibrosis in mice

    PubMed Central

    Seki, Ekihiro; De Minicis, Samuele; Gwak, Geum-Youn; Kluwe, Johannes; Inokuchi, Sayaka; Bursill, Christina A.; Llovet, Josep M.; Brenner, David A.; Schwabe, Robert F.

    2009-01-01

    Hepatic fibrosis develops as a response to chronic liver injury and almost exclusively occurs in a proinflammatory environment. However, the role of inflammatory mediators in fibrogenic responses of the liver is only poorly understood. We therefore investigated the role of CC chemokines and their receptors in hepatic fibrogenesis. The CC chemokines MIP-1α, MIP-1β, and RANTES and their receptors CCR1 and CCR5 were strongly upregulated in 2 experimental mouse models of fibrogenesis. Neutralization of CC chemokines by the broad-spectrum CC chemokine inhibitor 35k efficiently reduced hepatic fibrosis, and CCR1- and CCR5-deficient mice displayed substantially reduced hepatic fibrosis and macrophage infiltration. Analysis of fibrogenesis in CCR1- and CCR5-chimeric mice revealed that CCR1 mediates its profibrogenic effects in BM-derived cells, whereas CCR5 mediates its profibrogenic effects in resident liver cells. CCR5 promoted hepatic stellate cell (HSC) migration through a redox-sensitive, PI3K-dependent pathway. Both CCR5-deficient HSCs and CCR1- and CCR5-deficient Kupffer cells displayed strong suppression of CC chemokine–induced migration. Finally, we detected marked upregulation of RANTES, CCR1, and CCR5 in patients with hepatic cirrhosis, confirming activation of the CC chemokine system in human fibrogenesis. Our data therefore support a role for the CC chemokine system in hepatic fibrogenesis and suggest distinct roles for CCR1 and CCR5 in Kupffer cells and HSCs. PMID:19603542

  4. Synthesis and biological evaluation of 1,3,3,4-tetrasubstituted pyrrolidine CCR5 receptor antagonists. Discovery of a potent and orally bioavailable anti-HIV agent.

    PubMed

    Ma, Dawei; Yu, Shanghai; Li, Ben; Chen, Li; Chen, Renhai; Yu, Kunqian; Zhang, Linqi; Chen, Zhiwei; Zhong, Dafang; Gong, Zheng; Wang, Renxiao; Jiang, Hualiang; Pei, Gang

    2007-02-01

    A series of 1,3,3,4-tetrasubstituted pyrrolidine containing CCR5 receptor antagonists were designed, which were elaborated either by condensation of a lithium salt of 3-(N,N-dibenzyl)aminopropionic acid methyl ester with ethyl benzoformate or by Baylis-Hillman reaction of ethyl acrylate with ethyl benzoformate and subsequent 1,4-addition of benzylamine, in the key steps. These compounds bearing 4-(N,N-disubstituted)amino piperidine units showed low nanomolar potency against the CCR5 receptor, whereas molecules with a 4-phenylpiperidine moiety displayed poor activity. Asymmetric synthesis of the most potent compound 23 a gave rise to the (3R,4S)-enantiomer 30 and the (3S,4R)-enantiomer 31, which showed IC(50) values of 2.9 and 385.9 nM, respectively. These results indicated that (3R,4S)-configuration in the series of compounds is favored for their interaction with the CCR5 receptor. The possible binding mode of these antagonists with the CCR5 receptor was discussed using a computer-modeling method. Compound 30 displayed excellent replication inhibition of seven genetically diverse R5 HIV-1 strains in the PBMC model, in a concentration-dependent manner with EC(50) values ranging from 0.3 nM to 30 nM. This molecule showed oral bioavailabilities of 41.2 % and 21.6 % in rats and dogs, respectively. Thus, compound 30 is a promising candidate for the treatment of HIV-1 infection. PMID:17163560

  5. Spiropiperidine CCR5 antagonists.

    PubMed

    Rotstein, David M; Gabriel, Stephen D; Makra, Ferenc; Filonova, Lubov; Gleason, Shelley; Brotherton-Pleiss, Christine; Setti, Lina Q; Trejo-Martin, Alejandra; Lee, Eun Kyung; Sankuratri, Surya; Ji, Changhua; Derosier, Andre; Dioszegi, Marianna; Heilek, Gabrielle; Jekle, Andreas; Berry, Pamela; Weller, Paul; Mau, Cheng-I

    2009-09-15

    A novel series of CCR5 antagonists has been identified, utilizing leads from high-throughput screening which were further modified based on insights from competitor molecules. Lead optimization was pursued by balancing opposing trends of metabolic stability and potency. Selective and potent analogs with good pharmacokinetic properties were successfully developed. PMID:19674898

  6. Design, synthesis, and biological evaluation of the combinatorial library with a new spirodiketopiperazine scaffold. Discovery of novel potent and selective low-molecular-weight CCR5 antagonists.

    PubMed

    Habashita, Hiromu; Kokubo, Masaya; Hamano, Shin-ichi; Hamanaka, Nobuyuki; Toda, Masaaki; Shibayama, Shiro; Tada, Hideaki; Sagawa, Kenji; Fukushima, Daikichi; Maeda, Kenji; Mitsuya, Hiroaki

    2006-07-13

    We previously reported the discovery of several spirodiketopiperazine derivatives as potent CCR5 antagonists with anti-HIV activity. Herein, we describe in detail the identification of these lead compounds using a combinatorial chemistry approach. A novel spirodiketopiperazine scaffold was designed on the basis of the concept of the privileged structure of G-protein-coupled receptors (GPCRs). This new framework was obtained in acceptable yield with high purity from the readily prepared isonitrile resin through the Ugi reaction, sequential transformations, and cyclative cleavage. By measuring the inhibitory activity of each compound in the initial library against the intracellular calcium mobilization stimulated by MIP-1alpha, several compounds were found to show modest but selective CCR5 antagonistic activity. After the rapid evaluation of these hit compounds, several single-digit nanomolar, low-molecular-weight CCR5 antagonists that can potently block the infectivity and replication of laboratory and clinical strains of HIV as well as those of highly drug-resistant HIV variants with minimal cytotoxicity have been identified. PMID:16821774

  7. Discovery of indole inhibitors of chemokine receptor 9 (CCR9).

    PubMed

    Pandya, Bhaumik A; Baber, Christian; Chan, Audrey; Chamberlain, Brian; Chandonnet, Haoqun; Goss, Jennifer; Hopper, Timothy; Lippa, Blaise; Poutsiaka, Katherine; Romero, Jan; Stucka, Sabrina; Varoglu, Mustafa; Zhang, Jing; Zhang, Xin

    2016-07-15

    Irritable bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) are serious chronic diseases affecting millions of patients worldwide. Studies of human chemokine biology has suggested C-C chemokine receptor 9 (CCR9) may be a key mediator of pro-inflammatory signaling. Discovery of agents that inhibit CCR9 may lead to new therapies for CD and UC patients. Herein we describe the evolution of a high content screening hit (1) into potent inhibitors of CCR9, such as azaindole 12. PMID:27256913

  8. Characterization of the "CCR5" Chemokine Receptor Gene

    ERIC Educational Resources Information Center

    Thomas, John C.

    2004-01-01

    The life cycle of retroviruses is an essential topic of modern cell biology instruction. Furthermore, the process of HIV viral entry into the cell is a question of great interest in basic and clinical biology. This paper describes how students can easily recover their own DNA, amplify a portion of the "CCR5" chemokine receptor gene, characterize…

  9. MicroRNAs expression profile in CCR6+ regulatory T cells

    PubMed Central

    Hu, Yan; Chen, Chao; Zhou, Ya; Tao, Yijin; Guo, Mengmeng; Qin, Nalin

    2014-01-01

    Backgroud. CCR6+ CD4+ regulatory T cells (CCR6+ Tregs), a distinct Tregs subset, played an important role in various immune diseases. Recent evidence showed that microRNAs (miRNAs) are vital regulators in the function of immune cells. However, the potential role of miRNAs in the function of CCR6+ Tregs remains largely unknown. In this study, we detected the expression profile of miRNAs in CCR6+ Tregs. Materials and Methods. The expression profile of miRNAs as well as genes in CCR6+ Tregs or CCR6- Tregs from Balb/c mice were detected by microarray. The signaling pathways were analyzed using the Keggs pathway library. Results. We found that there were 58 miRNAs significantly upregulated and 62 downregulated up to 2 fold in CCR6+ Tregs compared with CCR6- Tregs. Moreover, 1,391 genes were observed with 3 fold change and 20 signaling pathways were enriched using the Keggs pathway library. Conclusion. The present data showed CCR6+ Tregs expressed specific miRNAs pattern, which provides insight into the role of miRNAs in the biological function of distinct Tregs subsets. PMID:25279261

  10. CCR7 regulates B16 murine melanoma cell tumorigenesis in skin.

    PubMed

    Fang, Lei; Lee, Vivian C; Cha, Emily; Zhang, Hong; Hwang, Sam T

    2008-10-01

    Tumor cell-associated chemokine receptors play distinct roles in cancer biology, including enhancement of lymph node (LN) metastasis. To determine if CCR7 influences tumor formation in skin, we inoculated B16 cells transduced with CCR7 and luciferase (CCR7-luc-B16) or with retroviral vector and luciferase (pLNCX2-luc-B16) into ear skin and footpads of wild-type (WT) mice. In contrast to pLNCX2-luc-B16 cells, 97% of CCR7-luc-B16 cell-inoculated mice formed skin tumors as well as cervical LN metastases by Day 21 following ear inoculation. CCR7-expressing and control B16 cells, however, formed tumors of similar size and with high-efficiency in SCID-beige mice. Cells from both lines accumulated in the skin of WT mice in similar numbers until Day 7. By Day 11, however, control cells decreased tenfold, whereas CCR7-luc-B16 cells formed small tumor nodules. Tumor cells were infrequently detected in draining cervical LNs up to 11 days after injection of both cell lines, but stable nodal metastases were only observed after CCR7-luc-B16 ear tumors had been established (Day 21). ELISPOT assays revealed that IFN--producing cells in draining LNs from CCR7-luc-B16-injected ears were reduced through Day 7. After footpad injection, tumor formation by CCR7-expressing B16 cells was enhanced only with small, initial tumor cell inocula. With larger inocula, tumor formation was equivalent, but the numbers of tumor-infiltrating leukocytes were reduced by approximately sixfold in CCR7-B16 tumors compared with pLNCX2-B16 tumors of equal size. IFN- and CXCL10 were reduced 35- and sixfold, respectively, in CCR7-B16 cell tumors (vs. control tumors). Thus, CCR7 expression enhances tumorigenesis in addition to facilitating LN metastasis. PMID:18519742

  11. The National Biological Information Infrastructure: Coming of Age.

    ERIC Educational Resources Information Center

    Cotter, Gladys; Frame, Mike; Sepic, Ron; Zolly, Lisa

    2000-01-01

    Coordinated by the U.S. Geological Survey, the National Biological Information Infrastructure (NBII) is a Web-based system that provides increased access to data and information on the nation's biological resources. This article-an individual case study-addresses the structure of the NBII related to thematic, infrastructure and place-based…

  12. Elucidating a Key Anti-HIV-1 and Cancer-Associated Axis: The Structure of CCL5 (Rantes) in Complex with CCR5

    NASA Astrophysics Data System (ADS)

    Tamamis, Phanourios; Floudas, Christodoulos A.

    2014-06-01

    CCL5 (RANTES) is an inflammatory chemokine which binds to chemokine receptor CCR5 and induces signaling. The CCL5:CCR5 associated chemotactic signaling is of critical biological importance and is a potential HIV-1 therapeutic axis. Several studies provided growing evidence for the expression of CCL5 and CCR5 in non-hematological malignancies. Therefore, the delineation of the CCL5:CCR5 complex structure can pave the way for novel CCR5-targeted drugs. We employed a computational protocol which is primarily based on free energy calculations and molecular dynamics simulations, and report, what is to our knowledge, the first computationally derived CCL5:CCR5 complex structure which is in excellent agreement with experimental findings and clarifies the functional role of CCL5 and CCR5 residues which are associated with binding and signaling. A wealth of polar and non-polar interactions contributes to the tight CCL5:CCR5 binding. The structure of an HIV-1 gp120 V3 loop in complex with CCR5 has recently been derived through a similar computational protocol. A comparison between the CCL5 : CCR5 and the HIV-1 gp120 V3 loop : CCR5 complex structures depicts that both the chemokine and the virus primarily interact with the same CCR5 residues. The present work provides insights into the blocking mechanism of HIV-1 by CCL5.

  13. Commentary: Biochemistry and Molecular Biology Educators Launch National Network

    ERIC Educational Resources Information Center

    Bailey, Cheryl; Bell, Ellis; Johnson, Margaret; Mattos, Carla; Sears, Duane; White, Harold B.

    2010-01-01

    The American Society of Biochemistry and Molecular Biology (ASBMB) has launched an National Science Foundation (NSF)-funded 5 year project to support biochemistry and molecular biology educators learning what and how students learn. As a part of this initiative, hundreds of life scientists will plan and develop a rich central resource for…

  14. Peripheral Blood CCR4+CCR6+ and CXCR3+CCR6+ CD4+ T Cells Are Highly Permissive to HIV-1 Infection

    PubMed Central

    Gosselin, Annie; Monteiro, Patricia; Chomont, Nicolas; Diaz-Griffero, Felipe; Said, Elias A.; Fonseca, Simone; Wacleche, Vanessa; El-Far, Mohamed; Boulassel, Mohamed-Rachid; Routy, Jean-Pierre; Sekaly, Rafick-Pierre; Ancuta, Petronela

    2015-01-01

    There is limited knowledge on the identity of primary CD4+ T cell subsets selectively targeted by HIV-1 in vivo. In this study, we established a link between HIV permissiveness, phenotype/homing potential, and lineage commitment in primary CD4+ T cells. CCR4+CCR6+, CCR4+CCR6−, CXCR3+CCR6+, and CXCR3+CCR6− T cells expressed cytokines and transcription factors specific for Th17, Th2, Th1Th17, and Th1 lineages, respectively. CCR4+CCR6+ and CXCR3+CCR6+ T cells expressed the HIV coreceptors CCR5 and CXCR4 and were permissive to R5 and X4 HIV replication. CCR4+CCR6− T cells expressed CXCR4 but not CCR5 and were permissive to X4 HIV only. CXCR3+CCR6− T cells expressed CCR5 and CXCR4 but were relatively resistant to R5 and X4 HIV in vitro. Total CCR6+ T cells compared with CCR6− T cells harbored higher levels of integrated HIV DNA in treatment-naive HIV-infected subjects. The frequency of total CCR6+ T cells and those of CCR4+CCR6+ and CXCR3+CCR6+ T cells were diminished in chronically infected HIV-positive subjects, despite viral-suppressive therapy. A high-throughput analysis of cytokine profiles identified CXCR3+CCR6+ T cells as a major source of TNF-α and CCL20 and demonstrated a decreased TNF-α/IL-10 ratio in CXCR3+CCR6− T cells. Finally, CCR4+CCR6+ and CXCR3+CCR6+ T cells exhibited gut- and lymph node-homing potential. Thus, we identified CCR4+CCR6+ and CXCR3+CCR6+ T cells as highly permissive to HIV replication, with potential to infiltrate and recruit more CCR6+ T cells into anatomic sites of viral replication. It is necessary that new therapeutic strategies against HIV interfere with viral replication/persistence in discrete CCR6+ T cell subsets. PMID:20042588

  15. Structural biology research at the National Synchroton Light Source

    SciTech Connect

    1996-05-01

    The world`s foremost facility for scientific research using x-rays and ultraviolet and infrared radiation is operated by the national synchrotron Light Source Department. This year alone, a total of 2200 guest researchers performed experiments at the world`s largest source of synchrotron light. Researchers are trying to define the three- dimensional structures of biological macromolecules to create a map of life, a guide for exploring the biological and chemical interactions of the vast variety of molecules found in living organisms. Studies in structural biology may lead to new insights into how biological systems are formed and nourished, how they survive and grow, how they are damaged and die. This document discusses some the the structural biological research done at the National Synchrotron Light Source.

  16. Information technology developments within the national biological information infrastructure

    USGS Publications Warehouse

    Cotter, G.; Frame, M.T.

    2000-01-01

    Looking out an office window or exploring a community park, one can easily see the tremendous challenges that biological information presents the computer science community. Biological information varies in format and content depending whether or not it is information pertaining to a particular species (i.e. Brown Tree Snake), or a specific ecosystem, which often includes multiple species, land use characteristics, and geospatially referenced information. The complexity and uniqueness of each individual species or ecosystem do not easily lend themselves to today's computer science tools and applications. To address the challenges that the biological enterprise presents the National Biological Information Infrastructure (NBII) (http://www.nbii.gov) was established in 1993. The NBII is designed to address these issues on a National scale within the United States, and through international partnerships abroad. This paper discusses current computer science efforts within the National Biological Information Infrastructure Program and future computer science research endeavors that are needed to address the ever-growing issues related to our Nation's biological concerns.

  17. The Simbios National Center: Systems Biology in Motion

    PubMed Central

    Schmidt, Jeanette P.; Delp, Scott L.; Sherman, Michael A.; Taylor, Charles A.; Pande, Vijay S.; Altman, Russ B.

    2010-01-01

    Physics-based simulation is needed to understand the function of biological structures and can be applied across a wide range of scales, from molecules to organisms. Simbios (the National Center for Physics-Based Simulation of Biological Structures, http://www.simbios.stanford.edu/) is one of seven NIH-supported National Centers for Biomedical Computation. This article provides an overview of the mission and achievements of Simbios, and describes its place within systems biology. Understanding the interactions between various parts of a biological system and integrating this information to understand how biological systems function is the goal of systems biology. Many important biological systems comprise complex structural systems whose components interact through the exchange of physical forces, and whose movement and function is dictated by those forces. In particular, systems that are made of multiple identifiable components that move relative to one another in a constrained manner are multibody systems. Simbios’ focus is creating methods for their simulation. Simbios is also investigating the biomechanical forces that govern fluid flow through deformable vessels, a central problem in cardiovascular dynamics. In this application, the system is governed by the interplay of classical forces, but the motion is distributed smoothly through the materials and fluids, requiring the use of continuum methods. In addition to the research aims, Simbios is working to disseminate information, software and other resources relevant to biological systems in motion. PMID:20107615

  18. The National Biological Information Infrastructure: Coming of age

    USGS Publications Warehouse

    Cotter, G.; Frame, M.; Sepic, R.; Zolly, L.

    2000-01-01

    Coordinated by the US Geological Survey, the National Biological Information Infrastructure (NBII) is a Web-based system that provides increased access to data and information on the nation's biological resources. The NBII can be viewed from a variety of perspectives. This article - an individual case study and not a broad survey with extensive references to the literature - addresses the structure of the NBII related to thematic sections, infrastructure sections and place-based sections, and other topics such as the Integrated Taxonomic Information System (one of our more innovative tools) and the development of our controlled vocabulary.

  19. CCR+: Metadata Based Extended Personal Health Record Data Model Interoperable with the ASTM CCR Standard

    PubMed Central

    Park, Yu Rang; Yoon, Young Jo; Jang, Tae Hun; Seo, Hwa Jeong

    2014-01-01

    Objectives Extension of the standard model while retaining compliance with it is a challenging issue because there is currently no method for semantically or syntactically verifying an extended data model. A metadata-based extended model, named CCR+, was designed and implemented to achieve interoperability between standard and extended models. Methods Furthermore, a multilayered validation method was devised to validate the standard and extended models. The American Society for Testing and Materials (ASTM) Community Care Record (CCR) standard was selected to evaluate the CCR+ model; two CCR and one CCR+ XML files were evaluated. Results In total, 188 metadata were extracted from the ASTM CCR standard; these metadata are semantically interconnected and registered in the metadata registry. An extended-data-model-specific validation file was generated from these metadata. This file can be used in a smartphone application (Health Avatar CCR+) as a part of a multilayered validation. The new CCR+ model was successfully evaluated via a patient-centric exchange scenario involving multiple hospitals, with the results supporting both syntactic and semantic interoperability between the standard CCR and extended, CCR+, model. Conclusions A feasible method for delivering an extended model that complies with the standard model is presented herein. There is a great need to extend static standard models such as the ASTM CCR in various domains: the methods presented here represent an important reference for achieving interoperability between standard and extended models. PMID:24627817

  20. The involvement of cell surface nucleolin in the initiation of CCR6 signaling in human hepatocellular carcinoma.

    PubMed

    Qiu, Wei; Wang, Guangyi; Sun, Xiaodong; Ye, Junfeng; Wei, Feng; Shi, Xiaoju; Lv, Guoyue

    2015-03-01

    In recent years, the chemokine CC receptor 6 (CCR6) and its ligand CCL20 were reported to play an essential role in hepatocellular carcinoma (HCC). However, the role of cell surface nucleolin in the CCR6 pathway of HCC is not well featured. Using immunohistochemistry, Western blotting, siRNA, wound healing and transwell assay, we investigated the relationships of cell surface nucleolin and CCR6 signaling in HCC. In the present study, our findings identified that cell surface nucleolin and CCR6 protein were stained in most of HCC tissues (64, 68 %, respectively) and differently expressed in HCC cell lines; meanwhile, both expression has an association with advanced stage, lymph node metastasis and poor 5-year prognosis. According to in vitro assays, we found that the silencing of either cell surface nucleolin or CCR6 inhibited the protein expression of p-ERK, p-AKT, MMP2, MMP9 and ICAM-1 in the CCL20-stimulated HCCLM6 cells. Functional analysis revealed that cell surface nucleolin or CCR6 silencing significantly hampered HCCLM6 cell motility and invasiveness ability, when compared with control. In conclusion, this work suggests that cell surface nucleolin participates in the initiation of CCR6 pathway and biological behaviors of HCC, leading to HCC cell adhesion, migration and invasive behavior. In the clinical practice, cell surface nucleolin and CCR6 are recommended to predict poor prognosis and be used as a useful target for HCC patients. PMID:25698534

  1. Effects of chemokine receptor signalling on cognition-like, emotion-like and sociability behaviours of CCR6 and CCR7 knockout mice.

    PubMed

    Jaehne, E J; Baune, B T

    2014-03-15

    Inflammation is regarded as an important mechanism of neuropsychiatric disorders. Chemokines, which are a part of the immune system, have effects on various aspects of brain function, but little is known about their effects on behaviour. We have compared the cognition-like behaviour (learning and spatial memory) of CCR6(-/-) and CCR7(-/-) mice with wild type (WT) C57BL/6 mice, in the Barnes maze, as well as a range of other behaviours, including exploratory, anxiety and depression-like behaviour, using a battery of tests. Levels of cytokines TNF-α, IL-1β and IL-6 were also measured. In the Barnes maze, CCR7(-/-) mice were shown to take longer to learn the location of the escape box on the 1st of 4 days of training. In the behavioural battery, CCR6(-/-) mice showed higher locomotor activity and lower anxiety in the open field test, and a lack of preference for social novelty in a sociability test. CCR7(-/-) mice behaved much like WT mice, although showed higher anxiety in Elevated Zero Maze. While baseline saccharin preference in a 2-bottle choice test, a test for anhedonia depression-like behaviour, was equal in all strains at baseline, weekly tests showed that both CCR6(-/-) and CCR7(-/-) mice developed a decreased preference for saccharin compared to WT over time. There were no differences between strains in any of the cytokines measured. These results suggest that chemokine receptors may play a role in cognition and learning behaviour, as well as anxiety and other behaviours, although the biological mechanisms are still unclear. PMID:24333375

  2. National Aeronautics and Space Administration Biological Specimen Repository

    NASA Technical Reports Server (NTRS)

    McMonigal, Kathleen A.; Pietrzyk, Robert a.; Johnson, Mary Anne

    2008-01-01

    The National Aeronautics and Space Administration Biological Specimen Repository (Repository) is a storage bank that is used to maintain biological specimens over extended periods of time and under well-controlled conditions. Samples from the International Space Station (ISS), including blood and urine, will be collected, processed and archived during the preflight, inflight and postflight phases of ISS missions. This investigation has been developed to archive biosamples for use as a resource for future space flight related research. The International Space Station (ISS) provides a platform to investigate the effects of microgravity on human physiology prior to lunar and exploration class missions. The storage of crewmember samples from many different ISS flights in a single repository will be a valuable resource with which researchers can study space flight related changes and investigate physiological markers. The development of the National Aeronautics and Space Administration Biological Specimen Repository will allow for the collection, processing, storage, maintenance, and ethical distribution of biosamples to meet goals of scientific and programmatic relevance to the space program. Archiving of the biosamples will provide future research opportunities including investigating patterns of physiological changes, analysis of components unknown at this time or analyses performed by new methodologies.

  3. Differential ligand-signaling network of CCL19/CCL21-CCR7 system

    PubMed Central

    Raju, Rajesh; Gadakh, Sachin; Gopal, Priyanka; George, Bijesh; Advani, Jayshree; Soman, Sowmya; Prasad, T. S. K.; Girijadevi, Reshmi

    2015-01-01

    Chemokine (C-C motif) receptor 7 (CCR7), a class A subtype G-Protein Coupled Receptor (GPCR), is involved in the migration, activation and survival of multiple cell types including dendritic cells, T cells, eosinophils, B cells, endothelial cells and different cancer cells. Together, CCR7 signaling system has been implicated in diverse biological processes such as lymph node homeostasis, T cell activation, immune tolerance, inflammatory response and cancer metastasis. CCL19 and CCL21, the two well-characterized CCR7 ligands, have been established to be differential in their signaling through CCR7 in multiple cell types. Although the differential ligand signaling through single receptor have been suggested for many receptors including GPCRs, there exists no resource or platform to analyse them globally. Here, first of its kind, we present the cell-type-specific differential signaling network of CCL19/CCL21-CCR7 system for effective visualization and differential analysis of chemokine/GPCR signaling. Database URL: http:// www. netpath. org/ pathways? path_ id= NetPath_ 46. PMID:26504105

  4. Insights into the structure and architecture of the CCR4–NOT complex

    PubMed Central

    Xu, Kun; Bai, Yuwei; Zhang, Aili; Zhang, Qionglin; Bartlam, Mark G.

    2014-01-01

    The CCR4–NOT complex is a highly conserved, multifunctional machinery with a general role in controlling mRNA metabolism. It has been implicated in a number of different aspects of mRNA and protein expression, including mRNA degradation, transcription initiation and elongation, ubiquitination, and protein modification. The core CCR4–NOT complex is evolutionarily conserved and consists of at least three NOT proteins and two catalytic subunits. The L-shaped complex is characterized by two functional modules bound to the CNOT1/Not1 scaffold protein: the deadenylase or nuclease module containing two enzymes required for deadenylation, and the NOT module. In this review, we will summarize the currently available information regarding the three-dimensional structure and assembly of the CCR4–NOT complex, in order to provide insight into its roles in mRNA degradation and other biological processes. PMID:24904637

  5. [Progress on Hypoxic-ischemic Brain Damage Associated with CCR2 and CCL2].

    PubMed

    Luo, Yu-jia; Li, Ru-bo; Ma, Shi-yu; Lü, Meng-yan

    2016-02-01

    Hypoxic-ischemic brain damage (HIBD) is referred to a common type of cerebral damage, which is caused by injury, leading to shallow bleeding in the cortex with intact cerebral pia mater. In recent years, studies show that a various kinds of immune cells and immune cellular factors are involved in the occurrence of HIBD. CC chemokine receptor 2 (CCR2) is a representative of CC chemokine receptor, and is widely distributed in cerebral neuron, astrocyte, and microglial cells, and is the main chemo-tactic factor receptor in brain tissue. CC chemokine ligand 2 (CCL2) is a kind of basophilic protein and the ligand of CCR2, and plays an important role in inflammation. In order to provide evidence for correlational studies in HIBD, this review will introduce the biological characteristics of CCR2 and CCL2, and illustrate the relationship between the immunoreactivity and HIBD. PMID:27295859

  6. Folding of newly translated membrane protein CCR5 is assisted by the chaperonin GroEL-GroES

    NASA Astrophysics Data System (ADS)

    Chi, Haixia; Wang, Xiaoqiang; Li, Jiqiang; Ren, Hao; Huang, Fang

    2015-11-01

    The in vitro folding of newly translated human CC chemokine receptor type 5 (CCR5), which belongs to the physiologically important family of G protein-coupled receptors (GPCRs), has been studied in a cell-free system supplemented with the surfactant Brij-35. The freshly synthesized CCR5 can spontaneously fold into its biologically active state but only slowly and inefficiently. However, on addition of the GroEL-GroES molecular chaperone system, the folding of the nascent CCR5 was significantly enhanced, as was the structural stability and functional expression of the soluble form of CCR5. The chaperonin GroEL was partially effective on its own, but for maximum efficiency both the GroEL and its GroES lid were necessary. These results are direct evidence for chaperone-assisted membrane protein folding and therefore demonstrate that GroEL-GroES may be implicated in the folding of membrane proteins.

  7. Folding of newly translated membrane protein CCR5 is assisted by the chaperonin GroEL-GroES

    PubMed Central

    Chi, Haixia; Wang, Xiaoqiang; Li, Jiqiang; Ren, Hao; Huang, Fang

    2015-01-01

    The in vitro folding of newly translated human CC chemokine receptor type 5 (CCR5), which belongs to the physiologically important family of G protein-coupled receptors (GPCRs), has been studied in a cell-free system supplemented with the surfactant Brij-35. The freshly synthesized CCR5 can spontaneously fold into its biologically active state but only slowly and inefficiently. However, on addition of the GroEL-GroES molecular chaperone system, the folding of the nascent CCR5 was significantly enhanced, as was the structural stability and functional expression of the soluble form of CCR5. The chaperonin GroEL was partially effective on its own, but for maximum efficiency both the GroEL and its GroES lid were necessary. These results are direct evidence for chaperone-assisted membrane protein folding and therefore demonstrate that GroEL-GroES may be implicated in the folding of membrane proteins. PMID:26585937

  8. A national facility for biological cryo-electron microscopy

    SciTech Connect

    Saibil, Helen R.; Grünewald, Kay; Stuart, David I.

    2015-01-01

    This review provides a brief update on the use of cryo-electron microscopy for integrated structural biology, along with an overview of the plans for the UK national facility for electron microscopy being built at the Diamond synchrotron. Three-dimensional electron microscopy is an enormously powerful tool for structural biologists. It is now able to provide an understanding of the molecular machinery of cells, disease processes and the actions of pathogenic organisms from atomic detail through to the cellular context. However, cutting-edge research in this field requires very substantial resources for equipment, infrastructure and expertise. Here, a brief overview is provided of the plans for a UK national three-dimensional electron-microscopy facility for integrated structural biology to enable internationally leading research on the machinery of life. State-of-the-art equipment operated with expert support will be provided, optimized for both atomic-level single-particle analysis of purified macromolecules and complexes and for tomography of cell sections. The access to and organization of the facility will be modelled on the highly successful macromolecular crystallography (MX) synchrotron beamlines, and will be embedded at the Diamond Light Source, facilitating the development of user-friendly workflows providing near-real-time experimental feedback.

  9. Lymphocyte adhesion to CCR5 ligands is reduced by anti-CCR5 gene delivery.

    PubMed

    Marusich, Elena; Louboutin, Jean-Pierre; Chekmasova, Alena A; Strayer, David S

    2011-09-15

    Immune-mediated damage to the central nervous system (CNS) is an important contributor to many CNS diseases, including epilepsy. Chemokines play a role in leukocyte recruitment to, and migration across, the blood-brain barrier (BBB) during many such processes. We previously investigated the role of the chemokine receptor CCR5 in a rat model of epilepsy based on intraperitoneal kainic acid (KA) administration. Before KA injection, rats were given intramarrow inoculations of SV(RNAiR5-RevM10.AU1), which carries an interfering RNA (RNAi) that targets CCR5. Decreased CCR5 expression in blood cells after vector administration reduced expression of CCR5 ligands MIP-1α and RANTES in the microvasculature, and strongly protected from BBB leakage, CNS loss and inflammation and facilitated CNS repair. We show here that rSV40-mediated downregulation of CCR5 in lymphocytes decreased cellular adhesion to surfaces carrying CCR5 ligands. These data suggest that reducing CCR5 in peripheral blood mononuclear cells (PBMCs) might alter their adhesion to the microvasculature and their participation in inflammatory processes. PMID:21741662

  10. A polymorphism in CCR1/CCR3 is associated with narcolepsy.

    PubMed

    Toyoda, Hiromi; Miyagawa, Taku; Koike, Asako; Kanbayashi, Takashi; Imanishi, Aya; Sagawa, Yohei; Kotorii, Nozomu; Kotorii, Tatayu; Hashizume, Yuji; Ogi, Kimihiro; Hiejima, Hiroshi; Kamei, Yuichi; Hida, Akiko; Miyamoto, Masayuki; Imai, Makoto; Fujimura, Yota; Tamura, Yoshiyuki; Ikegami, Azusa; Wada, Yamato; Moriya, Shunpei; Furuya, Hirokazu; Takeuchi, Masaki; Kirino, Yohei; Meguro, Akira; Remmers, Elaine F; Kawamura, Yoshiya; Otowa, Takeshi; Miyashita, Akinori; Kashiwase, Koichi; Khor, Seik-Soon; Yamasaki, Maria; Kuwano, Ryozo; Sasaki, Tsukasa; Ishigooka, Jun; Kuroda, Kenji; Kume, Kazuhiko; Chiba, Shigeru; Yamada, Naoto; Okawa, Masako; Hirata, Koichi; Mizuki, Nobuhisa; Uchimura, Naohisa; Shimizu, Tetsuo; Inoue, Yuichi; Honda, Yutaka; Mishima, Kazuo; Honda, Makoto; Tokunaga, Katsushi

    2015-10-01

    Etiology of narcolepsy-cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples. An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P=1.6×10(-5), odds ratio [OR]=1.86). This rs3181077 association was replicated with the independent sample set (P=0.032, OR=1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand. CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function. PMID:25986216

  11. Oxazolidinones as novel human CCR8 antagonists.

    PubMed

    Jin, Jian; Wang, Yonghui; Wang, Feng; Kerns, Jeffery K; Vinader, Victoria M; Hancock, Ashley P; Lindon, Matthew J; Stevenson, Graeme I; Morrow, Dwight M; Rao, Parvathi; Nguyen, Cuc; Barrett, Victoria J; Browning, Chris; Hartmann, Guido; Andrew, David P; Sarau, Henry M; Foley, James J; Jurewicz, Anthony J; Fornwald, James A; Harker, Andy J; Moore, Michael L; Rivero, Ralph A; Belmonte, Kristen E; Connor, Helen E

    2007-03-15

    High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described. PMID:17267215

  12. Investigation of the C-terminal domain of the bacterial DNA-(adenine N6)-methyltransferase CcrM.

    PubMed

    Maier, Johannes A H; Albu, Razvan F; Jurkowski, Tomasz P; Jeltsch, Albert

    2015-12-01

    CcrM-related DNA-(adenine N6)-methyltransferases play very important roles in the biology of Caulobacter crescentus and other alpha-proteobacteria. These enzymes methylate GANTC sequences, but the molecular mechanism by which they recognize their target sequence is unknown. We carried out multiple sequence alignments and noticed that CcrM enzymes contain a conserved C-terminal domain (CTD) which is not present in other DNA-(adenine N6)-methyltransferases and we show here that deletion of this part abrogates catalytic activity and DNA binding of CcrM. A mutational study identified 7 conserved residues in the CTD (out of 13 tested), mutation of which led to a strong reduction in catalytic activity. All of these mutants showed altered DNA binding, but no change in AdoMet binding and secondary structure. Some mutants exhibited reduced DNA binding, but others showed an enhanced DNA binding. Moreover, we show that CcrM does not specifically bind to DNA containing GANTC sequences. Taken together, these findings suggest that the specific CcrM-DNA complex undergoes a conformational change, which is endergonic but essential for catalytic activity and this step is blocked by some of the mutations. Moreover, our data indicate that the CTD of CcrM is involved in DNA binding and recognition. This suggests that the CTD functions as target recognition domain of CcrM and, therefore, CcrM can be considered the first example of a δ-type DNA-(adenine N6)-methyltransferase identified so far. PMID:26475175

  13. Diphtheria-toxin based anti-human CCR4 immunotoxin for targeting human CCR4(+) cells in vivo.

    PubMed

    Wang, Zhaohui; Wei, Min; Zhang, Huiping; Chen, Hongyuan; Germana, Sharon; Huang, Christene A; Madsen, Joren C; Sachs, David H; Wang, Zhirui

    2015-08-01

    CC chemokine receptor 4 (CCR4) has attracted much attention as a promising therapeutic drug target for CCR4(+) tumor cells and Tregs. CCR4 is expressed on some tumor cells such as T-cell acute lymphoblastic leukemia (ALL), adult T-cell leukemia/lymphoma (ATLL), adult peripheral T cell lymphoma (PTCL) and cutaneous T cell lymphoma (CTCL). CCR4 is also expressed on majority of Tregs, mainly effector Tregs. In this study we have successfully developed three versions of diphtheria-toxin based anti-human CCR4 immunotoxins (monovalent, bivalent and single-chain fold-back diabody). Binding analysis by flow cytometry showed that all three versions of the anti-human CCR4 immunotoxins bound to the human CCR4(+) tumor cell line as well as CCR4(+) human PBMC. The bivalent isoform bound stronger than its monovalent counterpart and the single-chain foldback diabody isoform was the strongest among the three versions. In vitro efficacy analysis demonstrated that the bivalent isoform was 20 fold more potent in inhibiting cellular proliferation and protein synthesis in human CCR4(+) tumor cells compared to the monovalent anti-human CCR4 immunotoxin. The single-chain fold-back diabody isoform was 10 fold more potent than its bivalent counterpart and 200 fold more potent than its monovalent counterpart. The in vivo efficacy was assessed using a human CCR4(+) tumor-bearing mouse model. The immunotoxin significantly prolonged the survival of tumor-bearing NOD/SCID IL-2 receptor γ(-/-) (NSG) mice injected with human CCR4(+) acute lymphoblastic leukemia cells compared with the control group. This novel anti-human CCR4 immunotoxin is a promising drug candidate for targeting human CCR4(+) tumor cells and Tregs in vivo. PMID:25958791

  14. A national facility for biological cryo-electron microscopy

    PubMed Central

    Saibil, Helen R.; Grünewald, Kay; Stuart, David I.

    2015-01-01

    Three-dimensional electron microscopy is an enormously powerful tool for structural biologists. It is now able to provide an understanding of the molecular machinery of cells, disease processes and the actions of pathogenic organisms from atomic detail through to the cellular context. However, cutting-edge research in this field requires very substantial resources for equipment, infrastructure and expertise. Here, a brief overview is provided of the plans for a UK national three-dimensional electron-microscopy facility for integrated structural biology to enable internationally leading research on the machinery of life. State-of-the-art equipment operated with expert support will be provided, optimized for both atomic-level single-particle analysis of purified macromolecules and complexes and for tomography of cell sections. The access to and organization of the facility will be modelled on the highly successful macromolecular crystallography (MX) synchrotron beamlines, and will be embedded at the Diamond Light Source, facilitating the development of user-friendly workflows providing near-real-time experimental feedback. PMID:25615867

  15. Role of the Chemokine Receptors CCR1, CCR2 and CCR4 in the Pathogenesis of Experimental Dengue Infection in Mice

    PubMed Central

    Guabiraba, Rodrigo; Marques, Rafael Elias; Besnard, Anne-Gaëlle; Fagundes, Caio T.; Souza, Danielle G.; Ryffel, Bernhard; Teixeira, Mauro M.

    2010-01-01

    Dengue virus (DENV), a mosquito-borne flavivirus, is a public health problem in many tropical countries. Recent clinical data have shown an association between levels of different chemokines in plasma and severity of dengue. We evaluated the role of CC chemokine receptors CCR1, CCR2 and CCR4 in an experimental model of DENV-2 infection in mice. Infection of mice induced evident clinical disease and tissue damage, including thrombocytopenia, hemoconcentration, lymphopenia, increased levels of transaminases and pro-inflammatory cytokines, and lethality in WT mice. Importantly, infected WT mice presented increased levels of chemokines CCL2/JE, CCL3/MIP-1α and CCL5/RANTES in spleen and liver. CCR1-/- mice had a mild phenotype with disease presentation and lethality similar to those of WT mice. In CCR2-/- mice, lethality, liver damage, levels of IL-6 and IFN-γ, and leukocyte activation were attenuated. However, thrombocytopenia, hemoconcentration and systemic TNF-α levels were similar to infected WT mice. Infection enhanced levels of CCL17/TARC, a CCR4 ligand. In CCR4-/- mice, lethality, tissue injury and systemic inflammation were markedly decreased. Despite differences in disease presentation in CCR-deficient mice, there was no significant difference in viral load. In conclusion, activation of chemokine receptors has discrete roles in the pathogenesis of dengue infection. These studies suggest that the chemokine storm that follows severe primary dengue infection associates mostly to development of disease rather than protection. PMID:21206747

  16. Analysis of peripheral T cells and the CC chemokine receptor (CCR5) delta32 polymorphism in prostate cancer patients treated with carboxymethyl-glucan (CM-G).

