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Sample records for maclachlan lyn tett

  1. Lyn Evans decelerates!

    CERN Multimedia

    CERN Bulletin

    2010-01-01

    After more than 40 years at CERN, 15 of which were dedicated to ensuring that the LHC comes to completion, Lyn Evans is retiring. The Imperial College Professor and recently-elected Fellow of the British Royal Society has set himself new challenges, but plans to keep strong links with CERN. His big thank you goes to the many hundreds of people who built one of the most complex scientific instruments ever conceived by mankind. Note from the Editor: It is unusual for the Bulletin to adopt a question-and-answer style. However, we recognise that, with someone of Lyn’s stature, the appropriate thing to do is simply to give him the floor. Bulletin: Lyn, are you really leaving CERN? I am retiring but I will not completely lose contacts with CERN and the LHC. It’s time to slow down for me now but I will join the CMS Collaboration. I will help with the link between the experiment and the machine. Bulletin: After many years as LHC Project Manager...

  2. PELUANG USAHA KULINER KHAS MADURA BERBAHAN SINGKONG PADA AGROINDUSTRI KREPEK TETTE DI PAMEKASAN

    Directory of Open Access Journals (Sweden)

    Novi Diana Badrut Tamami

    2013-11-01

    Full Text Available FAO and World Bank’s predictions about the threat of food crisis in 2025 had a special attention from the many countries over the world. Indonesia had several programs to keep the food security. One of this campaigns was changing consumer behavior from rice to yam group. In this program cassava was chosen as a national strategic food like rice and corn. One of the food agroindustry from cassava that have a potential market is Krepek Tette. But, This Business Opportunity of Maduraness traditional food had not cultivated seriously. Krepek Tette’s Agroindustry is just a side job with small scale production for local. The aim of this study was to calculated the economic value added and the profit opportunity by Krepek Tette’s Agroindustry so that this activity become one of the local livelihood choice. The Hayami’s value added was used to analysed this research. The result of this study shows in once production of Krepek tette’s agroindustry is small scale but feasible and prifitable.

  3. Awards for Lyn Evans and Philippe Lebrun

    CERN Multimedia

    2007-01-01

    Lyn Evans has received the American Physical Society’s Robert R. Wilson Prize, while Philippe Lebrun has been awarded an honorary doctorate by the Wrocław University of Technology in Poland. Lyn Evans in front of an LHC dipole magnet. Philippe Lebrun (centre) with the Dean of the Faculty of mechanical and power engineering of the Wrocław University during the ceremony (courtesy of Laurent Tavian).Numerous honours are going to the LHC and those behind it even before this exceptional machine begins operation. The LHC Project Leader, Lyn Evans, has recently been awarded the "Robert R. Wilson Prize for Achievement in the Physics of Particle Accelerators" by the American Physical Society (APS). According to the citation, the prize was awarded "for a sustained career of technical innovation and leadership in the SPS proton-antiproton collider, culminating in the construction and commissioning of the LHC&am...

  4. Nuclear localization of Lyn tyrosine kinase mediated by inhibition of its kinase activity

    International Nuclear Information System (INIS)

    Ikeda, Kikuko; Nakayama, Yuji; Togashi, Yuuki; Obata, Yuuki; Kuga, Takahisa; Kasahara, Kousuke; Fukumoto, Yasunori; Yamaguchi, Naoto

    2008-01-01

    Src-family kinases, cytoplasmic enzymes that participate in various signaling events, are found at not only the plasma membrane but also subcellular compartments, such as the nucleus, the Golgi apparatus and late endosomes/lysosomes. Lyn, a member of the Src-family kinases, is known to play a role in DNA damage response and cell cycle control in the nucleus. However, it is still unclear how the localization of Lyn to the nucleus is regulated. Here, we investigated the mechanism of the distribution of Lyn between the cytoplasm and the nucleus in epitheloid HeLa cells and hematopoietic THP-1 cells. Lyn was definitely detected in purified nuclei by immunofluorescence and immunoblotting analyses. Nuclear accumulation of Lyn was enhanced upon treatment of cells with leptomycin B (LMB), an inhibitor of Crm1-mediated nuclear export. Moreover, Lyn mutants lacking the sites for lipid modification were highly accumulated in the nucleus upon LMB treatment. Intriguingly, inhibition of the kinase activity of Lyn by SU6656, Csk overexpression, or point mutation in the ATP-binding site induced an increase in nuclear Lyn levels. These results suggest that Lyn being imported into and rapidly exported from the nucleus preferentially accumulates in the nucleus by inhibition of the kinase activity and lipid modification

  5. Review: Lyn Richards (2005. Handling Qualitative Data: A Practical Guide

    Directory of Open Access Journals (Sweden)

    Robert L. Miller

    2006-03-01

    Full Text Available Handling Qualitative Data: A Practical Guide is an introductory textbook covering all stages of qualitative research from the initial conceptualisation of a project, through data collection and analysis, to writing up. The author, Lyn RICHARDS, is a well-known developer of two key qualitative software analysis packages, NUD*IST and NVivo. While RICHARDS clearly advocates the use of qualitative analysis software, the text is "generic" and could be used in tandem with any qualitative software package. The book concentrates on practical advice about the use of software to manage and analyse qualitative data, and provides insights in these areas. The consideration of issues around team-based qualitative research is another strong point. However, due in part to its short length, the overall coverage of topics tends to be superficial. In itself, the book does not provide sufficient detailed support for a student who would like to use it as her/his main source of guidance for carrying out a qualitative research project. URN: urn:nbn:de:0114-fqs0602244

  6. Role of Membrane Cholesterol Levels in Activation of Lyn upon Cell Detachment

    Directory of Open Access Journals (Sweden)

    Takao Morinaga

    2018-06-01

    Full Text Available Cholesterol, a major component of the plasma membrane, determines the physicalproperties of biological membranes and plays a critical role in the assembly of membranemicrodomains. Enrichment or deprivation of membrane cholesterol affects the activities of manysignaling molecules at the plasma membrane. Cell detachment changes the structure of the plasmamembrane and influences the localizations of lipids, including cholesterol. Recent studies showedthat cell detachment changes the activities of a variety of signaling molecules. We previously reportedthat the localization and the function of the Src-family kinase Lyn are critically regulated by itsmembrane anchorage through lipid modifications. More recently, we found that the localization andthe activity of Lyn were changed upon cell detachment, although the manners of which vary betweencell types. In this review, we highlight the changes in the localization of Lyn and a role of cholesterolin the regulation of Lyn’s activation following cell detachment.

  7. A novel signaling pathway associated with Lyn, PI 3-kinase and Akt supports the proliferation of myeloma cells

    Energy Technology Data Exchange (ETDEWEB)

    Iqbal, Mohd S. [Department of Bio-Signal Analysis, Applied Medical Engineering Science, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8505 (Japan); Enteric and Food Microbiology Laboratory, Laboratory Sciences Division, International Center for Diarrhoeal Disease Research, Bangladesh, P.O. Box 128, Dhaka 1000 (Bangladesh); Tsuyama, Naohiro [Department of Analytical Molecular Medicine and Devices, Division of Frontier Medical Science, Graduate School of Medical Sciences, Hiroshima University, Hiroshima, Hiroshima 734-8553 (Japan); Obata, Masanori [Department of Bio-Signal Analysis, Applied Medical Engineering Science, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8505 (Japan); Ishikawa, Hideaki, E-mail: hishika@yamaguchi-u.ac.jp [Department of Bio-Signal Analysis, Applied Medical Engineering Science, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8505 (Japan)

    2010-02-12

    Interleukin-6 (IL-6) is a growth factor for human myeloma cells. We have recently found that in myeloma cells the activation of both signal transducer and activator of transcription (STAT) 3 and extracellular signal-regulated kinase (ERK) 1/2 is not sufficient for the IL-6-induced proliferation, which further requires the activation of the src family kinases, such as Lyn. Here we showed that the Lyn-overexpressed myeloma cell lines had the higher proliferative rate with IL-6 and the enhanced activation of the phosphatidylinositol (PI) 3-kinase and Akt. The IL-6-induced phosphorylation of STAT3 and ERK1/2 was not up-regulated in the Lyn-overexpressed cells, indicating that the Lyn-PI 3-kinase-Akt pathway is independent of these pathways. The PI 3-kinase was co-precipitated with Lyn in the Lyn-overexpressed cells of which proliferation with IL-6 was abrogated by the specific inhibitors for PI 3-kinase or Akt, suggesting that the activation of the PI 3-kinase-Akt pathway associated with Lyn is indeed related to the concomitant augmentation of myeloma cell growth. Furthermore, the decreased expression of p53 and p21{sup Cip1} proteins was observed in the Lyn-overexpressed cells, implicating a possible downstream target of Akt. This study identifies a novel IL-6-mediated signaling pathway that certainly plays a role in the proliferation of myeloma cells and this novel mechanism of MM tumor cell growth associated with Lyn would eventually contribute to the development of MM treatment.

  8. CD44 regulates cell migration in human colon cancer cells via Lyn kinase and AKT phosphorylation.

    Science.gov (United States)

    Subramaniam, Venkateswaran; Vincent, Isabella R; Gardner, Helena; Chan, Emily; Dhamko, Helena; Jothy, Serge

    2007-10-01

    Colon cancer is among the leading causes of cancer death in North America. CD44, an adhesion and antiapoptotic molecule is overexpressed in colon cancer. Cofilin is involved in the directional motility of cells. In the present study, we looked at how CD44 might modulate cell migration in human colon cancer via cofilin. We used a human colon cancer cell line, HT29, which expresses CD44, HT29 where CD44 expression was knocked down by siRNA, SW620, a human colon cancer cell line which does not express CD44, stably transfected exons of CD44 in SW620 cells and the colon from CD44 knockout and wild-type mouse. Western blot analysis of siRNA CD44 lysates showed increased level of AKT phosphorylation and decreased level of cofilin expression. Similar results were also observed with SW620 cells and CD44 knockout mouse colon lysates. Experiments using the AKT phosphorylation inhibitor LY294002 indicate that AKT phosphorylation downregulates cofilin. Immunoprecipitation studies showed CD44 complex formation with Lyn, providing an essential link between CD44 and AKT phosphorylation. LY294002 also stabilized Lyn from phosphorylated AKT, suggesting an interaction between Lyn and AKT phosphorylation. Immunocytochemistry showed that cofilin and Lyn expression were downregulated in siRNA CD44 cells and CD44 knockout mouse colon. siRNA CD44 cells had significantly less migration compared to HT29 vector. Given the well-defined roles of CD44, phosphorylated AKT in apoptosis and cancer, these results indicate that CD44-induced cell migration is dependent on its complex formation with Lyn and its consequent regulation of AKT phosphorylation and cofilin expression.