    PubMed

    Magnani, Marciane; Castro-Gomez, Raul Hernan; Aoki, Mateus Nobrega; Gregório, Emerson Pereira; Libos, Farid; Morimoto, Helena Kaminami; Reiche, Edna Maria Vissoci; Watanabe, Maria Angelica Ehara

    2012-01-01

    β-Glucan, derived from Saccharomyces cerevisiae, is a biological response modifier which affects the innate and adaptive immune responses. The CCR5 chemokine receptor is crucial for immune cell responses. In this study, the effects of the carboxymethylated form of β-glucan (CM-G) on the lymphocyte population of CCR5 genotype patients with prostate cancer (PCa), undergoing androgen deprivation therapy (ADT) was assessed. The CCR5 genotype and lymphocyte population was investigated by cytometry flow in 30 Brazilian patients with advanced PCa who were treated with CM-G for 28 days. The analysis of the CCR5 chemokine receptor revealed that the wild-type genotype Wt/Wt was present in 80% of patients, while the heterozygotic genotype Wt/delta32 was present in 20% of patients. After CM-G administration, a significant increase in CD3(+), CD4(+) and CD8(+) T lymphocytes was observed in patients who displayed the wild-type genotype for the CCR5 chemokine receptor. No association was found between patient's age or length of ADT and increase in T lymphocyte cells. The results demonstrated the ability of CM-G to stimulate CD4(+) and CD8(+) T cells in the peripheral blood of patients carrying a wild-type CCR5 genotype, suggesting an interaction between immunomodulation by CM-G and the CCR5 receptor. PMID:21827290

  17. A dual CCR2/CCR5 chemokine antagonist, BMS-813160? Evaluation of WO2011046916.

    PubMed

    Norman, Peter

    2011-12-01

    This application claims the dual CCR2/CCR5 antagonist (S)-1-[(1S,2R,4R)-4-isopropyl(methyl)amino)-2-propylcyclohexyl]-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one, crystalline form N-1, a process for its preparation and therapeutic uses of it. The compound is shown to be a potent, well-absorbed, drug with a good duration of action. It shows better properties than similar compounds previously claimed by Bristol-Myers Squibb and appears to be a clinical development candidate. PMID:21936726

  18. A National Comparison of Biochemistry and Molecular Biology Capstone Experiences

    ERIC Educational Resources Information Center

    Aguanno, Ann; Mertz, Pamela; Martin, Debra; Bell, Ellis

    2015-01-01

    Recognizing the increasingly integrative nature of the molecular life sciences, the "American Society for Biochemistry and Molecular Biology" (ASBMB) recommends that Biochemistry and Molecular Biology (BMB) programs develop curricula based on concepts, content, topics, and expected student outcomes, rather than courses. To that end,…

  19. A Simplified Technique for Evaluating Human "CCR5" Genetic Polymorphism

    ERIC Educational Resources Information Center

    Falteisek, Lukáš; Cerný, Jan; Janštová, Vanda

    2013-01-01

    To involve students in thinking about the problem of AIDS (which is important in the view of nondecreasing infection rates), we established a practical lab using a simplified adaptation of Thomas's (2004) method to determine the polymorphism of HIV co-receptor CCR5 from students' own epithelial cells. CCR5 is a receptor involved in…

  20. Targeting CCR5 for anti-HIV research.

    PubMed

    Gu, W-G; Chen, X-Q

    2014-11-01

    Highly active antiretroviral therapy (HAART) is the only approach for human immunodeficiency virus (HIV) infection treatment at present. Although HAART is effective in controlling the progression of infection, it is impossible to eradicate the virus from patients. The patients have to live with the virus. Alternative ways for the cure of HIV infection have been investigated. As the major co-receptor for HIV-1 infection, C-C motif chemokine receptor 5 (CCR5) is naturally an ideal target for anti-HIV research. The first CCR5 antagonist, maraviroc, has been approved for the treatment of HIV infection. Several other CCR5 antagonists are in clinical trials. CCR5 delta32 is a natural genotype, conferring resistance to CCR5 using HIV-1 strains. Gene therapy research targeting this mutant has been conducted for HIV infection treatment. A Berlin patient has been cured of HIV infection by the transplantation of stem cells from a CCR5 delta32 genotype donor. The infusion of an engineered zinc finger nuclease (ZFN)-modified autologous cluster of differentiation 4 (CD4) T cells has been proved to be a promising direction recently. In this study, the anti-HIV research targeting CCR5 is summarized, including CCR5 antagonist development, stem cell transplantation, and gene therapy. PMID:25027072

  1. Downregulation of CCR1 inhibits human hepatocellular carcinoma cell invasion

    SciTech Connect

    Wu Xiaofeng; Fan Jia; E-mail: jiafan99@yahoo.com; Wang Xiaoying; Zhou Jian; Qiu Shuangjian; Yu Yao; Liu Yinkun; Tang Zhaoyou

    2007-04-20

    CC chemokine receptor 1 (CCR1) has an important role in the recruitment of leukocytes to the site of inflammation. The migration and metastasis of tumor cells shares many similarities with leukocyte trafficking, which is mainly regulated by chemokine receptor-ligand interactions. CCR1 is highly expressed in hepatocellular carcinoma (HCC) cells and tissues with unknown functions. In this study, we silenced CCR1 expression in the human HCC cell line HCCLM3 using artificial microRNA (miRNA)-mediated RNA interference (RNAi) and examined the invasiveness and proliferation of CCR1-silenced HCCLM3 cells and the matrix metalloproteinase (MMP) activity. The miRNA-mediated knockdown expression of CCR1 significantly inhibited the invasive ability of HCCLM3 cells, but had only a minor effect on the cellular proliferation rate. Moreover, CCR1 knockdown significantly reduced the secretion of MMP-2. Together, these findings indicate that CCR1 has an important role in HCCLM3 invasion and that CCR1 might be a new target of HCC treatment.

  2. Natural anti-CCR5 antibodies in HIV-infection and -exposure

    PubMed Central

    2011-01-01

    Natural antibodies constitute a first-line of defence against pathogens; they may also play other roles in immune regulation and homeostasis, through their ability to bind host antigens, surface molecules and receptors. Natural anti-CCR5 antibodies can be decisive in preventing HIV infection in mucosal tissues and offer prompt and effective protection just at major sites of virus entry. Among natural anti-CCR5 antibodies, IgG and IgA to the ECL1 domain have been shown to block HIV effectively and durably without causing harm to the host. Their biological properties and their uncommon generation in subsets of HIV-infected and HIV-exposed individuals (so called ESN) will be introduced and discussed, with the aim at exploiting their potential in therapy and prevention. PMID:21284903

  3. Information science and technology developments within the National Biological Information Infrastructure

    USGS Publications Warehouse

    Frame, M.T.; Cotter, G.; Zolly, L.; Little, J.

    2002-01-01

    Whether your vantage point is that of an office window or a national park, your view undoubtedly encompasses a rich diversity of life forms, all carefully studied or managed by some scientist, resource manager, or planner. A few simple calculations - the number of species, their interrelationships, and the many researchers studying them - and you can easily see the tremendous challenges that the resulting biological data presents to the information and computer science communities. Biological information varies in format and content: it may pertain to a particular species or an entire ecosystem; it can contain land use characteristics, and geospatially referenced information. The complexity and uniqueness of each individual species or ecosystem do not easily lend themselves to today's computer science tools and applications. To address the challenges that the biological enterprise presents, the National Biological Information Infrastructure (NBII) (http://www.nbii.gov) was established in 1993 on the recommendation of the National Research Council (National Research Council 1993). The NBII is designed to address these issues on a national scale, and through international partnerships. This paper discusses current information and computer science efforts within the National Biological Information Infrastructure Program, and future computer science research endeavors that are needed to address the ever-growing issues related to our nation's biological concerns. ?? 2003 by The Haworth Press, Inc. All rights reserved.

  4. The Biological Consequences of Nuclear War: Initiating National Case Studies.

    ERIC Educational Resources Information Center

    Harwell, Mark A.; Freeman, Ann C.

    1988-01-01

    Describes the second volume of the environmental consequences of nuclear war (ENUWAR) study of the Scientific Committee on Problems of the Environment (SCOPE) which involves the potential consequences for the Earth's biological systems. Discusses case studies in areas where the indirect effects of nuclear war would be the greatest danger. (CW)

  5. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2.

    PubMed

    Miura, Kouichi; Yang, Ling; van Rooijen, Nico; Ohnishi, Hirohide; Seki, Ekihiro

    2012-06-01

    Inflammatory cell infiltration in the liver is a hallmark of nonalcoholic steatohepatitis (NASH). The chemokine-chemokine receptor interaction induces inflammatory cell recruitment. CC-chemokine receptor (CCR)2 is expressed on hepatic macrophages and hepatic stellate cells. This study aims to investigate the therapeutic potential of CCR2 to NASH. Twenty-two weeks on a choline-deficient amino acid-defined (CDAA) diet induced steatosis, inflammatory cell infiltration, and liver fibrosis with increased CCR2 and monocyte chemoattractant protein (MCP)-1 expression in the wild-type livers. The infiltrated macrophages expressed CD68, CCR2, and a marker of bone marrow-derived monocytes, Ly6C. CCR2(-/-) mice had less steatosis, inflammatory cell infiltration, and fibrosis, and hepatic macrophages expressing CD68 and Ly6C were decreased. Toll-like receptor (TLR)4(-/-), TLR9(-/-), and MyD88(-/-) mice had reduced hepatic macrophage infiltration with decreased MCP-1 and CCR2 expression because TLR signaling is a potent inducer of MCP-1. To assess the role of Kupffer cells at the onset of NASH, Kupffer cells were depleted by liposomal clodronate. The Kupffer cell depletion ameliorated steatohepatitis with a decrease in the MCP-1 expression and recruitment of Ly6C-expressing macrophages at the onset of NASH. Finally, to test the therapeutic potential of targeting CCR2, a CCR2 inhibitor was administered to mice on a CDAA diet. The pharmaceutical inhibition of CCR2 prevented infiltration of the Ly6C-positive macrophages, resulting in an inhibition of liver inflammation and fibrosis. We concluded that CCR2 and Kupffer cells contribute to the progression of NASH by recruiting bone marrow-derived monocytes. PMID:22442158

  6. Field Trip to Kazdagi National Park: Views of Prospective Biology Teachers

    ERIC Educational Resources Information Center

    Çetin, Gülcan

    2014-01-01

    The purpose of the study was to investigate the views of the prospective biology teachers about the field trip to Kazdagi National Park. Participants were 12 prospective Biology teachers studying in Necatibey Faculty of Education in Balikesir University, Turkey. A semi-structured interview form was used as a data collection instrument. Data were…

  7. Structural biology facilities at Brookhaven National Laboratory`s high flux beam reactor

    SciTech Connect

    Korszun, Z.R.; Saxena, A.M.; Schneider, D.K.

    1994-12-31

    The techniques for determining the structure of biological molecules and larger biological assemblies depend on the extent of order in the particular system. At the High Flux Beam Reactor at the Brookhaven National Laboratory, the Biology Department operates three beam lines dedicated to biological structure studies. These beam lines span the resolution range from approximately 700{Angstrom} to approximately 1.5{Angstrom} and are designed to perform structural studies on a wide range of biological systems. Beam line H3A is dedicated to single crystal diffraction studies of macromolecules, while beam line H3B is designed to study diffraction from partially ordered systems such as biological membranes. Beam line H9B is located on the cold source and is designed for small angle scattering experiments on oligomeric biological systems.

  8. Chemokine receptor CCR2 involvement in skeletal muscle regeneration.

    PubMed

    Warren, Gordon L; Hulderman, Tracy; Mishra, Dawn; Gao, Xin; Millecchia, Lyndell; O'Farrell, Laura; Kuziel, William A; Simeonova, Petia P

    2005-03-01

    Chemokines, signaling through the CCR2 receptor, are highly expressed in injured skeletal muscle. Their target specificity depends on the cellular expression of the specific receptors. Here we demonstrate that, in freeze-injured muscle, CCR2 co-localized with Mac-3, a marker of activated macrophages as well as with myogenin, a marker of activated muscle precursor cells. The degeneration/regeneration process in skeletal muscle of CCR2-/- and wild-type mice was not significantly different at day 3. However in contrast to the regenerated muscle of the wild-type mice, the muscle from CCR2-/- mice was characterized by impaired regeneration, inflammation, and fibrotic response at day 14, increased fat infiltration, fibrosis, and calcification at day 21, and impaired strength recovery until at least 28 days post-injury. Consistently, the increased expression of Mac-1 and TNF-alpha was prolonged in the injured muscle of CCR2-/- mice. The expression pattern of the myogenic factors MyoD and myogenin was similar for both types of mice, while NCAM, which is associated with the initiation of fusion of muscle precursor cells, was more increased in the injured muscle of CCR2-/- mice. In conclusion, the study delineates that signaling through CCR2 is involved in muscle precursor cell activities necessary for complete and rapid regeneration of injured skeletal muscle. PMID:15601671

  9. Efficient Use of a Crude Drug/Herb Library Reveals Ephedra Herb As a Specific Antagonist for TH2-Specific Chemokine Receptors CCR3, CCR4, and CCR8

    PubMed Central

    Matsuo, Kazuhiko; Koizumi, Keiichi; Fujita, Mitsugu; Morikawa, Toshio; Jo, Michiko; Shibahara, Naotoshi; Saiki, Ikuo; Yoshie, Osamu; Nakayama, Takashi

    2016-01-01

    Chemokine receptors CCR3 and CCR4 are preferentially expressed by TH2 cells, mast cells, and/or eosinophils, all of which are involved in the pathogenesis of allergic diseases. Therefore, CCR3 and CCR4 have long been highlighted as potent therapeutic targets for allergic diseases. Japanese traditional herbal medicine Kampo consists of multiple crude drugs/herbs, which further consist of numerous chemical substances. Recent studies have demonstrated that such chemical substances appear to promising sources in the development of novel therapeutic agents. Based on these findings, we hypothesize that Kampo-related crude drugs/herbs would contain chemical substances that inhibit the cell migration mediated by CCR3 and/or CCR4. To test this hypothesis, we screened 80 crude drugs/herbs to identify candidate substances using chemotaxis assay. Among those tested, Ephedra Herb inhibited the chemotaxis mediated by both CCR3 and CCR4, Cornus Fruit inhibited that mediated by CCR3, and Rhubarb inhibited that mediated by CCR4. Furthermore, Ephedra Herb specifically inhibited the chemotaxis mediated by not only CCR3 and CCR4 but CCR8, all of which are selectively expressed by TH2 cells. This result led us to speculate that ephedrine, a major component of Ephedra Herb, would play a central role in the inhibitory effects on the chemotaxis mediated by CCR3, CCR4, and CCR8. However, ephedrine exhibited little effects on the chemotaxis. Therefore, we fractionated Ephedra Herb into four subfractions and examined the inhibitory effects of each subfraction. As the results, ethyl acetate-insoluble fraction exhibited the inhibitory effects on chemotaxis and calcium mobilization mediated by CCR3 and CCR4 most significantly. In contrast, chloroform-soluble fraction exhibited a weak inhibitory effect on the chemotaxis mediated by CCR8. Furthermore, maoto, one of the Kampo formulations containing Ephedra Herb, exhibited the inhibitory effects on the chemotaxis mediated by CCR3, CCR4, and CCR8

  10. Cloning and expression analysis of cinnamoyl-CoA reductase (CCR) genes in sorghum

    PubMed Central

    Fan, Feifei; Wang, Lihua; Zhan, Qiuwen; Wu, Peijin; Du, Junli; Yang, Xiaocui; Liu, Yanlong

    2016-01-01

    Cinnamoyl-CoA reductase (CCR) is the first enzyme in the monolignol-specific branch of the lignin biosynthetic pathway. In this research, three sorghum CCR genes including SbCCR1, SbCCR2-1 and SbCCR2-2 were cloned and characterized. Analyses of the structure and phylogeny of the three CCR genes showed evolutionary conservation of the functional domains and divergence of function. Transient expression assays in Nicotiana benthamiana leaves demonstrated that the three CCR proteins were localized in the cytoplasm. The expression analysis showed that the three CCR genes were induced by drought. But in 48 h, the expression levels of SbCCR1 and SbCCR2-2 did not differ between CK and the drought treatment; while the expression level of SbCCR2-1 in the drought treatment was higher than in CK. The expression of the SbCCR1 and SbCCR2-1 genes was not induced by sorghum aphid [Melanaphis sacchari (Zehntner)] attack, but SbCCR2-2 was significantly induced by sorghum aphid attack. It is suggested that SbCCR2-2 is involved in the process of pest defense. Absolute quantitative real-time PCR revealed that the three CCR genes were mainly expressed in lignin deposition organs. The gene copy number of SbCCR1 was significantly higher than those of SbCCR2-1 and SbCCR2-2 in the tested tissues, especially in stem. The results provide new insight into the functions of the three CCR genes in sorghum. PMID:27231650

  11. Cloning and expression analysis of cinnamoyl-CoA reductase (CCR) genes in sorghum.

    PubMed

    Li, Jieqin; Fan, Feifei; Wang, Lihua; Zhan, Qiuwen; Wu, Peijin; Du, Junli; Yang, Xiaocui; Liu, Yanlong

    2016-01-01

    Cinnamoyl-CoA reductase (CCR) is the first enzyme in the monolignol-specific branch of the lignin biosynthetic pathway. In this research, three sorghum CCR genes including SbCCR1, SbCCR2-1 and SbCCR2-2 were cloned and characterized. Analyses of the structure and phylogeny of the three CCR genes showed evolutionary conservation of the functional domains and divergence of function. Transient expression assays in Nicotiana benthamiana leaves demonstrated that the three CCR proteins were localized in the cytoplasm. The expression analysis showed that the three CCR genes were induced by drought. But in 48 h, the expression levels of SbCCR1 and SbCCR2-2 did not differ between CK and the drought treatment; while the expression level of SbCCR2-1 in the drought treatment was higher than in CK. The expression of the SbCCR1 and SbCCR2-1 genes was not induced by sorghum aphid [Melanaphis sacchari (Zehntner)] attack, but SbCCR2-2 was significantly induced by sorghum aphid attack. It is suggested that SbCCR2-2 is involved in the process of pest defense. Absolute quantitative real-time PCR revealed that the three CCR genes were mainly expressed in lignin deposition organs. The gene copy number of SbCCR1 was significantly higher than those of SbCCR2-1 and SbCCR2-2 in the tested tissues, especially in stem. The results provide new insight into the functions of the three CCR genes in sorghum. PMID:27231650

  12. Risk assessment related to veterinary biologicals: specific issues in developing nations.

    PubMed

    Ward, D E

    1995-12-01

    The author reviews both technical and socio-economic issues in developing nations, in relation to veterinary biologicals. Health risk assessment is a specific process to estimate the likelihood that animals, humans or ecological systems will be affected adversely by a chemical or physical agent, or biological product, under a specific set of conditions. Some technical issues (quality assurance, good manufacturing practice, education of end-users, field monitoring) apply equally well in developed, industrialised and in developing, pre-industrialised nations. Many regions have documented unique diseases (trypanosomosis, tick diseases, theileriosis) or high disease prevalence which may influence risk assessment results. This emphasises the need for scientifically-valid risk assessment methodologies in developing nations. Developing nations also have various socio-economic concerns, which may not be based on scientific fact but, nonetheless, affect trade in, and use of, veterinary biologicals. These non-scientific but perceived problems and issues are briefly discussed, and possible solutions are presented. The way in which countries deal with such perceived problems and issues in a context of internationally harmonised norms for risk assessment impinges on livestock farmers in developing nations. Finally, the author presents possible ways to correct the potentially widening cost gap between conventional, proven veterinary biologicals and newly-developed products. The results of risk assessment of veterinary biologicals influence risk management in both developed and less-developed nations. It is important to agree upon scientifically-based risk management guidelines which may be applied in all countries. The effect of the agreements of the Uruguay Round of the General Agreement on Tariffs and Trade on trade in veterinary biologicals in developing nations is reviewed. PMID:8639967

  13. Neferine inhibits the upregulation of CCL5 and CCR5 in vascular endothelial cells during chronic high glucose treatment.

    PubMed

    Li, Guilin; Zhu, Gaochun; Gao, Yun; Xiao, Wen; Xu, Hong; Liu, Shuangmei; Tu, Guihua; Peng, Haiying; Zheng, Chaoran; Liang, Shangdong; Li, Guodong

    2013-04-01

    We investigated whether the expressions of CCL5 and CCR5 participate in dysfunctional changes in human umbilical vein endothelial cells (HUVECs) induced by chronic high glucose treatment and examined whether neferine exerts its therapeutic effects by blocking the development of dysfunctional vascular endothelium. HUVECs were cultured with control or high concentrations of glucose in the absence or presence of neferine for 5 days. Nitric acid reductase method was used to detect the concentration of nitric oxide (NO) released into culture media. The level of intracellular reactive oxygen species (ROS) was measured by fluorescent DCFH-DA probe. The expressions of 84 genes related to endothelial cell biology were assessed by Human Endothelial Cell Biology RT(2) Profiler PCR Array. The expressions of the chemokine CCL5 and its receptor CCR5 were further determined by real-time RT-PCR and western blotting. PCR array indicated that CCL5 was the most significantly upregulated when HUVECs were exposed to chronic high glucose; the intracellular ROS level and the expressions of CCL5 and CCR5 at both mRNA and protein levels were significantly increased, whereas NO production was decreased simultaneously. The increased level of ROS and elevated expressions of CCL5 and CCR5 at high glucose were significantly inhibited by neferine; meanwhile the decreased NO production upon chronic high glucose treatment was relieved. An antioxidant (vitamin E) exerted similar beneficial effects. These data indicate that neferine can reduce the upregulation of CCL5 and CCR5 of vascular endothelium exposure to chronic high glucose and prevent or inhibit subsequent occurrence of inflammation in blood vessels possibly through antioxidation. PMID:23053727

  14. CCR3: Shedding new light on a dark problem?

    PubMed

    Mason, A Brett; Hoh, Josephine

    2009-10-01

    A recent work by Ambati et al. represents a bold step towards a more effective diagnosis and treatment of age-related macular degeneration, with the new evidence showing that CCR3, a chemokine receptor, is an early marker of and potential therapeutic target for choroidal neovascularization development. In the wake of such a novel and significant finding, additional illumination to confirm and consolidate the promise shown by CCR3 will soon follow. PMID:19684049

  15. [Targeted modification of CCR5 gene in rabbits by TALEN].

    PubMed

    Tang, Chengcheng; Zhang, Quanjun; Li, Xiaoping; Fan, Nana; Yang, Yi; Quan, Longquan; Lai, Liangxue

    2014-04-01

    The lack of suitable animal model for HIV-1 infection has become a bottleneck for the development of AIDS vaccines and drugs. Wild-type rabbits can be infected by HIV-1 persistently and HIV-1 can be efficiently replicated resulting in syncytia in rabbit cell line co-expressing human CD4 and CCR5.Therefore, a rabbit highly expressing human CD4 and CCR5 may be an ideal animal model for AIDS disease study. In the present report, by using the efficient gene targeting technology, transcription activator-like effector nuclease (TALEN), we explored the feasibility of generating a HIV-1 model by knocking in human CD4 and CCR5 into rabbit genome. First we constructed two TALEN vectors targeting rabbit CCR5 gene and a vector with homologous arms. TALEN mRNAs and donor DNA were then co-injected into fertilized oocytes. After 3?5 days, 24 embryos were collected and used to conduct mutation analysis with PCR and sequencing. All the 24 embryos were detected with CCR5 knockouts and 5 were human CD4 and CCR5 knockins. Our results laid a foundation for establishing a new animal model for the study of AIDS. PMID:24846981

  16. CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice

    PubMed Central

    Sullivan, Timothy; Miao, Zhenhua; Dairaghi, Daniel J.; Krasinski, Antoni; Wang, Yu; Zhao, Bin N.; Baumgart, Trageen; Ertl, Linda S.; Pennell, Andrew; Seitz, Lisa; Powers, Jay; Zhao, Ruiping; Ungashe, Solomon; Wei, Zheng; Boring, Landin; Tsou, Chia-Lin; Charo, Israel; Schall, Thomas J.; Jaen, Juan C.

    2013-01-01

    Chemokine (C-C motif) receptor 2 (CCR2) is central for the migration of monocytes into inflamed tissues. The novel CCR2 antagonist CCX140-B, which is currently in two separate phase 2 clinical trials in diabetic nephropathy, has recently been shown to reduce hemoglobin A1c and fasting blood glucose levels in type 2 diabetics. In this report, we describe the effects of this compound on glycemic and renal function parameters in diabetic mice. Since CCX140-B has a low affinity for mouse CCR2, transgenic human CCR2 knockin mice were generated and rendered diabetic with either a high-fat diet (diet-induced obesity) or by deletion of the leptin receptor gene (db/db). CCX140-B treatment in both models resulted in decreased albuminuria, which was associated with decreased glomerular hypertrophy and increased podocyte density. Moreover, treatment of diet-induced obese mice with CCX140-B resulted in decreased levels of fasting blood glucose and insulin, normalization of homeostatic model assessment of insulin resistance values, and decreased numbers of adipose tissue inflammatory macrophages. Unlike other CCR2 antagonists, CCX140-B had no effect on plasma levels of the CCR2 ligand CCL2 or on the numbers of blood monocytes. These results support the ongoing evaluation of this molecule in diabetic subjects with impaired renal function. PMID:23986513

  17. CCR5Δ32 mutation and HIV infection: basis for curative HIV therapy.

    PubMed

    Allers, Kristina; Schneider, Thomas

    2015-10-01

    The C-C chemokine receptor 5 (CCR5) is expressed on potential human immunodeficiency virus (HIV) target cells and serves as the predominant co-receptor for viral entry during initial transmission and through the early stages of infection. A homozygous Δ32 mutation in the CCR5 gene prevents CCR5 cell surface expression and thus confers resistance to infection with CCR5-tropic HIV strains. Transplantation of hematopoietic stem cells from a CCR5Δ32/Δ32 donor was previously successful in eliminating HIV from the recipient's immune system, suggesting that targeted CCR5 disruption can lead to an HIV cure. Therefore, intense work is currently being carried out on CCR5 gene-editing tools to develop curative HIV therapy. Here, we review the natural function of CCR5, the progress made on CCR5 gene editing to date and discuss the current limitations. PMID:26143158

  18. Characterization of the CCR3 and CCR9 genes in miiuy croaker and different selection pressures imposed on different domains between mammals and teleosts.

    PubMed

    Zhu, Zhihuang; Wang, Rixin; Ren, Liping; Xu, Tianjun

    2013-12-01

    The innate immune system can recognize non-self through pattern recognition receptors and provides a first line of antimicrobial host defense. Thus innate immunity plays a very important role in resistance against major bacterial disease in vertebrates. In the innate immune responses, the chemokine receptors act as the main receptors of chemokines which are released at the sites of infection, inflammation and injury. In this study, the Miichthys miiuy CCR3 and CCR9 genes were cloned and characterized, showing that MIMI-CCR3 possesses a highly conserved DRYLA motif similar to that of other fishes. MIMI-CCR3 and CCR9 were ubiquitously expressed in all tested tissues and the expressions were significantly up-regulated after infection with Vibrio anguillarum except that of CCR9 in spleen. Evolutionary analysis showed that all the ancestral lineages of CCR3 and CCR9 in mammals and teleosts underwent positive selection, indicating that the ancestor of terrestrial animals further evolved to adapt to terrestrial environments and the continuous intrusion of microbes stimulated the evolution of CCR genes in the ancestor of teleost. Multiple ML methods were used to detect the robust candidates for sites under positive selection. In total, 11 and 8 positively selected sites were found in the subsets of current mammal and teleost CCR3 genes, and 3 and 2 sites were detected in the subsets of current mammals and teleosts in CCR9. Interestingly, for mammal CCR3 and CCR9 genes, the robust candidates of positively selected sites were mainly located in the extracellular domains which were the ligand binding and pathogen interaction regions. For teleost CCR3 and CCR9 genes, the positively selected sites were not only located in the extracellular domains but also in the C-terminal and intracellular domains, indicating mammals and teleosts experienced different selection pressures upon their N-terminus, C-terminus and intracellular loops of CCRs. PMID:23817141

  19. CC Chemokine Ligand 20 and Its Cognate Receptor CCR6 in Mucosal T Cell Immunology and Inflammatory Bowel Disease: Odd Couple or Axis of Evil?

    PubMed Central

    Lee, Adrian Y. S.; Eri, Rajaraman; Lyons, Alan B.; Grimm, Michael C.; Korner, Heinrich

    2013-01-01

    Chemokines and their cognate receptors have been identified as major factors initiating and governing cell movement and interaction. These ligands and their receptors are expressed on a wide variety of cells and act during steady-state migration as well as inflammatory recruitment. CCR6 is a non-promiscuous chemokine receptor that has only one known chemokine ligand, CCL20, and is present on B and T cells as well as dendritic cells (DCs). Two CD4+ T cell populations with opposing functions present in the intestines and the mesenteric lymph nodes express CCR6: the pro-inflammatory TH17 and regulatory Treg cells. CCL20 is also present in the intestine and is strongly up-regulated after an inflammatory stimulus. Interestingly, this ligand is also expressed by TH17 cells, which opens up the possibility of autocrine/paracrine signaling and, consequently, a self-perpetuating cycle of recruitment, thereby promoting inflammation. Recently, CCR6 has been implicated in inflammatory bowel disease (IBD) by genome wide association studies which showed an association between SNPs in the genomic region of the CCR6 gene and the inflammation. Furthermore, recent research targeting the biological function of CCR6 indicates a significant role for this chemokine receptor in the development of chronic IBD. It is therefore possible that IBD is facilitated by a disordered regulation of TH17 and Treg cells due to a disruption in the CCL20-CCR6 axis and consequently disturbed mucosal homeostasis. This review will summarize the literature on CCL20-CCR6 in mucosal immunology and will analyze the role this receptor-ligand axis has in chronic IBD. PMID:23874340

  20. Biological assessment for the effluent reduction program, Los Alamos National Laboratory, Los Alamos, New Mexico

    SciTech Connect

    Cross, S.P.

    1996-08-01

    This report describes the biological assessment for the effluent recution program proposed to occur within the boundaries of Los Alamos National Laboratory. Potential effects on wetland plants and on threatened and endangered species are discussed, along with a detailed description of the individual outfalls resulting from the effluent reduction program.

  1. The Great Smoky Mountains National Park: Its Use as a Natural Laboratory for General Biology.

    ERIC Educational Resources Information Center

    Adams, Harold S.; Lipford, Michael L.

    Extended field trips have the potential to provide students with direct experience in learning about the natural world, as well as opportunities for the development of group cohesiveness. This document describes a program developed by a community college in which general biology students spend 3 days in the Great Smoky Mountains National Park. The…

  2. Neutron Imaging at the Oak Ridge National Laboratory: Application to Biological Research

    SciTech Connect

    Bilheux, Hassina Z; Cekanova, Maria; Bilheux, Jean-Christophe; Bailey, William Barton; Keener, Wylie S; Davis, Larry E; Herwig, Kenneth W

    2014-01-01

    The Oak Ridge National Laboratory Neutron Sciences Directorate (NScD) has recently installed a neutron imaging beamline at the High Flux Isotope Reactor (HFIR) cold guide hall. The CG-1D beamline supports a broad range of user research spanning from engineering to material research, energy storage, additive manufacturing, vehicle technologies, archaeology, biology, and plant physiology. The beamline performance (spatial resolution, field of view, etc.) and its utilization for biological research are presented. The NScD is also considering a proposal to build the VENUS imaging beamline (beam port 10) at the Spallation Neutron Source (SNS). Unlike CG-1D which provides cold neutrons, VENUS will offer a broad range of neutron wavelengths, from epithermal to cold, and enhanced contrast mechanisms. This new capability will also enable the imaging of thicker biological samples than is currently available at CG-1D. A brief overview of the VENUS capability for biological research is discussed.

  3. CCR9 Antagonists in the Treatment of Ulcerative Colitis

    PubMed Central

    Bekker, Pirow; Ebsworth, Karen; Walters, Matthew J.; Berahovich, Robert D.; Ertl, Linda S.; Charvat, Trevor T.; Punna, Sreenivas; Powers, Jay P.; Campbell, James J.; Sullivan, Timothy J.; Jaen, Juan C.; Schall, Thomas J.

    2015-01-01

    While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for the movement of leukocytes into the small intestine and the development of small-intestinal inflammation, the role of this chemokine-receptor pair in colonic inflammation is not clear. Toward this end, we compared colonic CCL25 protein levels in healthy individuals to those in patients with ulcerative colitis. In addition, we determined the effect of CCR9 pharmacological inhibition in the mdr1a−/− mouse model of ulcerative colitis. Colon samples from patients with ulcerative colitis had significantly higher levels of CCL25 protein compared to healthy controls, a finding mirrored in the mdr1a−/− mice. In the mdr1a−/− mice, CCR9 antagonists significantly decreased the extent of wasting and colonic remodeling and reduced the levels of inflammatory cytokines in the colon. These findings indicate that the CCR9:CCL25 pair plays a causative role in ulcerative colitis and suggest that CCR9 antagonists will provide a therapeutic benefit in patients with colonic inflammation. PMID:26457007

  4. CCR5 deficiency accelerates lipopolysaccharide-induced astrogliosis, amyloid-beta deposit and impaired memory function.

    PubMed

    Hwang, Chul Ju; Park, Mi Hee; Hwang, Jae Yeon; Kim, Ju Hwan; Yun, Na Young; Oh, Sang Yeon; Song, Ju Kyung; Seo, Hyun Ok; Kim, Yun-Bae; Hwang, Dae Yeon; Oh, Ki-Wan; Han, Sang-Bae; Hong, Jin Tae

    2016-03-15

    Chemokine receptors are implicated in inflammation and immune responses. Neuro-inflammation is associated with activation of astrocyte and amyloid-beta (Aβ) generations that lead to pathogenesis of Alzheimer disease (AD). Previous our study showed that deficiency of CC chemokine receptor 5 (CCR5) results in activation of astrocytes and Aβ deposit, and thus memory dysfunction through increase of CC chemokine receptor 2 (CCR2) expression. CCR5 knockout mice were used as an animal model with memory dysfunction. For the purpose LPS was injected i.p. daily (0.25 mg/kg/day). The memory dysfunctions were much higher in LPS-injected CCR5 knockout mice compared to CCR5 wild type mice as well as non-injected CCR5 knockout mice. Associated with severe memory dysfuction in LPS injected CCR5 knockout mice, LPS injection significant increase expression of inflammatory proteins, astrocyte activation, expressions of β-secretase as well as Aβ deposition in the brain of CCR5 knockout mice as compared with that of CCR5 wild type mice. In CCR5 knockout mice, CCR2 expressions were high and co-localized with GFAP which was significantly elevated by LPS. Expression of monocyte chemoattractant protein-1 (MCP-1) which ligands of CCR2 also increased by LPS injection, and increment of MCP-1 expression is much higher in CCR5 knockout mice. BV-2 cells treated with CCR5 antagonist, D-ala-peptide T-amide (DAPTA) and cultured astrocytes isolated from CCR5 knockout mice treated with LPS (1 μg/ml) and CCR2 antagonist, decreased the NF-ĸB activation and Aβ level. These findings suggest that the deficiency of CCR5 enhances response of LPS, which accelerates to neuro-inflammation and memory impairment. PMID:26910914

  5. CCR5 deficiency accelerates lipopolysaccharide-induced astrogliosis, amyloid-beta deposit and impaired memory function

    PubMed Central

    Hwang, Jae Yeon; Kim, Ju Hwan; Yun, Na Young; Oh, Sang Yeon; Song, Ju Kyung; Seo, Hyun Ok; Kim, Yun-Bae; Hwang, Dae Yeon; Oh, Ki-Wan; Han, Sang-Bae; Hong, Jin Tae

    2016-01-01

    Chemokine receptors are implicated in inflammation and immune responses. Neuro-inflammation is associated with activation of astrocyte and amyloid-beta (Aβ) generations that lead to pathogenesis of Alzheimer disease (AD). Previous our study showed that deficiency of CC chemokine receptor 5 (CCR5) results in activation of astrocytes and Aβ deposit, and thus memory dysfunction through increase of CC chemokine receptor 2 (CCR2) expression. CCR5 knockout mice were used as an animal model with memory dysfunction. For the purpose LPS was injected i.p. daily (0.25 mg/kg/day). The memory dysfunctions were much higher in LPS-injected CCR5 knockout mice compared to CCR5 wild type mice as well as non-injected CCR5 knockout mice. Associated with severe memory dysfuction in LPS injected CCR5 knockout mice, LPS injection significant increase expression of inflammatory proteins, astrocyte activation, expressions of β-secretase as well as Aβ deposition in the brain of CCR5 knockout mice as compared with that of CCR5 wild type mice. In CCR5 knockout mice, CCR2 expressions were high and co-localized with GFAP which was significantly elevated by LPS. Expression of monocyte chemoattractant protein-1 (MCP-1) which ligands of CCR2 also increased by LPS injection, and increment of MCP-1 expression is much higher in CCR5 knockout mice. BV-2 cells treated with CCR5 antagonist, D-ala-peptide T-amide (DAPTA) and cultured astrocytes isolated from CCR5 knockout mice treated with LPS (1 μg/ml) and CCR2 antagonist, decreased the NF-ĸB activation and Aβ level. These findings suggest that the deficiency of CCR5 enhances response of LPS, which accelerates to neuro-inflammation and memory impairment. PMID:26910914

  6. CCR5 knockout suppresses experimental autoimmune encephalomyelitis in C57BL/6 mice.

    PubMed

    Gu, Sun Mi; Park, Mi Hee; Yun, Hyung Mun; Han, Sang Bae; Oh, Ki Wan; Son, Dong Ju; Yun, Jae Suk; Hong, Jin Tae

    2016-03-29

    Multiple sclerosis (MS) is an inflammatory disease in which myelin in the spinal cord is damaged. C-C chemokine receptor type 5 (CCR5) is implicated in immune cell migration and cytokine release in central nervous system (CNS). We investigated whether CCR5 plays a role in MS progression using a murine model, experimental autoimmune encephalomyelitis (EAE), in CCR5 deficient (CCR5-/-) mice. CCR5-/- and CCR5+/+ (wild-type) mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) followed by pertussis toxin, after which EAE paralysis was scored for 28 days. We found that clinical scoring and EAE neuropathology were lower in CCR5-/- mice than CCR5+/+ mice. Immune cells (CD3+, CD4+, CD8+, B cell, NK cell and macrophages) infiltration and astrocytes/microglial activation were attenuated in CCR5-/- mice. Moreover, levels of IL-1β, TNF-α, IFN-γ and MCP-1 cytokine levels were decreased in CCR5-/- mice spinal cord. Myelin basic protein (MBP) and CNPase were increased while NG2 and O4 were decreased in CCR5-/- mice, indicating that demyelination was suppressed by CCR5 gene deletion. These findings suggest that CCR5 is likely participating in demyelination in the spinal cord the MS development, and that it could serve as an effective therapeutic target for the treatment of MS. PMID:26985768

  7. CCR5 knockout suppresses experimental autoimmune encephalomyelitis in C57BL/6 mice

    PubMed Central

    Yun, Hyung Mun; Han, Sang Bae; Oh, Ki Wan; Son, Dong Ju; Yun, Jae Suk; Hong, Jin Tae

    2016-01-01

    Multiple sclerosis (MS) is an inflammatory disease in which myelin in the spinal cord is damaged. C-C chemokine receptor type 5 (CCR5) is implicated in immune cell migration and cytokine release in central nervous system (CNS). We investigated whether CCR5 plays a role in MS progression using a murine model, experimental autoimmune encephalomyelitis (EAE), in CCR5 deficient (CCR5−/−) mice. CCR5−/− and CCR5+/+ (wild-type) mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) followed by pertussis toxin, after which EAE paralysis was scored for 28 days. We found that clinical scoring and EAE neuropathology were lower in CCR5−/− mice than CCR5+/+ mice. Immune cells (CD3+, CD4+, CD8+, B cell, NK cell and macrophages) infiltration and astrocytes/microglial activation were attenuated in CCR5−/− mice. Moreover, levels of IL-1β, TNF-α, IFN-γ and MCP-1 cytokine levels were decreased in CCR5−/− mice spinal cord. Myelin basic protein (MBP) and CNPase were increased while NG2 and O4 were decreased in CCR5−/− mice, indicating that demyelination was suppressed by CCR5 gene deletion. These findings suggest that CCR5 is likely participating in demyelination in the spinal cord the MS development, and that it could serve as an effective therapeutic target for the treatment of MS. PMID:26985768

  8. Biological risk at work in Italy: results from theNational Register of Occupational Exposures.

    PubMed

    Scarselli, Alberto; Vonesch, Nicoletta; Melis, Paola; Massari, Stefania; Tomao, Paola; Marinaccio, Alessandro; Iavicoli, Sergio

    2010-01-01

    The aim of this study is to analyze the information on workers and exposures to biological agents in Italy, collected by the National Institute for Occupational Safety and Prevention in the period 1994-2008 on the basis of a regulation. Employers are asked to identify the biological agents and to report data on employees exposed to biological hazards. Biological agents included in the system belong to risk group 3 and 4 of the European Union classification, and are grouped by family and transmission type. Data analyzed in this study regard 90 firms (28% in "Laboratory analysis clinics" economic activity) and 2,194 workers exposed to biological agents in the period 1994-2008. The most frequent biological agent reported is Salmonella typhi, while the one which counted more exposures is Mycobacterium tuberculosis. Nonetheless the incompleteness of Italian legislative framework about "exposure registers" to biological agents in the workplace, the identification of large groups of workers "at risk" can contribute to undertake epidemiological studies aimed at the prevention of occupational infection diseases. PMID:20562513

  9. Engagement and disarmament: A US National Security Strategy for biological weapons of mass destruction. Strategy research project

    SciTech Connect

    Moilanen, J.H.; McIntyre, A.J.; Johnson, D.V.

    1995-04-18

    The specter of biological weapons -- one of the three weapons of mass destruction (WMD) -- is an unusual and extraordinary threat to the national security of the United States. Since the U.S. unilaterally renounced biological warfare in 1969, biotechnology advances, aggressive nation-states, and terrorism have complicated a precarious balance of world and regional stability. U.S. shortfalls in biological warfare preparedness during the Persian Gulf War may convince potential adversaries that the U.S. is incapable of protecting its vital interests from biological assault. This paper examines the menace of biological weapons and global challenges to nonproliferation and counterproliferation. Analysis concludes that the United States can dissuade, deter, and defend against biological warfare and terrorism with an integrated national security strategy for Biological Weapons Engagement and Disarmament.

  10. National health and medical services response to incidents of chemical and biological terrorism.

    PubMed

    Tucker, J B

    1997-08-01

    In response to the growing threat of terrorism with chemical and biological weapons, the US government has developed a national concept of operations for emergency health and medical services response. This capability was developed and tested for the first time during the Atlanta Olympic Games in the summer of 1996. In the event of a chemical or biological terrorist incident that exceeded local and state-level response capabilities, federal agencies would provide specialized teams and equipment to help manage the consequences of the attack and treat, decontaminate, and evacuate casualties. The US Congress has also established a Domestic Preparedness Program that provides for enhanced training of local first-responders and the formation of metropolitan medical strike teams in major cities around the country. While these national response capabilities are promising, their implementation to date has been problematic and their ultimate effectiveness is uncertain. PMID:9244313

  11. The National Biological Information Infrastructure as an E-Government tool

    USGS Publications Warehouse

    Sepic, R.; Kase, K.

    2002-01-01

    Coordinated by the U.S. Geological Survey (USGS), the National Biological Information Infrastructure (NBII) is a Web-based system that provides access to data and information on the nation's biological resources. Although it was begun in 1993, predating any formal E-Government initiative, the NBII typifies the E-Government concepts outlined in the President's Management Agenda, as well as in the proposed E-Government Act of 2002. This article-an individual case study and not a broad survey with extensive references to the literature-explores the structure and operation of the NBII in relation to several emerging trends in E-Government: end-user focus, defined and scalable milestones, public-private partnerships, alliances with stakeholders, and interagency cooperation. ?? 2002 Elsevier Science Inc. All rights reserved.