  9. A systems toxicology approach identifies Lyn as a key signaling phosphoprotein modulated by mercury in a B lymphocyte cell model

    Energy Technology Data Exchange (ETDEWEB)

    Caruso, Joseph A.; Stemmer, Paul M. [Institute of Environmental Health Sciences, Wayne State University, Detroit, MI (United States); Dombkowski, Alan [Department of Pediatrics, Wayne State University, Detroit, MI (United States); Caruthers, Nicholas J. [Institute of Environmental Health Sciences, Wayne State University, Detroit, MI (United States); Gill, Randall [Department of Immunology and Microbiology, Wayne State University, Detroit, MI (United States); Rosenspire, Allen J., E-mail: arosenspire@wayne.edu [Department of Immunology and Microbiology, Wayne State University, Detroit, MI (United States)

    2014-04-01

    Network and protein–protein interaction analyses of proteins undergoing Hg{sup 2+}-induced phosphorylation and dephosphorylation in Hg{sup 2+}-intoxicated mouse WEHI-231 B cells identified Lyn as the most interconnected node. Lyn is a Src family protein tyrosine kinase known to be intimately involved in the B cell receptor (BCR) signaling pathway. Under normal signaling conditions the tyrosine kinase activity of Lyn is controlled by phosphorylation, primarily of two well known canonical regulatory tyrosine sites, Y-397 and Y-508. However, Lyn has several tyrosine residues that have not yet been determined to play a major role under normal signaling conditions, but are potentially important sites for phosphorylation following mercury exposure. In order to determine how Hg{sup 2+} exposure modulates the phosphorylation of additional residues in Lyn, a targeted MS assay was developed. Initial mass spectrometric surveys of purified Lyn identified 7 phosphorylated tyrosine residues. A quantitative assay was developed from these results using the multiple reaction monitoring (MRM) strategy. WEHI-231 cells were treated with Hg{sup 2+}, pervanadate (a phosphatase inhibitor), or anti-Ig antibody (to stimulate the BCR). Results from these studies showed that the phosphoproteomic profile of Lyn after exposure of the WEHI-231 cells to a low concentration of Hg{sup 2+} closely resembled that of anti-Ig antibody stimulation, whereas exposure to higher concentrations of Hg{sup 2+} led to increases in the phosphorylation of Y-193/Y-194, Y-501 and Y-508 residues. These data indicate that mercury can disrupt a key regulatory signal transduction pathway in B cells and point to phospho-Lyn as a potential biomarker for mercury exposure. - Highlights: • Inorganic mercury (Hg{sup 2+}) induces changes in the WEHI-231 B cell phosphoproteome. • The B cell receptor (BCR) signaling pathway was the pathway most affected by Hg{sup 2+}. • The Src family phosphoprotein kinase Lyn was the

  10. Mixed poloidal-toroidal magnetic configuration and surface abundance distributions of the Bp star 36 Lyn

    Science.gov (United States)

    Oksala, M. E.; Silvester, J.; Kochukhov, O.; Neiner, C.; Wade, G. A.; the MiMeS Collaboration

    2018-01-01

    Previous studies of the chemically peculiar Bp star 36 Lyn revealed a moderately strong magnetic field, circumstellar material and inhomogeneous surface abundance distributions of certain elements. We present in this paper an analysis of 33 high signal-to-noise ratio, high-resolution Stokes IV observations of 36 Lyn obtained with the Narval spectropolarimeter at the Bernard Lyot Telescope at Pic du Midi Observatory. From these data, we compute new measurements of the mean longitudinal magnetic field, Bℓ, using the multiline least-squares deconvolution (LSD) technique. A rotationally phased Bℓ curve reveals a strong magnetic field, with indications for deviation from a pure dipole field. We derive magnetic maps and chemical abundance distributions from the LSD profiles, produced using the Zeeman-Doppler imaging code INVERSLSD. Using a spherical harmonic expansion to characterize the magnetic field, we find that the harmonic energy is concentrated predominantly in the dipole mode (ℓ = 1), with significant contribution from both the poloidal and toroidal components. This toroidal field component is predicted theoretically, but not typically observed for Ap/Bp stars. Chemical abundance maps reveal a helium enhancement in a distinct region where the radial magnetic field is strong. Silicon enhancements are located in two regions, also where the radial field is stronger. Titanium and iron enhancements are slightly offset from the helium enhancements, and are located in areas where the radial field is weak, close to the magnetic equator.

  11. Public Lecture | The long road to the LHC | Prof. Lyn Evans, Dr. Daniel Treille and Prof. Peter Jenni | 9 October

    CERN Document Server

    2014-01-01

    “The long road to the LHC” by Prof. Lyn Evans, Dr. Daniel Treille and Prof. Peter Jenni. Thursday 9 October, 7.30 p.m. in the Globe of Science and Innovation. Talk in English with simultaneous interpreting into French.  Entrance free. Limited number of seats. Reservation essential: +41 22 767 76 76 or cern.reception@cern.ch   Lyn Evans. Lecture by Lyn Evans Abstract The key to the discovery of the Higgs boson has been the development of particle accelerators at CERN over the years. I will explain how a particle accelerator works and will follow the path from the construction of the Proton Synchrotron in the 1950s to the world’s most powerful colliding beam machine, the Large Hadron Collider. Biography Born in 1945, Lyn Evans has spent his whole career in the field of high energy physics and particle accelerators, participating in all the great projects of CERN. From 1993 he led the team that designed, built and commissioned the LHC. He is currently ...

  12. The Src family kinase Hck regulates mast cell activation by suppressing an inhibitory Src family kinase Lyn

    Czech Academy of Sciences Publication Activity Database

    Hong, H.; Kitaura, J.; Xiao, W.; Hořejší, Václav; Ra, C.; Lowell, C.A.; Kawakami, Y.; Kawakami, T.

    2007-01-01

    Roč. 110, č. 7 (2007), s. 2511-2519 ISSN 0006-4971 Institutional research plan: CEZ:AV0Z50520514 Keywords : Hck * Lyn * kinasa Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 10.896, year: 2007

  13. Chemical Composition of RR Lyn - an Eclipsing Binary System with Am and λ Boo Type Components

    Science.gov (United States)

    Jeong, Yeuncheol; Yushchenko, Alexander V.; Doikov, Dmytry N.; Gopka, Vira F.; Yushchenko, Volodymyr O.

    2017-06-01

    High-resolution spectroscopic observations of the eclipsing binary system RR Lyn were made using the 1.8 m telescope at the Bohuynsan Optical Astronomical Observatory in Korea. The spectral resolving power was R = 82,000, with a signal to noise ratio of S/N > 150. We found the effective temperatures and surface gravities of the primary and secondary components to be equal to Teff = 7,920 & 7,210 K and log(g) = 3.80 & 4.16, respectively. The abundances of 34 and 17 different chemical elements were found in the atmospheric components. Correlations between the derived abundances with condensation temperatures and the second ionization potentials of these elements are discussed. The primary component is a typical metallic line star with the abundances of light and iron group elements close to solar values, while elements with atomic numbers Z > 30 are overabundant by 0.5-1.5 dex with respect to solar values. The secondary component is a λ Boo type star. In this type of stars, CNO abundances are close to solar values, while the abundance pattern shows a negative correlation with condensation temperatures.

  14. Selective expression of a protein-tyrosine kinase, p56lyn, in hematopoietic cells and association with production of human T-cell lymphotropic virus type I

    International Nuclear Information System (INIS)

    Yamanashi, Yuji; Mori, Shigeo; Inoue, Kazushi; Yamamoto, Tadashi; Toyoshima, Kumao; Yoshida, Mitsuaki; Kishimoto, Tadamitsu

    1989-01-01

    This paper reports the identification of the lyn gene product, a member of the src-related family of protein-tyrosine kinases, and its expression in hematopoietic cells. A lyn-specific sequence (Arg-25 to Ala-119 of the protein) was expressed in Escherichia coli as a fusion protein with β-galactosidase. Antiserum raised against the fusion protein immunoprecipitated a 56-kDa protein from human B lymphocytes. Incubation of the immunoprecipitate with [γ- 32 P]ATP resulted in the phosphorylation of this protein at tyrosine residues. Immunohistological and immunoblotting analyses showed that the lyn gene product was expressed in lymphatic tissues (spleen and tonsil) and in adult lung, which contains many macrophages. Furthermore, both the transcripts and the protein products of the lyn gene accumulated in macrophages/monocytes, platelets, and B lymphocytes but were not expressed appreciably in granulocytes, erythrocytes, or T lymphocytes, suggesting that lyn gene products function primarily in certain differentiated cells of lymphoid and myeloid lineages

  15. Roles for SH2 and SH3 domains in Lyn kinase association with activated FcepsilonRI in RBL mast cells revealed by patterned surface analysis.

    Science.gov (United States)

    Hammond, Stephanie; Wagenknecht-Wiesner, Alice; Veatch, Sarah L; Holowka, David; Baird, Barbara

    2009-10-01

    In mast cells, antigen-mediated cross-linking of IgE bound to its high-affinity surface receptor, FcepsilonRI, initiates a signaling cascade that culminates in degranulation and release of allergic mediators. Antigen-patterned surfaces, in which the antigen is deposited in micron-sized features on a silicon substrate, were used to examine the spatial relationship between clustered IgE-FcepsilonRI complexes and Lyn, the signal-initiating tyrosine kinase. RBL mast cells expressing wild-type Lyn-EGFP showed co-redistribution of this protein with clustered IgE receptors on antigen-patterned surfaces, whereas Lyn-EGFP containing an inhibitory point mutation in its SH2 domain did not significantly accumulate with the patterned antigen, and Lyn-EGFP with an inhibitory point mutation in its SH3 domain exhibited reduced interactions. Our results using antigen-patterned surfaces and quantitative cross-correlation image analysis reveal that both the SH2 and SH3 domains contribute to interactions between Lyn kinase and cross-linked IgE receptors in stimulated mast cells.

  16. The non-receptor tyrosine kinase Lyn controls neutrophil adhesion by recruiting the CrkL–C3G complex and activating Rap1 at the leading edge

    Science.gov (United States)

    He, Yuan; Kapoor, Ashish; Cook, Sara; Liu, Shubai; Xiang, Yang; Rao, Christopher V.; Kenis, Paul J. A.; Wang, Fei

    2011-01-01

    Establishing new adhesions at the extended leading edges of motile cells is essential for stable polarity and persistent motility. Despite recent identification of signaling pathways that mediate polarity and chemotaxis in neutrophils, little is known about molecular mechanisms governing cell–extracellular-matrix (ECM) adhesion in these highly polarized and rapidly migrating cells. Here, we describe a signaling pathway in neutrophils that is essential for localized integrin activation, leading edge attachment and persistent migration during chemotaxis. This pathway depends upon Gi-protein-mediated activation and leading edge recruitment of Lyn, a non-receptor tyrosine kinase belonging to the Src kinase family. We identified the small GTPase Rap1 as a major downstream effector of Lyn to regulate neutrophil adhesion during chemotaxis. Depletion of Lyn in neutrophil-like HL-60 cells prevented chemoattractant-induced Rap1 activation at the leading edge of the cell, whereas ectopic expression of Rap1 largely rescued the defects induced by Lyn depletion. Furthermore, Lyn controls spatial activation of Rap1 by recruiting the CrkL–C3G protein complex to the leading edge. Together, these results provide novel mechanistic insights into the poorly understood signaling network that controls leading edge adhesion during chemotaxis of neutrophils, and possibly other amoeboid cells. PMID:21628423

  17. Tekoäly varallisuuden hoitajana : Nuorten aikuisten mielipiteitä tekoälyn käytöstä sijoitusneuvonnassa ja varainhoidossa

    OpenAIRE

    Tynjälä, Tuomas

    2017-01-01

    Opinnäytetyön tavoitteena oli selvittää tekoälyn käyttöä sijoitusneuvonnassa ja varainhoidossa sekä tutkia suuntaa antavasti nuorten aikuisten mielipiteitä aiheesta. Tarkoituksena oli esitellä robottisijoitusneuvojien toimintaa ja menestystä sijoitusmarkkinoilla sekä selvittää, miten nuoret aikuiset potentiaalisina asiakkaina suhtautuvat tällaiseen palveluun. Koska tekoälyn tarjoamat sijoituspalvelut ovat olleet suuri puheenaihe sijoitusmarkkinoilla viime aikoina, opinnäytetyö on hyvin ajanko...

  18. Tyrosine Phosphorylation of the Lyn Src Homology 2 (SH2) Domain Modulates Its Binding Affinity and Specificity*

    Science.gov (United States)

    Jin, Lily L.; Wybenga-Groot, Leanne E.; Tong, Jiefei; Taylor, Paul; Minden, Mark D.; Trudel, Suzanne; McGlade, C. Jane; Moran, Michael F.

    2015-01-01

    Src homology 2 (SH2) domains are modular protein structures that bind phosphotyrosine (pY)-containing polypeptides and regulate cellular functions through protein-protein interactions. Proteomics analysis showed that the SH2 domains of Src family kinases are themselves tyrosine phosphorylated in blood system cancers, including acute myeloid leukemia, chronic lymphocytic leukemia, and multiple myeloma. Using the Src family kinase Lyn SH2 domain as a model, we found that phosphorylation at the conserved SH2 domain residue Y194 impacts the affinity and specificity of SH2 domain binding to pY-containing peptides and proteins. Analysis of the Lyn SH2 domain crystal structure supports a model wherein phosphorylation of Y194 on the EF loop modulates the binding pocket that engages amino acid side chains at the pY+2/+3 position. These data indicate another level of regulation wherein SH2-mediated protein-protein interactions are modulated by SH2 kinases and phosphatases. PMID:25587033

  19. Tyrosine phosphorylation of the Lyn Src homology 2 (SH2) domain modulates its binding affinity and specificity.

    Science.gov (United States)

    Jin, Lily L; Wybenga-Groot, Leanne E; Tong, Jiefei; Taylor, Paul; Minden, Mark D; Trudel, Suzanne; McGlade, C Jane; Moran, Michael F

    2015-03-01

    Src homology 2 (SH2) domains are modular protein structures that bind phosphotyrosine (pY)-containing polypeptides and regulate cellular functions through protein-protein interactions. Proteomics analysis showed that the SH2 domains of Src family kinases are themselves tyrosine phosphorylated in blood system cancers, including acute myeloid leukemia, chronic lymphocytic leukemia, and multiple myeloma. Using the Src family kinase Lyn SH2 domain as a model, we found that phosphorylation at the conserved SH2 domain residue Y(194) impacts the affinity and specificity of SH2 domain binding to pY-containing peptides and proteins. Analysis of the Lyn SH2 domain crystal structure supports a model wherein phosphorylation of Y(194) on the EF loop modulates the binding pocket that engages amino acid side chains at the pY+2/+3 position. These data indicate another level of regulation wherein SH2-mediated protein-protein interactions are modulated by SH2 kinases and phosphatases. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. Lyn tyrosine kinase promotes silencing of ATM-dependent checkpoint signaling during recovery from DNA double-strand breaks

    International Nuclear Information System (INIS)

    Fukumoto, Yasunori; Kuki, Kazumasa; Morii, Mariko; Miura, Takahito; Honda, Takuya; Ishibashi, Kenichi; Hasegawa, Hitomi; Kubota, Sho; Ide, Yudai; Yamaguchi, Noritaka; Nakayama, Yuji; Yamaguchi, Naoto

    2014-01-01

    Highlights: • Inhibition of Src family kinases decreased γ-H2AX signal. • Inhibition of Src family increased ATM-dependent phosphorylation of Chk2 and Kap1. • shRNA-mediated knockdown of Lyn increased phosphorylation of Kap1 by ATM. • Ectopic expression of Src family kinase suppressed ATM-mediated Kap1 phosphorylation. • Src is involved in upstream signaling for inactivation of ATM signaling. - Abstract: DNA damage activates the DNA damage checkpoint and the DNA repair machinery. After initial activation of DNA damage responses, cells recover to their original states through completion of DNA repair and termination of checkpoint signaling. Currently, little is known about the process by which cells recover from the DNA damage checkpoint, a process called checkpoint recovery. Here, we show that Src family kinases promote inactivation of ataxia telangiectasia mutated (ATM)-dependent checkpoint signaling during recovery from DNA double-strand breaks. Inhibition of Src activity increased ATM-dependent phosphorylation of Chk2 and Kap1. Src inhibition increased ATM signaling both in G2 phase and during asynchronous growth. shRNA knockdown of Lyn increased ATM signaling. Src-dependent nuclear tyrosine phosphorylation suppressed ATM-mediated Kap1 phosphorylation. These results suggest that Src family kinases are involved in upstream signaling that leads to inactivation of the ATM-dependent DNA damage checkpoint

  1. Src-family-tyrosine kinase Lyn is critical for TLR2-mediated NF-κB activation through the PI 3-kinase signaling pathway.

    Science.gov (United States)

    Toubiana, Julie; Rossi, Anne-Lise; Belaidouni, Nadia; Grimaldi, David; Pene, Frederic; Chafey, Philippe; Comba, Béatrice; Camoin, Luc; Bismuth, Georges; Claessens, Yann-Erick; Mira, Jean-Paul; Chiche, Jean-Daniel

    2015-10-01

    TLR2 has a prominent role in host defense against a wide variety of pathogens. Stimulation of TLR2 triggers MyD88-dependent signaling to induce NF-κB translocation, and activates a Rac1-PI 3-kinase dependent pathway that leads to transactivation of NF-κB through phosphorylation of the P65 NF-κB subunit. This transactivation pathway involves tyrosine phosphorylations. The role of the tyrosine kinases in TLR signaling is controversial, with discrepancies between studies using only chemical inhibitors and knockout mice. Here, we show the involvement of the tyrosine-kinase Lyn in TLR2-dependent activation of NF-κB in human cellular models, by using complementary inhibition strategies. Stimulation of TLR2 induces the formation of an activation cluster involving TLR2, CD14, PI 3-kinase and Lyn, and leads to the activation of AKT. Lyn-dependent phosphorylation of the p110 catalytic subunit of PI 3-kinase is essential to the control of PI 3-kinase biological activity upstream of AKT and thereby to the transactivation of NF-κB. Thus, Lyn kinase activity is crucial in TLR2-mediated activation of the innate immune response in human mononuclear cells. © The Author(s) 2015.

  2. Structure-function analysis of Lyn kinase association with lipid rafts and intiation of early signaling events after Fc epsilon receptor I aggregation

    Czech Academy of Sciences Publication Activity Database

    Kovářová, Martina; Tolar, Pavel; Arudchandran, R.; Dráberová, Lubica; Rivera, J.; Dráber, Petr

    2001-01-01

    Roč. 21, č. 24 (2001), s. 8318-8328 ISSN 0270-7306 Institutional research plan: CEZ:AV0Z5052915 Keywords : Lyn kinase * IgE receptor * acylation Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 9.836, year: 2001

  3. ENIGMATIC RECURRENT PULSATIONAL VARIABILITY OF THE ACCRETING WHITE DWARF EQ LYN (SDSS J074531.92+453829.6)

    Energy Technology Data Exchange (ETDEWEB)

    Mukadam, Anjum S.; Szkody, Paula [Department of Astronomy, University of Washington, Seattle, WA 98195-1580 (United States); Townsley, D. M.; Brockett, T. [Department of Physics and Astronomy, University of Alabama, Tuscaloosa, AL 35487 (United States); Gaensicke, B. T.; Parsons, S. [Department of Physics, University of Warwick, Coventry CV4 7AL (United Kingdom); Southworth, J. [Astrophysics Group, Keele University, Staffordshire ST5 5BG (United Kingdom); Hermes, J. J.; Montgomery, M. H.; Winget, D. E.; Harrold, S. [Department of Astronomy, University of Texas at Austin, Austin, TX 78759 (United States); Tovmassian, G.; Zharikov, S. [Observatorio Astronomico Nacional SPM, Instituto de Astronomia, Universidad Nacional Autonoma de Mexico, Ensenada, BC (Mexico); Drake, A. J. [Department of Astronomy and the Center for Advanced Computing Research, California Institute of Technology, Pasadena, CA 91225 (United States); Henden, A. [American Association of Variable Star Observers, 25 Birch Street, Cambridge, MA 02138 (United States); Rodriguez-Gil, P. [Departamento de Astrofisica, Universidad de La Laguna, La Laguna, E-38204 Santa Cruz de Tenerife (Spain); Sion, E. M. [Department of Astronomy and Astrophysics, Villanova University, Villanova, PA 19085 (United States); Zola, S.; Szymanski, T. [Astronomical Observatory, Jagiellonian University, ul. Orla 171, PL-30-244 Krakow (Poland); Pavlenko, E. [Crimean Astrophysical Observatory, Crimea 98409 (Ukraine); and others

    2013-09-15

    Photometric observations of the cataclysmic variable EQ Lyn (SDSS J074531.92+453829.6), acquired from 2005 October to 2006 January, revealed high-amplitude variability in the range 1166-1290 s. This accreting white dwarf underwent an outburst in 2006 October, during which its brightness increased by at least five magnitudes, and it started exhibiting superhumps in its light curve. Upon cooling to quiescence, the superhumps disappeared and it displayed the same periods in 2010 February as prior to the outburst within the uncertainties of a couple of seconds. This behavior suggests that the observed variability is likely due to nonradial pulsations in the white dwarf star, whose core structure has not been significantly affected by the outburst. The enigmatic observations begin with an absence of pulsational variability during a multi-site campaign conducted in 2011 January-February without any evidence of a new outburst; the light curve is instead dominated by superhumps with periods in the range of 83-87 minutes. Ultraviolet Hubble Space Telescope time-series spectroscopy acquired in 2011 March reveals an effective temperature of 15,400 K, placing EQ Lyn within the broad instability strip of 10,500-16,000 K for accreting pulsators. The ultraviolet light curve with 90% flux from the white dwarf shows no evidence of any pulsations. Optical photometry acquired during 2011 and Spring 2012 continues to reflect the presence of superhumps and an absence of pulsations. Subsequent observations acquired in 2012 December and 2013 January finally indicate the disappearance of superhumps and the return of pulsational variability with similar periods as previous data. However, our most recent data from 2013 March to May reveal superhumps yet again with no sign of pulsations. We speculate that this enigmatic post-outburst behavior of the frequent disappearance of pulsational variability in EQ Lyn is caused either by heating the white dwarf beyond the instability strip due to an

  4. Nuclear expression of Lyn, a Src family kinase member, is associated with poor prognosis in renal cancer patients.

    Science.gov (United States)

    Roseweir, Antonia K; Qayyum, Tahir; Lim, Zhi; Hammond, Rachel; MacDonald, Alasdair I; Fraser, Sioban; Oades, Grenville M; Aitchison, Michael; Jones, Robert J; Edwards, Joanne

    2016-03-16

    8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50%. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). SFKs have roles in multiple oncogenic processes and promote metastases in solid tumours. The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC). SFKs expression was assessed in a tissue microarray consisting of 192 ccRCC patients with full clinical follow-up. SFK inhibitors, dasatinib and saracatinib, were assessed in early ccRCC cell lines, 786-O and 769-P and a metastatic ccRCC cell line, ACHN (± Src) for effects on protein expression, apoptosis, proliferation and wound healing. High nuclear expression of Lyn and the downstream marker of activation, paxillin, were associated with decreased patient survival. Conversely, high cytoplasmic expression of other SFK members and downstream marker of activation, focal adhesion kinase (FAK) were associated with increased patient survival. Treatment of non-metastatic 786-O and 769-P cells with dasatinib, dose dependently reduced SFK activation, shown via SFK (Y(419)) and FAK (Y(861)) phosphorylation, with no effect in metastatic ACHN cells. Dasatinib also increased apoptosis, while decreasing proliferation and migration in 786-O and 769-P cell lines, both in the presence and absence of Src protein. Our data suggests that nuclear Lyn is a potential therapeutic target for ccRCC and dasatinib affects cellular functions associated with cancer progression via a Src kinase independent mechanism.

  5. “There is nothing better than a theory”: A few remarks on the theoretical practice of contemporary avantgarde women writers (Lyn Hejinian, Leslie Scalapino, Carla Harryman)

    OpenAIRE

    Małgorzata Myk

    2013-01-01

    The essay discusses theoretical practices of three major Americanexperimental women writers associated with L=A=N=G=U=A=G=E poets LynHejinian, Leslie Scalapino, and Carla Harryman, who played a crucial role in shapingthe present-day critical and theoretical literary debate regarding the status of formallyradical literature engaged in questions of feminist epistemology and written bywomen. Devoted to language and its ideological dimension, their work is based ona wager that poetic practice is ...