  12. Prevalence of CCR5-Δ32 and CCR2-V64I polymorphisms in a mixed population from northeastern Brazil.

    PubMed

    Ferreira-Fernandes, H; Santos, A C C; Motta, F J N; Canalle, R; Yoshioka, F K N; Burbano, R R; Rey, J A; da Silva, B B; Pinto, G R

    2015-01-01

    Chemokines are low-molecular weight proteins that play a key role in inflammatory processes. Genomic variations in chemokine receptors are associated with the susceptibility to various diseases. Polymorphisms in chemokine receptor type 5 (CCR5)-Δ32 and CCR2-V64I are related to human immunodeficiency virus infection resistance, which has led to genetic association studies for several other diseases. Given the heterogeneous distribution of these polymorphisms in different global populations and within Brazilian populations, we analyzed the prevalence of CCR5-Δ32 and CCR2-V64I polymorphisms in a mixed population from northeastern Brazil. The study included 223 individuals from the general population of the city of Parnaíba, Piauí, who had a mean age of 73 years. Of these individuals, 37.2% were men and 62.8% were women. Polymorphisms were analyzed using DNA extracted from peripheral blood leukocytes by using polymerase chain reaction alone (CCR5-Δ32) or accompanied by restriction endonuclease digestion (CCR2-V64I). In both cases, the genotypes were determined using 8% polyacrylamide gel electrophoresis and silver nitrate staining. The population conformed to Hardy-Weinberg equilibrium for both the loci studied. No individuals were homozygous for allele-Δ32, which was present in 1.8% of the population, whereas allele-64I was present in 13.9% of the participants studied; 74.9% were homozygous for the wild-type allele, while 22.4 and 2.7% were heterozygous and homozygous for the mutant allele, respectively. Additional studies are needed to investigate the relationship between these polymorphisms and disease etiopathogenesis in reference populations. PMID:26436495

  13. Influence of CCR5 and CCR2 Genetic Variants in the Resistance/Susceptibility to HIV in Serodiscordant Couples from Colombia

    PubMed Central

    Zapata, Wildeman; Aguilar-Jiménez, Wbeimar; Pineda-Trujillo, Nicolás; Rojas, Winston; Estrada, Hernando

    2013-01-01

    Abstract The main genetic factor related to HIV-1 resistance is the CCR5-Δ32 mutation; however, the homozygous genotype is uncommon. The CCR5-Δ32 mutation along with single nucleotide polymorphisms (SNPs) in the CCR5 promoter and the CCR2-V64I mutation have been included in seven human haplogroups (HH) previously associated with resistance/susceptibility to HIV-1 infection and different rates of AIDS progression. Here, we determined the association of the CCR5 promoter SNPs, the CCR5-Δ32 mutation, CCR2-V64I SNP, and HH frequencies with resistance/susceptibility to HIV-1 infection in a cohort of HIV-1-serodiscordant couples from Colombia. Seventy HIV-1-exposed, but seronegative (HESN) individuals, 57 seropositives (SP), and 112 healthy controls (HC) were included. The CCR5-Δ32 mutation and CCR2-V64I SNP were identified by PCR, and the CCR5 promoter SNPs were evaluated by sequencing. None of the individuals exhibited a homozygous Δ32 genotype; the CCR2-I allele was more frequent in HESN (34%) than HC (23%) (p=0.039, OR=1.672). The frequency of the 29G allele was higher in SP than HC (p=0.003, OR=3). HHF2 showed a higher frequency in HC (19%) than SP (9%) (p=0.027), while HHG1 was more frequent in SP (11.1%) than in HC (4.2%) (p=0.019). The AGACCAC-CCR2-I-CCR5 wild-type haplotype showed a higher frequency in SP (14.2%) than in HC (3.7%) (p=0.001). In conclusion, the CCR5-Δ32 allele is not responsible for HIV-1 resistance in this HESN group; however, the CCR2-I allele could be protective, while the 29G allele might increase the likelihood of acquiring HIV-1 infection. HHG1 and the AGACCAC-CCR2-I-CCR5 wild-type haplotype might promote HIV-1 infection while HHF2 might be related to resistance. However, additional studies are required to evaluate the implications of these findings. PMID:24098976

  14. Repression of Ccr9 transcription in mouse T lymphocyte progenitors by the Notch signaling pathway.

    PubMed

    Krishnamoorthy, Veena; Carr, Tiffany; de Pooter, Renee F; Emanuelle, Akinola Olumide; Akinola, Emanuelle Olumide; Gounari, Fotini; Kee, Barbara L

    2015-04-01

    The chemokine receptor CCR9 controls the immigration of multipotent hematopoietic progenitor cells into the thymus to sustain T cell development. Postimmigration, thymocytes downregulate CCR9 and migrate toward the subcapsular zone where they recombine their TCR β-chain and γ-chain gene loci. CCR9 is subsequently upregulated and participates in the localization of thymocytes during their selection for self-tolerant receptor specificities. Although the dynamic regulation of CCR9 is essential for early T cell development, the mechanisms controlling CCR9 expression have not been determined. In this article, we show that key regulators of T cell development, Notch1 and the E protein transcription factors E2A and HEB, coordinately control the expression of Ccr9. E2A and HEB bind at two putative enhancers upstream of Ccr9 and positively regulate CCR9 expression at multiple stages of T cell development. In contrast, the canonical Notch signaling pathway prevents the recruitment of p300 to the putative Ccr9 enhancers, resulting in decreased acetylation of histone H3 and a failure to recruit RNA polymerase II to the Ccr9 promoter. Although Notch signaling modestly modulates the binding of E proteins to one of the two Ccr9 enhancers, we found that Notch signaling represses Ccr9 in T cell lymphoma lines in which Ccr9 transcription is independent of E protein function. Our data support the hypothesis that activation of Notch1 has a dominant-negative effect on Ccr9 transcription and that Notch1 and E proteins control the dynamic expression of Ccr9 during T cell development. PMID:25710912

  15. Genetic deletion of chemokine receptor Ccr7 exacerbates atherogenesis in ApoE-deficient mice

    PubMed Central

    Wan, Wuzhou; Lionakis, Michail S.; Liu, Qian; Roffê, Ester; Murphy, Philip M.

    2013-01-01

    Aims Recent evidence suggests that both Ccr7 and its ligands, Ccl19 and Ccl21, are present in mouse and human atherosclerotic plaques; however, the role of Ccr7 in atherogenesis is still controversial. Here, we addressed this question by using the classic apolipoprotein E-deficient (ApoE−/−) mouse model of atherosclerosis. Methods and results Ccr7−/−ApoE−/− double knockout mice and Ccr7+/+ApoE−/− littermates were generated and maintained on a high-fat Western diet for 8 weeks to induce atherosclerosis. Ccr7−/−ApoE−/− mice showed an ∼80% increase in atherosclerotic lesion size in the whole aorta and a two-fold increase in the aortic root compared with Ccr7+/+ApoE−/− mice. Ccr7−/−ApoE−/− mice had increased T cells in the blood, bone marrow, and spleen, as well as in atherosclerotic lesions. Competitive repopulation experiments revealed that T cells from Ccr7−/−ApoE−/− mice migrated poorly into lymph nodes but better into mouse aortas compared with T cells from Ccr7+/+ApoE−/− mice. Transplantation of the bone marrow from Ccr7−/−ApoE−/− mice into lethally irradiated Ccr7+/+ApoE−/− mice resulted in ∼60% more atherosclerotic lesions compared with Ccr7+/+ApoE−/− donor bone marrow, suggesting that exacerbation was mediated by a Ccr7+ bone marrow-derived cell(s). Furthermore, in Ccr7−/−ApoE−/− mice the serum level of IL-12 was markedly increased, whereas the level of transforming growth factor beta (TGF-β) was significantly decreased, suggesting an imbalance of T cell responses in these mice. Conclusion Our data suggest that genetic deletion of Ccr7 exacerbates atherosclerosis by increasing T cell accumulation in atherosclerotic lesions. PMID:23180724

  16. Functional CCR9 expression is associated with small intestinal metastasis.

    PubMed

    Letsch, Anne; Keilholz, Ulrich; Schadendorf, Dirk; Assfalg, Geraldine; Asemissen, Anne Marie; Thiel, Eckhard; Scheibenbogen, Carmen

    2004-03-01

    In general, metastases to the small intestine are rare, and mostly occur in melanoma. CCR9 has been shown to be the principal chemokine receptor for the thymus expressed chemokine (TECK), a chemokine selectively expressed in the small intestine and thymus. Here we show that CCR9 is highly expressed on melanoma cells and all melanoma cell lines isolated from small intestinal metastases, and on a proportion of cell lines from other sites. Only melanoma cells and cell lines from small intestinal metastases, however, were responsive to the CCR9 ligand TECK, as assessed by receptor downregulation and by actin polymerization. CCR9 expression was also found on the adenocarcinoma cell line CaCo-2 expressing characteristics of enterocytic differentiation, but not on any other cell line isolated from colorectal, breast, and lung cancer. Our data provide evidence that the aberrant functional cell surface expression of an organ-specific chemokine receptor is associated with metastasis to this site. The regulation of receptor function seems to be a critical step in the metastatic process. PMID:15086554

  17. Myocardial infarction activates CCR2+ hematopoietic stem and progenitor cells

    PubMed Central

    Dutta, Partha; Sager, Hendrik B.; Stengel, Kristy R.; Naxerova, Kamila; Courties, Gabriel; Saez, Borja; Silberstein, Lev; Heidt, Timo; Sebas, Matthew; Sun, Yuan; Wojtkiewicz, Gregory; Feruglio, Paolo Fumene; King, Kevin; Baker, Joshua N.; van der Laan, Anja M.; Borodovsky, Anna; Fitzgerald, Kevin; Hulsmans, Maarten; Hoyer, Friedrich; Iwamoto, Yoshiko; Vinegoni, Claudio; Brown, Dennis; Di Carli, Marcelo; Libby, Peter; Hiebert, Scott; Scadden, David; Swirski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias

    2015-01-01

    SUMMARY Following myocardial infarction (MI), myeloid cells derived from the hematopoietic system drive a sharp increase in systemic leukocyte levels that correlate closely with mortality. The origin of these myeloid cells, and the response of hematopoietic stem and progenitor cells (HSPCs) to MI, however, is unclear. Here, we identify a CCR2+CD150+CD48− LSK hematopoietic subset as the most upstream contributor to emergency myelopoiesis after ischemic organ injury. CCR2+ HSPC have fourfold higher proliferation rates than CCR2−CD150+CD48− LSK cells, display a myeloid differentiation bias, and dominate the migratory HSPC population. We further demonstrate the myeloid translocation gene 16 (Mtg16) regulates CCR2+ HSPC emergence. Mtg16−/− mice have decreased levels of systemic monocytes and infarct-associated macrophages and display compromised tissue healing and post-MI heart failure. Together, these data provide insights into regulation of emergency hematopoiesis after ischemic injury, and identify potential therapeutic targets to modulate leukocyte output after MI. PMID:25957903

  18. Biology as an integrated component of the U.S. Geological Survey's National Water-Quality Assessment Program

    USGS Publications Warehouse

    Meador, Michael R.; Gurtz, Martin E.

    1994-01-01

    The U.S. Geological Survey?s (USGS) National Water-Quality Assessment (NAWQA) Program is designed to integrate chemical, physical, and biological data to assess the status of and trends in the Nation?s water quality at local, regional, and national levels. The Program consists of 60 study units (major river basins and large parts of aquifers) located throughout the Nation (fig. 1). Data are collected at stream, river, and ground-water sites that represent the Nation?s mix of major natural and human factors that influence water quality. Biological data are collected from streams and rivers, and include (1) fish and other aquatic organisms whose tissues are analyzed for a wide array of chemical contaminants; (2) characterizations of algal, benthic invertebrate, and fish communities; and (3) characterizations of vegetation growing in streams and along streambanks. These biological data are collected in conjunction with physical (streamflow, characterizations of instream, bank, and flood-plain habitats) and chemical data.

  19. NO gas loss from biologically crusted soils in Canyonlands National Park, Utah

    USGS Publications Warehouse

    Barger, N.N.; Belnap, J.; Ojima, D.S.; Mosier, A.

    2005-01-01

    In this study, we examined N gas loss as nitric oxide (NO) from N-fixing biologically crusted soils in Canyonlands National Park, Utah. We hypothesized that NO gas loss would increase with increasing N fixation potential of the biologically crusted soil. NO fluxes were measured from biologically crusted soils with three levels of N fixation potential (Scytonema-Nostoc-Collema spp. (dark)>Scytonema-Nostoc-Microcoleus spp. (medium)>Microcoleus spp. (light)) from soil cores and field chambers. In both cores and field chambers there was a significant effect of crust type on NO fluxes, but this was highly dependent on season. NO fluxes from field chambers increased with increasing N fixation potential of the biologically crusted soils (dark>medium>light) in the summer months, with no differences in the spring and autumn. Soil chlorophyllasis Type a content (an index of N fixation potential), percent N, and temperature explained 40% of the variability in NO fluxes from our field sites. Estimates of annual NO loss from dark and light crusts was 0.04-0.16 and 0.02-0.11-N/ha/year. Overall, NO gas loss accounts for approximately 3-7% of the N inputs via N fixation in dark and light biologically crusted soils. Land use practices have drastically altered biological soil crusts communities over the past century. Livestock grazing and intensive recreational use of public lands has resulted in a large scale conversion of dark cyanolichen crusts to light cyanobacterial crusts. As a result, changes in biologically crusted soils in arid and semi-arid regions of the western US may subsequently impact regional NO loss. ?? Springer 2005.

  20. Primary, syncytium-inducing human immunodeficiency virus type 1 isolates are dual-tropic and most can use either Lestr or CCR5 as coreceptors for virus entry.

    PubMed Central

    Simmons, G; Wilkinson, D; Reeves, J D; Dittmar, M T; Beddows, S; Weber, J; Carnegie, G; Desselberger, U; Gray, P W; Weiss, R A; Clapham, P R

    1996-01-01

    A panel of primary syncytium-inducing (SI) human immunodeficiency virus type 1 isolates that infected several CD4+ T-cell lines, including MT-2 and C8166, were tested for infection of blood-derived macrophages. Infectivity titers for C8166 cells and macrophages demonstrated that primary SI strains infected macrophages much more efficiently than T-cell line-adapted HIV-1 strains such as LAI and RF. These primary SI strains were therefore dual-tropic. Nine biological clones of two SI strains, prepared by limiting dilution, had macrophage/C8166 infectivity ratios similar to those of their parental viruses, indicating that the dual-tropic phenotype was not due to a mixture of non-SI/macrophage-tropic and SI/T-cell tropic viruses. We tested whether the primary SI strains used either Lestr (fusin) or CCR5 as coreceptors. Infection of cat CCC/CD4 cells transiently expressing Lestr supported infection by T-cell line-adapted strains including LAI, whereas CCC/CD4 cells expressing CCR5 were sensitive to primary non-SI strains as well as to the molecularly cloned strains SF-162 and JR-CSF. Several primary SI strains, as well as the molecularly cloned dual-tropic viruses 89.6 and GUN-1, infected both Lestr+ and CCR5+ CCC/CD4 cells. Thus, these viruses can choose between Lestr and CCR5 for entry into cells. Interestingly, some dual-tropic primary SI strains that infected Lestr+ cells failed to infect CCR5+ cells, suggesting that these viruses may use an alternative coreceptor for infection of macrophages. Alternatively, CCR5 may be processed or presented differently on cat cells so that entry of some primary SI strains but not others is affected. PMID:8970955

  1. An anti-CCR5 monoclonal antibody and small molecule CCR5 antagonists synergize by inhibiting different stages of human immunodeficiency virus type 1 entry

    SciTech Connect

    Safarian, Diana; Carnec, Xavier; Tsamis, Fotini; Kajumo, Francis; Dragic, Tatjana . E-mail: tdragic@aecom.yu.edu

    2006-09-01

    HIV-1 coreceptors are attractive targets for novel antivirals. Here, inhibition of entry by two classes of CCR5 antagonists was investigated. We confirmed previous findings that HIV-1 isolates vary greatly in their sensitivity to small molecule inhibitors of CCR5-mediated entry, SCH-C and TAK-779. In contrast, an anti-CCR5 monoclonal antibody (PA14) similarly inhibited entry of diverse viral isolates. Sensitivity to small molecules was V3 loop-dependent and inversely proportional to the level of gp120 binding to CCR5. Moreover, combinations of the MAb and small molecules were highly synergistic in blocking HIV-1 entry, suggesting different mechanisms of action. This was confirmed by time course of inhibition experiments wherein the PA14 MAb and small molecules were shown to inhibit temporally distinct stages of CCR5 usage. We propose that small molecules inhibit V3 binding to the second extracellular loop of CCR5, whereas PA14 preferentially inhibits subsequent events such as CCR5 recruitment into the fusion complex or conformational changes in the gp120-CCR5 complex that trigger fusion. Importantly, our findings suggest that combinations of CCR5 inhibitors with different mechanisms of action will be central to controlling HIV-1 infection and slowing the emergence of resistant strains.

  2. Highly specific blockade of CCR5 inhibits leukocyte trafficking and reduces mucosal inflammation in murine colitis.

    PubMed

    Mencarelli, Andrea; Cipriani, Sabrina; Francisci, Daniela; Santucci, Luca; Baldelli, Franco; Distrutti, Eleonora; Fiorucci, Stefano

    2016-01-01

    Targeted disruption of leukocyte trafficking to the gut represents a promising approach for the treatment of inflammatory bowel diseases (IBDs). CCR5, the shared receptor for MIP1α and β and RANTES, is expressed by multiple leukocytes. Here, we aimed to determine the role of CCR5 in mediating leukocyte trafficking in models of colitis, and evaluate the therapeutic potential of maraviroc, an orally active CCR5 antagonist used in the treatment of CCR5-tropic HIV. Acute and chronic colitis were induced by administration of DSS or TNBS to wild-type and CCR5(-/-) mice or adoptive transfer of splenic naïve CD4(+) T-cells from wild type or CCR5(-/-) mice into RAG-1(-/-). CCR5 gene ablation reduced the mucosal recruitment and activation of CCR5-bearing CD4(+) and CD11b(+) leukocytes, resulting in profound attenuation of signs and symptoms of inflammation in the TNBS and transfer models of colitis. In the DSS/TNBS colitis and in the transfer model, maraviroc attenuated development of intestinal inflammation by selectively reducing the recruitment of CCR5 bearing leukocytes. In summary, CCR5 regulates recruitment of blood leukocytes into the colon indicating that targeting CCR5 may offer therapeutic options in IBDs. PMID:27492684

  3. Highly specific blockade of CCR5 inhibits leukocyte trafficking and reduces mucosal inflammation in murine colitis

    PubMed Central

    Mencarelli, Andrea; Cipriani, Sabrina; Francisci, Daniela; Santucci, Luca; Baldelli, Franco; Distrutti, Eleonora; Fiorucci, Stefano

    2016-01-01

    Targeted disruption of leukocyte trafficking to the gut represents a promising approach for the treatment of inflammatory bowel diseases (IBDs). CCR5, the shared receptor for MIP1α and β and RANTES, is expressed by multiple leukocytes. Here, we aimed to determine the role of CCR5 in mediating leukocyte trafficking in models of colitis, and evaluate the therapeutic potential of maraviroc, an orally active CCR5 antagonist used in the treatment of CCR5-tropic HIV. Acute and chronic colitis were induced by administration of DSS or TNBS to wild-type and CCR5−/− mice or adoptive transfer of splenic naïve CD4+ T-cells from wild type or CCR5−/− mice into RAG-1−/−. CCR5 gene ablation reduced the mucosal recruitment and activation of CCR5-bearing CD4+ and CD11b+ leukocytes, resulting in profound attenuation of signs and symptoms of inflammation in the TNBS and transfer models of colitis. In the DSS/TNBS colitis and in the transfer model, maraviroc attenuated development of intestinal inflammation by selectively reducing the recruitment of CCR5 bearing leukocytes. In summary, CCR5 regulates recruitment of blood leukocytes into the colon indicating that targeting CCR5 may offer therapeutic options in IBDs. PMID:27492684

  4. Decreased HIV Type 1 Transcription in CCR5-Δ32 Heterozygotes During Suppressive Antiretroviral Therapy

    PubMed Central

    Wang, Charlene; Abdel-Mohsen, Mohamed; Strain, Matthew C.; Lada, Steven M.; Yukl, Steven; Cockerham, Leslie R.; Pilcher, Christopher D.; Hecht, Frederick M.; Sinclair, Elizabeth; Liegler, Teri; Richman, Douglas D.; Deeks, Steven G.; Pillai, Satish K.

    2014-01-01

    Individuals who are heterozygous for the CCR5-Δ32 mutation provide a natural model to examine the effects of reduced CCR5 expression on human immunodeficiency virus (HIV) persistence. We evaluated the HIV reservoir in 18 CCR5-Δ32 heterozygotes and 54 CCR5 wild-type individuals during suppressive antiretroviral therapy. Cell-associated HIV RNA levels (P = .035), RNA to DNA transcriptional ratios (P = .013), and frequency of detectable HIV 2–long terminal repeat circular DNA (P = .013) were significantly lower in CD4+ T cells from CCR5-Δ32 heterozygotes. Cell-associated HIV RNA was significantly correlated with CCR5 surface expression on CD4+ T cells (r2 = 0.136; P = .002). Our findings suggest that curative strategies should further explore manipulation of CCR5. PMID:24935955

  5. YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex.

    PubMed

    Du, Hao; Zhao, Ya; He, Jinqiu; Zhang, Yao; Xi, Hairui; Liu, Mofang; Ma, Jinbiao; Wu, Ligang

    2016-01-01

    Methylation at the N6 position of adenosine (m(6)A) is the most abundant RNA modification within protein-coding and long noncoding RNAs in eukaryotes and is a reversible process with important biological functions. YT521-B homology domain family (YTHDF) proteins are the readers of m(6)A, the binding of which results in the alteration of the translation efficiency and stability of m(6)A-containing RNAs. However, the mechanism by which YTHDF proteins cause the degradation of m(6)A-containing RNAs is poorly understood. Here we report that m(6)A-containing RNAs exhibit accelerated deadenylation that is mediated by the CCR4-NOT deadenylase complex. We further show that YTHDF2 recruits the CCR4-NOT complex through a direct interaction between the YTHDF2 N-terminal region and the SH domain of the CNOT1 subunit, and that this recruitment is essential for the deadenylation of m(6)A-containing RNAs by CAF1 and CCR4. Therefore, we have uncovered the mechanism of YTHDF2-mediated degradation of m(6)A-containing RNAs in mammalian cells. PMID:27558897

  6. Retinal Inhibition of CCR3 Induces Retinal Cell Death in a Murine Model of Choroidal Neovascularization

    PubMed Central

    Wang, Haibo; Han, Xiaokun; Gambhir, Deeksha; Becker, Silke; Kunz, Eric; Liu, Angelina Jingtong; Hartnett, M. Elizabeth

    2016-01-01

    Inhibition of chemokine C-C motif receptor 3 (CCR3) signaling has been considered as treatment for neovascular age-related macular degeneration (AMD). However, CCR3 is expressed in neural retina from aged human donor eyes. Therefore, broad CCR3 inhibition may be harmful to the retina. We assessed the effects of CCR3 inhibition on retina and choroidal endothelial cells (CECs) that develop into choroidal neovascularization (CNV). In adult murine eyes, CCR3 colocalized with glutamine-synthetase labeled Műller cells. In a murine laser-induced CNV model, CCR3 immunolocalized not only to lectin-stained cells in CNV lesions but also to the retina. Compared to non-lasered controls, CCR3 mRNA was significantly increased in laser-treated retina. An intravitreal injection of a CCR3 inhibitor (CCR3i) significantly reduced CNV compared to DMSO or PBS controls. Both CCR3i and a neutralizing antibody to CCR3 increased TUNEL+ retinal cells overlying CNV, compared to controls. There was no difference in cleaved caspase-3 in laser-induced CNV lesions or in overlying retina between CCR3i- or control-treated eyes. Following CCR3i, apoptotic inducible factor (AIF) was significantly increased and anti-apoptotic factor BCL2 decreased in the retina; there were no differences in retinal vascular endothelial growth factor (VEGF). In cultured human Műller cells exposed to eotaxin (CCL11) and VEGF, CCR3i significantly increased TUNEL+ cells and AIF but decreased BCL2 and brain derived neurotrophic factor, without affecting caspase-3 activity or VEGF. CCR3i significantly decreased AIF in RPE/choroids and immunostaining of phosphorylated VEGF receptor 2 (p-VEGFR2) in CNV with a trend toward reduced VEGF. In cultured CECs treated with CCL11 and/or VEGF, CCR3i decreased p-VEGFR2 and increased BCL2 without increasing TUNEL+ cells and AIF. These findings suggest that inhibition of retinal CCR3 causes retinal cell death and that targeted inhibition of CCR3 in CECs may be a safer if CCR3 inhibition

  7. Retinal Inhibition of CCR3 Induces Retinal Cell Death in a Murine Model of Choroidal Neovascularization.

    PubMed

    Wang, Haibo; Han, Xiaokun; Gambhir, Deeksha; Becker, Silke; Kunz, Eric; Liu, Angelina Jingtong; Hartnett, M Elizabeth

    2016-01-01

    Inhibition of chemokine C-C motif receptor 3 (CCR3) signaling has been considered as treatment for neovascular age-related macular degeneration (AMD). However, CCR3 is expressed in neural retina from aged human donor eyes. Therefore, broad CCR3 inhibition may be harmful to the retina. We assessed the effects of CCR3 inhibition on retina and choroidal endothelial cells (CECs) that develop into choroidal neovascularization (CNV). In adult murine eyes, CCR3 colocalized with glutamine-synthetase labeled Műller cells. In a murine laser-induced CNV model, CCR3 immunolocalized not only to lectin-stained cells in CNV lesions but also to the retina. Compared to non-lasered controls, CCR3 mRNA was significantly increased in laser-treated retina. An intravitreal injection of a CCR3 inhibitor (CCR3i) significantly reduced CNV compared to DMSO or PBS controls. Both CCR3i and a neutralizing antibody to CCR3 increased TUNEL+ retinal cells overlying CNV, compared to controls. There was no difference in cleaved caspase-3 in laser-induced CNV lesions or in overlying retina between CCR3i- or control-treated eyes. Following CCR3i, apoptotic inducible factor (AIF) was significantly increased and anti-apoptotic factor BCL2 decreased in the retina; there were no differences in retinal vascular endothelial growth factor (VEGF). In cultured human Műller cells exposed to eotaxin (CCL11) and VEGF, CCR3i significantly increased TUNEL+ cells and AIF but decreased BCL2 and brain derived neurotrophic factor, without affecting caspase-3 activity or VEGF. CCR3i significantly decreased AIF in RPE/choroids and immunostaining of phosphorylated VEGF receptor 2 (p-VEGFR2) in CNV with a trend toward reduced VEGF. In cultured CECs treated with CCL11 and/or VEGF, CCR3i decreased p-VEGFR2 and increased BCL2 without increasing TUNEL+ cells and AIF. These findings suggest that inhibition of retinal CCR3 causes retinal cell death and that targeted inhibition of CCR3 in CECs may be a safer if CCR3 inhibition

  8. Ecotoxicological evaluation of area 9 landfill at Crab Orchard National Wildlife Refuge: Biological impact and residues

    SciTech Connect

    McKee, M.J.

    1992-10-01

    Polychlorinated biphenyls (PCBs) and lead were investigated in soil and biota at Crab Orchard National Wildlife Refuge (CONWR) and related to biological effects. PCBs were rapidly mobilized from the soil into the terrestrial food chain as evidenced by high residue levels in adult beetles, caged house crickets, and white-footed mice. Bioaccumulation of lead was not observed in invertebrates, but was observed in white-footed mice. Invertebrate abundance and biomarkers were evaluated for signs of toxic response to soil contaminants. The control site and the Area 9 Landfill did not differ in abundance of five common terrestrial invertebrate families. The absence of detectable biological effects in invertebrates shows that these animals can tolerate relatively high environmental concentrations of these contaminants. The intensive use of Area 9 Landfill by invertebrates and their apparent tolerance of soil contaminants eludes to the importance of chemical transfer to higher trophic levels, especially for PCBs.

  9. Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor

    PubMed Central

    Gornalusse, German G.; Mummidi, Srinivas; Gaitan, Alvaro A.; Jimenez, Fabio; Ramsuran, Veron; Picton, Anabela; Rogers, Kristen; Manoharan, Muthu Saravanan; Avadhanam, Nymisha; Murthy, Krishna K.; Martinez, Hernan; Molano Murillo, Angela; Chykarenko, Zoya A.; Hutt, Richard; Daskalakis, Demetre; Shostakovich-Koretskaya, Ludmila; Abdool Karim, Salim; Martin, Jeffrey N.; Deeks, Steven G.; Hecht, Frederick; Sinclair, Elizabeth; Clark, Robert A.; Okulicz, Jason; Valentine, Fred T.; Martinson, Neil; Tiemessen, Caroline Tanya; Ndung’u, Thumbi; Hunt, Peter W.; He, Weijing; Ahuja, Sunil K.

    2015-01-01

    T-cell expression levels of CC chemokine receptor 5 (CCR5) are a critical determinant of HIV/AIDS susceptibility, and manifest wide variations (i) between T-cell subsets and among individuals and (ii) in T-cell activation-induced increases in expression levels. We demonstrate that a unifying mechanism for this variation is differences in constitutive and T-cell activation-induced DNA methylation status of CCR5 cis-regulatory regions (cis-regions). Commencing at an evolutionarily conserved CpG (CpG −41), CCR5 cis-regions manifest lower vs. higher methylation in T cells with higher vs. lower CCR5 levels (memory vs. naïve T cells) and in memory T cells with higher vs. lower CCR5 levels. HIV-related and in vitro induced T-cell activation is associated with demethylation of these cis-regions. CCR5 haplotypes associated with increased vs. decreased gene/surface expression levels and HIV/AIDS susceptibility magnify vs. dampen T-cell activation-associated demethylation. Methylation status of CCR5 intron 2 explains a larger proportion of the variation in CCR5 levels than genotype or T-cell activation. The ancestral, protective CCR5-HHA haplotype bears a polymorphism at CpG −41 that is (i) specific to southern Africa, (ii) abrogates binding of the transcription factor CREB1 to this cis-region, and (iii) exhibits a trend for overrepresentation in persons with reduced susceptibility to HIV and disease progression. Genotypes lacking the CCR5-Δ32 mutation but with hypermethylated cis-regions have CCR5 levels similar to genotypes heterozygous for CCR5-Δ32. In HIV-infected individuals, CCR5 cis-regions remain demethylated, despite restoration of CD4+ counts (≥800 cells per mm3) with antiretroviral therapy. Thus, methylation content of CCR5 cis-regions is a central epigenetic determinant of T-cell CCR5 levels, and possibly HIV-related outcomes. PMID:26307764

  10. Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor.

    PubMed

    Gornalusse, German G; Mummidi, Srinivas; Gaitan, Alvaro A; Jimenez, Fabio; Ramsuran, Veron; Picton, Anabela; Rogers, Kristen; Manoharan, Muthu Saravanan; Avadhanam, Nymisha; Murthy, Krishna K; Martinez, Hernan; Molano Murillo, Angela; Chykarenko, Zoya A; Hutt, Richard; Daskalakis, Demetre; Shostakovich-Koretskaya, Ludmila; Abdool Karim, Salim; Martin, Jeffrey N; Deeks, Steven G; Hecht, Frederick; Sinclair, Elizabeth; Clark, Robert A; Okulicz, Jason; Valentine, Fred T; Martinson, Neil; Tiemessen, Caroline Tanya; Ndung'u, Thumbi; Hunt, Peter W; He, Weijing; Ahuja, Sunil K

    2015-08-25

    T-cell expression levels of CC chemokine receptor 5 (CCR5) are a critical determinant of HIV/AIDS susceptibility, and manifest wide variations (i) between T-cell subsets and among individuals and (ii) in T-cell activation-induced increases in expression levels. We demonstrate that a unifying mechanism for this variation is differences in constitutive and T-cell activation-induced DNA methylation status of CCR5 cis-regulatory regions (cis-regions). Commencing at an evolutionarily conserved CpG (CpG -41), CCR5 cis-regions manifest lower vs. higher methylation in T cells with higher vs. lower CCR5 levels (memory vs. naïve T cells) and in memory T cells with higher vs. lower CCR5 levels. HIV-related and in vitro induced T-cell activation is associated with demethylation of these cis-regions. CCR5 haplotypes associated with increased vs. decreased gene/surface expression levels and HIV/AIDS susceptibility magnify vs. dampen T-cell activation-associated demethylation. Methylation status of CCR5 intron 2 explains a larger proportion of the variation in CCR5 levels than genotype or T-cell activation. The ancestral, protective CCR5-HHA haplotype bears a polymorphism at CpG -41 that is (i) specific to southern Africa, (ii) abrogates binding of the transcription factor CREB1 to this cis-region, and (iii) exhibits a trend for overrepresentation in persons with reduced susceptibility to HIV and disease progression. Genotypes lacking the CCR5-Δ32 mutation but with hypermethylated cis-regions have CCR5 levels similar to genotypes heterozygous for CCR5-Δ32. In HIV-infected individuals, CCR5 cis-regions remain demethylated, despite restoration of CD4+ counts (≥800 cells per mm(3)) with antiretroviral therapy. Thus, methylation content of CCR5 cis-regions is a central epigenetic determinant of T-cell CCR5 levels, and possibly HIV-related outcomes. PMID:26307764

  11. A role for CCR5(+)CD4 T cells in cutaneous psoriasis and for CD103(+) CCR4(+) CD8 Teff cells in the associated systemic inflammation.

    PubMed

    Sgambelluri, Francesco; Diani, Marco; Altomare, Andrea; Frigerio, Elena; Drago, Lorenzo; Granucci, Francesca; Banfi, Giuseppe; Altomare, Gianfranco; Reali, Eva

    2016-06-01

    Recent results have identified critical components of the T cell response involved in the initiation and amplification phases of psoriasis. However the link between T cell responses arising in the skin and the systemic inflammation associated with severe psoriasis is largely unknown. We hypothesized that specific subsets of memory T cells recirculating from the skin could play a role. We therefore dissected the circulating memory T cell compartment in patients by analyzing the TCM, TEM and Teff phenotype, the pattern of CCR4 and CCR5 chemokine receptor expression and the expression of the tissue homing molecule CD103. For each subset we calculated the correlation with the Psoriasis Area and Severity Index (PASI) and with the extent of systemic inflammation measured as serum level of the prototypic short pentraxin, C reactive protein (CRP). Validation was performed by comparison with gene expression data in psoriatic plaques. We found that circulating CD103(+)CCR4(+)CCR5(+) and CCR4(+)CCR6(-) CD8(+) Teff cells, were highly correlated with CRP levels as well as with the validated index PASI, reflecting a link between skin involvement and systemic inflammation in patients with severe psoriasis. In addition we observed a contraction of circulating CCR5(+) T cells in psoriasis patients, with a highly significant inverse correlation between CCR5(+)CD4 T cells and the PASI score. Increased expression of CCR5 and CCL5 genes in psoriatic skin lesions was consistent with an accumulation of CCR5(+) cells in psoriatic plaques indicating a role for CCR5/CCL5 axis in disease pathogenesis. PMID:27068801

  12. Distribution Of CCR-5Δ32, CCR2-64I, and SDF-1-3′A Alleles Among Jordanians

    PubMed Central

    Abu-Haweleh, Laila J.; Alzoubi, Karem H.

    2013-01-01

    Abstract Entry of HIV virus into cells is mediated by chemokine receptors. Genetic variations in chemokine receptors have been shown to modulate susceptibility to HIV infection and disease course. In this study, the frequencies of CCR5 (CCR5-Δ32), CCR2 (CCR2-64I), and SDF-1 (SDF-1-3′) gene polymorphisms were determined in a Jordanian population. A total of 540 subjects were randomly selected from different regions of Jordan (South, Middle, and North). Six individuals were found to carry the CCR5-Δ32 allele (0.6%) and only in the heterozygous genotype. The frequencies of CCR2-64I and SDF1-3′A were 17.5% and 34.2%, respectively. In addition, no significant difference in the distribution of the examined polymorphisms among different regions of Jordan was detected. In conclusion, the CCR5-Δ32 allele is rare, whereas the CCR2-64I and SDF1-3′A alleles are common among Jordanians. PMID:22770415

  13. CCR2 and CCR5 genes polymorphisms in women with cervical lesions from Pernambuco, Northeast Region of Brazil: a case-control study

    PubMed Central

    dos Santos, Erinaldo Ubirajara Damasceno; de Lima, Géssica Dayane Cordeiro; Oliveira, Micheline de Lucena; Heráclio, Sandra de Andrade; da Silva, Hildson Dornelas Angelo; Crovella, Sergio; Maia, Maria de Mascena Diniz; de Souza/, Paulo Roberto Eleutério

    2016-01-01

    Polymorphisms in chemokine receptors play an important role in the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer (CC). Our study examined the association of CCR2-64I (rs1799864) andCCR5-Δ32 (rs333) polymorphisms with susceptibility to develop cervical lesion (CIN and CC) in a Brazilian population. The genotyping of 139 women with cervical lesions and 151 women without cervical lesions for the CCR2-64I and CCR5-Δ32 polymorphisms were performed using polymerase chain reaction-restriction fragment length polymorphism. The individuals carrying heterozygous or homozygous genotypes (GA+AA) for CCR2-64I polymorphisms seem to be at lower risk for cervical lesion [odds ratio (OR) = 0.37, p = 0.0008)]. The same was observed for the A allele (OR = 0.39, p = 0.0002), while no association was detected (p > 0.05) with CCR5-Δ32 polymorphism. Regarding the human papillomavirus (HPV) type, patients carrying the CCR2-64Ipolymorphism were protected against infection by HPV type 16 (OR = 0.35, p = 0.0184). In summary, our study showed a protective effect ofCCR2-64I rs1799864 polymorphism against the development of cervical lesions (CIN and CC) and in the susceptibility of HPV 16 infection. PMID:26982176

  14. CCR2 overexpression promotes the efficient recruitment of retinal microglia in vitro

    PubMed Central

    Jiang, Xiao-shuang; Liu, Tian-jin; Zhang, Meng; Ren, Hui; Jiang, Rui; Huang, Xin; Xu, Ge-zhi

    2012-01-01

    Purpose Retinal microglia can be activated and recruited by chemokines and play a protective role in early retinal degeneration. CC-chemokine ligand 2 (CCL2) and its receptor, CC-chemokine receptor 2 (CCR2), have been implicated as key mediators for the trafficking and accumulation of microglial cells in lesioned tissue. The current study investigates whether the overexpression of CCR2 allows microglia to migrate toward CCL2 more efficiently. Methods Primary microglial cells were transduced with lentivirus carrying green fluorescent protein (GFP)-tagged CCR2 (CCR2-GFP). Overexpression of CCR2 was assessed by western blot analysis and fluorescence-assisted cell sorting. The chemotaxis of primary microglia transduced with lentivirus carrying CCR2-GFP was compared to either those transduced with GFP alone or those not transduced, using a chemotaxis chamber assay. Results Primary microglia showed a high transduction rate following lentivirus application and maintained normal microglial morphology and a significant overexpression of CCR2 protein. We found that CCL2-mediated chemotaxis is concentration and time dependent in microglia. The chemotactic response of microglia cells overexpressing CCR2-GFP was significantly increased compared to that of nontransduced and GFP-expressing microglia. Conclusions These findings suggest that microglia can be efficiently transduced with CCR2-GFP lentiviral vectors and that the overexpression of CCR2 in retinal microglia promotes their chemotaxis in response to chemokines, suggesting that these cells may be promising targets for cell-based therapeutic manipulation in retinal disease. PMID:23288990

  15. Two distinct CCR5 domains can mediate coreceptor usage by human immunodeficiency virus type 1.

    PubMed Central

    Doranz, B J; Lu, Z H; Rucker, J; Zhang, T Y; Sharron, M; Cen, Y H; Wang, Z X; Guo, H H; Du, J G; Accavitti, M A; Doms, R W; Peiper, S C

    1997-01-01

    The chemokine receptor CCR5 is the major fusion coreceptor for macrophage-tropic strains of human immunodeficiency virus type 1 (HIV-1). To define the structures of CCR5 that can support envelope (Env)-mediated membrane fusion, we analyzed the activity of homologs, chimeras, and mutants of human CCR5 in a sensitive gene reporter cell-cell fusion assay. Simian, but not murine, homologs of CCR5 were fully active as HIV-1 fusion coreceptors. Chimeras between CCR5 and divergent chemokine receptors demonstrated the existence of two distinct regions of CCR5 that could be utilized for Env-mediated fusion, the amino-terminal domain and the extracellular loops. Dual-tropic Env proteins were particularly sensitive to alterations in the CCR5 amino-terminal domain, suggesting that this domain may play a pivotal role in the evolution of coreceptor usage in vivo. We identified individual residues in both functional regions, Asp-11, Lys-197, and Asp-276, that contribute to coreceptor function. Deletion of a highly conserved cytoplasmic motif rendered CCR5 incapable of signaling but did not abrogate its ability to function as a coreceptor, implying the independence of fusion and G-protein-mediated chemokine receptor signaling. Finally, we developed a novel monoclonal antibody to CCR5 to assist in future studies of CCR5 expression. PMID:9261347

  16. Molecular Gymnastics: Mechanisms of HIV-1 Resistance to CCR5 Antagonists and Impact on Virus Phenotypes.

    PubMed

    Roche, Michael; Borm, Katharina; Flynn, Jacqueline K; Lewin, Sharon R; Churchill, Melissa J; Gorry, Paul R

    2016-01-01

    Human immunodeficiency virus type 1 (HIV-1) enters host cells through the binding of its envelope glycoproteins (Env) to the host cell receptor CD4 and then subsequent binding to a chemokine coreceptor, either CCR5 or CXCR4. CCR5 antagonists are a relatively recent class addition to the armamentarium of anti-HIV-1 drugs. These compounds act by binding to a hydrophobic pocket formed by the transmembrane helices of CCR5 and altering the conformation of the extracellular domains, such that they are no longer recognized by Env. Maraviroc is the first drug within this class to be licenced for use in HIV-1 therapy regimens. HIV resistance to CCR5 antagonists occurs either through outgrowth of pre-existing CXCR4-using viruses, or through acquisition of the ability of CCR5-using HIV-1 to use the antagonist bound form of CCR5. In the latter scenario, the mechanism underlying resistance is through complex alterations in the way that resistant Envs engage CCR5. These significant changes are unlikely to occur without consequence to the viral entry phenotype and may also open up new avenues to target CCR5 antagonist resistant viruses. This review discusses the mechanism of action of CCR5 antagonists, how HIV resistance to CCR5 antagonists occurs, and the subsequent effects on Env function. PMID:26324043

  17. Distinct CCR7 glycosylation pattern shapes receptor signaling and endocytosis to modulate chemotactic responses.

    PubMed

    Hauser, Mark A; Kindinger, Ilona; Laufer, Julia M; Späte, Anne-Katrin; Bucher, Delia; Vanes, Sarah L; Krueger, Wolfgang A; Wittmann, Valentin; Legler, Daniel F

    2016-06-01

    The homeostatic chemokines CCL19 and CCL21 and their common cognate chemokine receptor CCR7 orchestrate immune cell trafficking by eliciting distinct signaling pathways. Here, we demonstrate that human CCR7 is N-glycosylated on 2 specific residues in the N terminus and the third extracellular loop. Conceptually, CCR7 glycosylation adds steric hindrance to the receptor N terminus and extracellular loop 3, acting as a "swinging door" to regulate receptor sensitivity and cell migration. We found that freshly isolated human B cells, as well as expanded T cells, but not naïve T cells, express highly sialylated CCR7. Moreover, we identified that human dendritic cells imprint T cell migration toward CCR7 ligands by secreting enzymes that deglycosylate CCR7, thereby boosting CCR7 signaling on T cells, permitting enhanced T cell locomotion, while simultaneously decreasing receptor endocytosis. In addition, dendritic cells proteolytically convert immobilized CCL21 to a soluble form that is more potent in triggering chemotactic movement and does not desensitize the receptor. Furthermore, we demonstrate that soluble CCL21 functionally resembles neither the CCL19 nor the CCL21 phenotype but acts as a chemokine with unique features. Thus, we advance the concept of dendritic cell-dependent generation of micromilieus and lymph node conditioning by demonstrating a novel layer of CCR7 regulation through CCR7 sialylation. In summary, we demonstrate that leukocyte subsets express distinct patterns of CCR7 sialylation that contribute to receptor signaling and fine-tuning chemotactic responses. PMID:26819318

  18. Sequential Binding of Cobalt(II) to Metallo-beta-lactamase CcrA

    SciTech Connect

    Periyannan,G.; Costello, A.; Tierney, D.; Yang, K.; Bennett, b.; Crowder, M.