  6. Chemical Composition of RR Lyn – an Eclipsing Binary System with Am and λ Boo Type Components

    Directory of Open Access Journals (Sweden)

    Yeuncheol Jeong

    2017-06-01

    Full Text Available High-resolution spectroscopic observations of the eclipsing binary system RR Lyn were made using the 1.8 m telescope at the Bohuynsan Optical Astronomical Observatory in Korea. The spectral resolving power was R = 82,000, with a signal to noise ratio of S/N > 150. We found the effective temperatures and surface gravities of the primary and secondary components to be equal to Teff = 7,920 & 7,210 K and log(g = 3.80 & 4.16, respectively. The abundances of 34 and 17 different chemical elements were found in the atmospheric components. Correlations between the derived abundances with condensation temperatures and the second ionization potentials of these elements are discussed. The primary component is a typical metallic line star with the abundances of light and iron group elements close to solar values, while elements with atomic numbers Z > 30 are overabundant by 0.5–1.5 dex with respect to solar values. The secondary component is a λ Boo type star. In this type of stars, CNO abundances are close to solar values, while the abundance pattern shows a negative correlation with condensation temperatures.

  7. Protein tyrosine kinases p53/56lyn and p72syk in MHC class I-mediated signal transduction in B lymphoma cells

    DEFF Research Database (Denmark)

    Pedersen, Anders Elm; Bregenholt, S; Skov, S

    1998-01-01

    syk are among the tyrosine-phosphorylated proteins. The kinetics of phosphorylation of these kinases after MHC-I crosslinking differ from the kinetics observed after crosslinking of the B cell antigen receptor (BCR). Additional experiments were performed with chicken lyn- and syk-negative DT40 B cells...... mobilization of intracellular free calcium compared with MHC-I crosslinking of wild-type DT40 cells. Thus, expression of BCR at the cell surface is likely to be important for the signal cascade initiated by MHC-I crosslinking. Our data suggest that signal transduction initiated through ligation of the MHC...

  8. Comment on ‘Empirical versus modelling approaches to the estimation of measurement uncertainty caused by primary sampling’ by J. A. Lyn, M. H. Ramsey, A. P. Damant and R. Wood

    NARCIS (Netherlands)

    Geelhoed, B.

    2009-01-01

    Recently, Lyn et al. (Analyst, 2007, 132, 1231) compared two ways of estimating the standard uncertainty of sampling pistachio nuts for aflatoxins – a modelling method and an empirical method. Their case study used robust analysis of variance (RANOVA) to derive the uncertainty estimates,

  9. Phase I Study of INNO-406, a Dual Abl/Lyn Kinase Inhibitor, in Philadelphia Chromosome-Positive Leukemias Post-Imatinib Resistance or Intolerance

    Science.gov (United States)

    Kantarjian, H.; le Coutre, P.; Cortes, J.; Pinilla-Ibarz, J.; Nagler, A.; Hochhaus, A.; Kimura, S.; Ottmann, O.

    2010-01-01

    BACKGROUND INNO-406, an oral dual Abl/Lyn tyrosine kinase inhibitor (TKI), demonstrates specific Lyn kinase activity with no or limited activity against other Src-family member kinases. Several Bcr-Abl kinase domain mutations are sensitive to INNO-406 in vitro, including the F317L and F317V mutations. In this study, we evaluated INNO-406 in Philadelphia (Ph) chromosome–positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) post-imatinib resistance or intolerance. METHODS A dose escalation study was conducted with a starting dose of 30mg administered orally once daily. Cohorts of at least 3 patients were treated at each dose level until the maximum tolerated dose (MTD) was reached. Twice-daily (BID) dosing was also evaluated. Therapy was allowed for a maximum of 24 months. RESULTS INNO-406 was administered to 56 patients with imatinib resistance (n=40) or intolerance (n=16). Other previous treatments included nilotinib (n=20), dasatinib (n=26), and dasatinib/nilotinib (n=9). Common mutations upon study entry included Y253H (n=6), G250E (n=4), T315I (n=4) and F317L (n=3). Among 31 patients with CML in chronic phase treated with INNO-406, the major cytogenetic response rate was 19%. In this study, no responses were seen in patients with CML-AP, CML-BP, or Ph-positive ALL. Dose-limiting toxicities (DLTs) at INNO-406 480mg BID were liver function abnormalities and thrombocytopenia. CONCLUSIONS INNO-406 showed anti-CML efficacy in this heavily pretreated study population. Based on the classical determinations of both DLT and MTD, the recommended phase 2 dose of INNO-406 is 240mg orally BID. Lower doses of INNO-406 may be equally effective and should be explored. PMID:20310049

  10. Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance.

    Science.gov (United States)

    Kantarjian, Hagop; le Coutre, Phillipp; Cortes, Jorge; Pinilla-Ibarz, Javier; Nagler, Arnon; Hochhaus, Andreas; Kimura, Shinya; Ottmann, Oliver

    2010-06-01

    : INNO-406, a dual v-abl Abelson murine leukemia viral oncogene homolog (Abl)/v-yes-1 Yamaguchi sarcoma viral-related oncogene homolog (Lyn) tyrosine kinase inhibitor (TKI), has demonstrated specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. Several breakpoint cluster region (Bcr)-Abl kinase domain mutations are sensitive to INNO-406 in vitro, including mutations that involve a phenylalanine-to-leucine or phenylalanine-to-valine substitution at codon 317 (F317L and F317V, respectively). In the current study, the authors evaluated the use of INNO-406 in patients with Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) after imatinib resistance or intolerance. : A dose-escalation study was conducted at a starting dose of oral INNO-406 30 mg once daily. Cohorts of at least 3 patients were treated at each dose level until the maximum tolerated dose (MTD) was reached. Twice-daily dosing also was evaluated. Therapy was allowed to continue for a maximum of 24 months. : INNO-406 was administered to 56 patients with imatinib resistance (n = 40) or intolerance (n = 16). Other previous treatments included nilotinib (n = 20 patients), dasatinib (n = 26 patients), and dasatinib/nilotinib (n = 9 patients). Common mutations at the time of study entry included a tyrosine-to-histidine substitution at codon 253 (Y253H) (n = 6 patients), a glycine-to-glutamic acid substitution at codon 250 (G250E) (n = 4 patients), a threonine-to-isoleucine substitution at codon 315 (T315I) (n = 4 patients), and F317L (n = 3 patients). Of 31 patients with CML in chronic phase who received INNO-406, the major cytogenetic response rate was 19%. No responses were observed in patients who had CML in accelerated phase, CML in blastic phase, or Ph-positive ALL. The dose-limiting toxicities (DLTs) at an INNO-406 dose of 480 mg twice daily were liver function abnormalities and

  11. “There is nothing better than a theory”: A few remarks on the theoretical practice of contemporary avantgarde women writers (Lyn Hejinian, Leslie Scalapino, Carla Harryman

    Directory of Open Access Journals (Sweden)

    Małgorzata Myk

    2013-01-01

    Full Text Available The essay discusses theoretical practices of three major Americanexperimental women writers associated with L=A=N=G=U=A=G=E poets LynHejinian, Leslie Scalapino, and Carla Harryman, who played a crucial role in shapingthe present-day critical and theoretical literary debate regarding the status of formallyradical literature engaged in questions of feminist epistemology and written bywomen. Devoted to language and its ideological dimension, their work is based ona wager that poetic practice is a socially engaged strategy of intervention (Harryman,and as such functions as a language-oriented feminist epistemology. Hejinian,Scalapino, and Harryman created a significant literary and theoretical body of workthat includes complex genre-bending hybrid texts deeply rooted in contemporaryfeminist discourses and preoccupied with such issues as production of knowledge,meaning, identity, gender, and sexuality, hidden ideological mechanismsof the conventional narrative, and the imperative of its constant refiguration.The article is also an attempt to see their work in a broader context of feministthought, ranging from écriture féminine, through Judith Butler’s and Denise Riley’scritiques of identity politics, to the posthumanist horizon of Donna Haraway’scyborg writing.

  12. Fer and Fps/Fes participate in a Lyn-dependent pathway from FcepsilonRI to platelet-endothelial cell adhesion molecule 1 to limit mast cell activation.

    Science.gov (United States)

    Udell, Christian M; Samayawardhena, Lionel A; Kawakami, Yuko; Kawakami, Toshiaki; Craig, Andrew W B

    2006-07-28

    Mast cells express the high affinity IgE receptor FcepsilonRI, which upon aggregation by multivalent antigens elicits signals that cause rapid changes within the mast cell and in the surrounding tissue. We previously showed that FcepsilonRI aggregation caused a rapid increase in phosphorylation of both Fer and Fps/Fes kinases in bone marrow-derived mast cells. In this study, we report that FcepsilonRI aggregation leads to increased Fer/Fps kinase activities and that Fer phosphorylation downstream of FcepsilonRI is independent of Syk, Fyn, and Gab2 but requires Lyn. Activated Fer/Fps readily phosphorylate the C terminus of platelet-endothelial cell adhesion molecule 1 (Pecam-1) on immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and a non-ITIM residue (Tyr(700)) in vitro and in transfected cells. Mast cells devoid of Fer/Fps kinase activities display a reduction in FcepsilonRI aggregation-induced tyrosine phosphorylation of Pecam-1, with no defects in recruitment of Shp1/Shp2 phosphatases observed. Lyn-deficient mast cells display a dramatic reduction in Pecam-1 phosphorylation at Tyr(685) and a complete loss of Shp2 recruitment, suggesting a role as an initiator kinase for Pecam-1. Consistent with previous studies of Pecam-1-deficient mast cells, we observe an exaggerated degranulation response in mast cells lacking Fer/Fps kinases at low antigen dosages. Thus, Lyn and Fer/Fps kinases cooperate to phosphorylate Pecam-1 and activate Shp1/Shp2 phosphatases that function in part to limit mast cell activation.

  13. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity.

    Science.gov (United States)

    Yokota, Asumi; Kimura, Shinya; Masuda, Satohiro; Ashihara, Eishi; Kuroda, Junya; Sato, Kiyoshi; Kamitsuji, Yuri; Kawata, Eri; Deguchi, Yasuyuki; Urasaki, Yoshimasa; Terui, Yasuhito; Ruthardt, Martin; Ueda, Takanori; Hatake, Kiyohiko; Inui, Ken-ichi; Maekawa, Taira

    2007-01-01

    Central nervous system (CNS) relapse accompanying the prolonged administration of imatinib mesylate has recently become apparent as an impediment to the therapy of Philadelphia chromosome-positive (Ph+) leukemia. CNS relapse may be explained by limited penetration of imatinib mesylate into the cerebrospinal fluid because of the presence of P-glycoprotein at the blood-brain barrier. To overcome imatinib mesylate-resistance mechanisms such as bcr-abl amplification, mutations within the ABL kinase domain, and activation of Lyn, we developed a dual BCR-ABL/Lyn inhibitor, INNO-406 (formerly NS-187), which is 25 to 55 times more potent than imatinib mesylate in vitro and at least 10 times more potent in vivo. The aim of this study was to investigate the efficacy of INNO-406 in treating CNS Ph+ leukemia. We found that INNO-406, like imatinib mesylate, is a substrate for P-glycoprotein. The concentrations of INNO-406 in the CNS were about 10% of those in the plasma. However, this residual concentration was enough to inhibit the growth of Ph+ leukemic cells which expressed not only wild-type but also mutated BCR-ABL in the murine CNS. Furthermore, cyclosporine A, a P-glycoprotein inhibitor, augmented the in vivo activity of INNO-406 against CNS Ph+ leukemia. These findings indicate that INNO-406 is a promising agent for the treatment of CNS Ph+ leukemia.

  14. University of Geneva honours LHC project leader Lyn Evans at 450th anniversary ceremony. The honorary degrees, which recognize endeavours in human rights and in fostering dialogue between nations, were also awarded to Mary Robinson, Desmond Tutu, as well as Pascal Lamy .

    CERN Multimedia

    Maximilien Brice

    2009-01-01

    University of Geneva honours LHC project leader Lyn Evans at 450th anniversary ceremony. The honorary degrees, which recognize endeavours in human rights and in fostering dialogue between nations, were also awarded to Mary Robinson, Desmond Tutu, as well as Pascal Lamy .

  15. Overcoming imatinib resistance using Src inhibitor CGP76030, Abl inhibitor nilotinib and Abl/Lyn inhibitor INNO-406 in newly established K562 variants with BCR-ABL gene amplification.

    Science.gov (United States)

    Morinaga, Koji; Yamauchi, Takahiro; Kimura, Shinya; Maekawa, Taira; Ueda, Takanori

    2008-06-01

    Because imatinib (IM) resistance in chronic myeloid leukemia is primarily caused by the re-establishment of Abl kinase, new inhibitors may be efficacious. We evaluated 3 new agents against 2 new K562 variants, IM-R1 and IM-R2 cells, which were developed having 7- and 27-fold greater IM resistance, respectively, than the parental K562 cells. Both variants possessed BCR-ABL gene amplification along with elevated levels of its transcript and protein. Greater BCR-ABL gene amplification was observed in IM-R2 cells than in IM-R1 cells, which was consistent with the higher mRNA and protein levels of Bcr-Abl, and ultimately correlated with the greater IM resistance in IM-R2 cells. No mutation in the Abl kinase domain was detected in either variant. Despite the absence of Lyn overexpression, the Src kinase inhibitor CGP76030 showed positive cooperability with IM in inhibiting cell growth of not only K562 cells but also these 2 variants. This might be because of the augmented inhibition of Erk1/2 phosphorylation. The new Abl kinase inhibitor nilotinib was 10-fold more potent than IM in inhibiting the growth of K562 cells. Nilotinib inhibited the growth of IM-R1 and IM-R2 cells as potently as K562 cells. The combination of nilotinib with CGP76030 showed little additivity, because the potency of nilotinib masked the efficacy of CGP76030. The new dual Abl/Lyn inhibitor INNO-406 (formerly NS-187) was slightly more potent than nilotinib in inhibiting the growth of all 3 cell lines. Because BCR-ABL gene amplification occurs in blast crisis, these inhibitors might overcome IM resistance in such patients' leukemia. (c) 2008 Wiley-Liss, Inc.

  16. 76 FR 19373 - Cathryn Lyn Chatman (also known as Cathryn Lyn Garcia): Debarment Order

    Science.gov (United States)

    2011-04-07

    ... States District Court for the District of Oregon entered judgment against Ms. Chatman for misdemeanor... as follows: Ms. Chatman was a registered nurse licensed by the Oregon Board of Nursing. Throughout...

  17. Anatomy and histology of Embolyntha batesi MacLahlan, 1877 (Embiidina Anatomia e histologia de Embolyntha batesi MacLachlan, 1877 (Embiidina

    Directory of Open Access Journals (Sweden)

    Dyrce Lacombe

    1971-01-01

    Full Text Available The Embioptera are rather generalized insects whose internal anatomy is simple and not subject to great modifications. For this reason these insects form an ideal group for elementary anatomical and histological studies (fig. 2. The digestive tract is a long, simple tube without convolutions or diverticulae from the buccal cavity to the rectum. The buccal structures are of the chewing type. The oesophagus and ingluvia are differentiated only by slight dilation of their walls. In nymphs and females the proventriculus is very distinct due to folds which flatten as the structure becomes packed with food. The enteron is the largest in such forms and in both sexes limited caudally by the Malpighian tubules. The proctodeus has six large rectal papillae. The nervous system is complete with only the fifth abdominal segment lacking a ganglion in the metathorax includes the ganglion of the first abdominal segment. The brain exhibits very clear structure in histological sections. The tracheal system includes two pairs of thoracic spiracles and eight abdominal pairs. Only th metathoracic spiracle has an air expiration function; all others serve for inspiration. Various structures in the spiracles protect the atrium. The circulatory system includes a long, simple dorsal vessel which extends forward from the ninth abdominal segment into the cranium. It opens anteriorly near the circumoesophageal connectives. The dorsal vessel has a pair of ostia and valves corresponding to each abdominal and thoracic segment. It lacks the diverticulae or folds commonly found in more highly evolved insects. The excretory system is represented by Malphighian tubules, pericardial cells, and fat-body. The number and disposition of Malpighian tubules is variable within the order. The pericardial cells are localized around the entire dorsal vessel up to the opening of the aorta in the head. The fat-bodies form compact layers in the dorsal and ventral regions of the body. In males they are more developed in the abdominal region. The mandibles, maxillae, and salivary glands are of a simple type with very few cytological modifications. Only the salivary glands which extend into the mesothoracic region show appreciable specialization. The reproductive system is bi-sixual and shows considerable sexual dimorphism. Males have five pair of testes with a metameric disposition, two distinct ducts, two epidymis, and the ejaculatory organs. The accessory glands vary in number and size and open in the anterior portion of the ejaculatory duct. The female reproductive organs are of the panoistic type. The system includes five pairs of ovarioles, two long paired oviducts a small, unpaired oviduct and the spermatheca which opens in the vagina. Reproduction usually involves a union of male and female gametes, and eggs are usually laid in clusters attached to a substrate.Os Embioptera constituem uma ordem de insetos de anatomia interna muito simples e com poucas modificações. Por esta razão formam um grupo ideal para estudos anatômicos e histológicos dos insetos (fig. 2. O tubo digestivo é longo e simples, sem divertículo e dobras. A estrutura bucal é do tipo mastigador. O esôfago e a ingl~uvia diferenciam-se pela forte dilatação, epitélio e formação muscular. Em ninfas de ambos os sexos e em fêmeas, o proventrículo é repleto de dobras. O enterom é muito longo, sendo limitado, posteriormente, pelos tubos de Malpighi. O proctodeo apresenta 6 largas papilas retais. O sistema nervoso é completo. O 5º segmento não apresenta gânglios. O par de gânglios do metatõrax inclui também um par de gânglios abdominais do 1º segmento abdominal. O sistema traqueal possui dois pares de espiráculos torácicos e oito pares abdominais. Somente o espiráculo do metatórax tem função de expiração; os demais servem para inspiração. Várias estruturações quitinosas protegem o átrio dos espiráculos. O sistema circulatório é constituído por um longo tubo dorsal, que se estende do 9º segmento até a região do crânio, onde se abre próximo ao conectivo do anel esofagial. Os pares de óstia com as válvulas, correspondem aos segmentos torácicos e abdominais. O sistema excretor é representado pelos tubos de Malpighi, células pericardiais e corpo gorduroso. O número e disposição dos tubos de Malpighi é variável nesta ordem. As células pericardiais estão situadas no lado do vaso dorsal. O corpo gorduroso forma compacta camada dorsal e ventral, e nos machos é ainda masi desenvolvido na zona abdominal. As glândulas mandibulares, maxilares e salivares são do tipo simples, com poucas modificações citológicas. Os sexos são separados. Os machos têm cinco pares de testículos, dois ductos distintos e o órgão ejaculatório. As glândulas acessórias variam em número e tamanho e se abrem na porção final do ducto ejaculatório. O aparelho reprodutor feminino corresponde ao tipo panoístico: Inclui cinco pares de ovariolos, dois longos pares de ovidutos e a espermateca que se abre na vagina.

  18. re ipit tion re onstru tion using ringEwidth hronology of rim lyn ed r ...

    Indian Academy of Sciences (India)

    r nges from IHHEEIUS mF hue to he vy r inf ll it does not grow in the e stern rim l y eyond q rhw lF he ringEwidth hronology of rim l y n ed r @eh. IIUIEEIWVVAD prep red from tree ores olle ted from two disjun t m ture forests in western rim l y . @figure IAD h s een used in the present studyF het ils of the methodology ...

  19. I-mediated signaling events by Lyn kinase C-terminal tyrosine phosphorylation

    Czech Academy of Sciences Publication Activity Database

    Tolar, Pavel; Dráberová, Lubica; Tolarová, Helena; Dráber, Petr

    2004-01-01

    Roč. 34, č. 4 (2004), s. 1136-1145 ISSN 0014-2980 R&D Projects: GA MŠk LN00A026; GA ČR GA204/00/0204; GA ČR GA310/00/0205; GA ČR GA204/03/0594; GA ČR GA301/03/0596; GA AV ČR IAA5052005; GA AV ČR IAA7052006; GA AV ČR IAA5052310 Institutional research plan: CEZ:AV0Z5052915 Keywords : mast cell * Fc receptor * signal transduction Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.005, year: 2004

  20. Lyn kinase is activated following thrombopoietin stimulation of the megakaryocytic cell line B1647

    DEFF Research Database (Denmark)

    Santini, Valeria; Scappini, Barbara; Gozzini, Antonella

    2002-01-01

    BACKGROUND AND OBJECTIVES: B1647 is a cell line derived from bone marrow cells of a patient with acute myeloid leukemia (M2) with a complete erythro-megakaryocytic phenotype and bears both k and p isoforms of c-mpl. Interestingly, spontaneous B1647 cell proliferation is significantly potentiated...... by thrombopoietin (TPO). DESIGN AND METHODS: We aimed to evaluate the proliferative signal transduction events following the activation of c-mpl and we stimulated B1647 cells with TPO 40 ng/mL for 3, 7, 15 and 30 minutes; cells were then lysed and whole lysates were immunoprecipitated with anti...

  1. A word from Lyn Evans:
    A sprint to the finish

    CERN Document Server

    2008-01-01

    Most people consider that the starting point for the LHC was a meeting organised by the European Committee for Future Accelerators in Lausanne in March 1984, even though quite a few of us at CERN had already begun work on the design in 1981. Since that time this truly unique machine has moved from a dream to a reality. With its ‘two in one’ magnet structure cooled by superfluid helium for operation at 1.9 K, the LHC is like no other particle collider. In a very real sense, the LHC is its own prototype. Other colliders have either consisted of two rings to accelerate and store two beams of particles, as in the Intersecting Storage Rings (ISR) here at CERN, or they have stored particles and their antiparticles travelling in opposite directions with a single ring, as we did with the Large Electron-Positron (LEP) collider. In addition, the LHC is the first accelerator in which the superconducting magnets have been cooled as low as 1...

  2. First Kepler results on compact pulsators - III. Subdwarf B stars with V1093 Her and hybrid (DW Lyn) type pulsations

    DEFF Research Database (Denmark)

    Reed, M.D.; Kawaler, Stephen D.; Østensen, Roy H.

    2010-01-01

    1093 Her (PG 1716) class or a hybrid star with both short and long periods. The apparently non-binary long-period and hybrid pulsators are described here. The V1093 Her periods range from 1 to 4.5 h and are associated with g-mode pulsations. Three stars also exhibit short periods indicative of p...

  3. First Kepler results on compact pulsators - III. Subdwarf B stars with V1093 Her and hybrid (DW Lyn) type pulsations

    Science.gov (United States)

    Reed, M. D.; Kawaler, S. D.; Østensen, R. H.; Bloemen, S.; Baran, A.; Telting, J. H.; Silvotti, R.; Charpinet, S.; Quint, A. C.; Handler, G.; Gilliland, R. L.; Borucki, W. J.; Koch, D. G.; Kjeldsen, H.; Christensen-Dalsgaard, J.

    2010-12-01

    We present the discovery of non-radial pulsations in five hot subdwarf B (sdB) stars based on 27 d of nearly continuous time series photometry using the Kepler spacecraft. We find that every sdB star cooler than ≈27 500 K that Kepler has observed (seven so far) is a long-period pulsator of the V1093 Her (PG 1716) class or a hybrid star with both short and long periods. The apparently non-binary long-period and hybrid pulsators are described here. The V1093 Her periods range from 1 to 4.5 h and are associated with g-mode pulsations. Three stars also exhibit short periods indicative of p-modes with periods of 2-5 min and in addition, these stars exhibit periodicities between both classes from 15 to 45 min. We detect the coolest and longest-period V1093 Her-type pulsator to date, KIC010670103 (Teff≈ 20 900 K, Pmax≈ 4.5 h) as well as a suspected hybrid pulsator, KIC002697388, which is extremely cool (Teff≈ 23 900 K) and for the first time hybrid pulsators which have larger g-mode amplitudes than p-mode ones. All of these pulsators are quite rich with many frequencies and we are able to apply asymptotic relationships to associate periodicities with modes for KIC010670103. Kepler data are particularly well suited for these studies as they are long duration, extremely high duty cycle observations with well-behaved noise properties.