    2006-01-01

    In an effort to probe Co(II) binding to metallo-{beta}-lactamase CcrA, EPR, EXAFS, and 1H NMR studies were conducted on CcrA containing 1 equiv (1-Co(II)-CcrA) and 2 equiv (Co(II)Co(II)-CcrA) of Co(II). The EPR spectra of 1-Co(II)-CcrA and Co(II)Co(II)-CcrA are distinct and indicate 5/6-coordinate Co(II) ions. The EPR spectra also reveal the absence of significant spin-exchange coupling between the Co(II) ions in Co(II)Co(II)-CcrA. EXAFS spectra of 1-Co(II)-CcrA suggest 5/6-coordinate Co(II) with two or more histidine ligands. EXAFS spectra of Co(II)Co(II)-CcrA also indicate 5/6 ligands at a similar average distance to 1-Co(II)-CcrA, including an average of about two histidines per Co(II). {sup 1}H NMR spectra for 1-Co(II)-CcrA revealed seven paramagnetically shifted resonances, three of which were solvent-exchangeable, while the NMR spectra for Co(II)Co(II)-CcrA showed at least 16 shifted resonances, including an additional solvent-exchangeable resonance and a resonance at 208 ppm. The data indicate sequential binding of Co(II) to CcrA and that the first Co(II) binds to the consensus Zn{sub 1} site in the enzyme.

  19. A model of federal interagency cooperation: the National Interagency Confederation for Biological Research.

    PubMed

    Gilman, James K; Wright, Mary; Clifford Lane, H; Schoomaker, Eric B

    2014-01-01

    The terrorist attacks of September 11 and the anthrax mailings a month later prompted a sweeping response by the federal government to improve the preparedness of the US to meet the potential threat posed by a terrorist using a biological agent. This response transcended traditional interagency boundaries, creating new opportunities while producing unique fiscal and leadership challenges. The National Interagency Confederation for Biological Research has made significant progress over the past 12 years because of its ability to adapt to the need for interagency cooperation and overcome many of these challenges. As construction of the National Interagency Biodefense Campus at Fort Detrick nears completion, the US has the capability to pursue a unique whole-of-government approach to the development of medical measures to counter the threat of bioterrorism. In addition to the high-level support of many in the federal government, the key success factors for this effort have been (1) a critical mass of leaders with the right leadership characteristics, (2) development of a compelling vision and accompanying narrative understood and articulated by all partnering organizations, and (3) recognition of the need for a partnership office to do the important communication and collaboration work in the organization to synchronize the information available to all the partners. The major barrier to interagency cooperative efforts of this kind is the inability to comingle funds from different appropriations. PMID:24819736

  20. The impact of the United Nations Convention on Biological Diversity on natural products research.

    PubMed

    Cragg, Gordon M; Katz, Flora; Newman, David J; Rosenthal, Joshua

    2012-12-01

    The discovery and development of novel, biologically active agents from natural sources, whether they be drugs, agrochemicals or other bioactive entities, involve a high level of interdisciplinary as well as international collaboration. Such collaboration, particularly at the international level, requires the careful negotiation of collaborative agreements protecting the rights of all parties, with special attention being paid to the rights of host (source) country governments, communities and scientific organizations. While many biodiversity-rich source countries currently might not have the necessary resources for in-country drug discovery and advanced development, they provide valuable opportunities for collaboration in this endeavor with research organizations from more high-income nations. This chapter discusses the experiences of the US National Cancer Institute and the US government-sponsored International Cooperative Biodiversity Groups program in the establishment of international agreements in the context of the Convention of Biological Diversity's objectives of promoting fair and equitable collaboration with multiple parties in many countries, and includes some specific lessons of value in developing such collaborations. PMID:23037777

  1. A Model of Federal Interagency Cooperation: The National Interagency Confederation for Biological Research

    PubMed Central

    Wright, Mary; Clifford Lane, H.; Schoomaker, Eric B.

    2014-01-01

    The terrorist attacks of September 11 and the anthrax mailings a month later prompted a sweeping response by the federal government to improve the preparedness of the US to meet the potential threat posed by a terrorist using a biological agent. This response transcended traditional interagency boundaries, creating new opportunities while producing unique fiscal and leadership challenges. The National Interagency Confederation for Biological Research has made significant progress over the past 12 years because of its ability to adapt to the need for interagency cooperation and overcome many of these challenges. As construction of the National Interagency Biodefense Campus at Fort Detrick nears completion, the US has the capability to pursue a unique whole-of-government approach to the development of medical measures to counter the threat of bioterrorism. In addition to the high-level support of many in the federal government, the key success factors for this effort have been (1) a critical mass of leaders with the right leadership characteristics, (2) development of a compelling vision and accompanying narrative understood and articulated by all partnering organizations, and (3) recognition of the need for a partnership office to do the important communication and collaboration work in the organization to synchronize the information available to all the partners. The major barrier to interagency cooperative efforts of this kind is the inability to comingle funds from different appropriations. PMID:24819736

  2. First annual report on the Biological Monitoring and Abatement Program at Oak Ridge National Laboratory

    SciTech Connect

    Loar, J. M.; Adams, S. M.; Blaylock, B. G.; Boston, H. L.; Frank, M. L.; Garten, C. T.; Houston, M. A.; Kimmel, B. L.; Ryon, M. G.; Smith, J. G.; Southworth, G. R.; Stewart, A. J.; Walton, B. T.; Berry, J. B.; Talmage, S. S.; Amano, H.; Jimenez, B. D.; Kitchings, J. T.; Meyers-Schoene, L.; Mohrbacher, D. A.; Olsen, C. R.

    1992-08-01

    As a condition of the National Pollutant Discharge Elimination System (NPDES) permit issued to Oak Ridge National Laboratory (ORNL) on April 1, 1986, a Biological Monitoring and Abatement Program (BMAP) was developed for White Oak Creek (WOC); selected tributaries of WOC, including Fifth Creek, First Creek, Melton Branch, and Northwest Tributary; and the Clinch River. BMAP consists of seven major tasks that address both radiological and nonradiological contaminants in the aquatic and terrestrial environs on-site and the aquatic environs off-site. These tasks are (1) toxicity monitoring; (2) bioaccumulation monitoring of nonradiological contaminants in aquatic biota; (3) biological indicator studies; (4) instream ecological monitoring; (5) assessment of contaminants in the terrestrial environment; (6) radioecology of WOC and White Oak Lake (WOL); and (7) contaminant transport, distribution, and fate in the WOC embayment-Clinch River-Watts Bar Reservoir system. This document, the first of a series of annual reports presenting the results of BMAP, describes studies that were conducted from March through December 1986.

  3. Nation-Based Occurrence and Endogenous Biological Reduction of Mycotoxins in Medicinal Herbs and Spices

    PubMed Central

    Do, Kee Hun; An, Tae Jin; Oh, Sang-Keun; Moon, Yuseok

    2015-01-01

    Medicinal herbs have been increasingly used for therapeutic purposes against a diverse range of human diseases worldwide. Moreover, the health benefits of spices have been extensively recognized in recent studies. However, inevitable contaminants, including mycotoxins, in medicinal herbs and spices can cause serious problems for humans in spite of their health benefits. Along with the different nation-based occurrences of mycotoxins, the ultimate exposure and toxicities can be diversely influenced by the endogenous food components in different commodities of the medicinal herbs and spices. The phytochemicals in these food stuffs can influence mold growth, mycotoxin production and biological action of the mycotoxins in exposed crops, as well as in animal and human bodies. The present review focuses on the occurrence of mycotoxins in medicinal herbs and spices and the biological interaction between mold, mycotoxin and herbal components. These networks will provide insights into the methods of mycotoxin reduction and toxicological risk assessment of mycotoxin-contaminated medicinal food components in the environment and biological organisms. PMID:26473926

  4. Nation-Based Occurrence and Endogenous Biological Reduction of Mycotoxins in Medicinal Herbs and Spices.

    PubMed

    Do, Kee Hun; An, Tae Jin; Oh, Sang-Keun; Moon, Yuseok

    2015-10-01

    Medicinal herbs have been increasingly used for therapeutic purposes against a diverse range of human diseases worldwide. Moreover, the health benefits of spices have been extensively recognized in recent studies. However, inevitable contaminants, including mycotoxins, in medicinal herbs and spices can cause serious problems for humans in spite of their health benefits. Along with the different nation-based occurrences of mycotoxins, the ultimate exposure and toxicities can be diversely influenced by the endogenous food components in different commodities of the medicinal herbs and spices. The phytochemicals in these food stuffs can influence mold growth, mycotoxin production and biological action of the mycotoxins in exposed crops, as well as in animal and human bodies. The present review focuses on the occurrence of mycotoxins in medicinal herbs and spices and the biological interaction between mold, mycotoxin and herbal components. These networks will provide insights into the methods of mycotoxin reduction and toxicological risk assessment of mycotoxin-contaminated medicinal food components in the environment and biological organisms. PMID:26473926

  5. Evolution of coreceptor utilization to escape CCR5 antagonist therapy

    PubMed Central

    Zhang, Jie; Gao, Xiang; Martin, John; Rosa, Bruce; Chen, Zheng; Mitreva, Makedonka; Henrich, Timothy; Kuritzkes, Daniel; Ratner, Lee

    2016-01-01

    The HIV-1 envelope interacts with coreceptors CCR5 and CXCR4 in a dynamic, multi-step process, its molecular details not clearly delineated. Use of CCR5 antagonists results in tropism shift and therapeutic failure. Here we describe a novel approach using full-length patient-derived gp160 quasispecies libraries cloned into HIV-1 molecular clones, their separation based on phenotypic tropism in vitro, and deep sequencing of the resultant variants for structure-function analyses. Analysis of functionally validated envelope sequences from patients who failed CCR5 antagonist therapy revealed determinants strongly associated with coreceptor specificity, especially at the gp120-gp41 and gp41-gp41 interaction surfaces that invite future research on the roles of subunit interaction and envelope trimer stability in coreceptor usage. This study identifies important structure-function relationships in HIV-1 envelope, and demonstrates proof of concept for a new integrated analysis method that facilitates laboratory discovery of resistant mutants to aid in development of other therapeutic agents. PMID:27128349

  6. Evolution of coreceptor utilization to escape CCR5 antagonist therapy.

    PubMed

    Zhang, Jie; Gao, Xiang; Martin, John; Rosa, Bruce; Chen, Zheng; Mitreva, Makedonka; Henrich, Timothy; Kuritzkes, Daniel; Ratner, Lee

    2016-07-01

    The HIV-1 envelope interacts with coreceptors CCR5 and CXCR4 in a dynamic, multi-step process, its molecular details not clearly delineated. Use of CCR5 antagonists results in tropism shift and therapeutic failure. Here we describe a novel approach using full-length patient-derived gp160 quasispecies libraries cloned into HIV-1 molecular clones, their separation based on phenotypic tropism in vitro, and deep sequencing of the resultant variants for structure-function analyses. Analysis of functionally validated envelope sequences from patients who failed CCR5 antagonist therapy revealed determinants strongly associated with coreceptor specificity, especially at the gp120-gp41 and gp41-gp41 interaction surfaces that invite future research on the roles of subunit interaction and envelope trimer stability in coreceptor usage. This study identifies important structure-function relationships in HIV-1 envelope, and demonstrates proof of concept for a new integrated analysis method that facilitates laboratory discovery of resistant mutants to aid in development of other therapeutic agents. PMID:27128349

  7. The architecture of the Schizosaccharomyces pombe CCR4-NOT complex

    PubMed Central

    Ukleja, Marta; Cuellar, Jorge; Siwaszek, Aleksandra; Kasprzak, Joanna M.; Czarnocki-Cieciura, Mariusz; Bujnicki, Janusz M.; Dziembowski, Andrzej; M. Valpuesta, Jose

    2016-01-01

    CCR4-NOT is a large protein complex present both in cytoplasm and the nucleus of eukaryotic cells. Although it is involved in a variety of distinct processes related to expression of genetic information such as poly(A) tail shortening, transcription regulation, nuclear export and protein degradation, there is only fragmentary information available on some of its nine subunits. Here we show a comprehensive structural characterization of the native CCR4-NOT complex from Schizosaccharomyces pombe. Our cryo-EM 3D reconstruction of the complex, combined with techniques such as immunomicroscopy, RNA-nanogold labelling, docking of the available high-resolution structures and models of different subunits and domains, allow us to propose its full molecular architecture. We locate all functionally defined domains endowed with deadenylating and ubiquitinating activities, the nucleus-specific RNA-interacting subunit Mmi1, as well as surfaces responsible for protein–protein interactions. This information provides insight into cooperation of the different CCR4-NOT complex functions. PMID:26804377

  8. A Novel Role for the Receptor of the Complement Cleavage Fragment C5a, C5aR1, in CCR5-Mediated Entry of HIV into Macrophages.

    PubMed

    Moreno-Fernandez, Maria E; Aliberti, Julio; Groeneweg, Sander; Köhl, Jörg; Chougnet, Claire A

    2016-04-01

    The complement system is an ancient pattern recognition system that becomes activated during all stages of HIV infection. Previous studies have shown that C5a can enhance the infection of monocyte-derived macrophages and T cells indirectly through the production of interleukin (IL)-6 and tumor necrosis factor (TNF)-α and the attraction of dendritic cells. C5a exerts its multiple biologic functions mainly through activation of C5a receptor 1 (C5aR1). Here, we assessed the role of C5aR1 as an enhancer of CCR5-mediated HIV infection. We determined CCR5 and C5aR1 heterodimer formation in myeloid cells and the impact of C5aR1 blockade on HIV entry and genomic integration. C5aR1/CCR5 heterodimer formation was identified by immunoprecipitation and western blotting. THP-1 cells and monocyte-derived macrophages (MDM) were infected by R5 laboratory strains or HIV pseudotyped for the vesicular stomatitis virus (VSV) envelope. Levels of integrated HIV were measured by quantitative PCR after targeting of C5aR1 by a C5aR antagonist, neutralizing C5aR1 monoclonal antibody (mAb) or hC5a. C5aR1 was also silenced by specific siRNA prior to viral entry. We found that C5aR1 forms heterodimers with the HIV coreceptor CCR5 in myeloid cells. Targeting C5aR1 significantly decreased integration by R5 viruses but not by VSV-pseudotyped viruses, suggesting that C5aR1 is critical for viral entry. The level of inhibition achieved with C5aR1-blocking reagents was comparable to that of CCR5 antagonists. Mechanistically, C5aR1 targeting decreased CCR5 expression. MDM from CCR5Δ32 homozygous subjects expressed levels of C5aR1 similar to CCR5 WT individuals, suggesting that mere C5aR1 expression is not sufficient for HIV infection. HIV appeared to preferentially enter THP-1 cells expressing high levels of both C5aR1 and CCR5. Targeted reduction of C5aR1 expression in such cells reduced HIV infection by ~50%. Our data thus suggest that C5aR1 acts as an enhancer of CCR5-mediated HIV entry into

  9. Upregulation of chemokine receptor CCR10 is essential for glioma proliferation, invasion and patient survival

    PubMed Central

    Chen, Lingchao; Liu, Xing; Zhang, Hai-Yan; Du, Wenzong; Qin, Zhiyong; Yao, Yu; Mao, Ying; Zhou, Liangfu

    2014-01-01

    Human gliomas are characterized by their invasion of normal brain structures irrespective of their grade of malignancy. Tumor cell invasion share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptor CCR10 is highly expressed in human glioblastoma compared with control brain tissue. In vitro, signaling through CCL27-CCR10 mediates activation of p-Akt, and subsequently induces proliferation and invasive responses. Cell proliferation and invasion promoted by CCL27 were blocked by inhibition of p-Akt or CCR10. In vivo, down-regulation of CCR10 significantly impairs growth of glioma. Clinically, High CCR10 expression in GBM correlated with p-Akt, shorter overall survival and progression-free survival (P < 0.05). Together, these findings suggest that elevated CCR10 is a critical molecular event associated with gliomagenesis. PMID:25149529

  10. Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis

    PubMed Central

    Lefebvre, Eric; Moyle, Graeme; Reshef, Ran; Richman, Lee P.; Thompson, Melanie; Hong, Feng; Chou, Hsin-l; Hashiguchi, Taishi; Plato, Craig; Poulin, Dominic; Richards, Toni; Yoneyama, Hiroyuki; Jenkins, Helen; Wolfgang, Grushenka; Friedman, Scott L.

    2016-01-01

    Background & Aims Interactions between C-C chemokine receptor types 2 (CCR2) and 5 (CCR5) and their ligands, including CCL2 and CCL5, mediate fibrogenesis by promoting monocyte/macrophage recruitment and tissue infiltration, as well as hepatic stellate cell activation. Cenicriviroc (CVC) is an oral, dual CCR2/CCR5 antagonist with nanomolar potency against both receptors. CVC’s anti-inflammatory and antifibrotic effects were evaluated in a range of preclinical models of inflammation and fibrosis. Methods Monocyte/macrophage recruitment was assessed in vivo in a mouse model of thioglycollate-induced peritonitis. CCL2-induced chemotaxis was evaluated ex vivo on mouse monocytes. CVC’s antifibrotic effects were evaluated in a thioacetamide-induced rat model of liver fibrosis and mouse models of diet-induced non-alcoholic steatohepatitis (NASH) and renal fibrosis. Study assessments included body and liver/kidney weight, liver function test, liver/kidney morphology and collagen deposition, fibrogenic gene and protein expression, and pharmacokinetic analyses. Results CVC significantly reduced monocyte/macrophage recruitment in vivo at doses ≥20 mg/kg/day (p < 0.05). At these doses, CVC showed antifibrotic effects, with significant reductions in collagen deposition (p < 0.05), and collagen type 1 protein and mRNA expression across the three animal models of fibrosis. In the NASH model, CVC significantly reduced the non-alcoholic fatty liver disease activity score (p < 0.05 vs. controls). CVC treatment had no notable effect on body or liver/kidney weight. Conclusions CVC displayed potent anti-inflammatory and antifibrotic activity in a range of animal fibrosis models, supporting human testing for fibrotic diseases. Further experimental studies are needed to clarify the underlying mechanisms of CVC’s antifibrotic effects. A Phase 2b study in adults with NASH and liver fibrosis is fully enrolled (CENTAUR Study 652-2-203; NCT02217475). PMID:27347680

  11. CD4+ CCR5+ and CD4+ CCR3+ lymphocyte subset and monocyte apoptosis in patients with acute visceral leishmaniasis

    PubMed Central

    Potestio, Marcella; D'Agostino, Pietro; Romano, Giuseppina Colonna; Milano, Salvatore; Ferlazzo, Viviana; Aquino, Alessandra; Di Bella, Gloria; Caruso, Rosalba; Gambino, Giuseppe; Vitale, Giustina; Mansueto, Serafino; Cillari, Enrico

    2004-01-01

    The potential involvement of apoptosis in the pathogenesis of visceral leishmaniasis (VL) was examined by studying spontaneous and Leishmania antigen (LAg)-induced apoptosis using cryopreserved peripheral blood mononuclear cells (PBMC) of Sicilian patients with VL. Results indicate that monocytes and T lymphocytes from acute VL patients show a significantly higher level of apoptosis compared with that observed in healed subjects. The percentage of apoptotic cells was higher in monocytes than in T lymphocytes. T cells involved in programmed cell death (PCD) were mainly of the CD4+ phenotype. In particular, the T helper 1-type (Th1) subset, as evaluated by chemokine receptor-5 (CCR5) expression, is involved in this process. Cell death in Th1-type uses a CD95-mediated mechanism. Furthermore, Th1-type CCR5+ cells are prone to cell suicide in an autocrine or paracrine way, as attested by enhanced expression of CD95L in acute VL patients. The reduction in Th1-type cells by apoptosis was confirmed by the decrease in interferon-γ secretion. In conclusion, apoptosis of monocytes, CD4+ and CD4+ CCR5+ T cells could be involved in the failure of cell mediated immunity that is responsible for severe immune-depression in VL. PMID:15379987

  12. Enhanced CCR9 expression levels in psoriatic skin are associated with poor clinical outcome to infliximab treatment.

    PubMed

    Koga, Aiko; Kajihara, Ikko; Yamada, Saori; Makino, Katsunari; Ichihara, Asako; Aoi, Jun; Makino, Takamitsu; Fukushima, Satoshi; Jinnin, Masatoshi; Ihn, Hironobu

    2016-05-01

    Infliximab is an anti-tumor necrosis factor (TNF)-α antibody drug that suppresses TNF-α and its associated inflammatory responses. Although infliximab therapy generally results in a 75% or greater improvement in the Psoriasis Area and Severity Index from baseline in psoriasis patients, there is the heterogeneity of therapeutic efficacy in psoriasis patients among patients of a similar PASI baseline score. However, there are few published reports about the predictors of the clinical response among psoriasis patients who undergo biologic therapies. We thus evaluated the possible existence of biologic markers that would indicate poor prognosis of infliximab using skin biopsy specimens. This was because we assumed that the inhibitors for upregulated chemokine/chemokine receptors in non-responders may have the ability to reduce the occurrence of psoriatic eruptions. PCR array analyses identified that the levels of various chemokines and chemokine receptors were increased in non-responders in comparison to responders. Immunohistochemical analyses revealed that upregulation of the CCR9 protein levels was not associated with the pretherapeutic PASI score, but with poor response to infliximab. Our results indicated that the expression levels of CCR9 in lesional skin may be a useful biologic marker of the clinical efficacy of infliximab therapy in psoriasis patients. PMID:26507968

  13. Relationship between the chemokine receptor CCR5 and microglia in neurological disorders: consequences of targeting CCR5 on neuroinflammation, neuronal death and regeneration in a model of epilepsy.

    PubMed

    Louboutin, Jean-Pierre; Strayer, David S

    2013-09-01

    Chemokines may play a role in leukocyte migration across the blood-brain barrier (BBB) during neuroinflammation and other neuropathological processes, such as epilepsy. The CC chemokine receptor 5 (CCR5) is a member of CC-chemokine receptor family that binds several chemokines, including CCL3 (macrophage inflammatory protein-1alpha, MIP-1alpha), CCL4 (macrophage inflammatory protein-1beta, MIP-1beta) and CCL5 (RANTES). The current review examines the relationship between CCR5 and the microglia in different neurological disorders and models of CNS injury. CCR5 expression is upregulated in different neurological diseases, where it is often immunolocalized in microglial cells. A multistep cascade couples CCR5 activation by chemokines to Ca(2+) increases in human microglia. Because changes in [Ca(2+)] (i) affect chemotaxis, secretion, and gene expression, pharmacologic modulation of this pathway may alter inflammatory and degenerative processes in the CNS. Consequently, targeting CCR5 by using CCR5 antagonists may attenuate critical aspects of neuroinflammation in different models of neurological disorders. To illustrate the interaction between CCR5 and microglia in the CNS, we used a model of excitotoxicity, and demonstrate the intimate involvement of CCR5 in neuron injury and inflammation attendant to kainic acid (KA)-induced neurotoxicity. CCR5 participates in neuronal injury caused by the excitotoxin, KA, brings inflammatory cells to the sites of KA-induced CNS injury, defines the extent of tissue loss after KA exposure and limits reparative responses. We used a SV40-derived vector carrying an interfering RNA (RNAi) that targets CCR5. Delivered directly to the bone marrow, this vector decreased CCR5 expression in circulating cells. Animals so treated showed greatly reduced expression of CCR5 and its ligands (MIP-1alpha and RANTES) in the CNS, including in the brain vasculature, decreased BBB leakage, demonstrated greater KA-stimulated neurogenesis and increased

  14. DISTINCT CONFORMATIONS OF THE CHEMOKINE RECEPTOR CCR4 WITH IMPLICATIONS FOR ITS TARGETING IN ALLERGY

    PubMed Central

    Viney, Jonathan M.; Andrew, David P.; Phillips, Rhian M.; Meiser, Andrea; Patel, Pallavi; Lennartz-Walker, Melissa; Cousins, David J.; Barton, Nicholas P.; Hall, David A.; Pease, James E.

    2014-01-01

    The chemokine receptor CCR4 is expressed by Th2 and Tregs and directs their migration along gradients of the chemokines CCL17 and CCL22. Both chemokines and receptor are upregulated in allergic disease, making CCR4 a therapeutic target for the treatment of allergy. We set out to assess the mechanisms underlying a previous report that CCL22 is a dominant ligand of CCR4, which may have implications for its therapeutic targeting. Human T-cells expressing endogenous CCR4 and transfectants engineered to express CCR4 were assessed for receptor function using assays of calcium release, chemotaxis, receptor endocytosis and ligand binding. Despite the two ligands having equal potency in calcium flux and chemotaxis assays, CCL22 showed dominance in both receptor endocytosis assays and heterologous competitive binding assays. Using two different CCR4-specific antibodies, we showed that CCR4 exists in at least two distinct conformations, which are differentially activated by ligand. A major population is activated by both CCL17 and CCL22, whilst a minor population is activated only by CCL22. Mutation of a single C-terminal residue K310 within a putative CCR4 antagonist binding site, ablated activation of CCR4 by CCL17 but not by CCL22, despite having no effect on the binding of either ligand. We conclude that CCL17 and CCL22 are conformationally selective ligands of CCR4 and interact with the receptor by substantially different mechanisms. This suggests that the selective blockade of CCR4 in allergy may be feasible where one CCR4 ligand dominates, allowing the inhibition of Th2 signalling via one ligand whilst sparing Treg recruitment via another. PMID:24563252

  15. CCR2 Deficiency Impairs Macrophage Infiltration and Improves Cognitive Function after Traumatic Brain Injury

    PubMed Central

    Niemi, Erene C.; Wang, Sarah H.; Lee, Chih Cheng; Bingham, Deborah; Zhang, Jiasheng; Cozen, Myrna L.; Charo, Israel; Huang, Eric J.; Liu, Jialing; Nakamura, Mary C.

    2014-01-01

    Abstract Traumatic brain injury (TBI) provokes inflammatory responses, including a dramatic rise in brain macrophages in the area of injury. The pathway(s) responsible for macrophage infiltration of the traumatically injured brain and the effects of macrophages on functional outcomes are not well understood. C-C-chemokine receptor 2 (CCR2) is known for directing monocytes to inflamed tissues. To assess the role of macrophages and CCR2 in TBI, we determined outcomes in CCR2-deficient (Ccr2−/−) mice in a controlled cortical impact model. We quantified brain myeloid cell numbers post-TBI by flow cytometry and found that Ccr2−/− mice had greatly reduced macrophage numbers (∼80–90% reduction) early post-TBI, compared with wild-type mice. Motor, locomotor, and cognitive outcomes were assessed. Lack of Ccr2 improved locomotor activity with less hyperactivity in open field testing, but did not affect anxiety levels or motor coordination on the rotarod three weeks after TBI. Importantly, Ccr2−/− mice demonstrated greater spatial learning and memory, compared with wild-type mice eight weeks after TBI. Although there was no difference in the volume of tissue loss, Ccr2−/− mice had significantly increased neuronal density in the CA1-CA3 regions of the hippocampus after TBI, compared with wild-type mice. These data demonstrate that Ccr2 directs the majority of macrophage homing to the brain early after TBI and indicates that Ccr2 may facilitate harmful responses. Lack of Ccr2 improves functional recovery and neuronal survival. These results suggest that therapeutic blockade of CCR2-dependent responses may improve outcomes following TBI. PMID:24806994

  16. CCR7 Maintains Nonresolving Lymph Node and Adipose Inflammation in Obesity.

    PubMed

    Hellmann, Jason; Sansbury, Brian E; Holden, Candice R; Tang, Yunan; Wong, Blenda; Wysoczynski, Marcin; Rodriguez, Jorge; Bhatnagar, Aruni; Hill, Bradford G; Spite, Matthew

    2016-08-01

    Accumulation of immune cells in adipose tissue promotes insulin resistance in obesity. Although innate and adaptive immune cells contribute to adipose inflammation, the processes that sustain these interactions are incompletely understood. Here we show that obesity promotes the accumulation of CD11c(+) adipose tissue immune cells that express C-C chemokine receptor 7 (CCR7) in mice and humans, and that CCR7 contributes to chronic inflammation and insulin resistance. We identified that CCR7(+) macrophages and dendritic cells accumulate in adipose tissue in close proximity to lymph nodes (LNs) (i.e., perinodal) and visceral adipose. Consistent with the role of CCR7 in regulating the migration of immune cells to LNs, obesity promoted the accumulation of CD11c(+) cells in LNs, which was prevented by global or hematopoietic deficiency of Ccr7 Obese Ccr7(-/-) mice had reduced accumulation of CD8(+) T cells, B cells, and macrophages in adipose tissue, which was associated with reduced inflammatory signaling. This reduction in maladaptive inflammation translated to increased insulin signaling and improved glucose tolerance in obesity. Therapeutic administration of an anti-CCR7 antibody phenocopied the effects of genetic Ccr7 deficiency in mice with established obesity. These results suggest that CCR7 plays a causal role in maintaining innate and adaptive immunity in obesity. PMID:27207557

  17. ERK1-Based Pathway as a New Selective Mechanism To Modulate CCR5 with Natural Antibodies.

    PubMed

    Venuti, Assunta; Pastori, Claudia; Siracusano, Gabriel; Riva, Agostino; Sciortino, Maria Teresa; Lopalco, Lucia

    2015-10-01

    Natural human Abs, recognizing an epitope within the first extramembrane loop of CCR5 (the main HIV coreceptor), induce a long-lasting internalization (48 h) of the protein, whereas all known CCR5 modulating molecules show a short-term kinetics (60-90 min). Despite extensive studies on the regulation of CCR5 signaling cascades, which are the effect of concomitant CCR5 internalization by exogenous stimuli such as Abs, downstream signaling continues to be poorly understood. In this article, we report a hitherto unrecognized mechanism of CCR5 modulation mediated by G protein-dependent ERK1 activity. We further demonstrate that ERK1 is localized mainly in the cytoplasmic compartment and that it interacts directly with the CCR5 protein, thus provoking possible CCR5 degradation with a subsequent de novo synthesis, and that re-expression of CCR5 on the cell membrane required several days. In contrast, the RANTES treatment induces a recovery of the receptor on the cell membrane in short-term kinetics without the involvement of de novo protein synthesis. The said new pathway could be relevant not only to better understand the molecular basis of all pathologic conditions in which CCR5 is involved but also to generate new tools to block viral infections, such as the use of recombinant Abs. PMID:26324779

  18. Dengue virus requires the CC-chemokine receptor CCR5 for replication and infection development

    PubMed Central

    Marques, Rafael E; Guabiraba, Rodrigo; Del Sarto, Juliana L; Rocha, Rebeca F; Queiroz, Ana Luiza; Cisalpino, Daniel; Marques, Pedro E; Pacca, Carolina C; Fagundes, Caio T; Menezes, Gustavo B; Nogueira, Maurício L; Souza, Danielle G; Teixeira, Mauro M

    2015-01-01

    Dengue is a mosquito-borne disease that affects millions of people worldwide yearly. Currently, there is no vaccine or specific treatment available. Further investigation on dengue pathogenesis is required to better understand the disease and to identify potential therapeutic targets. The chemokine system has been implicated in dengue pathogenesis, although the specific role of chemokines and their receptors remains elusive. Here we describe the role of the CC-chemokine receptor CCR5 in Dengue virus (DENV-2) infection. In vitro experiments showed that CCR5 is a host factor required for DENV-2 replication in human and mouse macrophages. DENV-2 infection induces the expression of CCR5 ligands. Incubation with an antagonist prevents CCR5 activation and reduces DENV-2 positive-stranded (+) RNA inside macrophages. Using an immunocompetent mouse model of DENV-2 infection we found that CCR5−/− mice were resistant to lethal infection, presenting at least 100-fold reduction of viral load in target organs and significant reduction in disease severity. This phenotype was reproduced in wild-type mice treated with CCR5-blocking compounds. Therefore, CCR5 is a host factor required for DENV-2 replication and disease development. Targeting CCR5 might represent a therapeutic strategy for dengue fever. These data bring new insights on the association between viral infections and the chemokine receptor CCR5. PMID:25939314

  19. A role for MCP-1/CCR2 in interstitial lung disease in children

    PubMed Central

    Hartl, Dominik; Griese, Matthias; Nicolai, Thomas; Zissel, Gernot; Prell, Christine; Reinhardt, Dietrich; Schendel, Dolores J; Krauss-Etschmann, Susanne

    2005-01-01

    Background Interstitial lung diseases (ILD) are chronic inflammatory disorders leading to pulmonary fibrosis. Monocyte chemotactic protein 1 (MCP-1) promotes collagen synthesis and deletion of the MCP-1 receptor CCR2 protects from pulmonary fibrosis in ILD mouse models. We hypothesized that pulmonary MCP-1 and CCR2+ T cells accumulate in pediatric ILD and are related to disease severity. Methods Bronchoalveolar lavage fluid was obtained from 25 children with ILD and 10 healthy children. Levels of pulmonary MCP-1 and Th1/Th2-associated cytokines were quantified at the protein and the mRNA levels. Pulmonary CCR2+, CCR4+, CCR3+, CCR5+ and CXCR3+ T cells were quantified by flow-cytometry. Results CCR2+ T cells and MCP-1 levels were significantly elevated in children with ILD and correlated with forced vital capacity, total lung capacity and ILD disease severity scores. Children with lung fibrosis had significantly higher MCP-1 levels and CCR2+ T cells in bronchoalveolar lavage fluid compared to non-fibrotic children. Conclusion The results indicate that pulmonary CCR2+ T cells and MCP-1 contribute to the pathogenesis of pediatric ILD and might provide a novel target for therapeutic strategies. PMID:16095529

  20. Transition-ready technologies and expertise from the Chemical and Biological National Security Program at LLNL

    SciTech Connect

    Folta, P A; McBride, M T

    2006-02-22

    HSARPA has initiated a new Bioinformatics and Assay Development solicitation, BIAD2 (BAA 06-01), to address a number of technology gaps and requirements for biodetection (www.hsarpabaa.com). This solicitation will leverage the vast research and development capabilities of the private sector and academia in order to meet the needs of HSARPA and Homeland Security. In order to meet these requirements, this solicitation will: (1) Develop and validate actionable assays for the public and private sector; (2) Develop and validate new assays and novel assay methodologies to enhance existing detection systems and enable future detection platforms; (3) Develop next generation assays which are robust against novel, emerging and engineered threats; (4) Develop novel assays that detect low levels of ribonucleic acid (RNA)-based viral threats in complex backgrounds; (5) Develop novel assays to characterize the viability, degree of virulence or toxicity, and countermeasure resistance of a biological agent; and (6) Develop new bioinformatics tools to support assay development and assay validation The Lawrence Livermore National Laboratory (LLNL) Bioassays and Signature Program (BSP) develops nationally-validated detection and identification assays to cover the full range of biological threat agents, starting from human, animal, and plant pathogens on the Select Agent list. The assays that have been co-developed by the CDC and the BSP are used internationally and represent the gold standard for molecular detection of select agent pathogens for the public health community. They are also used in the DHS environmental monitoring operations such as BioWatch and DHS National Security Special Events support. These reagents have been used to process and analyze more than 5 million samples and have delivered exceptional performance for the end users, with zero false positives since their deployment. Currently, highly-multiplexed nucleic acid assays that represent the ''next-generation'' in

  1. The Danish Twin Registry: linking surveys, national registers, and biological information.

    PubMed

    Skytthe, Axel; Christiansen, Lene; Kyvik, Kirsten Ohm; Bødker, Frans L; Hvidberg, Lars; Petersen, Inge; Nielsen, Morten M F; Bingley, Paul; Hjelmborg, Jacob; Tan, Qihua; Holm, Niels V; Vaupel, James W; McGue, Matt; Christensen, Kaare

    2013-02-01

    Over the last 60 years, the resources and the research in the Danish Twin Registry (DTR) have periodically been summarized. Here, we give a short overview of the DTR and a more comprehensive description of new developments in the twenty-first century. First, we outline our experience over the last decade of combining questionnaire and survey data with national demographic, social, and health registers in Statistics Denmark. Second, we describe our most recent data collection effort, which was conducted during the period 2008-2011 and included both in-person assessments of 14,000+ twins born 1931-1969 and sampling of biological material, hereby expanding and consolidating the DTR biobank. Third, two examples of intensively studied twin cohorts are given. The new developments in the DTR in the last decade have facilitated the ongoing research and laid the groundwork for new research directions. PMID:23084092

  2. The Danish Twin Registry: Linking Surveys, National Registers, and Biological Information

    PubMed Central

    Skytthe, Axel; Christiansen, Lene; Kyvik, Kirsten Ohm; Bødker, Frans L.; Hvidberg, Lars; Petersen, Inge; Nielsen, Morten M. F.; Bingley, Paul; Hjelmborg, Jacob; Tan, Qihua; Holm, Niels V.; Vaupel, James W.; McGue, Matt; Christensen, Kaare

    2013-01-01

    Over the last 60 years, the resources and the research in the Danish Twin Registry (DTR) have periodically been summarized. Here, we give a short overview of the DTR and a more comprehensive description of new developments in the twenty-first century. First, we outline our experience over the last decade of combining questionnaire and survey data with national demographic, social, and health registers in Statistics Denmark. Second, we describe our most recent data collection effort, which was conducted during the period 2008–2011 and included both in-person assessments of 14,000+ twins born 1931–1969 and sampling of biological material, hereby expanding and consolidating the DTR biobank. Third, two examples of intensively studied twin cohorts are given. The new developments in the DTR in the last decade have facilitated the ongoing research and laid the groundwork for new research directions. PMID:23084092

  3. Biological investigations of the Sandia National Laboratories Sol se Mete Aerial Cable Facility

    SciTech Connect

    Sullivan, R.M.

    1994-10-01

    This report provides results of a comprehensive biological field survey performed on the Sandia National Laboratories Aerial Cable Facility, at the east end of Kirtland Air Force Base (KAFB), Bernalillo County, New Mexico. This survey was conducted late September through October, 1991. ACF occupies a 440-acre tract of land withdrawn by the US Forest Service (USFS) for use by KAFB, and in turn placed under operational control of SNL by the Department of Energy (DOE). All land used by SNL for ACF is part of a 15,851-acre tract of land withdrawn by the US Forest Service. In addition, a number of different organizations use the 15,851-acre area. The project area used by SNL encompasses portions of approximately six sections (3,840 acres) of US Forest Service land located within the foothills of the west side of the Manzano Mountains (East Mesa). The biological study area is used by the KAFB, the US Department of Interior, and SNL. This area includes: (1) Sol se Mete Springs and Canyon, (2) East Anchor Access Road, (3) East Anchor Site, (4) Rocket Sled Track, (5) North Arena, (6) East Instrumentation Site and Access Road, (7) West Anchor Access Road, (8) West Anchor Site, (9) South Arena, (10) Winch Sites, (11) West Instrumentation Sites, (12) Explosive Assembly Building, (13) Control Building, (14) Lurance Canyon Road and vicinity. Although portions of approximately 960 acres of withdrawn US Forest Service land have been altered, only 700 acres have been disturbed by activities associated with ACF; approximately 2,880 acres consist of natural habitat. Absence of grazing by livestock and possibly native ungulates, and relative lack of human disturbance have allowed this area to remain in a more natural vegetative state relative to the condition of private range lands throughout New Mexico. This report evaluates threatened and endangered species found on ACF, as well as a comprehensive assessment of biological habitats.