  4. Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells

    NARCIS (Netherlands)

    van Dijk, T. B.; van den Akker, E.; Amelsvoort, M. P.; Mano, H.; Löwenberg, B.; von Lindern, M.

    2000-01-01

    Stem cell factor (SCF) has an important role in the proliferation, differentiation, survival, and migration of hematopoietic cells. SCF exerts its effects by binding to cKit, a receptor with intrinsic tyrosine kinase activity. Activation of phosphatidylinositol 3'-kinase (PI3-K) by cKit was

  5. Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells

    NARCIS (Netherlands)

    T.B. van Dijk (Thamar); M. Parren-Van Amelsvoort (Martine); H. Mano; M.M. von Lindern (Marieke); B. Löwenberg (Bob); E. van den Akker (Emile)

    2000-01-01

    textabstractStem cell factor (SCF) has an important role in the proliferation, differentiation, survival, and migration of hematopoietic cells. SCF exerts its effects by binding to cKit, a receptor with intrinsic tyrosine kinase activity. Activation of

  6. Lightning study - climate change and the impact on the incidence of lightning adaptation needs in the power supply; Lynstudien - Klimaendringenes betydning for forekomsten av lyn tilpassingsbehov i kraftforsyningen

    Energy Technology Data Exchange (ETDEWEB)

    Midtboe, Knut Helge; Haugen, Jan Erik; Koeltzow, Morten Andreas Oedegaard

    2011-04-15

    Requirements. Network owners are required by the Energy Act to keep your system in proper working condition. The purpose with emergency response efforts in the power supply is to prevent and handle incidents regard to technical failure, natural damage and deliberate vandalism. This will contribute to good supply. Regulations for standby power supply (Emergency Regulations) gives each company a duty to identify risk and vulnerability at the extraordinary events related to technical failure, natural damage and deliberate vandalism. Furthermore, analysis also embrace the various emergency regulations require to be implemented. This means that each company should assess their risk and vulnerability against all natural phenomena, including lightning. This applies not only to current climate, but also on the basis of what needs to be estimated as the foreseeable risk of the plant technical service life. Furthermore, the Regulations an obligation to identify the need for emergency repairs to deal with the outcome as a result of extraordinary events and analyze whether this repair response is robust enough to meet regulatory requirements. Major challenges As you will see from the report's conclusions, shows Met.no's analysis a probable increase in lightning frequency of 25% until the year 2050 for the country as a whole. Until the year 2100 one can expect a further increase of lightning frequency in line with the increase in temperature and precipitation. Lightning is a major cause of failure in power supply. In particular, transformers high-voltage distribution networks with overhead lines where there is continuous conductors, are exposed to this. When a transformer is subjected to lightning surges this result in estimates of isolation followed by a short circuit or breakdown in transformer. This can quickly lead to disruption of shorter or longer duration of electricity supply to customers. Such interruptions are undesirable not only from customers perspective, but also for the network owner, since they cost money and require repair. In the results from Met.no not only an increase in lightning frequency is highlighted, in addition we must also allow for greater variations in different seasons and geographic areas. Areas that until now have been little troubled by lightning may be more exposed, and not least, already known 'problem areas' have more challenges to deal with. Planning under uncertainty. It is difficult with current knowledge to conclude a linear relationship between increased lightning frequency and increase in future outages, but that there will be a connection can not be excluded. Increase in lightning frequency will rise to the need to put this phenomenon in as an important factor in the planning of preventive measures for existing and future construction. Each business must assess the need for specific measures as a basis for prevention and for the dimensioning of the necessary emergency repairs. Through the emergency requirements of the regulations to conduct risk and vulnerability analysis for the individual business, it would be natural from NVE's side to expect that the companies take this or similar studies as the basis for such assessments own challenges. NVE's supervisory activities on emergency area has increased and will increase in the coming year. (Author)

  7. Armpits, Belly Buttons and Chronic Wounds: The ABCs of Our Body Bacteria

    Science.gov (United States)

    ... and Chronic Wounds: The ABCs of Our Body Bacteria By Alisa Machalek and Allison MacLachlan Posted April ... treating skin and other conditions. Chronic Wounds and Bacteria Bacteria from human skin grown on agar in ...

  8. Dr Luigi Orlando, Dr Sergio Ceccuzzi, Dr. Armando Sbrana, Europa Metalli, Italy, Dr Albert Scherger, Member of KM Europa Metal AG, Osnabr ck, Germany, Prof. Filippo Menzinger, Scientific Attaché, Permanent Mission of Italy in Geneva

    CERN Multimedia

    Patrice Loïez

    2001-01-01

    Photo 01: Dr Lyn Evans and Dr Luigi Orlando Photo 04: L. to r.: Dr Lyn Evans, Dr Luigi Orlando, Prof. Luciano Maiani and Prof. Filippo Menzinger Photo 06: L. to r.: Prof. Philippo Menzinger, Dr Armando Sbrana, Prof. Luciano Maiani, Dr Albert Scherger, Dr Lyn Evans, Dr Luigi Orlando, Dr Sergio Ceccuzzi, visiting the LHC superconducting magnet test hall, SM18

  9. Philippe Lebrun, Head of the AT Department, Lyn Evans, LHC Project Leader, and Lucio Rossi, Head of the AT-MAS Group, in front of the last batch of steel for the LHC at Cockerill Sambre.

    CERN Multimedia

    2005-01-01

    Casting the last batch of steel sheets for the LHC superconducting magnet yokes. The yokes constitute approximately 80% of the accelerator's weight and, if placed side by side, would stretch over 20 km !

  10. Nuclear Mis-Communication: Who's to Blame?

    International Nuclear Information System (INIS)

    MaLachlan, A.

    1997-01-01

    The text reproduces entirely the conference that was pronounced by Ann MacLachlan at the CSN in October 1996 about the problems of the public communication in the particular case of nuclear energy. The author meditates upon the causes of the lack of understanding between the involved sides and the suspected formulae in order to overcome the difficulties. (Author)

  11. Approaches to predicting current and future distributions of Puccinia psidii in South America under climate change scenarios

    Science.gov (United States)

    N. B. Klopfenstein; J. W. Hanna; R. N. Graca; A. L. Ross-Davis; P. G. Cannon; A. C. Alfenas; M. -S. Kim

    2011-01-01

    Puccinia psidii is the cause of Eucalyptus/guava/myrtle rust disease of many host species in the Myrtaceae family, including guava (Psidium spp.), eucalypt (Eucalyptus spp.), rose apple (Syzygium jambos), and ohia (Metrosideros polymorpha) (Farr and Rossman 2010). First reported in 1884 on guava in Brazil (Maclachlan 1938), the rust has since been detected in other...

  12. Proteomanalyse: To-dimensjonal gelelektroforese av Nordsjøsild i forhold til modningstid

    DEFF Research Database (Denmark)

    Jessen, Flemming; Skåra, Torstein

    Forsøksresultater fra tidligere FHF-prosjekter på matjessild har vist at salte- og modningsprosessene er reproduserbare. Det er dog stadig en utfordring å kunne måle enzymaktivitet og modningsgrad, som er to parametre som har vist seg å henge tett sammen. Analysene som er gjennomført i forsøkene, i...

  13. A középkori magyar városfejlődés migráció- és ipartörténeti vonatkozásai a történeti személynévtan tükrében I. Személynévadás és migráció [Relations of migration and industrial history and medieval urban development in Hungary in the light of historical anthroponymy I. Giving personal names and migration

    Directory of Open Access Journals (Sweden)

    Gulyás, László Szabolcs

    2014-12-01

    Full Text Available This paper intends to explore for what purposes and by what means medieval personal names can be used in social historical research. Bynames derived from place names are examined in the present paper, as they prove to be essential sources in research into medieval migration history. From registers and to a lesser extent from charters of other types (sales contracts, civil procedural documents, the author has collected approximately 12,000 personal names of serfs and burghers. Information on migration history deduced from the names (e.g. distance, legal status of the previous place of residence is compared with the characteristics of medieval urban development. In doing so, the author relies on the so-called centrality score system, elaborated by András Kubinyi, which at present is the most accepted and effective method in research into urban, and more broadly, settlement history. With respect to the seven categories of settlements defined by Kubinyi, one can observe substantial and logical differences concerning the proportion of the incomers, the distance of migration and the legal status of the emissive settlements. These facts also suggest that Kubinyi’s categories (in fact, hierarchical levels demonstrating prosperity do identify settlements at different levels of their development.

  14. Cell type-specific termination of transcription by transposable element sequences.

    Science.gov (United States)

    Conley, Andrew B; Jordan, I King

    2012-09-30

    Transposable elements (TEs) encode sequences necessary for their own transposition, including signals required for the termination of transcription. TE sequences within the introns of human genes show an antisense orientation bias, which has been proposed to reflect selection against TE sequences in the sense orientation owing to their ability to terminate the transcription of host gene transcripts. While there is evidence in support of this model for some elements, the extent to which TE sequences actually terminate transcription of human gene across the genome remains an open question. Using high-throughput sequencing data, we have characterized over 9,000 distinct TE-derived sequences that provide transcription termination sites for 5,747 human genes across eight different cell types. Rarefaction curve analysis suggests that there may be twice as many TE-derived termination sites (TE-TTS) genome-wide among all human cell types. The local chromatin environment for these TE-TTS is similar to that seen for 3' UTR canonical TTS and distinct from the chromatin environment of other intragenic TE sequences. However, those TE-TTS located within the introns of human genes were found to be far more cell type-specific than the canonical TTS. TE-TTS were much more likely to be found in the sense orientation than other intragenic TE sequences of the same TE family and TE-TTS in the sense orientation terminate transcription more efficiently than those found in the antisense orientation. Alu sequences were found to provide a large number of relatively weak TTS, whereas LTR elements provided a smaller number of much stronger TTS. TE sequences provide numerous termination sites to human genes, and TE-derived TTS are particularly cell type-specific. Thus, TE sequences provide a powerful mechanism for the diversification of transcriptional profiles between cell types and among evolutionary lineages, since most TE-TTS are evolutionarily young. The extent of transcription

  15. Cell type-specific termination of transcription by transposable element sequences

    Directory of Open Access Journals (Sweden)

    Conley Andrew B

    2012-09-01

    Full Text Available Abstract Background Transposable elements (TEs encode sequences necessary for their own transposition, including signals required for the termination of transcription. TE sequences within the introns of human genes show an antisense orientation bias, which has been proposed to reflect selection against TE sequences in the sense orientation owing to their ability to terminate the transcription of host gene transcripts. While there is evidence in support of this model for some elements, the extent to which TE sequences actually terminate transcription of human gene across the genome remains an open question. Results Using high-throughput sequencing data, we have characterized over 9,000 distinct TE-derived sequences that provide transcription termination sites for 5,747 human genes across eight different cell types. Rarefaction curve analysis suggests that there may be twice as many TE-derived termination sites (TE-TTS genome-wide among all human cell types. The local chromatin environment for these TE-TTS is similar to that seen for 3′ UTR canonical TTS and distinct from the chromatin environment of other intragenic TE sequences. However, those TE-TTS located within the introns of human genes were found to be far more cell type-specific than the canonical TTS. TE-TTS were much more likely to be found in the sense orientation than other intragenic TE sequences of the same TE family and TE-TTS in the sense orientation terminate transcription more efficiently than those found in the antisense orientation. Alu sequences were found to provide a large number of relatively weak TTS, whereas LTR elements provided a smaller number of much stronger TTS. Conclusions TE sequences provide numerous termination sites to human genes, and TE-derived TTS are particularly cell type-specific. Thus, TE sequences provide a powerful mechanism for the diversification of transcriptional profiles between cell types and among evolutionary lineages, since most TE-TTS are

  16. Bayesian Aggregation of Evidence for Detection and Characterization of Patterns in Multiple Noisy Observations

    Science.gov (United States)

    2015-07-01

    Konstantin N Borozdin, Alexei V Klimenko, William C Priedhorsky, Nicolas Hengartner, Charles C Alexander, R Andres Cortez, Herbert G Tanner, and Xanthi... Tan - don, Rob MacLachlan, and Jay Jin. Presentation: Machine learning for effective nuclear search and broad area monitoring. ARI Annual Review, 2014...Distributed Constraints Reasoning (DCR09), at IJCAI, volume 9, 2009. [70] Di Tian and Nicolas D Georganas. A node scheduling scheme for energy

  17. Aktív anyagok szerepe a rozmaring ízesítésű napraforgó olajban = The role of active materials of rosemary in sunflower oil

    OpenAIRE

    Somogyi, László

    2008-01-01

    Kutatómunkám célja az immerzióval, azaz a fűszer áztatásával előállított rozmaring ízesítésű napraforgó olaj aromakarakterének és fontosabb kémiai tulajdonságainak elemzése volt. Az elvégzendő feladatokat az alábbi kérdések megválaszolása érdekében jelöltem ki: 1. Hogyan változik az ízesített napraforgó olaj aromája az adagolt rozmaring arányának és az áztatási időnek függvényében? 2. Milyen oxidációs stabilitással rendelkezik az ízesített olaj ? 3. Mennyire képes az ízesített nap...