  4. Biological soil crusts of sand dunes in Cape Cod National Seashore, Massachusetts, USA.

    PubMed

    Smith, S M; Abed, R M M; Gercia-Pichel, F

    2004-08-01

    Biological soil crusts cover hundreds of hectares of sand dunes at the northern tip of Cape Cod National Seashore (Massachusetts, USA). Although the presence of crusts in this habitat has long been recognized, neither the organisms nor their ecological roles have been described. In this study, we report on the microbial community composition of crusts from this region and describe several of their physical and chemical attributes that bear on their environmental role. Microscopic and molecular analyses revealed that eukaryotic green algae belonging to the genera Klebsormidium or Geminella formed the bulk of the material sampled. Phylogenetic reconstruction of partial 16S rDNA sequences obtained from denaturing gradient gel electrophoresis (DGGE) fingerprints also revealed the presence of bacterial populations related to the subclass of the Proteobacteria, the newly described phylum Geothrix/ Holophaga/ Acidobacterium, the Cytophaga/ Flavobacterium/ Bacteroides group, and spirochetes. The presence of these crusts had significant effects on the hydric properties and nutrient status of the natural substrate. Although biological soil crusts are known to occur in dune environments around the world, this study enhances our knowledge of their geographic distribution and suggests a potential ecological role for crust communities in this landscape. PMID:15546040

  5. Cloning, Stem Cells, and the Current National Debate: Incorporating Ethics into a Large Introductory Biology Course

    PubMed Central

    2002-01-01

    Discussing the ethical issues involved in topics such as cloning and stem cell research in a large introductory biology course is often difficult. Teachers may be wary of presenting material biased by personal beliefs, and students often feel inhibited speaking about moral issues in a large group. Yet, to ignore what is happening “out there” beyond the textbooks and lab work is to do a disservice to students. This essay describes a semester-long project in which upperclass students presented some of the most complex and controversial ideas imaginable to introductory students by staging a mock debate and acting as members of the then newly appointed President's Council on Bioethics. Because the upperclass students were presenting the ideas of real people who play an important role in shaping national policy, no student's personal beliefs were put on the line, and many ideas were articulated. The introductory audience could accept or reject what they were hearing and learn information important for making up their own minds on these issues. This project is presented as an example of how current events can be used to put basic cell biology into context and of how exciting it can be when students teach students. PMID:12669102

  6. A CCL chemokine-derived peptide (CDIP-2) exerts anti-inflammatory activity via CCR1, CCR2 and CCR3 chemokine receptors: Implications as a potential therapeutic treatment of asthma.

    PubMed

    Méndez-Enríquez, E; Medina-Tamayo, J; Soldevila, G; Fortoul, T I; Anton, B; Flores-Romo, L; García-Zepeda, E A

    2014-05-01

    Allergic asthma is a chronic inflammatory disease characterized by the accumulation of eosinophils, Th2 cells and mononuclear cells in the airways, leading to changes in lung architecture and subsequently reduced respiratory function. We have previously demonstrated that CDIP-2, a chemokine derived peptide, reduced in vitro chemotaxis and decreased cellular infiltration in a murine model of allergic airway inflammation. However, the mechanisms involved in this process have not been identified yet. Now, we found that CDIP-2 reduces chemokine-mediated functions via interactions with CCR1, CCR2 and CCR3. Moreover, using bone marrow-derived eosinophils, we demonstrated that CDIP-2 modifies the calcium fluxes induced by CCL11 and down-modulated CCR3 expression. Finally, CDIP-2 treatment in a murine model of OVA-induced allergic airway inflammation reduced leukocyte recruitment and decreases production of cytokines. These data suggest that chemokine-derived peptides represent new therapeutic tools to generate more effective antiinflammatory drugs. PMID:24560857

  7. Heroin use in Indonesia is associated with higher expression of CCR5 on CD4+ cells and lower ex-vivo production of CCR5 ligands.

    PubMed

    Meijerink, Hinta; Indrati, Agnes R; Soedarmo, Suharyani; Utami, Fitri; de Jong, Cor A J; Alisjahbana, Bachti; van Crevel, Reinout; Wisaksana, Rudi; Van der Ven, Andre J A M

    2015-01-28

    Opioid use may affect HIV infection through altered expression of HIV co-receptors. This was examined in Indonesia among antiretroviral therapy-naive HIV patients, many of whom use drugs. C-C chemokine receptor type 5 (CCR5) expression on CD4+ cells was higher in heroin (P = 0.007), methadone (P = 0.024) and former opioid users (P = 0.003) compared to nonusers, whereas production of RANTES and other CCR5 ligands was similar or lower. This suggests that opioids can affect HIV susceptibility through up-regulation of CCR5 or down-regulation of its ligands. PMID:25834861

  8. CCR4 frameshift mutation identifies a distinct group of adult T cell leukaemia/lymphoma with poor prognosis.

    PubMed

    Yoshida, Noriaki; Miyoshi, Hiroaki; Kato, Takeharu; Sakata-Yanagimoto, Mamiko; Niino, Daisuke; Taniguchi, Hiroaki; Moriuchi, Yukiyoshi; Miyahara, Masaharu; Kurita, Daisuke; Sasaki, Yuya; Shimono, Joji; Kawamoto, Keisuke; Utsunomiya, Atae; Imaizumi, Yoshitaka; Seto, Masao; Ohshima, Koichi

    2016-04-01

    Adult T cell leukaemia/lymphoma (ATLL) is an intractable T cell neoplasm caused by human T cell leukaemia virus type 1. Next-generation sequencing-based comprehensive mutation studies have revealed recurrent somatic CCR4 mutations in ATLL, although clinicopathological findings associated with CCR4 mutations remain to be delineated. In the current study, 184 cases of peripheral T cell lymphoma, including 113 cases of ATLL, were subjected to CCR4 mutation analysis. This sequence analysis identified mutations in 27% (30/113) of cases of ATLL and 9% (4/44) of cases of peripheral T cell lymphoma not otherwise specified. Identified mutations included nonsense (NS) and frameshift (FS) mutations. No significant differences in clinicopathological findings were observed between ATLL cases stratified by presence of CCR4 mutation. All ATLL cases with CCR4 mutations exhibited cell-surface CCR4 positivity. Semi-quantitative CCR4 protein analysis of immunohistochemical sections revealed higher CCR4 expression in cases with NS mutations of CCR4 than in cases with wild-type (WT) CCR4. Furthermore, among ATLL cases, FS mutation was significantly associated with a poor prognosis, compared with NS mutation and WT CCR4. These results suggest that CCR4 mutation is an important determinant of the clinical course in ATLL cases, and that NS and FS mutations of CCR4 behave differently with respect to ATLL pathophysiology. PMID:26847489

  9. CCR6 Functions as a New Coreceptor for Limited Primary Human and Simian Immunodeficiency Viruses

    PubMed Central

    Islam, Salequl; Shimizu, Nobuaki; Hoque, Sheikh Ariful; Jinno-Oue, Atsushi; Tanaka, Atsushi; Hoshino, Hiroo

    2013-01-01

    More than 12 chemokine receptors (CKRs) have been identified as coreceptors for the entry of human immunodeficiency virus type 1 (HIV-1), type 2 (HIV-2), and simian immunodeficiency viruses (SIVs) into target cells. The expression of CC chemokine receptor 6 (CCR6) on Th17 cells and regulatory T cells make the host cells vulnerable to HIV/SIV infection preferentially. However, only limited information is available concerning the specific role of CCR6 in HIV/SIV infection. We examined CCR6 as a coreceptor candidate in this study using NP-2 cell line-based in-vitro studies. Normally, CD4-transduced cell line, NP-2/CD4, is strictly resistant to all HIV/SIV infection. When CCR6 was transduced there, the resultant NP-2/CD4/CCR6 cells became susceptible to HIV-1HAN2, HIV-2MIR and SIVsmE660, indicating coreceptor roles of CCR6. Viral antigens in infected cells were detected by IFA and confirmed by detection of proviral DNA. Infection-induced syncytia in NP-2/CD4/CCR6 cells were detected by Giemsa staining. Amount of virus release through CCR6 has been detected by RT assay in spent culture medium. Sequence analysis of proviral DNA showed two common amino acid substitutions in the C2 envelope region of HIV-2MIR clones propagated through NP-2/CD4/CCR6 cells. Conversely, CCR6-origin SIVsmE660 clones resulted two amino acid changes in the V1 region and one change in the C2 region. The substitutions in the C2 region for HIV-2MIR and the V1 region of SIVsmE660 may confer selection advantage for CCR6-use. Together, the results describe CCR6 as an independent coreceptor for HIV and SIV in strain-specific manner. The alteration of CCR6 uses by viruses may influence the susceptibility of CD4+ CCR6+ T-cells and dendritic cell subsets in vivo and therefore, is important for viral pathogenesis in establishing latent infections, trafficking, and transmission. However, clinical relevance of CCR6 as coreceptor in HIV/SIV infections should be investigated further. PMID:24009735

  10. Activation of CCR9/CCL25 in Cutaneous Melanoma Mediates Preferential Metastasis to the Small Intestine

    PubMed Central

    Amersi, Farin F.; Terando, Alicia M.; Goto, Yasufumi; Scolyer, Richard A.; Thompson, John F.; Tran, Andy N.; Faries, Mark B.; Morton, Donald L.; Hoon, Dave S.B.

    2009-01-01

    Purpose Specific chemokines and their respective receptors have been implicated in distant tumor cell metastasis. Cutaneous melanoma has a distinct pattern of metastasis, preferentially targeting the submucosa of the small intestine. However, the underlying pathogenic mechanism remains unknown. Migration of CCR9(+) lymphocytes to the small intestine is known to occur in response to the chemoattractant effects of CCL25 (thymus-expressed chemokine). The integrin heterodimers αβ are also known to be important mediators of cellular adhesion. We hypothesize that the mechanism of small intestinal metastasis by melanoma is via the CCR9-CCL25 axis and specific integrins. Experimental Design Quantitative reverse transcription-PCR, flow cytometry, and immunohistochemistry were used to assess melanoma tumors for CCR9 and CCL25. Integrin expression was assessed using flow cytometry. CCR9 expression by quantitative reverse transcription-PCR was assessed in primary (n = 23) and metastatic (n = 198) melanomas, and melanoma lines derived from small intestinal metastases (n = 23). Results We showed CCR9 expression in 88 of 102 paraffin-embedded metastatic melanomas from the small intestine, 8 of 8 melanoma lines derived from metastases in the small intestine, and 0 of 96 metastatic melanomas from other sites. In vitro migration and invasion studies done on CCR9(+) melanoma lines showed migration in response to CCL25 that was inhibited by anti-CCR9 antibody or by short interfering RNA CCR9. Flow cytometric analysis confirmed CCR9 expression by melanomas to the small intestine and showed concomitant α4β1 integrin expression. Conclusions Our findings show that functionally active CCR9 on melanoma cells facilitates metastasis to the small intestine. The CCR9-CCL25 axis may explain the high incidence of melanoma metastasis to this specific location. PMID:18245522

  11. Y-12 National Security Complex Biological Monitoring and Abatement Program 2007 Calendar Yeare Report

    SciTech Connect

    Peterson, M.J.; Greeley, M. S. Jr.; Morris, G. W.; Roy, W. K.; Ryan, M. G.; Smith, J. G.; Southworth, G. R.

    2008-07-01

    The National Pollutant Discharge Elimination System (NPDES) permit issued for the Oak Ridge Y-12 National Security Complex (Y-12 Complex) which became effective May 1, 2006, continued a requirement for a Biological Monitoring and Abatement Program (BMAP). The BMAP was originally developed in 1985 to demonstrate that the effluent limitations established for the Y-12 Complex protected the classified uses of the receiving stream (East Fork Poplar Creek: EFPC), in particular, the growth and propagation of aquatic life (Loar et al. 1989). The objectives of the current BMAP are similar, specifically to assess stream ecological conditions relative to regulatory limits and criteria, to assess ecological impacts as well as recovery in response to Y-12 operations, and to investigate the causes of continuing impacts. The BMAP consists of three tasks that reflect complementary approaches to evaluating the effects of the Y-12 Complex discharges on the biotic integrity of EFPC. These tasks include: (1) bioaccumulation monitoring, (2) benthic macroinvertebrate community monitoring, and (3) fish community monitoring. As required by the NPDES permit, the BMAP benthic macroinvertebrate community monitoring task includes studies to annually evaluate the receiving stream's biological integrity in comparison to TN Water Quality Criteria. BMAP monitoring is currently being conducted at five primary EFPC sites, although sites may be excluded or added depending upon the specific objectives of the various tasks. Criteria used in selecting the sites include: (1) location of sampling sites used in other studies, (2) known or suspected sources of downstream impacts, (3) proximity to U.S. Department of Energy (DOE) Oak Ridge Reservation (ORR) boundaries, (4) appropriate habitat distribution, and (5) access. The primary sampling sites include upper EFPC at kilometers (EFKs) 24.4 and 23.4 [upstream and downstream of Lake Reality (LR) respectively]; EFK 18.7 (also EFK 18.2 and 19), located off

  12. Principles of risk assessment for illness caused by foodborne biological agents. National Advisory Committee on Microbiological Criteria for Foods.

    PubMed

    Buchanan, R

    1998-08-01

    The Risk Assessment Subcommittee of the National Advisory Committee on Microbiological Criteria in Foods has prepared a generic document on the principles of risk assessment as applied to biological agents that can cause human foodborne disease. Typical biological agents include bacteria, viruses, fungi, helminths, protozoa, algae, parasites, and the toxic products that these agents may produce. Basic principles elaborated to characterize food pathogen risks include the four broadly accepted components of risk assessment. The role of surveillance and investigational activities to link biological agents and their food sources to consumer illness is described as is the role of predictive modeling for food pathogens. PMID:9713775

  13. Chemokine Receptor CCR5 Antagonist Maraviroc: Medicinal Chemistry and Clinical Applications

    PubMed Central

    Xu, Guoyan G.; Guo, Jia; Wu, Yuntao

    2015-01-01

    The human immunodeficiency virus (HIV) causes acquired immumodeficiency syndrome (AIDS), one of the worst global pandemic. The virus infects human CD4 T cells and macrophages, and causes CD4 depletion. HIV enters target cells through the binding of the viral envelope glycoprotein to CD4 and the chemokine coreceptor, CXCR4 or CCR5. In particular, the CCR5-utilizing viruses predominate in the blood during the disease course. CCR5 is expressed on the surface of various immune cells including macrophages, monocytes, microglia, dendric cells, and active memory CD4 T cells. In the human population, the CCR5 genomic mutation, CCR5Δ32, is associated with relative resistance to HIV. These findings paved the way for the discovery and development of CCR5 inhibitors to block HIV transmission and replication. Maraviroc, discovered as a CCR5 antagonist, is the only CCR5 inhibitor that has been approved by both US FDA and the European Medicines Agency (EMA) for treating HIV/AIDS patients. In this review, we summarize the medicinal chemistry and clinical studies of Maraviroc. PMID:25159165

  14. CCR4 is critically involved in effective antitumor immunity in mice bearing intradermal B16 melanoma.

    PubMed

    Matsuo, Kazuhiko; Itoh, Tatsuki; Koyama, Atsushi; Imamura, Reira; Kawai, Shiori; Nishiwaki, Keiji; Oiso, Naoki; Kawada, Akira; Yoshie, Osamu; Nakayama, Takashi

    2016-08-01

    CCR4 is a major chemokine receptor expressed by Treg cells and Th17 cells. While Treg cells are known to suppress antitumor immunity, Th17 cells have recently been shown to enhance the induction of antitumor cytotoxic T lymphocytes. Here, CCR4-deficient mice displayed enhanced tumor growth upon intradermal inoculation of B16-F10 melanoma cells. In CCR4-deficient mice, while IFN-γ+CD8+ effector T cells were decreased in tumor sites, IFN-γ+CD8+ T cells and Th17 cells were decreased in regional lymph nodes. In wild-type mice, CD4+IL-17A+ cells, which were identified as CCR4+CD44+ memory Th17, were found to be clustered around dendritic cells expressing MDC/CCL22, a ligand for CCR4, in regional lymph nodes. Compound 22, a CCR4 antagonist, also enhanced tumor growth and decreased Th17 cells in regional lymph nodes in tumor-bearing mice treated with Dacarbazine. In contrast, CCR6 deficiency did not affect the tumor growth and the numbers of Th17 cells in regional lymph nodes. These findings indicate that CCR4 is critically involved in regional lymph node DC-Th17 cell interactions that are necessary for Th17 cell-mediated induction of antitumor CD8+ effector T cells in mice bearing B16 melanoma. PMID:27132989

  15. Profile of State College and Career Readiness Assessments (CCR) Policy. Alaska

    ERIC Educational Resources Information Center

    Center on Education Policy, 2011

    2011-01-01

    This individual profile provides information on Alaska's college and career readiness assessment policy. Some of the categories presented include: (1) CCR assessment policy; (2) Purpose; (3) Major changes in CCR assessment policy since the 2009-10 school year for financial reasons; (4) State financial support for students to take the CCR…

  16. CCR2 antagonism alters brain macrophage polarization and ameliorates cognitive dysfunction induced by traumatic brain injury.

    PubMed

    Morganti, Josh M; Jopson, Timothy D; Liu, Sharon; Riparip, Lara-Kirstie; Guandique, Cristian K; Gupta, Nalin; Ferguson, Adam R; Rosi, Susanna

    2015-01-14

    Traumatic brain injury (TBI) is a major risk factor for the development of multiple neurodegenerative diseases. With respect to the increasing prevalence of TBI, new therapeutic strategies are urgently needed that will prevent secondary damage to primarily unaffected tissue. Consistently, neuroinflammation has been implicated as a key mediator of secondary damage following the initial mechanical insult. Following injury, there is uncertainty regarding the role that accumulating CCR2(+) macrophages play in the injury-induced neuroinflammatory sequelae and cognitive dysfunction. Using CX3CR1(GFP/+)CCR2(RFP/+) reporter mice, we show that TBI initiated a temporally restricted accumulation of peripherally derived CCR2(+) macrophages, which were concentrated in the hippocampal formation, a region necessary for learning and memory. Multivariate analysis delineated CCR2(+) macrophages' neuroinflammatory response while identifying a novel therapeutic treatment window. As a proof of concept, targeting CCR2(+) macrophages with CCX872, a novel Phase I CCR2 selective antagonist, significantly reduced TBI-induced inflammatory macrophage accumulation. Concomitantly, there was a significant reduction in multiple proinflammatory and neurotoxic mediators with this treatment paradigm. Importantly, CCR2 antagonism resulted in a sparing of TBI-induced hippocampal-dependent cognitive dysfunction and reduced proinflammatory activation profile 1 month after injury. Thus, therapeutically targeting the CCR2(+) subset of monocytes/macrophages may provide a new avenue of clinical intervention following TBI. PMID:25589768

  17. CCR2 Antagonism Alters Brain Macrophage Polarization and Ameliorates Cognitive Dysfunction Induced by Traumatic Brain Injury

    PubMed Central

    Jopson, Timothy D.; Liu, Sharon; Riparip, Lara-Kirstie; Guandique, Cristian K.; Gupta, Nalin; Ferguson, Adam R.

    2015-01-01

    Traumatic brain injury (TBI) is a major risk factor for the development of multiple neurodegenerative diseases. With respect to the increasing prevalence of TBI, new therapeutic strategies are urgently needed that will prevent secondary damage to primarily unaffected tissue. Consistently, neuroinflammation has been implicated as a key mediator of secondary damage following the initial mechanical insult. Following injury, there is uncertainty regarding the role that accumulating CCR2+ macrophages play in the injury-induced neuroinflammatory sequelae and cognitive dysfunction. Using CX3CR1GFP/+CCR2RFP/+ reporter mice, we show that TBI initiated a temporally restricted accumulation of peripherally derived CCR2+ macrophages, which were concentrated in the hippocampal formation, a region necessary for learning and memory. Multivariate analysis delineated CCR2+ macrophages' neuroinflammatory response while identifying a novel therapeutic treatment window. As a proof of concept, targeting CCR2+ macrophages with CCX872, a novel Phase I CCR2 selective antagonist, significantly reduced TBI-induced inflammatory macrophage accumulation. Concomitantly, there was a significant reduction in multiple proinflammatory and neurotoxic mediators with this treatment paradigm. Importantly, CCR2 antagonism resulted in a sparing of TBI-induced hippocampal-dependent cognitive dysfunction and reduced proinflammatory activation profile 1 month after injury. Thus, therapeutically targeting the CCR2+ subset of monocytes/macrophages may provide a new avenue of clinical intervention following TBI. PMID:25589768

  18. 77 FR 55833 - Announcement of Public Meeting on the Consumer Confidence Report (CCR) Rule Retrospective Review...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-11

    ... Reports (CCR) via electronic delivery. EPA plans to discuss its analysis of electronic delivery and... community water system is required by Federal regulations (63 FR 44512, August 19, 1998) to provide to its... increase in the diversity of communication tools. EPA included the CCR Rule in its retrospective...

  19. CCR6 Recruits Regulatory T Cells and Th17 Cells to the Kidney in Glomerulonephritis

    PubMed Central

    Turner, Jan-Eric; Paust, Hans-Joachim; Steinmetz, Oliver M.; Peters, Anett; Riedel, Jan-Hendrik; Erhardt, Annette; Wegscheid, Claudia; Velden, Joachim; Fehr, Susanne; Mittrücker, Hans-Willi; Tiegs, Gisa; Stahl, Rolf A.K.

    2010-01-01

    T cells recruited to the kidney contribute to tissue damage in crescentic and proliferative glomerulonephritides. Chemokines and their receptors regulate T cell trafficking, but the expression profile and functional importance of chemokine receptors for renal CD4+ T cell subsets are incompletely understood. In this study, we observed that renal FoxP3+CD4+ regulatory T cells (Tregs) and IL-17–producing CD4+ T (Th17) cells express the chemokine receptor CCR6, whereas IFNγ-producing Th1 cells are CCR6−. Induction of experimental glomerulonephritis (nephrotoxic nephritis) in mice resulted in upregulation of the only CCR6 ligand, CCL20, followed by T cell recruitment, renal tissue injury, albuminuria, and loss of renal function. CCR6 deficiency aggravated renal injury and increased mortality (from uremia) among nephritic mice. Compared with wild-type (WT) mice, CCR6 deficiency reduced infiltration of Tregs and Th17 cells but did not affect recruitment of Th1 cells in the setting of glomerulonephritis. Adoptive transfer of WT but not CCR6-deficient Tregs attenuated morphologic and functional renal injury in nephritic mice. Furthermore, reconstitution with WT Tregs protected CCR6−/− mice from aggravated nephritis. Taken together, these data suggest that CCR6 mediates renal recruitment of both Tregs and Th17 cells and that the reduction of anti-inflammatory Tregs in the presence of a fully functional Th1 response aggravates experimental glomerulonephritis. PMID:20299360

  20. Profile of State College and Career Readiness Assessments (CCR) Policy. New Mexico

    ERIC Educational Resources Information Center

    Center on Education Policy, 2011

    2011-01-01

    This individual profile provides information on New Mexico's college and career readiness assessment policy. Some of the categories presented include: (1) CCR assessment policy; (2) Purpose; (3) Major changes in CCR assessment policy since the 2009-10 school year for financial reasons; (4) State financial support for students to take the CCR…

  1. Unexpected Regulatory Role of CCR9 in Regulatory T Cell Development

    PubMed Central

    Evans-Marin, Heather L.; Cao, Anthony T.; Yao, Suxia; Chen, Feidi; He, Chong; Liu, Han; Wu, Wei; Gonzalez, Maria G.; Dann, Sara M.; Cong, Yingzi

    2015-01-01

    T cells reactive to microbiota regulate the pathogenesis of inflammatory bowel disease (IBD). As T cell trafficking to intestines is regulated through interactions between highly specific chemokine-chemokine receptors, efforts have been made to develop intestine-specific immunosuppression based on blocking these key processes. CCR9, a gut-trophic chemokine receptor expressed by lymphocytes and dendritic cells, has been implicated in the regulation of IBD through mediating recruitment of T cells to inflamed sites. However, the role of CCR9 in inducing and sustaining inflammation in the context of IBD is poorly understood. In this study, we demonstrate that CCR9 deficiency in effector T cells and Tregs does not affect the development of colitis in a microbiota antigen-specific, T cell-mediated model. However, Treg cells express higher levels of CCR9 compared to those in effector T cells. Interestingly, CCR9 inhibits Treg cell development, in that CCR9-/- mice demonstrate a high level of Foxp3+ Tregs, and ligation of CCR9 by its ligand CCL25 inhibits Treg cell differentiation in vitro. Collectively, our data indicate that in addition to acting as a gut-homing molecule, CCR9 signaling shapes immune responses by inhibiting Treg cell development. PMID:26230654

  2. CCR7 Deficiency Exacerbates Injury in Acute Nephritis Due to Aberrant Localization of Regulatory T Cells

    PubMed Central

    Eller, Kathrin; Weber, Tobias; Pruenster, Monika; Wolf, Anna M.; Mayer, Gert

    2010-01-01

    The homing of dendritic cells and T cells to secondary lymphoid organs requires chemokine receptor 7 (CCR7) expression on these cells. T cells mediate the pathogenesis of experimental accelerated nephrotoxic serum nephritis (NTS), including its suppression by regulatory T cells (Tregs), but the contribution of CCR7 to this disease is unknown. Here, we compared the development of NTS in CCR7-knockout (KO) and wild-type (WT) mice. Compared with WT mice, CCR7KO mice developed more severe disease with significantly more inflammatory cells infiltrating the kidney. These cells included FoxP3+ Tregs, which were virtually absent from WT kidneys. The adoptive transfer of WT Tregs into CCR7KO mice at the time of immunization protected the recipients from disease; these cells homed to secondary lymphoid organs but not to kidneys. Conversely, adoptive transfer of CCR7KO Tregs into WT mice did not inhibit development of NTS. These data suggest that NTS can develop without CCR7 expression, but Treg-mediated disease suppression, which seems to occur in secondary lymphoid organs, requires CCR7. PMID:19917782

  3. Profile of State College and Career Readiness Assessments (CCR) Policy. Minnesota

    ERIC Educational Resources Information Center

    Center on Education Policy, 2011

    2011-01-01

    This individual profile provides information on Minnesota's college and career readiness assessment policy. Some of the categories presented include: (1) CCR assessment policy; (2) Purpose; (3) Major changes in CCR assessment policy since the 2009-10 school year for financial reasons; (4) State financial support for students to take the CCR…

  4. Profile of State College and Career Readiness Assessments (CCR) Policy. Florida

    ERIC Educational Resources Information Center

    Center on Education Policy, 2011

    2011-01-01

    This individual profile provides information on Florida's college and career readiness assessment policy. Some of the categories presented include: (1) CCR assessment policy; (2) Purpose; (3) Major changes in CCR assessment policy since the 2009-10 school year for financial reasons; (4) State financial support for students to take the CCR…

  5. Profile of State College and Career Readiness Assessments (CCR) Policy. Georgia

    ERIC Educational Resources Information Center

    Center on Education Policy, 2011

    2011-01-01

    This individual profile provides information on Georgia's college and career readiness assessment policy. Some of the categories presented include: (1) CCR assessment policy; (2) Purpose; (3) Major changes in CCR assessment policy since the 2009-10 school year for financial reasons; (4) State financial support for students to take the CCR…

  6. Profile of State College and Career Readiness Assessments (CCR) Policy. Kentucky

    ERIC Educational Resources Information Center

    Center on Education Policy, 2011

    2011-01-01

    This individual profile provides information on Kentucky's college and career readiness assessment policy. Some of the categories presented include: (1) CCR assessment policy; (2) Purpose; (3) Major changes in CCR assessment policy since the 2009-10 school year for financial reasons; (4) State financial support for students to take the CCR…

  7. Profile of State College and Career Readiness Assessments (CCR) Policy. South Carolina

    ERIC Educational Resources Information Center

    Center on Education Policy, 2011

    2011-01-01

    This individual profile provides information on South Carolina's college and career readiness assessment policy. Some of the categories presented include: (1) CCR assessment policy; (2) Purpose; (3) Major changes in CCR assessment policy since the 2009-10 school year for financial reasons; (4) State financial support for students to take the CCR…

  8. Profile of State College and Career Readiness Assessments (CCR) Policy. California

    ERIC Educational Resources Information Center

    Center on Education Policy, 2011

    2011-01-01

    This individual profile provides information on California's college and career readiness assessment policy. Some of the categories presented include: (1) CCR assessment policy; (2) Purpose; (3) Major changes in CCR assessment policy since the 2009-10 school year for financial reasons; (4) State financial support for students to take the CCR…

  9. Profile of State College and Career Readiness Assessments (CCR) Policy. Alabama

    ERIC Educational Resources Information Center

    Center on Education Policy, 2011

    2011-01-01

    This individual profile provides information on Alabama's college and career readiness assessment policy. Some of the categories presented include: (1) CCR assessment policy; (2) Purpose; (3) Major changes in CCR assessment policy since the 2009-10 school year for financial reasons; (4) State financial support for students to take the CCR…

  10. Profile of State College and Career Readiness Assessments (CCR) Policy. Arkansas

    ERIC Educational Resources Information Center

    Center on Education Policy, 2011

    2011-01-01

    This individual profile provides information on Arkansas' college and career readiness assessment policy. Some of the categories presented include: (1) CCR assessment policy; (2) Purpose; (3) Major changes in CCR assessment policy since the 2009-10 school year for financial reasons; (4) State financial support for students to take the CCR…

  11. Profile of State College and Career Readiness Assessments (CCR) Policy. Tennessee

    ERIC Educational Resources Information Center

    Center on Education Policy, 2011

    2011-01-01

    This individual profile provides information on Tennessee's college and career readiness assessment policy. Some of the categories presented include: (1) CCR assessment policy; (2) Purpose; (3) Major changes in CCR assessment policy since the 2009-10 school year for financial reasons; (4) State financial support for students to take the CCR…

  12. Profile of State College and Career Readiness Assessments (CCR) Policy. North Dakota

    ERIC Educational Resources Information Center

    Center on Education Policy, 2011

    2011-01-01

    This individual profile provides information on North Dakota's college and career readiness assessment policy. Some of the categories presented include: (1) CCR assessment policy; (2) Purpose; (3) Major changes in CCR assessment policy since the 2009-10 school year for financial reasons; (4) State financial support for students to take the CCR…

  13. Profile of State College and Career Readiness Assessments (CCR) Policy. West Virginia

    ERIC Educational Resources Information Center

    Center on Education Policy, 2011

    2011-01-01

    This individual profile provides information on West Virginia's college and career readiness assessment policy. Some of the categories presented include: (1) CCR assessment policy; (2) Purpose; (3) Major changes in CCR assessment policy since the 2009-10 school year for financial reasons; (4) State financial support for students to take the CCR…

  14. Y-12 National Security Complex Biological Monitoring And Abatement Program 2008 Calendar Year Report

    SciTech Connect

    Peterson, M. J.; Greeley Jr., M. S.; Mathews, T. J.; Morris, G. W.; Roy, W. K.; Ryon, M. G.; Smith, J. G.; Southworth, G. R.

    2009-07-01

    The National Pollutant Discharge Elimination System (NPDES) permit issued for the Oak Ridge Y-12 National Security Complex (Y-12 Complex) which became effective May 1, 2006, continued a requirement for a Biological Monitoring and Abatement Program (BMAP). The BMAP was originally developed in 1985 to demonstrate that the effluent limitations established for the Y-12 Complex protected the classified uses of the receiving stream (East Fork Poplar Creek: EFPC), in particular, the growth and propagation of aquatic life (Loar et al. 1989). The objectives of the current BMAP are similar, specifically to assess stream ecological conditions relative to regulatory limits and criteria, to assess ecological impacts as well as recovery in response to Y-12 operations, and to investigate the causes of continuing impacts. The BMAP consists of three tasks that reflect complementary approaches to evaluating the effects of the Y-12 Complex discharges on the biotic integrity of EFPC. These tasks include: (1) bioaccumulation monitoring, (2) benthic macroinvertebrate community monitoring, and (3) fish community monitoring. As required by the NPDES permit, the BMAP benthic macroinvertebrate community monitoring task includes studies to annually evaluate the receiving stream's biological integrity in comparison to TN Water Quality Criteria. BMAP monitoring is currently being conducted at five primary EFPC sites, although sites may be excluded or added depending upon the specific objectives of the various tasks. Criteria used in selecting the sites include: (1) location of sampling sites used in other studies, (2) known or suspected sources of downstream impacts, (3) proximity to U.S. Department of Energy (DOE) Oak Ridge Reservation (ORR) boundaries, (4) appropriate habitat distribution, and (5) access. The primary sampling sites include upper EFPC at kilometers (EFKs) 24.4 and 23.4 [upstream and downstream of Lake Reality (LR) respectively]; EFK 18.7 (also EFK 18.2 and 19), located off

  15. CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T-cell recruitment to target tissues.

    PubMed

    Villares, Ricardo; Cadenas, Vanessa; Lozano, María; Almonacid, Luis; Zaballos, Angel; Martínez-A, Carlos; Varona, Rosa

    2009-06-01

    The T-cell subsets, characterized by their cytokine production profiles and immune regulatory functions, depend on correct in vivo location to interact with accessory or target cells for effective immune responses. Differentiation of naive CD4(+) T cells into effectors is accompanied by sequentially regulated expression of the chemokine receptors responsible for cell recruitment to specific tissues. We studied CCR6 function in EAE, a CD4(+) T-cell-mediated CNS disease characterized by mononuclear infiltration and demyelination. CCR6(-/-) mice showed an altered time course of EAE development, with delayed onset, a higher clinical score, and more persistent symptoms than in controls. An imbalanced cytokine profile and reduced Foxp3(+) cell frequency characterized CNS tissues from CCR6(-/-) compared with CCR6(+/+) mice during the disease effector phase. Transfer of CCR6(+/+) Treg to CCR6(-/-) mice the day before EAE induction reduced the clinical score associated with an increased in infiltrating Foxp3(+) cells and recovery of the cytokine balance in CCR6(-/-) mouse CNS. Competitive assays between CCR6(+/+) and CCR6(-/-) Treg adoptively transferred to CCR6(-/-) mice showed impaired ability of CCR6(-/-) Treg to infiltrate CNS tissues in EAE-affected mice. Our data indicate a CCR6 requirement by CD4(+) Treg to downregulate the CNS inflammatory process and neurological signs associated with EAE. PMID:19499521

  16. Polymorphisms in the CCR5 promoter region influence disease progression in perinatally human immunodeficiency virus type 1-infected children.

    PubMed

    Ometto, L; Bertorelle, R; Mainardi, M; Zanchetta, M; Tognazzo, S; Rampon, O; Ruga, E; Chieco-Bianchi, L; De Rossi, A

    2001-03-01

    The effect of CC-chemokine receptor 5 (CCR5) promoter polymorphisms on the natural history of human immunodeficiency virus (HIV) disease was studied in 73 HIV-1-infected children. The CCR5(59338-59537) promoter haplotype, CCR5-59029A/G polymorphism, and CCR5Delta32 and CCR2-64I alterations were investigated. After exclusion of carriers of CCR5Delta32 or CCR2-64I, Kaplan-Meier analysis disclosed that children with the P1/P1(59353C,59356C,59402A) genotype progressed faster to disease than did children with other haplotypes (P=.016). When CCR2-64I carriers were included, this effect had borderline significance (P=.065) and was lost when CCR5Delta32 carriers were also considered (P=.387). The P1/P1 effect was strongest early after infection, when progression to disease was mainly associated with CCR5 coreceptor-using viruses. These results indicate that the P1/P1 genotype is predictive of rapid progression in HIV-1-infected children lacking CCR5Delta32 or CCR5-64I alleles. The observation of a linkage disequilibrium between P1 and 59029A might explain the previously reported association between 59029A homozygosity and rapid disease progression. PMID:11181160

  17. Regulation of skeletal muscle regeneration by CCR2-activating chemokines is directly related to macrophage recruitment

    PubMed Central

    Martinez, Carlo O.; McHale, Matthew J.; Wells, Jason T.; Ochoa, Oscar; Michalek, Joel E.; McManus, Linda M.

    2010-01-01

    Muscle regeneration requires CC chemokine receptor 2 (CCR2) expression on bone marrow-derived cells; macrophages are a prominent CCR2-expressing cell in this process. CCR2−/− mice have severe impairments in angiogenesis, macrophage recruitment, and skeletal muscle regeneration following cardiotoxin (CTX)-induced injury. However, multiple chemokines activate CCR2, including monocyte chemotactic proteins (MCP)-1, -3, and -5. We hypothesized that MCP-1 is the chemokine ligand that mediates the impairments present in CCR2−/− mice. We examined muscle regeneration, capillary density, and cellular recruitment in MCP-1−/− and CCR2−/− mice following injury. Muscle regeneration and adipocyte accumulation, but not capillary density, were significantly impaired in MCP-1−/− compared with wild-type (WT) mice; however, muscle regeneration and adipocyte accumulation impairments were not as severe as observed in CCR2−/− mice. Although tissue levels of MCP-5 were elevated in MCP-1−/− mice compared with WT, the administration of MCP-5 neutralizing antibody did not alter muscle regeneration in MCP-1−/− mice. While neutrophil accumulation after injury was similar in all three mouse strains, macrophage recruitment was highest in WT mice, intermediate in MCP-1−/− mice, and severely impaired in CCR2−/− mice. In conclusion, while the absence of MCP-1 resulted in impaired macrophage recruitment and muscle regeneration, MCP-1−/− mice exhibit an intermediate phenotype compared with CCR2−/− mice. Intermediate macrophage recruitment in MCP-1−/− mice was associated with similar capillary density to WT, suggesting that fewer macrophages may be needed to restore angiogenesis vs. muscle regeneration. Finally, other chemokines, in addition to MCP-1 and MCP-5, may activate CCR2-dependent regenerative processes resulting in an intermediate phenotype in MCP-1−/− mice. PMID:20631294

  18. Regulation of skeletal muscle regeneration by CCR2-activating chemokines is directly related to macrophage recruitment.

    PubMed

    Martinez, Carlo O; McHale, Matthew J; Wells, Jason T; Ochoa, Oscar; Michalek, Joel E; McManus, Linda M; Shireman, Paula K

    2010-09-01

    Muscle regeneration requires CC chemokine receptor 2 (CCR2) expression on bone marrow-derived cells; macrophages are a prominent CCR2-expressing cell in this process. CCR2-/- mice have severe impairments in angiogenesis, macrophage recruitment, and skeletal muscle regeneration following cardiotoxin (CTX)-induced injury. However, multiple chemokines activate CCR2, including monocyte chemotactic proteins (MCP)-1, -3, and -5. We hypothesized that MCP-1 is the chemokine ligand that mediates the impairments present in CCR2-/- mice. We examined muscle regeneration, capillary density, and cellular recruitment in MCP-1-/- and CCR2-/- mice following injury. Muscle regeneration and adipocyte accumulation, but not capillary density, were significantly impaired in MCP-1-/- compared with wild-type (WT) mice; however, muscle regeneration and adipocyte accumulation impairments were not as severe as observed in CCR2-/- mice. Although tissue levels of MCP-5 were elevated in MCP-1-/- mice compared with WT, the administration of MCP-5 neutralizing antibody did not alter muscle regeneration in MCP-1-/- mice. While neutrophil accumulation after injury was similar in all three mouse strains, macrophage recruitment was highest in WT mice, intermediate in MCP-1-/- mice, and severely impaired in CCR2-/- mice. In conclusion, while the absence of MCP-1 resulted in impaired macrophage recruitment and muscle regeneration, MCP-1-/- mice exhibit an intermediate phenotype compared with CCR2-/- mice. Intermediate macrophage recruitment in MCP-1-/- mice was associated with similar capillary density to WT, suggesting that fewer macrophages may be needed to restore angiogenesis vs. muscle regeneration. Finally, other chemokines, in addition to MCP-1 and MCP-5, may activate CCR2-dependent regenerative processes resulting in an intermediate phenotype in MCP-1-/- mice. PMID:20631294

  19. Expression and histopathological correlation of CCR9 and CCL25 in ovarian cancer.

    PubMed

    Singh, Rajesh; Stockard, Cecil R; Grizzle, William E; Lillard, James W; Singh, Shailesh

    2011-08-01

    Ovarian carcinoma is the most lethal gynecological malignancy among women and its poor prognosis is mainly due to metastasis. Chemokine receptor CCR9 is primarily expressed by a small subset of immune cells. The interactions between CCL25 and CCR9 have been implicated in leukocyte trafficking to the small bowel, a frequent metastatic site for ovarian cancer cells. We have previously shown that ovarian cancer cells express CCR9 and play an important role in cell migration, invasion and survival in the presence of its natural ligand in vitro. In this study, we have evaluated the expression of CCR9 and CCL25 in ovarian cancer cells and clinical samples. Ovarian cancer tissue microarrays from University of Alabama at Birmingham and AccuMax were stained for CCR9 and CCL25. Aperio ScanScope was used to acquire 80X digital images and expression analysis of CCR9 and CCL25. Flow cytometry and the Image stream system were used to conform the expression of CCR9 and CCL25 in ovarian cancer cells. Our results show significantly higher (p<0.001) expression of CCR9 and CCL25 in serous adenocarcinoma followed by serous papillary cystadenoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, cystadenoma, mucinous boderline adenocarcinoma, clear cell carcinoma, granulosa cell tumor, dysgerminoma, transitional cell carcinoma, Brenner tumor, yolk sac tumor, adenocarcinoma and fibroma cases, compared to non-neoplastic ovarian tissue. Similar to tissue expression, CCR9 was also significantly expressed by the ovarian cancer cell lines (OVCAR-3 and SK-OV-3) in comparison to normal adult ovarian epithelial cell. We provide the first evidence that CCR9 and its natural ligand CCL25 are highly expressed by ovarian cancer tissue and their expression correlates with histological subtypes. Expression of this chemokine receptor and its ligand CCL25 within primary tumor tissue further suggests a potential role of this chemokine-receptor axis in ovarian cancer progression. PMID:21637913

  20. CCL20/CCR6 Signaling Regulates Bone Mass Accrual in Mice.

    PubMed

    Doucet, Michele; Jayaraman, Swaathi; Swenson, Emily; Tusing, Brittany; Weber, Kristy L; Kominsky, Scott L

    2016-07-01

    CCL20 is a member of the macrophage inflammatory protein family and is reported to signal monogamously through the receptor CCR6. Although studies have identified the genomic locations of both Ccl20 and Ccr6 as regions important for bone quality, the role of CCL20/CCR6 signaling in regulating bone mass is unknown. By micro-computed tomography (μCT) and histomorphometric analysis, we show that global loss of Ccr6 in mice significantly decreases trabecular bone mass coincident with reduced osteoblast numbers. Notably, CCL20 and CCR6 were co-expressed in osteoblast progenitors and levels increased during osteoblast differentiation, indicating the potential of CCL20/CCR6 signaling to influence osteoblasts through both autocrine and paracrine actions. With respect to autocrine effects, CCR6 was found to act as a functional G protein-coupled receptor in osteoblasts and although its loss did not appear to affect the number or proliferation rate of osteoblast progenitors, differentiation was significantly inhibited as evidenced by delays in osteoblast marker gene expression, alkaline phosphatase activity, and mineralization. In addition, CCL20 promoted osteoblast survival concordant with activation of the PI3K-AKT pathway. Beyond these potential autocrine effects, osteoblast-derived CCL20 stimulated the recruitment of macrophages and T cells, known facilitators of osteoblast differentiation and survival. Finally, we generated mice harboring a global deletion of Ccl20 and found that Ccl20(-/-) mice exhibit a reduction in bone mass similar to that observed in Ccr6(-/-) mice, confirming that this phenomenon is regulated by CCL20 rather than alternate CCR6 ligands. Collectively, these data indicate that CCL20/CCR6 signaling may play an important role in regulating bone mass accrual, potentially by modulating osteoblast maturation, survival, and the recruitment of osteoblast-supporting cells. © 2016 American Society for Bone and Mineral Research. PMID:26890063

  1. CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2

    PubMed Central

    Bedognetti, D; Spivey, T L; Zhao, Y; Uccellini, L; Tomei, S; Dudley, M E; Ascierto, M L; De Giorgi, V; Liu, Q; Delogu, L G; Sommariva, M; Sertoli, M R; Simon, R; Wang, E; Rosenberg, S A; Marincola, F M

    2013-01-01

    Background: Adoptive therapy with tumour-infiltrating lymphocytes (TILs) induces durable complete responses (CR) in ∼20% of patients with metastatic melanoma. The recruitment of T cells through CXCR3/CCR5 chemokine ligands is critical for immune-mediated rejection. We postulated that polymorphisms and/or expression of CXCR3/CCR5 in TILs and the expression of their ligands in tumour influence the migration of TILs to tumours and tumour regression. Methods: Tumour-infiltrating lymphocytes from 142 metastatic melanoma patients enrolled in adoptive therapy trials were genotyped for CXCR3 rs2280964 and CCR5-Δ32 deletion, which encodes a protein not expressed on the cell surface. Expression of CXCR3/CCR5 in TILs and CXCR3/CCR5 and ligand genes in 113 available parental tumours was also assessed. Tumour-infiltrating lymphocyte data were validated by flow cytometry (N=50). Results: The full gene expression/polymorphism model, which includes CXCR3 and CCR5 expression data, CCR5-Δ32 polymorphism data and their interaction, was significantly associated with both CR and overall response (OR; P=0.0009, and P=0.007, respectively). More in detail, the predicted underexpression of both CXCR3 and CCR5 according to gene expression and polymorphism data (protein prediction model, PPM) was associated with response to therapy (odds ratio=6.16 and 2.32, for CR and OR, respectively). Flow cytometric analysis confirmed the PPM. Coordinate upregulation of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumour biopsies was associated with OR. Conclusion: Coordinate overexpression of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumours was associated with responsiveness to treatment. Conversely, CCR5-Δ32 polymorphism and CXCR3/CCR5 underexpression influence downregulation of the corresponding receptors in TILs and were associated with likelihood and degree of response. PMID:24129241

  2. Biological diversity, ecological health and condition of aquatic assemblages at national wildlife refuges in southern indiana, USA.