  18. On 20 November CERN hosted a symposium to mark the 70th birthday of Chris Llewellyn Smith

    CERN Multimedia

    Maximilien Brice

    2012-01-01

    Left to right: (back) Rolf Heuer, Peter Jenni, Lyn Evans, Chris Llewellyn Smith, Steve Cowley, Zehra Sayers, David Gross, Chris Allsopp, Robert Jaffe, Bikash Sinha; (front) Geoffrey West, Álvaro de Rújula, John Ellis.

  19. 78 FR 13706 - Notice of Appointment of Individuals To Serve as Members of Performance Review Board

    Science.gov (United States)

    2013-02-28

    .... Pearson Vice-Chair of the PRB: Commissioner Dean A. Pinkert Member--Catherine DeFilippo Member--Robert B... Member--Lyn M Schlitt FOR FURTHER INFORMATION CONTACT: Patricia Connelly, Director of Human Resources, U...

  20. Kunstnik avaldas kaaluta olekus austust Francis Baconile

    Index Scriptorium Estoniae

    2008-01-01

    Projekti "teha kunsti ebapraktilistes kohtades" raames tegid Londoni kunstnikud Nasser Azam ja Lyn Hagan kunsti paraboloidsel spetsiaallennul kaaluta olekus. Hagan filmis kassi ja hiirt ning Azam lõpetas kuus õlimaali

  1. Breves considerações sobre a evolução, impacto e profilaxia do parvovírus canino

    OpenAIRE

    Costa, M.; Nóbrega, C.; Mega, A.; Esteves, F.; Cruz, R.; Santos, C.; Vala, Helena; Santos, M.; Mesquita, J. R.

    2011-01-01

    A família Parvoviridae está dividida em duas subfamílias. A subfamília Parvovirinae, que inclui os vírus que afectam vertebrados e a subfamília Densovirinae, que contém os vírus que afectam insectos (MacLachlan & Dubovi, 2011). Dentro da subfamília Parvovirinae foram definidos cinco géneros: Erytrovírus, Dependovírus, Parvovírus, Amdovírus e Bocavírus.

  2. ADULT CADDISFLY (TRICHOPTERA) PHENOLOGY AT THE HANFORD REACH NATIONAL MONUMENT, WASHINGTON STATE

    International Nuclear Information System (INIS)

    Zack, Richard S.; Ruiter, David E.; Strenge, Dennis L.; Landolt, Peter J.

    2006-01-01

    Adult caddisflies were sampled on the Wahluke Wildlife Area and Saddle Mountain National Wildlife Refuge subunits of the newly created (2000) Hanford Reach National Monument using 15-watt ''black lights'' from April 2002 through April 2003. A diverse fauna consisting of nine families, 21 genera, and 33 species were collected. Protoptila Coloma Ross, Agraylea multipunctata Curtis, Hydroptila xera Ross, Ceraclea alagma (Ross), Nectopsych Iahontanensis Haddock Oecetis cinerascens (Hagen), and Ylodes reuteri (MacLachlan) represent new records for Washington State. Species composition and phenology are presented in tabular form

  3. Analyse av overvannsnettet i Ås sentrum ved bruk av simuleringsprogrammet SWMM

    OpenAIRE

    Dvergsnes, Eirunn

    2016-01-01

    Jorden står ovenfor klimaendringer med økende temperaturer og en hyppigere forekomst av intense nedbørshendelser. For overvannssystemer i urbane strøk er den økte nedbørintensiteten en stor utfordring. Urbanisering har medført en stor andel tette flater, og lukking av naturlige bekkesystemer. Dette krever en raskere bortledning av regnvannet gjennom rør i bakken. Store deler av det norske overvannssystemet er ikke dimensjonert etter dagens norske standard. Denne ble revidert se...

  4. TEHDASPROSESSIN 3D-MALLINNUS, PROSESSI- JA LAITEKUVAUS

    OpenAIRE

    Huhtala, Aki

    2010-01-01

    Opinnäytetyö tehtiin tilauksesta AkkuSer Oy:lle. Tarkoituksena oli kartoittaa tehdasprosessi, selvittää laitetiedot ja luoda 3D-malli tehdasprosessista. Prosessin toiminta kuvattiin. Selvitettiin, miten prosessi eteni ja millä tavoin AkkuSer Oy kierrättää ongelma jätettä. Selitetään, mitkä ovat prosessin lähtökohdat ja mitä tuotteita prosessissa syntyi. Tämän lisäksi mitattiin kuljettimien sekä taajuusmuuttajatoimisten kuljettimien pyörimisnopeuksia. Tehdasprosessi kuvattiin Visual Compon...

  5. Corporate Governance ja suurten listayhtiöiden sisäisestä valvonnasta tiedottaminen vuosikertomuksissa

    OpenAIRE

    Rautio, Elina

    2012-01-01

    Corporate Governance tuli Suomessa ajankohtaiseksi 1990-luvun lopussa. Sisäisen valvonnan osuutta ei silloin vielä edes mainittu. Sisäinen valvonnan toimintaperiaatteet lisättiin vuoden 2003 Corporate Governanceen. Laissa, säädöksissä tai Corporate Governancen suosituksissa ei määritelty tarkasti, miten sisäisestä valvonnasta oli kerrottava, joten se jäi yhtiöiden päätettäväksi. Työ rajattiin sisäisen valvonnan osuuteen. Riskienhallinnan osuus oli sivuroolissa, vaikka se liittyikin tiivi...

  6. Analyse av LOD-tiltak

    OpenAIRE

    Kunduraci, Meltem

    2016-01-01

    Endrede klimatiske forhold og større urbanisering medfører økte oversvømmelsesskader i urbane områder. Ekstreme nedbørhendelser opptrer oftere og kraftigere. Utbygging med tette flater hindrer infiltrasjon til grunnen. Den naturlige utjevningen av overvann reduseres. Dette resulterer i økende belastninger på det eksisterende avløpssystemet. Kapasiteten på avløpsnettet er mange steder overbelastet og er ikke i stand til å håndtere overvannsmengder under styrtregn. Lokal overvannsdisponering el...

  7. Yritystoiminnan laajentaminen Kissakahvila Purnauskiksessa : opas yrittäjälle

    OpenAIRE

    Lehmus, Ida-Rebecka

    2016-01-01

    Tämä opinnäytetyö on tehty toimeksiantona Kissakahvila Purnauskiksen yrittäjälle, Tiina Aaltoselle. Kissakahvila Purnauskiksen toimintaa aiotaan laajentaa Ouluun, joten työssä keskitytään teemoihin laajennustoimiin liittyen. Työn painopisteen kartoittami-seksi tehtiin alkuselvitys yrittäjän kanssa tämän tarpeista ja toiveista. Päätökset lopulli-sesta laajentamistavasta, aikataulusta ja rahoituskeinoista ovat vielä kesken, joten työn rajaus oli kirjoittajan päätettävissä. Opinnäytetyön tar...

  8. Interfacial and Thin Film Chemistry in Electron Device Fabrication

    Science.gov (United States)

    1992-01-01

    Chemistry During Electronic Processing" by Professor Richard Osgood, Jr.; "In Situ Optical Diagnostics of Semiconductors Prepared by Laser Chemical Processing...N(Igde Area Code) 22c OFF ft SYMBO. Professors Georee Flynn and Richard Os~ood I MSL DD Form 1473, JUN 86 Previous edotions are obsolete SECURITY...and D. L. Smith, Phys.I Rev. Lett. 62, 649 (1989). 19. E. A. Caridi, T. Y. Chang, K. W. Goossen and L. F. Eastman, AOLi Phvs. Tett. 56, 659 (1990). 1

  9. Golden Hadron awards for the LHC's top suppliers.

    CERN Multimedia

    Maximilien Brice

    2003-01-01

    The following firms have been selected to receive a GOLDEN HADRON AWARD 2003, in recognition of their outstanding achievement: JDL TECHNOLOGIES, Belgium "in producing automatic cable inspection systems", FURUKAWA ELECTRIC COMPANY, Japan "in producing high quality superconducting cable", IHI Corporation, Japan, and LINDE KRYOTECHNIK, Switzerland "in producing novel 1.8 K refrigeration units based on advanced cold compressor technology" for the Large Hadron Collider.Photos 01, 02: Recipients of the 2003 Golden Hadron awards at the presentation ceremony on 16 May.Photo 03: LHC project leader Lyn Evans updates the award recipients on work for CERN's new accelerator.Photo 04: René Joannes of JDL Technologies (left) receives a Golden Hadron award from LHC project leader Lyn Evans.Shinichiro Meguro, managing director of Furukawa Electric Company, receives a Golden Hadron award from LHC project leader Lyn Evans.Photo 06: Kirkor Kurtcuoglu of Linde Kryotechnik (left) and Motoki Yoshinaga, associate director of IHI...

  10. Gold awards for CERN's top suppliers!

    CERN Multimedia

    2003-01-01

    CERN's awards to the LHC project's best suppliers are now into their second year. Three companies received 'Golden Hadrons' for 2003. The Golden Hadron awards were presented to the delighted representatives of the winning firms by LHC Project Leader Lyn Evans on Friday 16 May. Only three out of the LHC's four hundred suppliers were lucky enough to receive a gold award. The consortium IHI (Japan)-Linde Kryotechnik (Switzerland), the Belgian company JDL Technologies and the Japanese firm Furukawa Electric Company were rewarded not only for their technical and financial achievements but also for their compliance with contractual deadlines. The 2003 Golden Hadron winners with Lyn Evans. From left to right: Armin Senn, Thomas Voigt, Kirkor Kurtcuoglu of LINDE KRYOTECHNIK ; Tadaaki Honda, Project Leader and Motoki Yoshinaga, Associate Director of IHI Corporation ; Lyn Evans, LHC Project Leader; Shinichiro Meguro, Managing Director of FURUKAWA ELECTRIC COMPANY ; Nobuyoshi Saji, Consulting Engineer of IHI Corporatio...