    PubMed

    Simon, Thomas P; Morris, Charles C; Robb, Joseph R; McCoy, William

    2015-01-01

    The National Wildlife Refuge system is a vital resource for the protection and conservation of biodiversity and biological integrity in the United States. Surveys were conducted to determine the spatial and temporal patterns of fish, macroinvertebrate, and crayfish populations in two watersheds that encompass three refuges in southern Indiana. The Patoka River National Wildlife Refuge had the highest number of aquatic species with 355 macroinvertebrate taxa, six crayfish species, and 82 fish species, while the Big Oaks National Wildlife Refuge had 163 macroinvertebrate taxa, seven crayfish species, and 37 fish species. The Muscatatuck National Wildlife Refuge had the lowest diversity of macroinvertebrates with 96 taxa and six crayfish species, while possessing the second highest fish species richness with 51 species. Habitat quality was highest in the Muscatatuck River drainage with increased amounts of forested habitats compared to the Patoka River drainage. Biological integrity of the three refuges ranked the Patoka NWR as the lowest biological integrity (mean IBI reach scores = 35 IBI points), while Big Oaks had the highest biological integrity (mean IBI reach score = 41 IBI points). The Muscatatuck NWR had a mean IBI reach score of 31 during June, which seasonally increased to a mean of 40 IBI points during summer. Watershed IBI scores and habitat condition were highest in the Big Oaks NWR. PMID:25632261

  3. Towards national mapping of aquatic condition (II): Predicting the probable biological condition of USA streams and rivers

    EPA Science Inventory

    The US EPA’s National River and Stream Assessment (NRSA) uses spatially balanced sampling to estimate the proportion of streams within the conterminous US (CONUS) that deviate from least-disturbed biological condition (BC). These assessments do not infer BC at un-sampled st...

  4. Biological Diversity, Ecological Health and Condition of Aquatic Assemblages at National Wildlife Refuges in Southern Indiana, USA

    PubMed Central

    Morris, Charles C.; Robb, Joseph R.; McCoy, William

    2015-01-01

    Abstract The National Wildlife Refuge system is a vital resource for the protection and conservation of biodiversity and biological integrity in the United States. Surveys were conducted to determine the spatial and temporal patterns of fish, macroinvertebrate, and crayfish populations in two watersheds that encompass three refuges in southern Indiana. The Patoka River National Wildlife Refuge had the highest number of aquatic species with 355 macroinvertebrate taxa, six crayfish species, and 82 fish species, while the Big Oaks National Wildlife Refuge had 163 macroinvertebrate taxa, seven crayfish species, and 37 fish species. The Muscatatuck National Wildlife Refuge had the lowest diversity of macroinvertebrates with 96 taxa and six crayfish species, while possessing the second highest fish species richness with 51 species. Habitat quality was highest in the Muscatatuck River drainage with increased amounts of forested habitats compared to the Patoka River drainage. Biological integrity of the three refuges ranked the Patoka NWR as the lowest biological integrity (mean IBI reach scores = 35 IBI points), while Big Oaks had the highest biological integrity (mean IBI reach score = 41 IBI points). The Muscatatuck NWR had a mean IBI reach score of 31 during June, which seasonally increased to a mean of 40 IBI points during summer. Watershed IBI scores and habitat condition were highest in the Big Oaks NWR. PMID:25632261

  5. Molecular cloning, structure and expressional profiles of two novel single-exon genes (PoCCR6A and PoCCR6B) in the Japanese flounder (Paralichthys olivaceus).

    PubMed

    Wang, Lei; Zhang, Yong-zhen; Xu, Wen-teng; Jia, Xiao-dong; Chen, Song-lin

    2016-05-01

    CCR6 is an important binding receptor of CCL20 and beta-defensins, and has multiple functions in the innate and acquired immune responses. In this study, we cloned the PoCCR6A and PoCCR6B genes of the Japanese flounder and studied the gene structure and expression patterns of these two genes in bacterial infection. The full-length PoCCR6A cDNA is 1415 bp and the open reading frame (ORF) is 1113 bp, encoding a 370-amino-acid peptide. The full-length PoCCR6B cDNA is 2193 bp and the ORF is 1029 bp, encoding a 363-amino-acid peptide. The structures of PoCCR6A and PoCCR6B indicate that they are single-exon genes. The predicted proteins encoded by PoCCR6A and PoCCR6B have the typical G-protein-coupled receptor (GPCR) family signature of seven transmembrane domains and several conserved structural features. A tissue distribution analysis showed that PoCCR6A is predominately expressed in the intestine, gill, and blood, and PoCCR6B in the gill, spleen, and liver. The expression patterns of the two chemokine receptors were analyzed during bacterial infection. In spleen and kidney, the expression of PoCCR6A was significantly upregulated at 24 h after infection, whereas the expression of PoCCR6B was steady at these time points. While in intestine, both of them were upregulated at 6 h-12 h after infection, and in gill the expression levels of them were upregulated at 24 h. The patterns of expression suggested that PoCCR6A and PoCCR6B play an important role in the immune response of the Japanese flounder, especially in the mucosal tissues. PMID:26997201

  6. Biological and Environmental Research Program at Oak Ridge National Laboratory, FY 1992--1994

    SciTech Connect

    Not Available

    1992-01-01

    This report is the 1992--1994 Program Director's Overview Report for Oak Ridge National Laboratory's (ORNL's) Biological and Environmental Research (BER) Program, and as such it addresses KP-funded work at ORNL conducted during FY 1991 and in progress during FY 1992; it also serves as a planning document for the remainder of FY 1992 through FY 1994. Non-BER funded work at ORNL relevant to the mission of OHER is also discussed. The second section of the report describes ORNL facilities and resources used by the BER program. The third section addresses research management practices at ORNL. The fourth, fifth, and sixth sections address BER-funded research in progress, program accomplishments and research highlights, and program orientation for the remainder of FY 1992 through FY 1994, respectively. Work for non-BER sponsors is described in the seventh section, followed by a discussion of significant near and long-term issues facing BER work at ORNL in the eighth section. The last section provides a statistical summary of BER research at ORNL. Appendices supplement the above topics with additional detail.

  7. Biological and Environmental Research Program at Oak Ridge National Laboratory, FY 1992--1994

    SciTech Connect

    Not Available

    1992-01-01

    This report is the 1992--1994 Program Director`s Overview Report for Oak Ridge National Laboratory`s (ORNL`s) Biological and Environmental Research (BER) Program, and as such it addresses KP-funded work at ORNL conducted during FY 1991 and in progress during FY 1992; it also serves as a planning document for the remainder of FY 1992 through FY 1994. Non-BER funded work at ORNL relevant to the mission of OHER is also discussed. The second section of the report describes ORNL facilities and resources used by the BER program. The third section addresses research management practices at ORNL. The fourth, fifth, and sixth sections address BER-funded research in progress, program accomplishments and research highlights, and program orientation for the remainder of FY 1992 through FY 1994, respectively. Work for non-BER sponsors is described in the seventh section, followed by a discussion of significant near and long-term issues facing BER work at ORNL in the eighth section. The last section provides a statistical summary of BER research at ORNL. Appendices supplement the above topics with additional detail.

  8. International and national expert group evaluations: biological/health effects of radiofrequency fields.

    PubMed

    Vijayalaxmi; Scarfi, Maria R

    2014-09-01

    The escalated use of various wireless communication devices, which emit non-ionizing radiofrequency (RF) fields, have raised concerns among the general public regarding the potential adverse effects on human health. During the last six decades, researchers have used different parameters to investigate the effects of in vitro and in vivo exposures of animals and humans or their cells to RF fields. Data reported in peer-reviewed scientific publications were contradictory: some indicated effects while others did not. International organizations have considered all of these data as well as the observations reported in human epidemiological investigations to set-up the guidelines or standards (based on the quality of published studies and the "weight of scientific evidence" approach) for RF exposures in occupationally exposed individuals and the general public. Scientists with relevant expertise in various countries have also considered the published data to provide the required scientific information for policy-makers to develop and disseminate authoritative health information to the general public regarding RF exposures. This paper is a compilation of the conclusions, on the biological effects of RF exposures, from various national and international expert groups, based on their analyses. In general, the expert groups suggested a reduction in exposure levels, precautionary approach, and further research. PMID:25211777

  9. Research Coordination Network: Geothermal Biology and Geochemistry in Yellowstone National Park

    NASA Astrophysics Data System (ADS)

    Inskeep, W. P.; Young, M. J.; Jay, Z.

    2006-12-01

    The number and diversity of geothermal features in Yellowstone National Park (YNP) represent a fascinating array of high temperature geochemical environments that host a corresponding number of unique and potentially novel organisms in all of the three recognized domains of life: Bacteria, Archaea and Eukarya. The geothermal features of YNP have long been the subject of scientific inquiry, especially in the fields of microbiology, geochemistry, geothermal hydrology, microbial ecology, and population biology. However, there are no organized forums for scientists working in YNP geothermal areas to present research results, exchange ideas, discuss research priorities, and enhance synergism among research groups. The primary goal of the YNP Research Coordination Network (GEOTHERM) is to develop a more unified effort among scientists and resource agencies to characterize, describe, understand and inventory the diverse biota associated with geothermal habitats in YNP. The YNP RCN commenced in January 2005 as a collaborative effort among numerous university scientists, governmental agencies and private industry. The YNP RCN hosted a workshop in February 2006 to discuss research results and to form three working groups focused on (i) web-site and digital library content, (ii) metagenomics of thermophilic microbial communities and (iii) development of geochemical methods appropriate for geomicrobiological studies. The working groups represent one strategy for enhancing communication, collaboration and most importantly, productivity among the RCN participants. If you have an interest in the geomicrobiology of geothermal systems, please feel welcome to join and or participate in the YNP RCN.

  10. International and National Expert Group Evaluations: Biological/Health Effects of Radiofrequency Fields

    PubMed Central

    Vijayalaxmi; Scarfi, Maria R.

    2014-01-01

    The escalated use of various wireless communication devices, which emit non-ionizing radiofrequency (RF) fields, have raised concerns among the general public regarding the potential adverse effects on human health. During the last six decades, researchers have used different parameters to investigate the effects of in vitro and in vivo exposures of animals and humans or their cells to RF fields. Data reported in peer-reviewed scientific publications were contradictory: some indicated effects while others did not. International organizations have considered all of these data as well as the observations reported in human epidemiological investigations to set-up the guidelines or standards (based on the quality of published studies and the “weight of scientific evidence” approach) for RF exposures in occupationally exposed individuals and the general public. Scientists with relevant expertise in various countries have also considered the published data to provide the required scientific information for policy-makers to develop and disseminate authoritative health information to the general public regarding RF exposures. This paper is a compilation of the conclusions, on the biological effects of RF exposures, from various national and international expert groups, based on their analyses. In general, the expert groups suggested a reduction in exposure levels, precautionary approach, and further research. PMID:25211777

  11. Evolution, Science and Society: Evolutionary Biology and the National Research Agenda.

    ERIC Educational Resources Information Center

    Futuyma, Douglas J.; Meagher, Thomas R.

    2001-01-01

    Discusses ways of advancing understanding of evolutionary biology which seeks to explain all the characteristics of organisms. Describes the goals of evolutionary biology, why it is important, and how it contributes to society and basic science. (ASK)

  12. The enzyme activities of Caf1 and Ccr4 are both required for deadenylation by the human Ccr4–Not nuclease module

    PubMed Central

    Maryati, Maryati; Airhihen, Blessing; Winkler, G. Sebastiaan

    2015-01-01

    In eukaryotic cells, the shortening and removal of the poly(A) tail (deadenylation) of cytoplasmic mRNA is a key event in regulated mRNA degradation. A major enzyme involved in deadenylation is the Ccr4–Not deadenylase complex, which can be recruited to its target mRNA by RNA-binding proteins or the miRNA repression complex. In addition to six non-catalytic components, the complex contains two enzymatic subunits with ribonuclease activity: Ccr4 and Caf1 (Pop2). In vertebrates, each deadenylase subunit is encoded by two paralogues: Caf1, which can interact with the anti-proliferative protein BTG2, is encoded by CNOT7 and CNOT8, whereas Ccr4 is encoded by the highly similar genes CNOT6 and CNOT6L. Currently, it is unclear whether the catalytic subunits work co-operatively or whether the nuclease components have unique roles in deadenylation. We therefore developed a method to express and purify a minimal human BTG2–Caf1–Ccr4 nuclease sub-complex from bacterial cells. By using chemical inhibition and well-characterized inactivating amino acid substitutions, we demonstrate that the enzyme activities of Caf1 and Ccr4 are both required for deadenylation in vitro. These results indicate that Caf1 and Ccr4 cooperate in mRNA deadenylation and suggest that the enzyme activities of Caf1 and Ccr4 are regulated via allosteric interactions within the nuclease module. PMID:25944446

  13. CCR2 is required for CD8-induced graft-versus-host disease

    PubMed Central

    Terwey, Theis H.; Kim, Theo D.; Kochman, Adam A.; Hubbard, Vanessa M.; Lu, Sydney; Zakrzewski, Johannes L.; Ramirez-Montagut, Teresa; Eng, Jeffrey M.; Muriglan, Stephanie J.; Heller, Glenn; Murphy, George F.; Liu, Chen; Budak-Alpdogan, Tulin; Alpdogan, Onder; van den Brink, Marcel R. M.

    2005-01-01

    Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Migration of donor-derived T cells into GVHD target organs plays a critical role in the development of GVHD and chemokines and their receptors are important molecules involved in this process. Here, we demonstrate in murine bone marrow transplantation models that the expression of the inflammatory CC chemokine receptor 2 (CCR2) on donor-derived CD8+ T cells is relevant for the control of CD8+ T-cell migration and development of GVHD. Recipients of CCR2-deficient (CCR2-/-) CD8+ T cells developed less damage of gut and liver than recipients of wild-type CD8+ T cells, which correlated with a reduction in overall GVHD morbidity and mortality. Assessment of donor CD8+ T-cell target organ infiltration revealed that CCR2-/- CD8+ T cells have an intrinsic migratory defect to the gut and liver. Other causes for the reduction in GVHD could be excluded, as alloreactive proliferation, activation, IFN-γ production and cytotoxicity of CCR2-/- CD8+ T cells were intact. Interestingly, the graft-versus-tumor effect mediated by CCR2-/- CD8+ T cells was preserved, which suggests that interference with T-cell migration by blockade of CCR2 signaling can separate GVHD from GVT activity. PMID:16037386

  14. HEK293T Cells Are Heterozygous for CCR5 Delta 32 Mutation

    PubMed Central

    Qi, Chunxia; Jia, Xiaopeng; Lu, Lingling; Ma, Ping; Wei, Min

    2016-01-01

    C-C chemokine receptor 5 (CCR5) is a receptor for chemokines and a co-receptor for HIV-1 entry into the target CD4+ cells. CCR5 delta 32 deletion is a loss-of-function mutation, resistant to HIV-1 infection. We tried to induce the CCR5 delta 32 mutation harnessing the genome editing technique, CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR and CRISPR associated protein 9, Cas9) in the commonly used cell line human embryonic kidney HEK 293T cells. Surprisingly, we found that HEK293T cells are heterozygous for CCR5 delta 32 mutation, in contrast to the wild type CCR5 cells, human acute T cell leukemia cell line Jurkat and human breast adenocarcinoma cell line MDA-MB-231 cells. This finding indicates that at least one human cell line is heterozygous for the CCR5 delta 32 mutation. We also found that in PCR amplification, wild type CCR5 DNA and mutant delta 32 DNA can form mismatched heteroduplex and move slowly in gel electrophoresis. PMID:27042825

  15. The CCR5Δ32 Polymorphism in Brazilian Patients with Sickle Cell Disease

    PubMed Central

    Lopes, Mariana Pezzute; Santos, Magnun Nueldo Nunes; Faber, Eliel Wagner; Bezerra, Marcos André Cavalcanti; Hatzlhofer, Betânia Lucena Domingues; Albuquerque, Dulcinéia Martins; Zaccariotto, Tânia Regina; Ribeiro, Daniela Maria; Araújo, Aderson da Silva; Costa, Fernando Ferreira

    2014-01-01

    Background. Previous studies on the role of inflammation in the pathophysiology of sickle cell disease (SCD) suggested that the CCR5Δ32 allele, which is responsible for the production of truncated C-C chemokine receptor type 5 (CCR5), could confer a selective advantage on patients with SCD because it leads to a less efficient Th1 response. We determined the frequency of the CCR5Δ32 polymorphism in 795 Afro-Brazilian SCD patients followed up at the Pernambuco Hematology and Hemotherapy Center, in Northeastern Brazil, divided into a pediatric group (3 months–17 years, n = 483) and an adult group (18–70 years, n = 312). The adult patients were also compared to a healthy control group (blood donors, 18–61 years, n = 247). Methods. The CCR5/CCR5Δ32 polymorphism was determined by allele-specific PCR. Results. No homozygous patient for the CCR5Δ32 allele was detected. The frequency of heterozygotes in the study population (patients and controls) was 5.8%, in the total SCD patients 5.1%, in the children 5.4%, in the adults with SCD 4.8%, and in the adult controls 8.1%. These differences did not reach statistical significance. Conclusions. Our findings failed to demonstrate an important role of the CCR5Δ32 allele in the population sample studied here. PMID:25548430

  16. Chemokine Receptor Ccr6 Deficiency Alters Hepatic Inflammatory Cell Recruitment and Promotes Liver Inflammation and Fibrosis

    PubMed Central

    Blaya, Delia; Morales-Ibanez, Oriol; Coll, Mar; Millán, Cristina; Altamirano, José; Arroyo, Vicente; Caballería, Joan; Bataller, Ramón; Ginès, Pere; Sancho-Bru, Pau

    2015-01-01

    Chronic liver diseases are characterized by a sustained inflammatory response in which chemokines and chemokine-receptors orchestrate inflammatory cell recruitment. In this study we investigated the role of the chemokine receptor CCR6 in acute and chronic liver injury. In the absence of liver injury Ccr6-/- mice presented a higher number of hepatic macrophages and increased expression of pro-inflammatory cytokines and M1 markers Tnf-α, Il6 and Mcp1. Inflammation and cell recruitment were increased after carbon tetrachloride-induced acute liver injury in Ccr6-/- mice. Moreover, chronic liver injury by carbon tetrachloride in Ccr6-/- mice was associated with enhanced inflammation and fibrosis, altered macrophage recruitment, enhanced CD4+ cells and a reduction in Th17 (CD4+IL17+) and mature dendritic (MHCII+CD11c+) cells recruitment. Clodronate depletion of macrophages in Ccr6-/- mice resulted in a reduction of hepatic pro-inflammatory and pro-fibrogenic markers in the absence and after liver injury. Finally, increased CCR6 hepatic expression in patients with alcoholic hepatitis was found to correlate with liver expression of CCL20 and severity of liver disease. In conclusion, CCR6 deficiency affects hepatic inflammatory cell recruitment resulting in the promotion of hepatic inflammation and fibrosis. PMID:26691857

  17. The chemokine receptor CCR7 promotes mammary tumorigenesis through amplification of stem-like cells.

    PubMed

    Boyle, S T; Ingman, W V; Poltavets, V; Faulkner, J W; Whitfield, R J; McColl, S R; Kochetkova, M

    2016-01-01

    The chemokine receptor CCR7 is widely implicated in breast cancer pathobiology. Although recent reports correlated high CCR7 levels with more advanced tumor grade and poor prognosis, limited in vivo data are available regarding its specific function in mammary gland neoplasia and the underlying mechanisms involved. To address these questions we generated a bigenic mouse model of breast cancer combined with CCR7 deletion, which revealed that CCR7 ablation results in a considerable delay in tumor onset as well as significantly reduced tumor burden. Importantly, CCR7 was found to exert its function by regulating mammary cancer stem-like cells in both murine and human tumors. In vivo experiments showed that loss of CCR7 activity either through deletion or pharmacological antagonism significantly decreased functional pools of stem-like cells in mouse primary mammary tumors, providing a mechanistic explanation for the tumor-promoting role of this chemokine receptor. These data characterize the oncogenic properties of CCR7 in mammary epithelial neoplasia and point to a new route for therapeutic intervention to target evasive cancer stem cells. PMID:25772241

  18. Targeted delivery of CCR2 antagonist to activated pulmonary endothelium prevents metastasis.

    PubMed

    Roblek, Marko; Calin, Manuela; Schlesinger, Martin; Stan, Daniela; Zeisig, Reiner; Simionescu, Maya; Bendas, Gerd; Borsig, Lubor

    2015-12-28

    Enhanced levels of the inflammatory chemokine CCL2 are known to correlate with increased tumorigenesis and metastases, and thereby poor prognosis for cancer patients. The CCL2-CCR2 chemokine axis was shown to facilitate the metastatic initiation through the recruitment of inflammatory monocytes and the activation of endothelial cells at metastatic sites. Both steps are required for efficient cancer cell trans-endothelial migration and seeding in the targeted tissue. The translation of preclinical evidence proved to be challenging due to systemic effects of chemokine inhibition and limited target specificity. Here we tested an approach of a targeted delivery of the CCR2 antagonist Teijin Compound 1 to metastatic sites. VCAM-1 binding peptide tagged liposomes carrying the CCR2 antagonist enabled a specific delivery to cancer cell-activated endothelium. The subsequent binding of target-sensitive liposomes triggered the release of the Teijin Compound 1 and thereby local inhibition of CCR2 in the lungs. Blocking of CCR2 resulted in reduced induction of the lungs vascular permeability, and thereby reduced tumor cell extravasation. However, the recruitment of inflammatory monocytes to the pre-metastatic lungs remained unaltered. Endothelial VCAM-1 targeted delivery of the CCR2 antagonist resulted in inhibition of pulmonary metastases both in a murine (MC-38GFP cells) and a human xenograft (patient-derived cells) model. Thus, timely- and spatially-defined inhibition of CCR2 signaling represents a potential therapeutic approach for treatment of metastasis without affecting homeostatic functions. PMID:26522070

  19. Ligand-dependent serum response factor activation by the human CC chemokine receptors CCR2a and CCR2b is mediated by G proteins of the Gq family.

    PubMed

    Vatter, Petra; Schuhholz, Julia; Koenig, Carolin; Pfreimer, Mariana; Moepps, Barbara

    2016-06-01

    Expression of the human CCR2 receptors, CCR2a and CCR2b, in mammalian cells results in ligand-dependent changes in the activity of multiple cellular signal transduction pathways, mediated in most cases by pertussis toxin-sensitive heterotrimeric G proteins of the Gi/o subfamily. In addition, CCR2a and CCR2b receptors have been shown to couple to Gq family members, triggering the canonical activation of phospholipase Cβ isoenzymes. Activation of pertussis toxin-insensitive Gq proteins by cell-surface receptors is not only coupled to activation of phospholipase isoenzymes but also to Rho guanine nucleotide exchange factors, which in turn mediate activation of the Rho GTPases. Activated Rho GTPases regulate numerous cellular functions, including the organization of the actin cytoskeleton and gene transcription, such as the transcription factor serum response factor. These findings prompted us to investigate whether CCR2a and/or CCR2b stimulate serum response factor activity. The results presented herein demonstrate that stimulation of human CCR2a- or CCR2b-expressing COS-7 cells caused a vigorous induction of serum response factor activity. This effect was specifically mediated by Gq and/or G14, as well as Rho A and/or a closely related Rho GTPase. Furthermore, the stimulatory effect of CCR2a and CCR2b and Gαq was sensitive to coexpression of the Gαq-interacting leukemia-associated Rho guanine nucleotide exchange factor. The findings of the work indicate a role for Gαq and/or Gα14 and in CCR2a/CCR2b-stimulated Rho A GTPase-mediated serum response factor activation and introduce a noncanonical pathway activated by CCR2 receptors by coupling to Gq proteins. PMID:26823487

  20. [National preparedness for biological mass casualty event: between the devil and the deep blue sea].

    PubMed

    Eldad, Arieh

    2002-05-01

    Species of plants and animals, as well as nations of human beings were extinguished throughout the prehistory and history of this planet. One of the possible explanations for this phenomenon is a large scale epidemic of viral, bacterial or fungal infections. One well-documented example was the smallpox epidemic among native Indians of South America following the European invasion. Deliberate dissemination of disease was used as a weapon during the Middle Ages when corpses of plague casualties were thrown over the walls and into the besieged towns. The Book of Kings II, of the Bible, in chapter 19 recalls the story of 185,000 soldiers of Sennacherib that died in one night, near the walls of Jerusalem. The possibility of causing mass casualty by dissemination of infectious disease has driven countries and terrorist organizations to produce and store large quantities of bacteria or viruses. The death of thousands in the USA on September 11, 2001, demonstrated that terror has no moral prohibitions, only technical limitations. Terror organizations will not hesitate to use weapons for mass destruction to kill many, and if only few will die, it will still serve the purpose of these evil organizations: to strew panic, to destroy normal life and to increase fear and instability. Any government that faces decisions about how to be better prepared against biological warfare is pushed between the devil and the deep blue sea. On the one hand: the better we will be prepared, equipped with antibiotics and vaccines--the more lives of casualties we will be able to save. Better public education will help to reduce the damage, but, on the other hand--in order to cause more people to make the effort to equip themselves or to refresh their protective kit--we will have to increase their level of concern. In order to improve the medical education of all members of the medical teams we will have to start a broad and intense campaign, thereby taking the risk of increasing stress in the

  1. Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection

    PubMed Central

    Glass, William G.; Lim, Jean K.; Cholera, Rushina; Pletnev, Alexander G.; Gao, Ji-Liang; Murphy, Philip M.

    2005-01-01

    The molecular immunopathogenesis of West Nile virus (WNV) infection is poorly understood. Here, we characterize a mouse model for WNV using a subcutaneous route of infection and delineate leukocyte subsets and immunoregulatory factors present in the brains of infected mice. Central nervous system (CNS) expression of the chemokine receptor CCR5 and its ligand CCL5 was prominently up-regulated by WNV, and this was associated with CNS infiltration of CD4+ and CD8+ T cells, NK1.1+ cells and macrophages expressing the receptor. The significance of CCR5 in pathogenesis was established by mortality studies in which infection of CCR5−/− mice was rapidly and uniformly fatal. In the brain, WNV-infected CCR5−/− mice had increased viral burden but markedly reduced NK1.1+ cells, macrophages, and CD4+ and CD8+ T cells compared with WNV-infected CCR5+/+ mice. Adoptive transfer of splenocytes from WNV-infected CCR5+/+ mice into infected CCR5−/− mice increased leukocyte accumulation in the CNS compared with transfer of splenocytes from infected CCR5−/− mice into infected CCR5−/− mice, and increased survival to 60%, the same as in infected CCR5+/+ control mice. We conclude that CCR5 is a critical antiviral and survival determinant in WNV infection of mice that acts by regulating trafficking of leukocytes to the infected brain. PMID:16230476

  2. Localized CCR2 Activation in the Bone Marrow Niche Mobilizes Monocytes by Desensitizing CXCR4

    PubMed Central

    Park, Jeong Eun; Miller, Richard J.

    2015-01-01

    Inflammatory (classical) monocytes residing in the bone marrow must enter the bloodstream in order to combat microbe infection. These monocytes express high levels of CCR2, a chemokine receptor whose activation is required for them to exit the bone marrow. How CCR2 is locally activated in the bone marrow and how their activation promotes monocyte egress is not understood. Here, we have used double transgenic lines that can visualize CCR2 activation in vivo and show that its chemokine ligand CCL2 is acutely released by stromal cells in the bone marrow, which make direct contact with CCR2-expressing monocytes. These monocytes also express CXCR4, whose activation immobilizes cells in the bone marrow, and are in contact with stromal cells expressing CXCL12, the CXCR4 ligand. During the inflammatory response, CCL2 is released and activates the CCR2 on neighboring monocytes. We demonstrate that acutely isolated bone marrow cells co-express CCR2 and CXCR4, and CCR2 activation desensitizes CXCR4. Inhibiting CXCR4 by a specific receptor antagonist in mice causes CCR2-expressing cells to exit the bone marrow in absence of inflammatory insults. Taken together, these results suggest a novel mechanism whereby the local activation of CCR2 on monocytes in the bone marrow attenuates an anchoring signalling provided by CXCR4 expressed by the same cell and mobilizes the bone marrow monocyte to the blood stream. Our results also provide a generalizable model that cross-desensitization of chemokine receptors fine-tunes cell mobility by integrating multiple chemokine signals. PMID:26029924

  3. IMOS National Reference Stations: A Continental-Wide Physical, Chemical and Biological Coastal Observing System

    PubMed Central

    Lynch, Tim P.; Morello, Elisabetta B.; Evans, Karen; Richardson, Anthony J.; Rochester, Wayne; Steinberg, Craig R.; Roughan, Moninya; Thompson, Peter; Middleton, John F.; Feng, Ming; Sherrington, Robert; Brando, Vittorio; Tilbrook, Bronte; Ridgway, Ken; Allen, Simon; Doherty, Peter; Hill, Katherine; Moltmann, Tim C.

    2014-01-01

    Sustained observations allow for the tracking of change in oceanography and ecosystems, however, these are rare, particularly for the Southern Hemisphere. To address this in part, the Australian Integrated Marine Observing System (IMOS) implemented a network of nine National Reference Stations (NRS). The network builds on one long-term location, where monthly water sampling has been sustained since the 1940s and two others that commenced in the 1950s. In-situ continuously moored sensors and an enhanced monthly water sampling regime now collect more than 50 data streams. Building on sampling for temperature, salinity and nutrients, the network now observes dissolved oxygen, carbon, turbidity, currents, chlorophyll a and both phytoplankton and zooplankton. Additional parameters for studies of ocean acidification and bio-optics are collected at a sub-set of sites and all data is made freely and publically available. Our preliminary results demonstrate increased utility to observe extreme events, such as marine heat waves and coastal flooding; rare events, such as plankton blooms; and have, for the first time, allowed for consistent continental scale sampling and analysis of coastal zooplankton and phytoplankton communities. Independent water sampling allows for cross validation of the deployed sensors for quality control of data that now continuously tracks daily, seasonal and annual variation. The NRS will provide multi-decadal time series, against which more spatially replicated short-term studies can be referenced, models and remote sensing products validated, and improvements made to our understanding of how large-scale, long-term change and variability in the global ocean are affecting Australia's coastal seas and ecosystems. The NRS network provides an example of how a continental scaled observing systems can be developed to collect observations that integrate across physics, chemistry and biology. PMID:25517905

  4. Biological Communities and Geomorphology of Patch Reefs in Biscayne National Park, Florida, U.S.A.

    USGS Publications Warehouse

    Kuffner, Ilsa B.; Brock, John C.; Grober-Dunsmore, Rikki; Hickey, T. Don; Bonito, Victor; Bracone, Jeremy E.; Wright, C. Wayne

    2008-01-01

    Coral reef ecosystem management benefits from continual, quantitative assessment of the resources being managed, plus assessment of factors that affect distribution patterns of organisms in the ecosystem. In this study, we investigated the relationships among physical, benthic, and fish variables in effort to help explain the distribution patterns of ecologically and economically important species on twelve patch reefs within Biscayne National Park (BNP), Florida, U.S.A. We visited 196 randomly-located sampling stations across twelve shallow (< 10m) patch reefs, using SCUBA to conduct our surveys. We measured physical variables (e.g., substratum type), estimated the percent cover of benthic community members (e.g., coral, algae), and counted and estimated mean size for each fish species observed. We also used high-density bathymetric data collected remotely via airborne laser surveying (Experimental Advanced Airborne Research Lidar (EAARL)) to calculate rugosity (bumpiness) of the reef habitat. Here we present our findings visually by graphing our quantitative community and physical structure data simultaneously in a GIS map format. You will see that biological organisms arrange themselves on each patch reef in a non-random manner. For example, many species of fish prefer to locate themselves in areas of the reef where the rugosity index is high. Rugose parts of the reef provide them with good hiding places from predators. These maps (and the data used to create them) are permanent records of the status of reef resources found on these twelve patch reefs in BNP as of September, 2003. The survey data found in the shapefile located on this CD product includes benthic percent cover data for algae, coral, encrusting invertebrates, and substratum type, in addition to gorgonian abundance and volume, total fish abundance and species richness, and specific counts for Acanthurids (surgeonfish), Scarids (parrotfish), Lutjanids (snappers), Haemulids (grunts), Serranids

  5. YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex

    PubMed Central

    Du, Hao; Zhao, Ya; He, Jinqiu; Zhang, Yao; Xi, Hairui; Liu, Mofang; Ma, Jinbiao; Wu, Ligang

    2016-01-01

    Methylation at the N6 position of adenosine (m6A) is the most abundant RNA modification within protein-coding and long noncoding RNAs in eukaryotes and is a reversible process with important biological functions. YT521-B homology domain family (YTHDF) proteins are the readers of m6A, the binding of which results in the alteration of the translation efficiency and stability of m6A-containing RNAs. However, the mechanism by which YTHDF proteins cause the degradation of m6A-containing RNAs is poorly understood. Here we report that m6A-containing RNAs exhibit accelerated deadenylation that is mediated by the CCR4–NOT deadenylase complex. We further show that YTHDF2 recruits the CCR4–NOT complex through a direct interaction between the YTHDF2 N-terminal region and the SH domain of the CNOT1 subunit, and that this recruitment is essential for the deadenylation of m6A-containing RNAs by CAF1 and CCR4. Therefore, we have uncovered the mechanism of YTHDF2-mediated degradation of m6A-containing RNAs in mammalian cells. PMID:27558897

  6. AZD-4818, a chemokine CCR1 antagonist: WO2008103126 and WO2009011653.

    PubMed

    Norman, Peter

    2009-11-01

    The applications WO2008103126 and WO2009011653, respectively, claim: i) Combinations of a spirocyclic piperidine chemokine CCR1 antagonist with a corticosteroid, and their use for the treatment of asthma and chronic obstructive pulmonary disease. ii) Processes for the preparation of a spirocyclic piperidine derivative, a chemokine CCR1 antagonist. These applications point to the preferred compound being a development compound. The evidence for this compound being AZD-4818, a chemokine CCR1 antagonist that was in Phase II development for the treatment of chronic obstructive pulmonary disease, is reviewed in the light of these and earlier patents relating to it. PMID:19586423

  7. The CCR4-NOT complex mediates deadenylation and degradation of stem cell mRNAs and promotes planarian stem cell differentiation.

    PubMed

    Solana, Jordi; Gamberi, Chiara; Mihaylova, Yuliana; Grosswendt, Stefanie; Chen, Chen; Lasko, Paul; Rajewsky, Nikolaus; Aboobaker, A Aziz

    2013-01-01

    Post-transcriptional regulatory mechanisms are of fundamental importance to form robust genetic networks, but their roles in stem cell pluripotency remain poorly understood. Here, we use freshwater planarians as a model system to investigate this and uncover a role for CCR4-NOT mediated deadenylation of mRNAs in stem cell differentiation. Planarian adult stem cells, the so-called neoblasts, drive the almost unlimited regenerative capabilities of planarians and allow their ongoing homeostatic tissue turnover. While many genes have been demonstrated to be required for these processes, currently almost no mechanistic insight is available into their regulation. We show that knockdown of planarian Not1, the CCR4-NOT deadenylating complex scaffolding subunit, abrogates regeneration and normal homeostasis. This abrogation is primarily due to severe impairment of their differentiation potential. We describe a stem cell specific increase in the mRNA levels of key neoblast genes after Smed-not1 knock down, consistent with a role of the CCR4-NOT complex in degradation of neoblast mRNAs upon the onset of differentiation. We also observe a stem cell specific increase in the frequency of longer poly(A) tails in these same mRNAs, showing that stem cells after Smed-not1 knock down fail to differentiate as they accumulate populations of transcripts with longer poly(A) tails. As other transcripts are unaffected our data hint at a targeted regulation of these key stem cell mRNAs by post-transcriptional regulators such as RNA-binding proteins or microRNAs. Together, our results show that the CCR4-NOT complex is crucial for stem cell differentiation and controls stem cell-specific degradation of mRNAs, thus providing clear mechanistic insight into this aspect of neoblast biology. PMID:24367277

  8. The CCR4-NOT Complex Mediates Deadenylation and Degradation of Stem Cell mRNAs and Promotes Planarian Stem Cell Differentiation

    PubMed Central

    Solana, Jordi; Gamberi, Chiara; Mihaylova, Yuliana; Grosswendt, Stefanie; Chen, Chen; Lasko, Paul; Rajewsky, Nikolaus; Aboobaker, A. Aziz

    2013-01-01

    Post-transcriptional regulatory mechanisms are of fundamental importance to form robust genetic networks, but their roles in stem cell pluripotency remain poorly understood. Here, we use freshwater planarians as a model system to investigate this and uncover a role for CCR4-NOT mediated deadenylation of mRNAs in stem cell differentiation. Planarian adult stem cells, the so-called neoblasts, drive the almost unlimited regenerative capabilities of planarians and allow their ongoing homeostatic tissue turnover. While many genes have been demonstrated to be required for these processes, currently almost no mechanistic insight is available into their regulation. We show that knockdown of planarian Not1, the CCR4-NOT deadenylating complex scaffolding subunit, abrogates regeneration and normal homeostasis. This abrogation is primarily due to severe impairment of their differentiation potential. We describe a stem cell specific increase in the mRNA levels of key neoblast genes after Smed-not1 knock down, consistent with a role of the CCR4-NOT complex in degradation of neoblast mRNAs upon the onset of differentiation. We also observe a stem cell specific increase in the frequency of longer poly(A) tails in these same mRNAs, showing that stem cells after Smed-not1 knock down fail to differentiate as they accumulate populations of transcripts with longer poly(A) tails. As other transcripts are unaffected our data hint at a targeted regulation of these key stem cell mRNAs by post-transcriptional regulators such as RNA-binding proteins or microRNAs. Together, our results show that the CCR4-NOT complex is crucial for stem cell differentiation and controls stem cell-specific degradation of mRNAs, thus providing clear mechanistic insight into this aspect of neoblast biology. PMID:24367277

  9. CCR5Δ32 Genotypes in a German HIV-1 Seroconverter Cohort and Report of HIV-1 Infection in a CCR5Δ32 Homozygous Individual

    PubMed Central

    Oh, Djin-Ye; Jessen, Heiko; Kücherer, Claudia; Neumann, Konrad; Oh, Nari; Poggensee, Gabriele; Bartmeyer, Barbara; Jessen, Arne; Pruss, Axel

    2008-01-01

    Background Homozygosity (Δ32/Δ32) for the 32 bp deletion in the chemokine receptor 5 (CCR5) gene is associated with strong resistance against HIV infection. Heterozygosity is associated with protection of HIV-1 disease progression. Methodology/Principal Findings We genotyped a population of 737 HIV-positive adults and 463 healthy controls for the CCR5Δ32 deletion and found heterozygous frequencies of 16.2% (HIV-negative) and 17.5% (HIV-positive) among Caucasian individuals. Analysis of CCR5Δ32 influence on disease progression showed notably lower viral setpoints and a longer time to a CD4 count of <200 µl−1 in seroconverters heterozygous for the deletion. Furthermore, we identified one HIV-positive man homozygous for the Δ32 deletion. Conclusions/Significance The protective effect of CCR5 Δ32 heterozygosity is confimed in a large cohort of German seroconverters. The HIV-infected CCR5 Δ32 homozygous individual, however, displays extremely rapid disease progression. This is the 12th case of HIV-infection in this genotype described worldwide. PMID:18648518

  10. CCR6(-) regulatory T cells blunt the restoration of gut Th17 cells along the CCR6-CCL20 axis in treated HIV-1-infected individuals.

    PubMed

    Loiseau, C; Requena, M; Mavigner, M; Cazabat, M; Carrere, N; Suc, B; Barange, K; Alric, L; Marchou, B; Massip, P; Izopet, J; Delobel, P

    2016-09-01

    The gut CD4(+) T cells, particularly the T helper type 17 (Th17) subset, are not completely restored in most HIV-1-infected individuals despite combined antiretroviral therapy, when initiated at the chronic phase of infection. We show here that the CCR6-CCL20 chemotactic axis is altered, with reduced CCL20 production by small intestine epithelial cells in treated HIV-1-infected individuals. This leads to impaired CCR6(+)CD4(+) T-cell homing, particularly Th17 cells, to the small intestine mucosa. In contrast, the frequency of gut FoxP3(+) T regulatory (Treg) cells, specifically the CCR6(-) subset, was increased. The resulting imbalance in the Th17/CCR6(-) Treg ratio and the associated shift from interleukin (IL)-17 to IL-10 and transforming growth factor-β (TGF-β) blunts CCL20 production by enterocytes, perpetuating a negative feedback for the recruitment of CCR6(+)CD4(+) T cells to the small intestine in treated HIV-1-infected individuals. PMID:26883727

  11. Gene Cloning and Characterization of the Geobacillus thermoleovorans CCR11 Carboxylesterase CaesCCR11, a New Member of Family XV.

    PubMed

    Espinosa-Luna, Graciela; Sánchez-Otero, María Guadalupe; Quintana-Castro, Rodolfo; Matus-Toledo, Rodrigo Eloir; Oliart-Ros, Rosa María

    2016-01-01

    A gene encoding a carboxylesterase produced by Geobacillus thermoleovoras CCR11 was cloned in the pET-3b cloning vector, sequenced and expressed in Escherichia coli BL21(DE3). Gene sequence analysis revealed an open reading frame of 750 bp that encodes a polypeptide of 250 amino acid residues (27.3 kDa) named CaesCCR11. The enzyme showed its maximum activity at 50 °C and pH 5-8, with preference for C4 substrates, confirming its esterase nature. It displayed good resistance to temperature, pH, and the presence of organic solvents and detergents, that makes this enzyme biotechnologically applicable in the industries such as fine and oleo-chemicals, cosmetics, pharmaceuticals, organic synthesis, biodiesel production, detergents, and food industries. A 3D model of CaesCCR11 was predicted using the Bacillus sp. monoacyl glycerol lipase bMGL H-257 structure as template (PBD code 3RM3, 99 % residue identity with CaesCCR11). Based on its canonical α/β hydrolase fold composed of 7 β-strands and 6 α-helices, the α/β architecture of the cap domain, the GLSTG pentapeptide, and the formation of distinctive salt bridges, we are proposing CaesCCR11 as a new member of family XV of lipolytic enzymes. PMID:26603441

  12. Oak Ridge National Laboratory Biological Monitoring and Abatement Program for White Oak Creek Watershed and the Clinch River

    SciTech Connect

    Loar, J.M.; Adams, S.M.; Allison, L.J.; Blaylock, B.G.; Boston, H.L.; Huston, M.A.; Kimmel, B.L.; Smith, J.G.; Southworth, G.R.; Stewart, A.J.; Walton, B.T.; Kitchings, J.T.; Olsen, C.R.

    1991-09-01

    On April 1, 1986, a National Pollutant Discharge Elimination System (NPDES) permit was issued for the Oak Ridge National Laboratory (ORNL) (EPA 1986). As specified in Part 3: Special Conditions (Item H) of the permit, a plan for biological monitoring of the Clinch River, White Oak Creek (WOC), Northwest Tributary (NWT) of WOC, Melton Branch (MB), Fifth Creek, and First Creek shall be submitted for approval to the US Environmental Protection Agency (EPA) and the Tennessee Department of Health and Environment (TDHE) within 90 days of the effective date of the permit. The plan, which is referred to in Part 3 (H) of the permit as the Biological Monitoring Plan and Abatement Program (BMPAP), describes characterization monitoring studies to be conducted for the duration of the permit (5 years). In order to be consistent with the terminology used for the Biological Monitoring and Abatement Programs for the Oak Ridge Y-12 Plan and the Oak Ridge K-25 Plant, BMPAP will subsequently be referred to as the Biological Monitoring and Abatement Program (BMAP). The proposed BMAP outlined in this document is based on preliminary discussions held on December 9, 1985, between staff of Martin Marietta Energy Systems, Inc. (ORNL and Central Management), the US Department of Energy (DOE), EPA, and TDHE. 232 refs., 11 figs., 7 tabs.

  13. Development of maraviroc, a CCR5 antagonist for treatment of HIV, using a novel tropism assay.

    PubMed

    van der Ryst, Elna; Heera, Jayvant; Demarest, James; Knirsch, Charles

    2015-06-01

    Assays to identify infectious organisms are critical for diagnosis and enabling the development of therapeutic agents. The demonstration that individuals with a 32-bp deletion within the CCR5 locus were resistant to human immunodeficiency virus (HIV) infection, while those heterozygous for the mutation progressed more slowly, led to the discovery of maraviroc (MVC), a CCR5 antagonist. As MVC is only active against CCR5-tropic strains of HIV, it was critical to develop a diagnostic assay to identify appropriate patients. Trofile™, a novel phenotypic tropism assay, was used to identify patients with CCR5-tropic virus for the MVC development program. Results of these clinical studies demonstrated that the assay correctly identified patients likely to respond to MVC. Over time, the performance characteristics of the phenotypic assay were enhanced, necessitating retesting of study samples. Genotypic tropism tests that have the potential to allow for local use and more rapid turnaround times are also being developed. PMID:25962411

  14. Structure of the CCR5 Chemokine Receptor-HIV Entry Inhibitor Maraviroc Complex

    SciTech Connect

    Tan, Qiuxiang; Zhu, Ya; Li, Jian; Chen, Zhuxi; Han, Gye Won; Kufareva, Irina; Li, Tingting; Ma, Limin; Fenalti, Gustavo; Li, Jing; Zhang, Wenru; Xie, Xin; Yang, Huaiyu; Jiang, Hualiang; Cherezov, Vadim; Liu, Hong; Stevens, Raymond C.; Zhao, Qiang; Wu, Beili

    2013-10-21

    The CCR5 chemokine receptor acts as a co-receptor for HIV-1 viral entry. Here we report the 2.7 angstrom–resolution crystal structure of human CCR5 bound to the marketed HIV drug maraviroc. The structure reveals a ligand-binding site that is distinct from the proposed major recognition sites for chemokines and the viral glycoprotein gp120, providing insights into the mechanism of allosteric inhibition of chemokine signaling and viral entry. A comparison between CCR5 and CXCR4 crystal structures, along with models of co-receptor–gp120-V3 complexes, suggests that different charge distributions and steric hindrances caused by residue substitutions may be major determinants of HIV-1 co-receptor selectivity. These high-resolution insights into CCR5 can enable structure-based drug discovery for the treatment of HIV-1 infection.

  15. CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue.

    PubMed

    Cook, D N; Prosser, D M; Forster, R; Zhang, J; Kuklin, N A; Abbondanzo, S J; Niu, X D; Chen, S C; Manfra, D J; Wiekowski, M T; Sullivan, L M; Smith, S R; Greenberg, H B; Narula, S K; Lipp, M; Lira, S A

    2000-05-01

    Chemokine-directed migration of leukocyte subsets may contribute to the qualitative differences between systemic and mucosal immunity. Here, we demonstrate that in mice lacking the chemokine receptor CCR6, dendritic cells expressing CD11c and CD11b are absent from the subepithelial dome of Peyer's patches. These mice also have an impaired humoral immune response to orally administered antigen and to the enteropathic virus rotavirus. In addition, CCR6(-/-) mice have a 2-fold to 15-fold increase in cells of select T lymphocyte populations within the mucosa, including CD4+ and CD8+ alphabeta-TCR T cells. By contrast, systemic immune responses to subcutaneous antigens in CCR6(-/-) mice are normal. These findings demonstrate that CCR6 is a mucosa-specific regulator of humoral immunity and lymphocyte homeostasis in the intestinal mucosa. PMID:10843382

  16. Frequency of CCR5Δ32 allele in healthy Bosniak population

    PubMed Central

    Adler, Grażyna; Valjevac, Amina; Skonieczna-Żydecka, Karolina; Mackic-Djurovic, Mirela; Parczewski, Miłosz; Urbańska, Anna; Salkic, Nermin N

    2014-01-01

    Recent evidence has demonstrated the role of CCR5Δ32 in a variety of human diseases: from infectious and inflammatory diseases to cancer. Several studies have confirmed that genetic variants in chemokine receptor CCR5 gene are correlated with susceptibility and resistance to HIV infection. A 32-nucleotide deletion within the CCR5 reading frame is associated with decreased susceptibility to HIV acquisition and a slower progression to AIDS. Mean frequency of CCR5Δ32 allele in Europe is approximately 10%. The highest allele frequency is observed among Nordic populations (about 12%) and the lowest in the regions of Southeast Mediterranean (about 5%). Although the frequency of CCR5Δ32 was determined in numerous European populations, there is a lack of studies on this variant in the Bosnia and Herzegovina population. Therefore, the aim of our study was to assess the frequency of CCR5Δ32 allele in the cohort of Bosniaks and compare the results with European reports. CCR5Δ32 was detected by sequence-specific PCR in a sample of 100 healthy Bosniaks (DNA collected 2011-2013). Mean age of the cohort being 58.8 (±10.7) years, with 82% of women. We identified 17 heterozygotes and one mutant homozygote in study group, with mean ∆32 allele frequency of 9.5%. CCR5∆32 allele frequency among Bosniaks is comparable to that found in Caucasian populations and follows the pattern of the north-southern gradient observed for Europe. Further studies on larger cohorts with adequate female-to-male ratio are necessary. PMID:25172974

  17. Delayed angiogenesis and VEGF production in CCR2-/- mice during impaired skeletal muscle regeneration.

    PubMed

    Ochoa, Oscar; Sun, Dongxu; Reyes-Reyna, Sara M; Waite, Lindsay L; Michalek, Joel E; McManus, Linda M; Shireman, Paula K

    2007-08-01

    The regulation of vascular endothelial growth factor (VEGF) levels and angiogenic events during skeletal muscle regeneration remains largely unknown. This study examined angiogenesis, VEGF levels, and muscle regeneration after cardiotoxin (CT)-induced injury in mice lacking the CC chemokine receptor 2 (CCR2). Muscle regeneration was significantly decreased in CCR2-/- mice as was the early accumulation of macrophages after injury. In both mouse strains, tissue VEGF was similar at baseline (no injections) and significantly decreased at day 3 post-CT. Tissue VEGF in wild-type (WT) mice was restored within 7 days postinjury but remained significantly reduced in CCR2-/- mice until day 21. Capillary density (capillaries/mm(2)) within regenerating muscle was maximal in WT mice at day 7 and double that of baseline muscle. In comparison, maximal capillary density in CCR2-/- mice occurred at 21 days postinjury. Maximal capillary density developed concurrent with the restoration of tissue VEGF in both strains. A highly significant, inverse relationship existed between the size of regenerated muscle fibers and capillaries per square millimeter. Although this relationship was comparable in WT and CCR2-/- animals, there was a significant decrease in the magnitude of this response in the absence of CCR2, reflecting the observation that regenerated muscle fiber size in CCR2-/- mice was only 50% of baseline at 42 days postinjury, whereas WT mice had attained baseline fiber size by day 21. Thus CCR2-dependent events in injured skeletal muscle, including impaired macrophage recruitment, contribute to restoration of tissue VEGF levels and the dynamic processes of capillary formation and muscle regeneration. PMID:17522124

  18. Subunits of the Drosophila CCR4-NOT complex and their roles in mRNA deadenylation

    PubMed Central

    Temme, Claudia; Zhang, Lianbing; Kremmer, Elisabeth; Ihling, Christian; Chartier, Aymeric; Sinz, Andrea; Simonelig, Martine; Wahle, Elmar

    2010-01-01

    The CCR4-NOT complex is the main enzyme catalyzing the deadenylation of mRNA. We have investigated the composition of this complex in Drosophila melanogaster by immunoprecipitation with a monoclonal antibody directed against NOT1. The CCR4, CAF1 (=POP2), NOT1, NOT2, NOT3, and CAF40 subunits were associated in a stable complex, but NOT4 was not. Factors known to be involved in mRNA regulation were prominent among the other proteins coprecipitated with the CCR4-NOT complex, as analyzed by mass spectrometry. The complex was localized mostly in the cytoplasm but did not appear to be a major component of P bodies. Of the known CCR4 paralogs, Nocturnin was found associated with the subunits of the CCR4-NOT complex, whereas Angel and 3635 were not. RNAi experiments in Schneider cells showed that CAF1, NOT1, NOT2, and NOT3 are required for bulk poly(A) shortening and hsp70 mRNA deadenylation, but knock-down of CCR4, CAF40, and NOT4 did not affect these processes. Overexpression of catalytically dead CAF1 had a dominant-negative effect on mRNA decay. In contrast, overexpression of inactive CCR4 had no effect. We conclude that CAF1 is the major catalytically important subunit of the CCR4-NOT complex in Drosophila Schneider cells. Nocturnin may also be involved in mRNA deadenylation, whereas there is no evidence for a similar role of Angel and 3635. PMID:20504953

  19. Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation.

    PubMed

    Bessler, Waylan K; Kim, Grace; Hudson, Farlyn Z; Mund, Julie A; Mali, Raghuveer; Menon, Keshav; Kapur, Reuben; Clapp, D Wade; Ingram, David A; Stansfield, Brian K

    2016-03-15

    Persons with neurofibromatosis type 1 (NF1) have a predisposition for premature and severe arterial stenosis. Mutations in the NF1 gene result in decreased expression of neurofibromin, a negative regulator of p21(Ras), and increases Ras signaling. Heterozygous Nf1 (Nf1(+/-)) mice develop a marked arterial stenosis characterized by proliferating smooth muscle cells (SMCs) and a predominance of infiltrating macrophages, which closely resembles arterial lesions from NF1 patients. Interestingly, lineage-restricted inactivation of a single Nf1 allele in monocytes/macrophages is sufficient to recapitulate the phenotype observed in Nf1(+/-) mice and to mobilize proinflammatory CCR2+ monocytes into the peripheral blood. Therefore, we hypothesized that CCR2 receptor activation by its primary ligand monocyte chemotactic protein-1 (MCP-1) is critical for monocyte infiltration into the arterial wall and neointima formation in Nf1(+/-) mice. MCP-1 induces a dose-responsive increase in Nf1(+/-) macrophage migration and proliferation that corresponds with activation of multiple Ras kinases. In addition, Nf1(+/-) SMCs, which express CCR2, demonstrate an enhanced proliferative response to MCP-1 when compared with WT SMCs. To interrogate the role of CCR2 activation on Nf1(+/-) neointima formation, we induced neointima formation by carotid artery ligation in Nf1(+/-) and WT mice with genetic deletion of either MCP1 or CCR2. Loss of MCP-1 or CCR2 expression effectively inhibited Nf1(+/-) neointima formation and reduced macrophage content in the arterial wall. Finally, administration of a CCR2 antagonist significantly reduced Nf1(+/-) neointima formation. These studies identify MCP-1 as a potent chemokine for Nf1(+/-) monocytes/macrophages and CCR2 as a viable therapeutic target for NF1 arterial stenosis. PMID:26740548

  20. Genetic evidence supports a role for the yeast CCR4-NOT complex in transcriptional elongation.

    PubMed Central

    Denis, C L; Chiang, Y C; Cui, Y; Chen, J

    2001-01-01

    The CCR4-NOT complex is involved in the regulation of gene expression both positively and negatively. The repressive effects of the complex appear to result in part from restricting TBP access to noncanonical TATAA binding sites presumably through interaction with multiple TAF proteins. We provide here genetic evidence that the CCR4-NOT complex also plays a role in transcriptional elongation. First, defects in CCR4-NOT components as well as overexpression of the NOT4 gene elicited 6-azauracil (6AU) and mycophenolic acid sensitivities, hallmarks of transcriptional elongation defects. A number of other transcription initiation factors known to interact with the CCR4-NOT complex did not elicit these phenotypes nor did defects in factors that reduced mRNA degradation and hence the recycling of NTPs. Second, deletion of ccr4 resulted in severe synthetic effects with mutations or deletions in the known elongation factors RPB2, TFIIS, and SPT16. Third, the ccr4 deletion displayed allele-specific interactions with rpb1 alleles that are thought to be important in the control of elongation. Finally, we found that a ccr4 deletion as well as overexpression of the NOT1 gene specifically suppressed the cold-sensitive phenotype associated with the spt5-242 allele. The only other known suppressors of this spt5-242 allele are factors involved in slowing transcriptional elongation. These genetic results are consistent with the model that the CCR4-NOT complex, in addition to its known effects on initiation, plays a role in aiding the elongation process. PMID:11404327

  1. CCR5 Targeted Cell Therapy for HIV and Prevention of Viral Escape

    PubMed Central

    Hütter, Gero; Bodor, Josef; Ledger, Scott; Boyd, Maureen; Millington, Michelle; Tsie, Marlene; Symonds, Geoff

    2015-01-01

    Allogeneic transplantation with CCR5-delta 32 (CCR5-d32) homozygous stem cells in an HIV infected individual in 2008, led to a sustained virus control and probably eradication of HIV. Since then there has been a high degree of interest to translate this approach to a wider population. There are two cellular ways to do this. The first one is to use a CCR5 negative cell source e.g., hematopoietic stem cells (HSC) to copy the initial finding. However, a recent case of a second allogeneic transplantation with CCR5-d32 homozygous stem cells suffered from viral escape of CXCR4 quasi-species. The second way is to knock down CCR5 expression by gene therapy. Currently, there are five promising techniques, three of which are presently being tested clinically. These techniques include zinc finger nucleases (ZFN), clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9 nuclease (CRISPR/Cas9), transcription activator-like effectors nuclease (TALEN), short hairpin RNA (shRNA), and a ribozyme. While there are multiple gene therapy strategies being tested, in this review we reflect on our current knowledge of inhibition of CCR5 specifically and whether this approach allows for consequent viral escape. PMID:26225991

  2. Roles of RUNX1 and PU.1 in CCR3 Transcription

    PubMed Central

    Kong, Su-Kang; Kim, Byung Soo; Hwang, Sae Mi; Lee, Hyune Hwan

    2016-01-01

    CCR3 is a chemokine receptor that mediates the accumulation of allergic inflammatory cells, including eosinophils and Th2 cells, at inflamed sites. The regulatory sequence of the CCR3 gene, contains two Runt-related transcription factor (RUNX) 1 sites and two PU.1 sites, in addition to a functional GATA site for transactivation of the CCR3 gene. In the present study, we examined the effects of the cis-acting elements of RUNX1 and PU.1 on transcription of the gene in EoL-1 eosinophilic cells and Jurkat T cells, both of which expressed functional surface CCR3 and these two transcription factors. Introduction of RUNX1 siRNA or PU.1 siRNA resulted in a modest decrease in CCR3 reporter activity in both cell types, compared with transfection of GATA-1 siRNA. Cotransfection of the two siRNAs led to inhibition in an additive manner. EMSA analysis showed that RUNX1, in particular, bound to its binding motifs. Mutagenesis analysis revealed that all point mutants lacking RUNX1- and PU.1-binding sites exhibited reduced reporter activities. These results suggest that RUNX1 and PU.1 participate in transcriptional regulation of the CCR3 gene. PMID:27340386

  3. Functional characterization of CCR in birch (Betula platyphylla × Betula pendula) through overexpression and suppression analysis.

    PubMed

    Zhang, Wenbo; Wei, Rui; Chen, Su; Jiang, Jing; Li, Huiyu; Huang, Haijiao; Yang, Guang; Wang, Shuo; Wei, Hairong; Liu, Guifeng

    2015-06-01

    We cloned a Cinnamoyl-CoA Reductase gene (BpCCR1) from an apical meristem and first internode of Betula platyphylla and characterized its functions in lignin biosynthesis, wood formation and tree growth through transgenic approaches. We generated overexpression and suppression transgenic lines and analyzed them in comparison with the wild-type in terms of lignin content, anatomical characteristics, height and biomass. We found that BpCCR1 overexpression could increase lignin content up to 14.6%, and its underexpression decreased lignin content by 6.3%. Surprisingly, modification of BpCCR1 expression led to conspicuous changes in wood characteristics, including xylem vessel number and arrangement, and secondary wall thickness. The growth of transgenic trees in terms of height was also significantly influenced by the modification of BpCCR1 genes. We discuss the functions of BpCCR1 in the context of a phylogenetic tree built with CCR genes from multiple species. PMID:25393559

  4. CCR2-V64I genetic polymorphism: a possible involvement in HER2+ breast cancer.

    PubMed

    Banin-Hirata, Bruna Karina; Losi-Guembarovski, Roberta; Oda, Julie Massayo Maeda; de Oliveira, Carlos Eduardo Coral; Campos, Clodoaldo Zago; Mazzuco, Tânia Longo; Borelli, Sueli Donizete; Ceribelli, Jesus Roberto; Watanabe, Maria Angelica Ehara

    2016-05-01

    Many tumor cells express chemokines and chemokine receptors, and these molecules can affect both tumor progression and anti-tumor immune response. Genetic polymorphisms of some chemokine receptors were found to be closely related to malignant tumors, especially in metastasis process, including breast cancer (BC). Considering this, it was investigated a possible role for CCR2-V64I (C-C chemokine receptor 2) and CCR5-Δ32 (C-C chemokine receptor 5) genetic variants in BC context. Patients were divided into subgroups according to immunohistochemical profile of estrogen (ER) and progesterone (PR) receptors and the human epidermal growth factor receptor 2 (HER2) overexpression. No significant associations were found in relation to susceptibility (CCR2-V64I: OR 1.32; 95 % CI 0.57-3.06; CCR5-∆32: OR 1.04; 95 % CI 0.60-1.81), clinical outcome (tumor size, lymph nodes commitment and/or distant metastasis, TNM staging and nuclear grade) or therapeutic response (recurrence and survival). However, it was found a significant correlation between CCR2-V64I allelic variant and HER2 immunohistochemical positive samples (p = 0.026). All in all, we demonstrate, for the first time, a positive correlation between CCR2 receptor gene polymorphism and a subgroup of BC related to poor prognosis, which deserves further investigation in larger samples for validation. PMID:25716470

  5. ACCOUNTING FOR BIOLOGICAL AND ANTHROPOGENIC FACTORS IN NATIONAL LAND-BASED CARBON BUDGETS

    EPA Science Inventory

    Efforts to quantify net greenhouse gas emissions at the national scale, as required by the United Nations Framework Convention on Climate Change, must include both industrial emissions and the net flux associated with the land base. In this study, data on current land use, rates ...

  6. Biological monitoring and abatement program plan for Oak Ridge National Laboratory

    SciTech Connect

    Kszos, L.A.; Anderson, G.E.; Gregory, S.M.; Peterson, M.J.; Ryon, M.G.; Schilling, E.M.; Smith, J.G.; Southworth, G.R.; Phipps, T.L.

    1997-06-01

    The overall purpose of this plan is to evaluate the receiving streams` biological communities for the duration of the permit and meet the objectives for the ORNL BMAP as outlined in the NPDES permit (Appendix). The ORNL BMAP will focus on those streams in the WOC watershed that (1) receive NPDES discharges and (2) have been identified as ecologically impacted. In response to the newly issued NPDES permit, the tasks that are included in this BMAP plan include monitoring biological communities (fish and benthic invertebrates), monitoring mercury contamination in fish and water, monitoring polychlorinated biphenyl (PCB) contamination in fish, and evaluating temperature loading from ORNL outfalls. The ORNL BMAP will evaluate the effects of sediment and oil and grease, as well as the chlorine control strategy through the use of biological community data. Monitoring will be conducted at sites in WOC, First Creek, Fifth Creek, Melton Branch, and WOL.

  7. Selective Chemokine Receptor Usage by Central Nervous System Myeloid Cells in CCR2-Red Fluorescent Protein Knock-In Mice

    PubMed Central

    Croft, Kelsey; Mizutani, Makiko; Cotleur, Anne C.; Tsou, Chia-Lin; Ransohoff, Richard M.; Charo, Israel F.

    2010-01-01

    Background Monocyte subpopulations distinguished by differential expression of chemokine receptors CCR2 and CX3CR1 are difficult to track in vivo, partly due to lack of CCR2 reagents. Methodology/Principal Findings We created CCR2-red fluorescent protein (RFP) knock-in mice and crossed them with CX3CR1-GFP mice to investigate monocyte subset trafficking. In mice with experimental autoimmune encephalomyelitis, CCR2 was critical for efficient intrathecal accumulation and localization of Ly6Chi/CCR2hi monocytes. Surprisingly, neutrophils, not Ly6Clo monocytes, largely replaced Ly6Chi cells in the central nervous system of these mice. CCR2-RFP expression allowed the first unequivocal distinction between infiltrating monocytes/macrophages from resident microglia. Conclusion/Significance These results refine the concept of monocyte subsets, provide mechanistic insight about monocyte entry into the central nervous system, and present a novel model for imaging and quantifying inflammatory myeloid populations. PMID:21060874

  8. Genetically divergent strains of simian immunodeficiency virus use CCR5 as a coreceptor for entry.

    PubMed Central

    Chen, Z; Zhou, P; Ho, D D; Landau, N R; Marx, P A

    1997-01-01

    Entry of human immunodeficiency virus type 1 (HIV-1) requires CD4 and one of a family of related seven-transmembrane-domain coreceptors. Macrophage-tropic HIV-1 isolates are generally specific for CCR5, a receptor for the CC chemokines RANTES, MIP-1alpha, and MIP-1beta, while T-cell line-tropic viruses tend to use CXCR4 (also known as fusin, LESTR, or HUMSTR). Like HIV-1, simian immunodeficiency virus (SIV) requires CD4 on the target cell surface; however, whether it also requires a coreceptor is not known. We report here that several genetically divergent SIV isolates, including SIVmac, SIVsmSL92a, SIVsmLib-1, and SIVcpzGAB, can use human and rhesus CCR5 for entry. CXCR4 did not facilitate entry of any of the simian viruses tested, nor did any of the other known chemokine receptors. Moreover, SIVmac251 that had been extensively passaged in a human transformed T-cell line retained its use of CCR5. Rhesus and human CCR5 differed at only eight amino acid residues, four of which were in regions of the receptor that could be exposed, two in the amino-terminal extracellular region and two in the second extracellular loop. The human coreceptor was as active as the simian for SIV entry. In addition, HIV-1 was able to use the rhesus homologs of the human coreceptors, CCR5 and CXCR4. The SIV strains tested were specific for CCR5 regardless of whether they were able to replicate in transformed T-cell lines or macrophages and whether they were phenotypically syncytium inducing or noninducing in MT-2 cells. However, SIV replication was not restricted to cells expressing CCR5. SIV strains replicated efficiently in the human transformed lymphoid cell line CEMx174, which does not express detectable amounts of transcripts of CCR5. SIV also replicated in human peripheral blood mononuclear cells that were genetically deficient in CCR5. These findings indicated that, in addition to CCR5, SIV can use one or more unknown coreceptors that are expressed on human PBMCs and CEMx174 cells

  9. National Aeronautics and Space Administration Biological and Physical Research Enterprise Strategy

    NASA Technical Reports Server (NTRS)

    2003-01-01

    As the 21st century begins, NASA's new Vision and Mission focuses the Agency's Enterprises toward exploration and discovery.The Biological and Physical Research Enterprise has a unique and enabling role in support of the Agency's Vision and Mission. Our strategic research seeks innovations and solutions to enable the extension of life into deep space safely and productively. Our fundamental research, as well as our research partnerships with industry and other agencies, allow new knowledge and tech- nologies to bring improvements to life on Earth. Our interdisciplinary research in the unique laboratory of microgravity addresses opportunities and challenges on our home planet as well as in space environments. The Enterprise maintains a key role in encouraging and engaging the next generation of explorers from primary school through the grad- uate level via our direct student participation in space research.The Biological and Physical Research Enterprise encompasses three themes. The biological sciences research theme investigates ways to support a safe human presence in space. This theme addresses the definition and control of physiological and psychological risks from the space environment, including radiation,reduced gravity, and isolation. The biological sciences research theme is also responsible for the develop- ment of human support systems technology as well as fundamental biological research spanning topics from genomics to ecologies. The physical sciences research theme supports research that takes advantage of the space environment to expand our understanding of the fundamental laws of nature. This theme also supports applied physical sciences research to improve safety and performance of humans in space. The research partnerships and flight support theme establishes policies and allocates space resources to encourage and develop entrepreneurial partners access to space research.Working together across research disciplines, the Biological and Physical

  10. Transmitted/Founder and Chronic HIV-1 Envelope Proteins Are Distinguished by Differential Utilization of CCR5

    PubMed Central

    Parker, Zahra F.; Iyer, Shilpa S.; Wilen, Craig B.; Parrish, Nicholas F.; Chikere, Kelechi C.; Lee, Fang-Hua; Didigu, Chuka A.; Berro, Reem; Klasse, Per Johan; Lee, Benhur; Moore, John P.; Shaw, George M.

    2013-01-01

    Infection by HIV-1 most often results from the successful transmission and propagation of a single virus variant, termed the transmitted/founder (T/F) virus. Here, we compared the attachment and entry properties of envelope (Env) glycoproteins from T/F and chronic control (CC) viruses. Using a panel of 40 T/F and 47 CC Envs, all derived by single genome amplification, we found that 52% of clade C and B CC Envs exhibited partial resistance to the CCR5 antagonist maraviroc (MVC) on cells expressing high levels of CCR5, while only 15% of T/F Envs exhibited this same property. Moreover, subtle differences in the magnitude with which MVC inhibited infection on cells expressing low levels of CCR5, including primary CD4+ T cells, were highly predictive of MVC resistance when CCR5 expression levels were high. These results are consistent with previous observations showing a greater sensitivity of T/F Envs to MVC inhibition on cells expressing very high levels of CCR5 and indicate that CC Envs are often capable of recognizing MVC-bound CCR5, albeit inefficiently on cells expressing physiologic levels of CCR5. When CCR5 expression levels are high, this phenotype becomes readily detectable. The utilization of drug-bound CCR5 conformations by many CC Envs was seen with other CCR5 antagonists, with replication-competent viruses, and did not obviously correlate with other phenotypic traits. The striking ability of clade C and B CC Envs to use MVC-bound CCR5 relative to T/F Envs argues that the more promiscuous use of CCR5 by these Env proteins is selected against at the level of virus transmission and is selected for during chronic infection. PMID:23269796

  11. Stromal CCR6 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages.

    PubMed

    Nandi, Bisweswar; Shapiro, Mia; Samur, Mehmet K; Pai, Christine; Frank, Natasha Y; Yoon, Charles; Prabhala, Rao H; Munshi, Nikhil C; Gold, Jason S

    2016-08-01

    Interactions between the inflammatory chemokine CCL20 and its receptor CCR6 have been implicated in promoting colon cancer; however, the mechanisms behind this effect are poorly understood. We have previously demonstrated that deficiency of CCR6 is associated with decreased tumor macrophage accumulation in a model of sporadic intestinal tumorigenesis. In this study, we aimed to determine the role of stromal CCR6 expression in a murine syngeneic transplantable colon cancer model. We show that deficiency of host CCR6 is associated with decreased growth of syngeneic CCR6-expressing colon cancers. Colon cancers adoptively transplanted into CCR6-deficient mice have decreased tumor-associated macrophages without alterations in the number of monocytes in blood or bone marrow. CCL20, the unique ligand for CCR6, promotes migration of monocytes in vitro and promotes accumulation of macrophages in vivo. Depletion of tumor-associated macrophages decreases the growth of tumors in the transplantable tumor model. Macrophages infiltrating the colon cancers in this model secrete the inflammatory mediators CCL2, IL-1α, IL-6 and TNFα. Ccl2, Il1α and Il6 are consequently downregulated in tumors from CCR6-deficient mice. CCL2, IL-1α and IL-6 also promote proliferation of colon cancer cells, linking the decreased macrophage migration into tumors mediated by CCL20-CCR6 interactions to the delay in tumor growth in CCR6-deficient hosts. The relevance of these findings in human colon cancer is demonstrated through correlation of CCR6 expression with that of the macrophage marker CD163 as well as that of CCL2, IL1α and TNFα. Our findings support the exploration of targeting the CCL20-CCR6 pathway for the treatment of colon cancer. PMID:27622061

  12. Cloning and Analysis of Sooty Mangabey Alternative Coreceptors That Support Simian Immunodeficiency Virus SIVsmm Entry Independently of CCR5

    PubMed Central

    Elliott, Sarah T. C.; Riddick, Nadeene E.; Francella, Nicholas; Paiardini, Mirko; Vanderford, Thomas H.; Li, Bing; Apetrei, Cristian; Sodora, Donald L.; Derdeyn, Cynthia A.; Silvestri, Guido

    2012-01-01

    Natural host sooty mangabeys (SM) infected with simian immunodeficiency virus SIVsmm do not develop AIDS despite high viremia. SM and other natural hosts express very low levels of CCR5 on CD4+ T cells, and we recently showed that SIVsmm infection and robust replication occur in vivo in SM genetically lacking CCR5, indicating the use of additional entry pathways. SIVsmm uses several alternative coreceptors of human origin in vitro, but which molecules of SM origin support entry is unknown. We cloned a panel of putative coreceptors from SM and tested their ability to mediate infection, in conjunction with smCD4, by pseudotypes carrying Envs from multiple SIVsmm subtypes. smCXCR6 supported efficient infection by all SIVsmm isolates with entry levels comparable to those for smCCR5, and smGPR15 enabled entry by all isolates at modest levels. smGPR1 and smAPJ supported low and variable entry, whereas smCCR2b, smCCR3, smCCR4, smCCR8, and smCXCR4 were not used by most isolates. In contrast, SIVsmm from rare infected SM with profound CD4+ T cell loss, previously reported to have expanded use of human coreceptors, including CXCR4, used smCXCR4, smCXCR6, and smCCR5 efficiently and also exhibited robust entry through smCCR3, smCCR8, smGPR1, smGPR15, and smAPJ. Entry was similar with both known alleles of smCD4. These alternative coreceptors, particularly smCXCR6 and smGPR15, may support virus replication in SM that have restricted CCR5 expression as well as SM genetically lacking CCR5. Defining expression of these molecules on SM CD4+ subsets may delineate distinct natural host target cell populations capable of supporting SIVsmm replication without CD4+ T cell loss. PMID:22090107

  13. Distribution of the CCR5delta32 allele (gene variant CCR5) in Rondônia, Western Amazonian region, Brazil.

    PubMed

    de Farias, Josileide Duarte; Santos, Marlene Guimarães; de França, Andonai Krauze; Delani, Daniel; Tada, Mauro Shugiro; Casseb, Almeida Andrade; Simões, Aguinaldo Luiz; Engracia, Vera

    2012-01-01

    Since around 1723, on the occasion of its initial colonization by Europeans, Rondonia has received successive waves of immigrants. This has been further swelled by individuals from northeastern Brazil, who began entering at the beginning of the twentieth century. The ethnic composition varies across the state according to the various sites of settlement of each wave of immigrants. We analyzed the frequency of the CCR5Δ32 allele of the CCR5 chemokine receptor, which is considered a Caucasian marker, in five sample sets from the population. Four were collected in Porto Velho, the state capital and the site of several waves of migration. Of these, two, from the Hospital de Base were comprised of HB Mothers and HB Newborns presenting allele frequencies of 3.5% and 3.1%, respectively, a third from the peri-urban neighborhoods of Candelária/Bate-Estaca (1.8%), whereas a fourth, from the Research Center on Tropical Medicine/CEPEM (0.6%), was composed of malaria patients under treament. The fifth sample (3.4%) came from the inland Quilombola village of Pedras Negras. Two homozygous individuals (CCR5Δ32/CCR5Δ32) were detected among the HB Mother samples. The frequency of this allele was heterogeneous and higher where the European inflow was more pronounced. The presence of the allele in Pedras Negras revealed European miscegenation in a community largely comprising Quilombolas. PMID:22481870

  14. Distribution of the CCR5delta32 allele (gene variant CCR5) in Rondônia, Western Amazonian region, Brazil

    PubMed Central

    de Farias, Josileide Duarte; Santos, Marlene Guimarães; de França, Andonai Krauze; Delani, Daniel; Tada, Mauro Shugiro; Casseb, Almeida Andrade; Simões, Aguinaldo Luiz; Engracia, Vera

    2012-01-01

    Since around 1723, on the occasion of its initial colonization by Europeans, Rondonia has received successive waves of immigrants. This has been further swelled by individuals from northeastern Brazil, who began entering at the beginning of the twentieth century. The ethnic composition varies across the state according to the various sites of settlement of each wave of immigrants. We analyzed the frequency of the CCR5Δ32 allele of the CCR5 chemokine receptor, which is considered a Caucasian marker, in five sample sets from the population. Four were collected in Porto Velho, the state capital and the site of several waves of migration. Of these, two, from the Hospital de Base were comprised of HB Mothers and HB Newborns presenting allele frequencies of 3.5% and 3.1%, respectively, a third from the peri-urban neighborhoods of Candelária/Bate-Estaca (1.8%), whereas a fourth, from the Research Center on Tropical Medicine/CEPEM (0.6%), was composed of malaria patients under treament. The fifth sample (3.4%) came from the inland Quilombola village of Pedras Negras. Two homozygous individuals (CCR5Δ32/CCR5Δ32) were detected among the HB Mother samples. The frequency of this allele was heterogeneous and higher where the European inflow was more pronounced. The presence of the allele in Pedras Negras revealed European miscegenation in a community largely comprising Quilombolas. PMID:22481870

  15. Regional and national significance of biological nitrogen fixation by crops in the United States

    EPA Science Inventory

    Background/Questions/Methods Biological nitrogen fixation by crops (C-BNF) represents one of the largest anthropogenic inputs of reactive nitrogen (N) to land surfaces around the world. In the United States (US), existing estimates of C-BNF are uncertain because of incomplete o...

  16. Cloning, Stem Cells, and the Current National Debate: Incorporating Ethics into a Large Introductory Biology Course

    ERIC Educational Resources Information Center

    Fink, Rachel D.

    2002-01-01

    Discussing the ethical issues involved in topics such as cloning and stem cell research in a large introductory biology course is often difficult. Teachers may be wary of presenting material biased by personal beliefs, and students often feel inhibited speaking about moral issues in a large group. Yet, to ignore what is happening "out there"…

  17. CORAL REEF BIOLOGICAL CRITERIA: USING THE CLEAN WATER ACT TO PROTECT A NATIONAL TREASURE

    EPA Science Inventory

    Coral reefs are declining at unprecedented rates worldwide due to multiple interactive stressors including climate change and land-based sources of pollution. The Clean Water Act (CWA) can be a powerful legal instrument for protecting water resources, including the biological inh...

  18. Pharmacotherapy of HIV-1 Infection: Focus on CCR5 Antagonist Maraviroc

    PubMed Central

    Latinovic, Olga; Kuruppu, Janaki; Davis, Charles; Le, Nhut; Heredia, Alonso

    2009-01-01

    Sustained inhibition of HIV-1, the goal of antiretroviral therapy, is often impeded by the emergence of viral drug resistance. For patients infected with HIV-1 resistant to conventional drugs from the viral reverse transcriptase and protease inhibitor classes, the recently approved entry and integration inhibitors effectively suppress HIV-1 and offer additional therapeutic options. Entry inhibitors are particularly attractive because, unlike conventional antiretrovirals, they target HIV-1 extracellularly, thereby sparing cells from both viral- and drug-induced toxicities. The fusion inhibitor enfuvirtide and the CCR5 antagonist maraviroc are the first entry inhibitors licensed for patients with drug-resistant HIV-1, with maraviroc restricted to those infected with CCR5-tropic HIV-1 (R5 HIV-1) only. Vicriviroc (another CCR5 antagonist) is in Phase III clinical trials, whereas the CCR5 antibodies PRO 140 and HGS 004 are in early stages of clinical development. Potent antiviral synergy between maraviroc and CCR5 antibodies, coupled with distinct patterns of resistance, suggest their combinations might be particularly effective in patients. In addition, given that oral administration of maraviroc achieves high drug levels in cervicovaginal fluid, combinations of maraviroc and other CCR5 inhibitors could be effective in preventing HIV-1 transmission. Moreover, since CCR5 antagonists prevent rejection of transplanted organs, maraviroc could both suppress HIV-1 and prolong organ survival for the growing number of HIV-1 patients with kidney or liver failure necessitating organ transplantation. Thus, maraviroc offers an important treatment option for patients with drug-resistant R5 HIV-1, who presently account for >50% of drug-resistance cases. PMID:19920876

  19. Disruption of CCL20-CCR6 interaction inhibits metastasis of advanced cutaneous T-cell lymphoma

    PubMed Central

    Ito, Mitsugu; Abe, Fumito; Nara, Miho; Watanabe, Atsushi; Takahashi, Naoto; Miyagaki, Tomomitsu; Sugaya, Makoto; Tagawa, Hiroyuki

    2016-01-01

    We recently demonstrated that upregulation of a chemokine receptor CCR6 and its ligand CCL20 led to metastasis of advanced cutaneous T-cell lymphoma (CTCL) cells, suggesting the involvement of CCL20-CCR6 interaction in initiating CTCL cell metastasis. In this study, we determined whether this interaction is functional in metastatic CTCL cells. We first demonstrated increased STAT3 expression during the progression of primary CTCL. STAT3 was spontaneously activated and mediated the transcription of CCL20 in CTCL cell lines. Next, to determine whether the transient knockdown of STAT3, CCL20, or CCR6 or treatment with neutralizing antibody against CCL20 (neutralizing CCL20 antibody) could reduce the migration ability of CTCL cells, we conducted an in vitro migration assay. All treatments reduced the nutrition-dependent migration activity of CTCL cells. Notably, treatment with neutralizing CCL20 antibody reduced the migration ability of the cells without decreasing the expression of CCL20 and CCR6. This demonstrated that the CCL20-CCR6 interaction is actually functional in metastatic CTCL cells. Finally, to examine the in vivo effect of neutralizing CCL20 antibody, we used NOD/Shi-scid IL-2γnul mice inoculated with CTCL cells. These mice were expected to die due to metastasis of CTCL cells into multiple organs. However, administration of neutralizing CCL20 antibody significantly prolonged the survival of the xenografted mice. These findings suggested that automatic activation of the STAT3/CCL20/CCR6 cascade was involved in CTCL lymphomagenesis and that disruption of CCL20-CCR6 interaction could be a key therapeutic strategy against advanced CTCL. PMID:26789110

  20. Cytokine-induced killer cells interact with tumor lysate-pulsed dendritic cells via CCR5 signaling.

    PubMed

    Lee, Hong Kyung; Kim, Yong Guk; Kim, Ji Sung; Park, Eun Jae; Kim, Boyeong; Park, Ki Hwan; Kang, Jong Soon; Hong, Jin Tae; Kim, Youngsoo; Han, Sang-Bae

    2016-08-10

    The antitumor activity of cytokine-induced killer (CIK) cells can be increased by co-culturing them with tumor lysate-pulsed dendritic cells (tDCs); this phenomenon has been studied mainly at the population level. Using time-lapse imaging, we examined how CIK cells gather information from tDCs at the single-cell level. tDCs highly expressed CCL5, which bound CCR5 expressed on CIK cells. tDCs strongly induced migration of Ccr5(+/+) CIK cells, but not that of Ccr5(-/-) CIK cells or Ccr5(+/+) CIK cells treated with the CCR5 antagonist Maraviroc. Individual tDCs contacted Ccr5(+/+) CIK cells more frequently and lengthily than with Ccr5(-/-) CIK cells. Consequently, tDCs increased the antitumor activity of Ccr5(+/+) CIK cells in vitro and in vivo, but did not increase that of Ccr5(-/-) CIK cells. Taken together, our data provide insight into the mechanism of CIK cell activation by tDCs at the single-cell level. PMID:27216980

  1. CCR7 is required for the in vivo function of CD4+ CD25+ regulatory T cells

    PubMed Central

    Schneider, Martin A.; Meingassner, Josef G.; Lipp, Martin; Moore, Henrietta D.; Rot, Antal

    2007-01-01

    CCR7-mediated migration of naive T cells into the secondary lymphoid organs is a prerequisite for their encounter with mature dendritic cells, the productive presentation of cognate antigen, and consequent T cell proliferation and effector differentiation. Therefore, CCR7 was suggested to play an important role in the initiation of adaptive immune responses. In this study, we show that primary immunity can also develop in the absence of CCR7. Moreover, CCR7-deficient knockout (KO) mice display augmented immune responses. Our data cumulatively suggest that enhanced immunity in CCR7 KO mice is caused by the defective lymph node (LN) positioning of FoxP3+ CD4+ CD25+ regulatory T cells (T reg cells) and the consequent impediment of their function. The FoxP3+ T reg cells express CCR7 and, after their adoptive transfer, migrate into the LNs of wild-type mice. Here, they proliferate in situ upon antigen stimulation and inhibit the generation of antigen-specific T cells. Conversely, transferred CCR7-deficient T reg cells fail to migrate into the LNs and suppress antigen-induced T cell responses. The transfer of combinations of naive and T reg cells from wild-type and CCR7 KO mice into syngeneic severe combined immunodeficient mice directly demonstrates that CCR7-deficient T reg cells are less effective than their wild-type counterparts in preventing the development of inflammatory bowel disease. PMID:17371928

  2. PROCEEDINGS OF THE SEMINAR ON BIOLOGICAL MONITORING AND ITS USE IN THE NPDES (NATIONAL POLLUTANT DISCHARGE ELIMINATION SYSTEM) PERMIT PROGRAM HELD AT CHICAGO, ILLINOIS ON OCTOBER 2, 1979

    EPA Science Inventory

    This seminar brought together representatives from industry, state and local governments and biological monitoring consulting firms to present the U.S. Environmental Protection Agency, Region V perspective on biomonitoring requirements for the National Pollutant Discharge Elimina...

  3. PROCEEDINGS: FIRST NATIONAL SYMPOSIUM/WORKSHOP ON ROTATING BIOLOGICAL CONTACTOR TECHNOLOGY HELD AT CHAMPION, PENNSYLVANIA ON FEBRUARY 4-6, 1980. VOLUME II

    EPA Science Inventory

    This document is a compilation of 68 papers presented at the First National Symposium/Workshop on Rotating Biological Contactor (RBC) Technology sponsored by the University of Pittsburgh in cooperation with the US Army Construction Engineering Research Laboratory (Champaign, IL) ...

  4. PROCEEDINGS: FIRST NATIONAL SYMPOSIUM/WORKSHOP ON ROTATING BIOLOGICAL CONTACTOR TECHNOLOGY HELD AT CHAMPION, PENNSYLVANIA ON FEBRUARY 4-6, 1980. VOLUME I

    EPA Science Inventory

    This document is a compilation of 68 papers presented at the First National Symposium/Workshop on Rotating Biological Contactor (RBC) Technology sponsored by the University of Pittsburgh in cooperation with the US Army Construction Engineering Research Laboratory (Champaign, IL) ...

  5. IL-33 enhances proliferation and invasiveness of decidual stromal cells by up-regulation of CCL2/CCR2 via NF-κB and ERK1/2 signaling.

    PubMed

    Hu, Wen-Ting; Li, Ming-Qing; Liu, Wei; Jin, Li-Ping; Li, Da-Jin; Zhu, Xiao-Yong

    2014-04-01

    Interleukin (IL)-33, a newly described member of the IL-1 family, has been reported to facilitate primary tumor progression and metastatic dissemination. However, its biological function on decidual stromal cells (DSCs) remains unclear. In this study, we tested the hypothesis whether IL-33 promotes proliferation and invasion of DSCs, and the possible mechanism. IL-33 and its orphan receptor ST2 was found to be co-expressed by DSCs in human first-trimester pregnancy. Addition of IL-33, enhanced the proliferation and invasion of DSCs in a dosage-dependent manner, concomitantly with increasing expression of proliferation relative gene (PCNA, survivin) and invasion relative gene (titin, MMP2). Blocking IL-33/ST2 signaling by soluble sST2 apparently abolished the stimulatory effect on the proliferation, invasiveness and related gene expression in DSCs. We also demonstrated that chemokines CCL2/CCR2 was significantly increased with IL-33 administration. Moreover, inhibition of CCL2/CCR2 activation using CCL2 neutralizing antibody or CCR2 blocker prevented IL-33-stimulated proliferation and invasiveness capacity of DSCs. Increasing phosphorylation of nuclear factor NF-κB p65 and extracellular signal-regulated kinases ERK1/2 after treatment with IL-33 was confirmed by western blotting. And the IL-33-induced CCL2/CCR2 expression was abrogated by treatment with the NF-κB inhibitor BAY 11-7082 or ERK1/2 inhibitor U0126. Finally, we showed that decreased IL-33/ST2 expression was observed in DSCs from spontaneous abortion compared with normal pregnancy at both gene and protein levels. This study provides evidence for the molecular mechanism of IL-33 in promoting proliferation and invasiveness of DSCs by up-regulation of CCL2/CCR2 via NF-κB and ERK1/2 signal pathways and thus contributes insight to the potential of IL-33 involved in successful pregnancy via inducing DSCs mitosis and invasion. PMID:24344240

  6. Biological Assessment of the Continued Operation of Los Alamos National Laboratory on Federally Listed Threatened and Endangered Species

    SciTech Connect

    Hansen, Leslie A.

    2006-09-19

    This biological assessment considers the effects of continuing to operate Los Alamos National Laboratory on Federally listed threatened or endangered species, based on current and future operations identified in the 2006 Site-wide Environmental Impact Statement for the Continued Operation of Los Alamos National Laboratory (SWEIS; DOE In Prep.). We reviewed 40 projects analyzed in the SWEIS as well as two aspects on ongoing operations to determine if these actions had the potential to affect Federally listed species. Eighteen projects that had not already received U.S. Fish and Wildlife Service (USFWS) consultation and concurrence, as well as the two aspects of ongoing operations, ecological risk from legacy contaminants and the Outfall Reduction Project, were determined to have the potential to affect threatened or endangered species. Cumulative impacts were also analyzed.

  7. CCR2 Deficiency Promotes Exacerbated Chronic Erosive Neutrophil-Dominated Chikungunya Virus Arthritis

    PubMed Central

    Poo, Yee Suan; Nakaya, Helder; Gardner, Joy; Larcher, Thibaut; Schroder, Wayne A.; Le, Thuy T.; Major, Lee D.

    2014-01-01

    ABSTRACT Chikungunya virus (CHIKV) is a member of a globally distributed group of arthritogenic alphaviruses that cause weeks to months of debilitating polyarthritis/arthralgia, which is often poorly managed with current treatments. Arthritic disease is usually characterized by high levels of the chemokine CCL2 and a prodigious monocyte/macrophage infiltrate. Several inhibitors of CCL2 and its receptor CCR2 are in development and may find application for treatment of certain inflammatory conditions, including autoimmune and viral arthritides. Here we used CCR2−/− mice to determine the effect of CCR2 deficiency on CHIKV infection and arthritis. Although there were no significant changes in viral load or RNA persistence and only marginal changes in antiviral immunity, arthritic disease was substantially increased and prolonged in CCR2−/− mice compared to wild-type mice. The monocyte/macrophage infiltrate was replaced in CCR2−/− mice by a severe neutrophil (followed by an eosinophil) infiltrate and was associated with changes in the expression levels of multiple inflammatory mediators (including CXCL1, CXCL2, granulocyte colony-stimulating factor [G-CSF], interleukin-1β [IL-1β], and IL-10). The loss of anti-inflammatory macrophages and their activities (e.g., efferocytosis) was also implicated in exacerbated inflammation. Clear evidence of cartilage damage was also seen in CHIKV-infected CCR2−/− mice, a feature not normally associated with alphaviral arthritides. Although recruitment of CCR2+ monocytes/macrophages can contribute to inflammation, it also appears to be critical for preventing excessive pathology and resolving inflammation following alphavirus infection. Caution might thus be warranted when considering therapeutic targeting of CCR2/CCL2 for the treatment of alphaviral arthritides. IMPORTANCE Here we describe the first analysis of viral arthritis in mice deficient for the chemokine receptor CCR2. CCR2 is thought to be central to the

  8. Functional inhibition of chemokine receptor CCR2 by dicer-substrate-siRNA prevents pain development

    PubMed Central

    Midavaine, Élora; Dansereau, Marc-André; Tétreault, Pascal; Longpré, Jean-Michel; Jacobi, Ashley M; Rose, Scott D; Behlke, Mark A; Beaudet, Nicolas; Sarret, Philippe

    2016-01-01

    Background Accumulating evidence suggests that the C-C chemokine ligand 2 (CCL2, or monocyte chemoattractant protein 1) acts as a neuromodulator in the central nervous system through its binding to the C-C chemokine receptor 2 (CCR2). Notably, it is well established that the CCL2/CCR2 axis plays a key role in neuron-glia communication as well as in spinal nociceptive transmission. Gene silencing through RNA interference has recently emerged as a promising avenue in research and drug development, including therapeutic management of chronic pain. In the present study, we used 27-mer Dicer-substrate small interfering RNA (DsiRNA) targeting CCR2 and assessed their ability to reverse the nociceptive behaviors induced by spinal CCL2 injection or following intraplantar injection of complete Freund’s adjuvant. Results To this end, we first developed high-potency DsiRNAs designed to target different sequences distributed across the rat CCR2 (rCCR2) messenger RNA. For optimization, methyl groups were added to the two most potent DsiRNA candidates (Evader and M7 2′-O-methyl modified duplexes) in order to improve in vivo duplex stability and to reduce potential immunostimulatory activity. Our results demonstrated that all modified candidates formulated with the cell-penetrating peptide reagent Transductin showed strong RNAi activity following intrathecal delivery, exhibiting >50% rCCR2 knockdown in lumbar dorsal root ganglia. Accordingly, we found that these DsiRNA duplexes were able to reduce spinal microglia activation and were effective at blocking CCL2-induced mechanical hypersensitivity. Along with similar reductions of rCCR2 messenger RNA, both sequences and methylation patterns were similarly effective in inhibiting the CCL2 nociceptive action for the whole seven days testing period, compared to mismatch DsiRNA. DsiRNAs against CCR2 also reversed the hypernociceptive responses observed in the complete Freund’s adjuvant-induced inflammatory chronic pain model

  9. TR4 nuclear receptor promotes prostate cancer metastasis via upregulation of CCL2/CCR2 signaling.

    PubMed

    Ding, Xianfan; Yang, Dong-Rong; Lee, Soo Ok; Chen, Ya-Ling; Xia, Liqun; Lin, Shin-Jen; Yu, Shicheng; Niu, Yuan-Jie; Li, Gonghui; Chang, Chawnshang

    2015-02-15

    Testicular nuclear receptor 4 (TR4) plays protective roles against oxidative stress and DNA damage and might contribute to aging. Our recent clinical tumor tissue staining results showed higher expression of TR4 in prostate cancer (PCa) patients with high Gleason scores compared to the tissues with the low Gleason scores. In vitro migration/invasion assays after manipulation of the TR4 expression in PCa cells showed that TR4 promoted PCa cells migration/invasion. Mechanism dissection found that the CCL2/CCR2 signal plays the key role in the mediation of TR4-promoted PCa cells migration/invasion. Chromatin immunoprecipitation and Luciferase assays further confirmed TR4 modulation of CCL2 at the transcriptional level and addition of the CCR2 antagonist led to interruption of the TR4-enhanced PCa cells migration/invasion. Finally, the orthotopic xenografted mice studies using the luciferase expressing CWR22Rv1 cells found that TR4 enhanced PCa metastasis and this increased metastasis was reversed when the CCR2 antagonist was injected into the mice. Together, these in vitro and in vivo results revealed a positive role of TR4 in PCa metastasis and demonstrated CCL2/CCR2 signaling as an important mediator in exerting TR4 action. This finding suggests that TR4 may represent a biomarker related to PCa metastasis and targeting the TR4-CCL2/CCR2 axis may become a new therapeutic approach to battle PCa metastasis. PMID:24975468

  10. Inflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR2

    PubMed Central

    Mojumdar, Kamalika; Liang, Feng; Giordano, Christian; Lemaire, Christian; Danialou, Gawiyou; Okazaki, Tatsuma; Bourdon, Johanne; Rafei, Moutih; Galipeau, Jacques; Divangahi, Maziar; Petrof, Basil J

    2014-01-01

    Myofiber necrosis and fibrosis are hallmarks of Duchenne muscular dystrophy (DMD), leading to lethal weakness of the diaphragm. Macrophages (MPs) are required for successful muscle regeneration, but the role of inflammatory monocyte (MO)-derived MPs in either promoting or mitigating DMD is unclear. We show that DMD (mdx) mouse diaphragms exhibit greatly increased expression of CCR2 and its chemokine ligands, along with inflammatory (Ly6Chigh) MO recruitment and accumulation of CD11bhigh MO-derived MPs. Loss-of-function of CCR2 preferentially reduced this CD11bhigh MP population by impeding the release of Ly6Chigh MOs from the bone marrow but not the splenic reservoir. CCR2 deficiency also helped restore the MP polarization balance by preventing excessive skewing of MPs toward a proinflammatory phenotype. These effects were linked to amelioration of histopathological features and increased muscle strength in the diaphragm. Chronic inhibition of CCR2 signaling by mutated CCL2 secreted from implanted mesenchymal stem cells resulted in similar improvements. These data uncover a previously unrecognized role of inflammatory MOs in DMD pathogenesis and indicate that CCR2 inhibition could offer a novel strategy for DMD management. PMID:25312642

  11. Inhibition of HIV-1 infection by synthetic peptides derived CCR5 fragments

    SciTech Connect

    Imai, Masaki; Baranyi, Lajos; Okada, Noriko; Okada, Hidechika; E-mail: hiokada@med.nagoya-cu.ac.jp

    2007-02-23

    HIV-1 infection requires interaction of viral envelope protein gp160 with CD4 and a chemokine receptor, CCR5 or CXCR4 as entry coreceptor. We designed HIV-inhibitory peptides targeted to CCR5 using a novel computer program (ANTIS), which searched all possible sense-antisense amino acid pairs between proteins. Seven AHBs were found in CCR5 receptor. All AHB peptides were synthesized and tested for their ability to prevent HIV-1 infection to human T cells. A peptide fragment (LC5) which is a part of the CCR5 receptor corresponding to the loop between the fifth and sixth transmembrane regions (amino acids 222-240) proved to inhibit HIV-1{sub IIIB} infection of MT-4 cells. Interaction of these antisense peptides could be involved in sustaining HIV-1 infectivity. LC5 effectively indicated dose-dependent manner, and the suppression was enhanced additively by T20 peptide, which inhibits infection in vitro by disrupting the gp41 conformational changes necessary for membrane fusion. Thus, these results indicate that CCR5-derived AHB peptides could provide a useful tool to define the mechanism(s) of HIV infection, and may provide insight which will contribute to the development of an anti-HIV-1 reagent.

  12. Combinatorial Guidance by CCR7 Ligands for T Lymphocytes Migration in Co-Existing Chemokine Fields

    PubMed Central

    Lin, Francis

    2011-01-01

    Chemokines mediate the trafficking and positioning of lymphocytes in lymphoid tissues that is crucial for immune surveillance and immune responses. In particular, a CCR7 ligand, CCL21, plays important roles in recruiting T cells to secondary lymphoid tissues (SLT). Furthermore, CCL21 together with another CCR7 ligand, CCL19, direct the navigation and compartmentation of T cells within SLT. However, the distinct roles of these two chemokines for regulating cell trafficking and positioning are not clear. In this study, we explore the effect of co-existing CCL19 and CCL21 concentration fields on guiding T cell migration. Using microfluidic devices that can configure single and superimposed chemokine fields we show that under physiological gradient conditions, human peripheral blood T cells chemotax to CCL21 but not CCL19. Furthermore, T cells migrate away from the CCL19 gradient in a uniform background of CCL21. This repulsive migratory response is predicted by mathematical modeling based on the competition of CCL19 and CCL21 for CCR7 signaling and the differential ability of the two chemokines for desensitizing CCR7. These results suggest a new combinatorial guiding mechanism by CCL19 and CCL21 for the migration and trafficking of CCR7 expressing leukocytes. PMID:21464944

  13. CCR1 inhibition ameliorates the progression of lupus nephritis in NZB/W mice.

    PubMed

    Bignon, Alexandre; Gaudin, Françoise; Hémon, Patrice; Tharinger, Hugo; Mayol, Katia; Walzer, Thierry; Loetscher, Pius; Peuchmaur, Michel; Berrebi, Dominique; Balabanian, Karl

    2014-02-01

    Systemic lupus erythematosus is a chronic inflammatory autoimmune disease, the development of which is characterized by a progressive loss of renal function. Such dysfunction is associated with leukocyte infiltration in the glomerular and tubulointerstitial compartments in both human and experimental lupus nephritis. In this study, we investigated the role of the Ccr1 chemokine receptor in this infiltration process during the progression of nephritis in the lupus-prone New Zealand Black/New Zealand White (NZB/W) mouse model. We found that peripheral T cells, mononuclear phagocytes, and neutrophils, but not B cells, from nephritic NZB/W mice were more responsive to Ccr1 ligands than the leukocytes from younger prenephritic NZB/W mice. Short-term treatment of nephritic NZB/W mice with the orally available Ccr1 antagonist BL5923 decreased renal infiltration by T cells and macrophages. Longer Ccr1 blockade decreased kidney accumulation of effector/memory CD4(+) T cells, Ly6C(+) monocytes, and both M1 and M2 macrophages; reduced tubulointerstitial and glomerular injuries; delayed fatal proteinuria; and prolonged animal lifespan. In contrast, renal humoral immunity was unaffected in BL5923-treated mice, which reflected the unchanged numbers of infiltrated B cells in the kidneys. Altogether, these findings define a pivotal role for Ccr1 in the recruitment of T and mononuclear phagocyte cells to inflamed kidneys of NZB/W mice, which in turn contribute to the progression of renal injury. PMID:24367031

  14. Design of a base station for MEMS CCR localization in an optical sensor network.

    PubMed

    Park, Chan Gook; Jeon, Hyun Cheol; Kim, Hyoun Jin; Kim, Jae Yoon

    2014-01-01

    This paper introduces a design and implementation of a base station, capable of positioning sensor nodes using an optical scheme. The base station consists of a pulse laser module, optical detectors and beam splitter, which are mounted on a rotation-stage, and a Time to Digital Converter (TDC). The optical pulse signal transmitted to the sensor node with a Corner Cube Retro-reflector (CCR) is reflected to the base station, and the Time of Flight (ToF) data can be obtained from the two detectors. With the angle and flight time data, the position of the sensor node can be calculated. The performance of the system is evaluated by using a commercial CCR. The sensor nodes are placed at different angles from the base station and scanned using the laser. We analyze the node position error caused by the rotation and propose error compensation methods, namely the outlier sample exception and decreasing the confidence factor steadily using the recursive least square (RLS) methods. Based on the commercial CCR results, the MEMS CCR is also tested to demonstrate the compatibility between the base station and the proposed methods. The result shows that the localization performance of the system can be enhanced with the proposed compensation method using the MEMS CCR. PMID:24815681

  15. Design of a Base Station for MEMS CCR Localization in an Optical Sensor Network

    PubMed Central

    Park, Chan Gook; Jeon, Hyun Cheol; Kim, Hyoun Jin; Kim, Jae Yoon

    2014-01-01

    This paper introduces a design and implementation of a base station, capable of positioning sensor nodes using an optical scheme. The base station consists of a pulse laser module, optical detectors and beam splitter, which are mounted on a rotation-stage, and a Time to Digital Converter (TDC). The optical pulse signal transmitted to the sensor node with a Corner Cube Retro-reflector (CCR) is reflected to the base station, and the Time of Flight (ToF) data can be obtained from the two detectors. With the angle and flight time data, the position of the sensor node can be calculated. The performance of the system is evaluated by using a commercial CCR. The sensor nodes are placed at different angles from the base station and scanned using the laser. We analyze the node position error caused by the rotation and propose error compensation methods, namely the outlier sample exception and decreasing the confidence factor steadily using the recursive least square (RLS) methods. Based on the commercial CCR results, the MEMS CCR is also tested to demonstrate the compatibility between the base station and the proposed methods. The result shows that the localization performance of the system can be enhanced with the proposed compensation method using the MEMS CCR. PMID:24815681

  16. HIPK family kinases bind and regulate the function of the CCR4-NOT complex.

    PubMed

    Rodriguez-Gil, Alfonso; Ritter, Olesja; Hornung, Juliane; Stekman, Hilda; Krüger, Marcus; Braun, Thomas; Kremmer, Elisabeth; Kracht, Michael; Schmitz, M Lienhard

    2016-06-15

    The serine/threonine kinase HIPK2 functions as a regulator of developmental processes and as a signal integrator of a wide variety of stress signals, such as DNA damage, hypoxia, and reactive oxygen intermediates. Because the kinase is generated in a constitutively active form, its expression levels are restricted by a variety of different mechanisms. Here we identify the CCR4-NOT complex as a new regulator of HIPK2 abundance. Down-regulation or knockout of the CCR4-NOT complex member CNOT2 leads to reduced HIPK2 protein levels without affecting the expression level of HIPK1 or HIPK3. A fraction of all HIPK family members associates with the CCR4-NOT components CNOT2 and CNOT3. HIPKs also phosphorylate the CCR4-NOT complex, a feature that is shared with their yeast progenitor kinase, YAK1. Functional assays reveal that HIPK2 and HIPK1 restrict CNOT2-dependent mRNA decay. HIPKs are well known regulators of transcription, but the mutual regulation between CCR4-NOT and HIPKs extends the regulatory potential of these kinases by enabling posttranscriptional gene regulation. PMID:27122605

  17. Chemokine/chemokine receptor pair CCL20/CCR6 in human colorectal malignancy: An overview

    PubMed Central

    Frick, Vilma Oliveira; Rubie, Claudia; Keilholz, Ulrich; Ghadjar, Pirus

    2016-01-01

    Chemokines belong to a superfamily of small, cytokine-like proteins, which induce multiple physiological functions, particularly cytoskeletal rearrangement and compartment-specific migration through their interaction with G-protein-coupled receptors. Chemokines and their receptors have been widely acknowledged as essential and selective mediators in leukocyte migration in inflammatory response. It is now established that the chemokine/chemokine receptor system is also used by cancer cells to direct lymphatic and haematogenous spreading and additionally has an impact on the site of metastatic growth of different tumours. In recent years an increasing number of studies have drawn attention to CC-chemokine cysteine motif chemokine ligand 20 (CCL20) and its physiological sole receptor CCR6 to play a role in the onset, development and metastatic spread of various gastrointestinal cancer entities. Among various cancer types CCR6 was also demonstrated to be significantly overexpressed in colorectal cancer (CRC) and stimulation by its physiological ligand CCL20 has been reported to promote CRC cell proliferation and migration in vitro. Further, the CCL20/CCR6 system apparently plays a role in the organ-selective liver metastasis of CRC. Here we review the literature on expression patterns of CCL20 and CCR6 and their physiological interactions as well as the currently presumed role of CCL20 and CCR6 in the formation of CRC and the development of liver metastasis, providing a potential basis for novel treatment strategies. PMID:26811629

  18. Colorectal carcinoma metastases: Detection with In-111-labeled monoclonal antibody CCR 086

    SciTech Connect

    Abdel-Nabi, H.H.; Levine, G.; Lamki, L.M.; Murray, J.L.; Tauxe, W.N.; Shah, A.N.; Patt, Y.Z.; Doerr, R.J.; Klein, H.A.; Gona, J. )

    1990-07-01

    A phase I/II clinical trial with indium-111-labeled antimucin murine monoclonal antibody (MoAb) CCR 086 was conducted. Seventeen patients with histologically proved colorectal carcinoma and known metastatic disease underwent external scintigraphy after administration of 5.5 mCi (203.5 MBq) of In-111 CCR 086 at doses of 5 and 20 mg. Of 25 known lesions, 17 were detected (sensitivity, 68%). The smallest detected lesion in the lung was 1 cm and in the liver was 1.5 cm. The serum half-life of In-111-labeled CCR 086 MoAb was approximately 64 hours. The formation of human antimouse antibody (HAMA) was detected in the serum of four of five patients who received 20 mg of MoAb. No HAMAs were detected in four patients receiving 5 mg of MoAb. No side effects were encountered. Because of effective detection of liver and lung metastases with lower doses (5-20 mg) of CCR 086 conjugated with In-111, further investigations are warranted to assess clinical and therapeutic potentials of CCR 086 in the management of colorectal cancer.

  19. CCR4 promotes medullary entry and thymocyte-dendritic cell interactions required for central tolerance.

    PubMed

    Hu, Zicheng; Lancaster, Jessica N; Sasiponganan, Chayanit; Ehrlich, Lauren I R

    2015-10-19

    Autoimmunity results from a breakdown in central or peripheral tolerance. To establish central tolerance, developing T cells must enter the thymic medulla, where they scan antigen-presenting cells (APCs) displaying a diverse array of autoantigens. If a thymocyte is activated by a self-antigen, the cell undergoes either deletion or diversion into the regulatory T cell (T reg) lineage, thus maintaining self-tolerance. Mechanisms promoting thymocyte medullary entry and interactions with APCs are incompletely understood. CCR4 is poised to contribute to central tolerance due to its expression by post-positive selection thymocytes, and expression of its ligands by medullary thymic dendritic cells (DCs). Here, we use two-photon time-lapse microscopy to demonstrate that CCR4 promotes medullary entry of the earliest post-positive selection thymocytes, as well as efficient interactions between medullary thymocytes and DCs. In keeping with the contribution of thymic DCs to central tolerance, CCR4 is involved in regulating negative selection of polyclonal and T cell receptor (TCR) transgenic thymocytes. In the absence of CCR4, autoreactive T cells accumulate in secondary lymphoid organs and autoimmunity ensues. These studies reveal a previously unappreciated role for CCR4 in the establishment of central tolerance. PMID:26417005

  20. Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells.

    PubMed

    Olkhanud, Purevdorj B; Baatar, Dolgor; Bodogai, Monica; Hakim, Fran; Gress, Ronald; Anderson, Robin L; Deng, Jie; Xu, Mai; Briest, Susanne; Biragyn, Arya

    2009-07-15

    Cancer metastasis is a leading cause of cancer morbidity and mortality. More needs to be learned about mechanisms that control this process. In particular, the role of chemokine receptors in metastasis remains controversial. Here, using a highly metastatic breast cancer (4T1) model, we show that lung metastasis is a feature of only a proportion of the tumor cells that express CCR4. Moreover, the primary tumor growing in mammary pads activates remotely the expression of TARC/CCL17 and MDC/CCL22 in the lungs. These chemokines acting through CCR4 attract both tumor and immune cells. However, CCR4-mediated chemotaxis was not sufficient to produce metastasis, as tumor cells in the lung were efficiently eliminated by natural killer (NK) cells. Lung metastasis required CCR4(+) regulatory T cells (Treg), which directly killed NK cells using beta-galactoside-binding protein. Thus, strategies that abrogate any part of this process should improve the outcome through activation of effector cells and prevention of tumor cell migration. We confirm this prediction by killing CCR4(+) cells through delivery of TARC-fused toxins or depleting Tregs and preventing lung metastasis. PMID:19567680

  1. HIPK family kinases bind and regulate the function of the CCR4-NOT complex

    PubMed Central

    Rodriguez-Gil, Alfonso; Ritter, Olesja; Hornung, Juliane; Stekman, Hilda; Krüger, Marcus; Braun, Thomas; Kremmer, Elisabeth; Kracht, Michael; Schmitz, M. Lienhard

    2016-01-01

    The serine/threonine kinase HIPK2 functions as a regulator of developmental processes and as a signal integrator of a wide variety of stress signals, such as DNA damage, hypoxia, and reactive oxygen intermediates. Because the kinase is generated in a constitutively active form, its expression levels are restricted by a variety of different mechanisms. Here we identify the CCR4-NOT complex as a new regulator of HIPK2 abundance. Down-regulation or knockout of the CCR4-NOT complex member CNOT2 leads to reduced HIPK2 protein levels without affecting the expression level of HIPK1 or HIPK3. A fraction of all HIPK family members associates with the CCR4-NOT components CNOT2 and CNOT3. HIPKs also phosphorylate the CCR4-NOT complex, a feature that is shared with their yeast progenitor kinase, YAK1. Functional assays reveal that HIPK2 and HIPK1 restrict CNOT2-dependent mRNA decay. HIPKs are well known regulators of transcription, but the mutual regulation between CCR4-NOT and HIPKs extends the regulatory potential of these kinases by enabling posttranscriptional gene regulation. PMID:27122605

  2. CCL25/CCR9 Signal Promotes Migration and Invasion in Hepatocellular and Breast Cancer Cell Lines.

    PubMed

    Zhang, Ziqi; Sun, Tong; Chen, Yuxi; Gong, Shu; Sun, Xiye; Zou, Fangdong; Peng, Rui

    2016-07-01

    Cancer is one of the most lethal diseases worldwide, and metastasis is the most common cause of patients' deaths. Identification and inhibition of markers involved in metastasis process in cancer cells are promising works to block metastasis and improve prognoses of patients. Chemokines are a superfamily of small, chemotactic cytokines, whose functions are based on interaction with corresponding receptors. It has been found that one of the functions of chemokines is to regulate migration and invasion abilities of lymphocytes, as well as cancer cells. Chemokine receptor 9 (CCR9) regulates trafficking of lymphocytes and cancer cell lines when interacting with its exclusive ligand chemokine 25 (CCL25). However, the mechanisms of CCL25/CCR9 signal that regulates metastasis of cancer cells are not completely known yet. In this study, we stimulated or inhibited CCL25/CCR9 signal in breast cancer cell line (MDA-MB-231) and hepatocellular cancer cell lines (HepG2 and HUH7), and found that CCL25/CCR9 signal resulted in different promotion of migration and invasion in different cell lines. These phenomena could be explained by selective regulation of several markers of epithelial-mesenchymal transition (EMT). Our findings suggested that CCL25/CCR9 signal may provide cancer cells with chemotactic abilities through influencing several EMT markers. PMID:27008282

  3. CCR4 promotes medullary entry and thymocyte–dendritic cell interactions required for central tolerance

    PubMed Central

    Hu, Zicheng; Lancaster, Jessica N.; Sasiponganan, Chayanit

    2015-01-01

    Autoimmunity results from a breakdown in central or peripheral tolerance. To establish central tolerance, developing T cells must enter the thymic medulla, where they scan antigen-presenting cells (APCs) displaying a diverse array of autoantigens. If a thymocyte is activated by a self-antigen, the cell undergoes either deletion or diversion into the regulatory T cell (T reg) lineage, thus maintaining self-tolerance. Mechanisms promoting thymocyte medullary entry and interactions with APCs are incompletely understood. CCR4 is poised to contribute to central tolerance due to its expression by post-positive selection thymocytes, and expression of its ligands by medullary thymic dendritic cells (DCs). Here, we use two-photon time-lapse microscopy to demonstrate that CCR4 promotes medullary entry of the earliest post-positive selection thymocytes, as well as efficient interactions between medullary thymocytes and DCs. In keeping with the contribution of thymic DCs to central tolerance, CCR4 is involved in regulating negative selection of polyclonal and T cell receptor (TCR) transgenic thymocytes. In the absence of CCR4, autoreactive T cells accumulate in secondary lymphoid organs and autoimmunity ensues. These studies reveal a previously unappreciated role for CCR4 in the establishment of central tolerance. PMID:26417005

  4. 2012 National Survey of Science and Mathematics Education: Status of High School Biology

    ERIC Educational Resources Information Center

    Lyons, Kiira M.

    2013-01-01

    The 2012 National Survey of Science and Mathematics Education was designed to provide up-to-date information and to identify trends in the areas of teacher background and experience, curriculum and instruction, and the availability and use of instructional resources. A total of 7,752 science and mathematics teachers in schools across the United…

  5. 2012 National Survey of Science and Mathematics Education: Compendium of Tables for High School Biology

    ERIC Educational Resources Information Center

    Horizon Research, Inc., 2013

    2013-01-01

    The 2012 National Survey of Science and Mathematics Education was designed to provide up-to-date information and to identify trends in the areas of teacher background and experience, curriculum and instruction, and the availability and use of instructional resources. This compendium, one of a series, details the results of a survey of high school…

  6. Chemokine receptor CCR6 expression is regulated by miR-518a-5p in colorectal cancer cells

    PubMed Central

    2014-01-01

    Background Recently, involvement of the chemokine/receptor system CCL20/CCR6 in colorectal cancer (CRC) progression was shown. Here, we analyzed the functional interaction of miRNA-518-5p (miR-518a-5p) with CCR6 and its impact on CCR6 expression in CRC cells. Methods MiR-518a-5p was identified by computer software to potentially interact with CCR6. Hence, functional implications of miR-518a-5p with the 3′UTR of CCR6 were analyzed using the Dual Luciferase Reporter assay system. Confirmation of the predicted target site for miR-518a-5p was achieved by site-directed mutagenesis of the seed sequence in the 3′UTR of CCR6 and subsequent application of the mutated seed sequence in a luciferase assay with miR-518a-5p mimics. Accordingly, two CRC cell lines (Caco-2 and HT-29) were transfected with miR-518a-5p miRNA mimics and gene and protein expression of CCR6 was monitored using qRT PCR and immunocytochemistry, respectively. Results Addition of miR-518a-5p led to significant down-regulation of luciferase activity (P < 0.05), which was significantly reversed in a reporter test system containing the mutated seed sequences in the 3′UTR of CCR6. Following transfection of CRC cell lines with miR-518a-5p mimics and subsequent monitoring of CCR6 expression showed significant down-regulation of CCR6 mRNA and CCR6 protein expression in both CRC cell lines under investigation (P < 0.05). Conclusions We have shown that miR-518a-5p functionally interacts with CCR6 and that transfection of CRC cells with miR-518a-5p leads to significant CCR6 down-regulation. Consequently, CCR6 expression is regulated by miR-518a-5p in CRC cells indicating that regulation of CCR6 expression by miR-518a-5p might be a regulatory mechanism involved in CRC pathogenesis. PMID:24559209

  7. Aberrant Accumulation of Undifferentiated Myeloid Cells in the Adipose Tissue of CCR2-Deficient Mice Delays Improvements in Insulin Sensitivity

    PubMed Central

    Gutierrez, Dario A.; Kennedy, Arion; Orr, Jeb S.; Anderson, Emily K.; Webb, Corey D.; Gerrald, William K.; Hasty, Alyssa H.

    2011-01-01

    OBJECTIVE Mice with CCR2 deficiency are protected from insulin resistance but only after long periods of high-fat diet (HFD) feeding, despite the virtual absence of circulating inflammatory monocytes. We performed a time course study in mice with hematopoietic and global CCR2 deficiency to determine adipose tissue–specific mechanisms for the delayed impact of CCR2 deficiency on insulin resistance. RESEARCH DESIGN AND METHODS Mice with global or hematopoietic CCR2 deficiency (CCR2−/− and BM-CCR2−/−, respectively) and wild-type controls (CCR2+/+ and BM-CCR2+/+, respectively) were placed on an HFD for 6, 12, and 20 weeks. Adipose tissue myeloid populations, degree of inflammation, glucose tolerance, and insulin sensitivity were assessed. RESULTS Flow cytometry analysis showed that two different populations of F4/80+ myeloid cells (CD11bloF4/80lo and CD11bhiF4/80hi) accumulated in the adipose tissue of CCR2−/− and BM-CCR2−/− mice after 6 and 12 weeks of HFD feeding, whereas only the CD11bhiF4/80hi population was detected in the CCR2+/+ and BM-CCR2+/+ controls. After 20 weeks of HFD feeding, the CD11bloF4/80lo cells were no longer present in the adipose tissue of CCR2−/− mice, and only then were improvements in adipose tissue inflammation detected. Gene expression and histological analysis of the CD11bloF4/80lo cells indicated that they are a unique undifferentiated monocytic inflammatory population. The CD11bloF4/80lo cells are transiently found in wild-type mice, but CCR2 deficiency leads to the aberrant accumulation of these cells in adipose tissue. CONCLUSIONS The discovery of this novel adipose tissue monocytic cell population provides advances toward understanding the pleiotropic role of CCR2 in monocyte/macrophage accumulation and regulation of adipose tissue inflammation. PMID:21926275

  8. Identifying bias in CCR1 antagonists using radiolabelled binding, receptor internalization, β-arrestin translocation and chemotaxis assays

    PubMed Central

    Gilchrist, A; Gauntner, T D; Fazzini, A; Alley, K M; Pyen, D S; Ahn, J; Ha, S J; Willett, A; Sansom, S E; Yarfi, J L; Bachovchin, K A; Mazzoni, M R; Merritt, J R

    2014-01-01

    Background and Purpose Investigators have suggested that the chemokine receptor CCR1 plays a role in multiple myeloma. Studies using antisense and neutralizing antibodies to CCR1 showed that down-regulation of the receptor altered disease progression in a mouse model. More recently, experiments utilizing scid mice injected with human myeloma cells demonstrated that the CCR1 antagonist BX471 reduced osteolytic lesions, while the CCR1 antagonist MLN-3897 prevented myeloma cell adhesion to osteoclasts. However, information is limited regarding the pharmacology of CCR1 antagonists in myeloma cells. Experimental Approach We compared several well-studied CCR1 antagonists including AZD4818, BX471, CCX354, CP-481715, MLN-3897 and PS899877 for their ability to inhibit binding of [125I]-CCL3 in vitro using membranes prepared from RPMI 8226 cells, a human multiple myeloma cell line that endogenously expresses CCR1. In addition, antagonists were assessed for their ability to modulate CCL3-mediated internalization of CCR1 and CCL3-mediated cell migration using RPMI 8226 cells. As many GPCRs signal through β–arrestin-dependent pathways that are separate and distinct from those driven by G-proteins, we also evaluated the compounds for their ability to alter β-arrestin translocation. Key Results There were clear differences between the CCR1 antagonists in their ability to inhibit CCL3 binding to myeloma cells, as well as in their ability to inhibit G–protein-dependent and -independent functional responses. Conclusions and Implications Our studies demonstrate that tissue phenotype seems to be relevant with regards to CCR1. Moreover, it appears that for CCR1 antagonists, inhibition of β-arrestin translocation is not necessarily linked to chemotaxis or receptor internalization. PMID:24990525

  9. Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation

    PubMed Central

    2010-01-01

    Objectives The chemokine receptors CCR2 and CX3CR1 are important in the development of coronary artery disease. The purpose of this study is to analyze the effect of a novel CCR2 inhibitor in conjunction with CX3CR1 deletion on vascular inflammation. Methods The novel CCR2 antagonist MRL-677 was characterized using an in vivo model of monocyte migration. To determine the relative roles of CCR2 and CX3CR1 in vascular remodeling, normal or CX3CR1 deficient mice were treated with MRL-677. After 14 days, the level of intimal hyperplasia in the artery was visualized by paraffin sectioning and histology of the hind limbs. Results MRL-677 is a CCR2 antagonist that is effective in blocking macrophage trafficking in a peritoneal thioglycollate model. Intimal hyperplasia resulting from vascular injury was also assessed in mice. Based on the whole-blood potency of MRL-677, sufficient drug levels were maintained for the entire 14 day experimental period to afford good coverage of mCCR2 with MRL-677. Blocking CCR2 with MRL-677 resulted in a 56% decrease in the vascular injury response (n = 9, p < 0.05) in normal animals. Mice in which both CCR2 and CX3CR1 pathways were targeted (CX3CR1 KO mice given MRL-677) had an 88% decrease in the injury response (n = 6, p = 0.009). Conclusion In this study we have shown that blocking CCR2 with a low molecular weight antagonist ameliorates the inflammatory response to vascular injury. The protective effect of CCR2 blockade is increased in the presence of CX3CR1 deficiency suggesting that CX3CR1 and CCR2 have non-redundant functions in the progression of vascular inflammation. PMID:20836883

  10. Chemical and biological characteristics of desert rock pools in intermittent streams of Capitol Reef National Park, Utah

    USGS Publications Warehouse

    Baron, Jill S.; LaFrancois, Toben; Kondratieff, Boris C.

    1998-01-01

    Chemical variability and biological communities of rock pools found in small desert drainage basins of Capitol Reef National Park were characterized over 8 mon in 1994. Neither flooding, drying, nor the presence or absence of surrounding vegetated wetlands had a great effect on chemical composition, which was very dilute and fluctuated somewhat in response to rain events. Neither flooding nor drying affected the composition of biological communities in the pools. Summer storms affected only a few drainages at a time, and only a few study pools of significant volume dried completely during the hot, dry summer. This suggests that only a portion of the Waterpocket Fold aquatic community is ever disturbed at a time, leaving undisturbed areas as a source of recovery. Pools bordered by vegetated wetlands always supported greater numbers of species throughout the year than those bordered only by bedrock, but the same taxa were found in both vegetated and bedrock pools. The rock pool fauna in Capitol Reef National Park appear to be resilient to climatic variability.