  11. Heterologous expression of plasmodial proteins for structural studies and functional annotation

    CSIR Research Space (South Africa)

    Birkholtz, LM

    2008-01-01

    Full Text Available Malaria Journal Open AcceReview Heterologous expression of plasmodial proteins for structural studies and functional annotation Lyn-Marie Birkholtz1, Gregory Blatch2, Theresa L Coetzer3, Heinrich C Hoppe1,4, Esmaré Human1, Elizabeth J Morris1,5, Zoleka Ngcete..., Kwadlangezwa, South Africa Email: Lyn-Marie Birkholtz - lbirkholtz@up.ac.za; Gregory Blatch - G.Blatch@ru.ac.za; Theresa L Coetzer - theresa.coetzer@nhls.ac.za; Heinrich C Hoppe - hhoppe@csir.co.za; Esmaré Human - esmare.human@up.ac.za; Elizabeth J Morris...

  12. Toward improved construction health, safety, and ergonomics in ...

    African Journals Online (AJOL)

    Hierdie dien as plaaslike insig en 'n lyn van gestruktureerde vrae vir gebruik in die hoofstudie, wat geposisioneer is in die aksie-navorsing (AN) paradigma en gebruik die fokusgroep (FG) metode om groot kwalitatiewe data in te samel van SARAP-geregistreerde deelnemers. Sintese van die FG data met die literatuur asook ...

  13. Awards and Honours

    CERN Multimedia

    2009-01-01

    Lyn Evans, LHC project leader and Welsh physicist, received an Honorary Doctorate from the University of Glamorgan on July 14. The University of Glamorgan is the second largest University in Wales with over 22,000 students. Visit the University website and read the full Press Release issued by the University.

  14. On 10 November, the first sector of the LHC was completely interconnected.

    CERN Multimedia

    2006-01-01

    Sector 7-8 became the first one ready for operation. The LHC project leader Lyn Evans, the teams involved in this achievement from CERN's group AT/MCS, AT/VAC and AT/MEL and members of the IEG consortium are shown in the 7-8 sector.

  15. The fourth CERN Golden Hadron awards saw seven of the LHC's best suppliers receive recognition

    CERN Multimedia

    Maximilien Brice

    2005-01-01

    'The Golden Hadron awards are a symbol of our appreciation of not only the quality and timely delivery of components but also the collaborative and flexible way the firms have contributed to this very difficult project,' said Lyn Evans, head of the LHC project.

  16. CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation

    NARCIS (Netherlands)

    Manjarrez-Orduno, N.; Marasco, E.; Chung, S.A.; Katz, M.S.; Kiridly, J.F.; Simpfendorfer, K.R.; Freudenberg, J.; Ballard, D.H.; Nashi, E.; Hopkins, T.J.; Cunninghame Graham, D.S.; Lee, A.T.; Coenen, M.J.H.; Franke, B.; Swinkels, D.W.; Graham, R.R.; Kimberly, R.P.; Gaffney, P.M.; Vyse, T.J.; Behrens, T.W.; Criswell, L.A.; Diamond, B.; Gregersen, P.K.

    2012-01-01

    The c-Src tyrosine kinase, Csk, physically interacts with the intracellular phosphatase Lyp (encoded by PTPN22) and can modify the activation state of downstream Src kinases, such as Lyn, in lymphocytes. We identified an association of CSK with systemic lupus erythematosus (SLE) and refined its

  17. aarde beteken die einde van tradisionele metafisiese taal oor God?

    African Journals Online (AJOL)

    Test

    7 Jun 2011 ... (2009:4) aan dat die eietydse 'populist meander culture' die onvanpastheid van 'n skeidslyn tussen hoofstroom- en charismatiese kerklike groeperinge blootlê. Albei verteenwoordig geïnstitusionaliseerde religie. Die lyn moet eerder tussen geïnstitusionaliseerde religie en spiritualiteit op die markplein ...

  18. DFB component production at IHEP complete

    CERN Multimedia

    2007-01-01

    1. LHC project leader Lyn Evans receiving a model of a DFB from IHEP general director Nikolaj Tyurin.2. Collective photo of DFB celebration at IHEP. Participants from left: V. Sytchev, V. Benda, N. Tyurin, A. Zaytcev, L. Evans, A. Perin, R. van Weelderen, Ph. Trilhe, M. Genet, L. Tavian, Ph. Lebrun, A. Kleshov.

  19. Analyzing Predictors of High Opioid Use in the U.S. Navy

    Science.gov (United States)

    2016-09-01

    degree of MASTER OF SCIENCE IN OPERATIONS RESEARCH from the NAVAL POSTGRADUATE SCHOOL September 2016 Approved by: Lyn R...Wakely risk assessment model (Version 102). Retrieved from https://predictivemodeler.com/sitecontent/book/Ch06_Applications/ Actuarial /WR A_Model

  20. CDC Recommendations to Reduce the Risk of H3N2v Flu Virus Infection for Fairgoers and Swine Exhibitors

    Centers for Disease Control (CDC) Podcasts

    2012-09-10

    In this podcast, Dr. Lyn Finelli discusses CDC’s recommendations for reducing the risk of infection with H3N2v flu viruses for fairgoers and swine exhibitors.  Created: 9/10/2012 by National Center for Immunization and Respiratory Diseases (NCIRD).   Date Released: 9/10/2012.

  1. The Director-General visits the ATLAS construction site at Point 1

    CERN Multimedia

    Patrice Loiez

    1998-01-01

    Photo 05 : Claude Guitton (left), Project Manager for the EDF/Knight Piesold joint venture responsible for design and site supervision for LHC civil engineering at Point 1 takes the Director-General Chris Llewellyn Smith and LHC Project Leader Lyn Evans on a tour of the site.

  2. More than Just Hot Air: How Hairdryers and Role Models Inspire Girls in Engineering

    Science.gov (United States)

    Kekelis, Linda; Larkin, Molly; Gomes, Lyn

    2014-01-01

    This article describes a reverse-engineering project where female students take a part a hair dryer--giving them an opportunity to see the many different kinds of engineering disciplines involved in making a hairdryer and that they work together. Mechanical Engineer, Lyn Gome, describes her experience leading a group of middle school girls through…

  3. U-N-F-O-R-G-E-T-T-A-B-L-E!

    CERN Multimedia

    2008-01-01

    This is the word that best describes 10 September for all CERN personnel and surely also the outside world watching CERN through the eyes of the media. The unforgettable "3-2-1 BEAM!" of the LHC project leader, Lyn Evans, will stay in our memories forever.

  4. A trendy approach to education!

    CERN Document Server

    Alizée Dauvergne

    2010-01-01

    On 11 March, Lyn Evans, the LHC project leader, talked live to hundreds of students in Wales using the standard videoconference equipment available at CERN (see box below). The students were delighted with the presentation and obviously very much appreciated this modern means of communication with the Laboratory. A further lecture is planned for May.   Question time after the videoconference between Lyn Evans and 27 schools and colleges in Wales. The Welsh Video Network (WVN) is one of the most advanced videoconferencing networks in the world, comprising over 80 networked video studios throughout Wales. For the LHC lecture given by Lyn Evans, no fewer than 27 schools and colleges were connected live with CERN. “This was a lecture for A-level students”, says Lyn Evans. “I introduced CERN and spoke about the physics we are doing here and what we want to discover. I talked about antimatter, dark matter, etc.” The LHC lecture was part of the WVN lecture series...

  5. Superquantile Regression: Theory, Algorithms, and Applications

    Science.gov (United States)

    2014-12-01

    Highway, Suite 1204, Arlington, Va 22202-4302, and to the Office of Management and Budget, Paperwork Reduction Project (0704-0188) Washington DC 20503. 1...Navy submariners, reliability engineering, uncertainty quantification, and financial risk management . Superquantile, superquantile regression...Royset Carlos F. Borges Associate Professor of Operations Research Dissertation Supervisor Professor of Applied Mathematics Lyn R. Whitaker Javier

  6. The last LHC dipole magnet is lowered

    CERN Multimedia

    Claudia Marcelloni

    2007-01-01

    A ceremony is held as the last of 1746 superconducting magnets is lowered into the 27-km circumference tunnel that houses the LHC. The LHC project leader, Lyn Evans, changes a banner reading ‘first magnet for the LHC’ to ‘last magnet for the LHC’ in his native Welsh.

  7. Erythropoietin receptor signaling is membrane raft dependent

    NARCIS (Netherlands)

    K.L. McGraw (Kathy); G.M. Fuhler (Gwenny); J.O. Johnson (Joseph); J.A. Clark (Justine); G.C. Caceres (Gisela); L. Sokol (Lubomir); A.F. List (Alan)

    2012-01-01

    textabstractUpon erythropoietin (Epo) engagement, Epo-receptor (R) homodimerizes to activate JAK2 and Lyn, which phosphorylate STAT5. Although recent investigations have identified key negative regulators of Epo-R signaling, little is known about the role of membrane localization in controlling

  8. Membrane-associated signaling in human B-lymphoma lines

    Energy Technology Data Exchange (ETDEWEB)

    Tauzin, Sebastien; Ding, Heidrun; Burdevet, Dimitri [Department of Pathology and Immunology, Centre medical universitaire, 1, rue Michel-Servet, 1211 Geneva 11 (Switzerland); Borisch, Bettina [Department of Social and Preventive Medicine, Centre medical universitaire, 1, rue Michel-Servet, 1211 Geneva 11 (Switzerland); Hoessli, Daniel C., E-mail: danielhoessli@gmail.com [Department of Pathology and Immunology, Centre medical universitaire, 1, rue Michel-Servet, 1211 Geneva 11 (Switzerland)

    2011-01-15

    In B-non-Hodgkin lymphomas, Lyn and Cbp/PAG constitute the core of an oncogenic signalosome that captures the Phosphatidylinositol-3-kinase, the Spleen tyrosine kinase and the Signal transducer and activator of transcription-3 to generate pro-survival and proliferative signals. Lymphoma lines corresponding to follicular, mantle-cell and Burkitt-derived lymphomas display type-specific signalosome organizations that differentially activate PI3K, Syk and STAT3. In the follicular lymphoma line, PI3K, Syk and STAT3 were optimally activated upon association with the Lyn-Cbp/PAG signalosome, while in the Burkitt lymphoma-derived line, the association with Cbp/PAG and activation of PI3K were interfered with by the latent membrane proteins encoded by the Epstein-Barr virus. In the Jeko-1 mantle-cell line, a weak association of Syk with the Lyn-Cbp/PAG signalosome resulted in poor activation of Syk, but in those cells, as in the follicular and Burkitt-derived lines, efficient apoptosis induction by the Syk inhibitor R406 indicated that Syk is nonetheless an important prosurvival element and therefore a valuable therapeutic target. In all configurations described herein is the Lyn-Cbp/PAG signalosome independent of external signals and provides efficient means of activation for its associated lipid and protein kinases. In follicular and Burkitt-derived lines, Syk appears to be activated following binding to Cbp/PAG and no longer requires B-cell receptor-associated activation motifs for activation. Assessment of the different modalities of Lyn-Cbp/PAG signalosome organization could help in selecting the appropriate combination of kinase inhibitors to eliminate a particular type of lymphoma cells.

  9. EVALUACIÓN DEL COEFICIENTE DE UNIFORMIDAD EN CUATRO EMISORES DE RIEGO USANDO FILTRACIÓN GRUESA DE FLUJO ASCENDENTE EN CAPAS AVALIAÇÃO DO COEFICIENTE DE UNIFORMIDADE EM QUATRO EMISSORES DE IRRIGAÇÃO USANDO FILTRAÇÃO GROSSA DE FLUXO ASCENDENTE EM CAMADAS EVALUATION OF THE UNIFORMITY COEFFICIENT IN FOUR IRRIGATION EMITTERS USING UPFLOW COARSE FILTRATION IN LAYERS

    Directory of Open Access Journals (Sweden)

    Julián Loboa

    2011-12-01

    Full Text Available Se emplearon tecnologías de filtración no convencionales basadas en el flujo ascendente del agua a través de filtros con capas de materiales de diferente granulometría para evaluar los coeficientes de uniformidad en cuatro módulos de riego de alta frecuencia, en la planta piloto de tratamiento de agua del instituto de investigación Cinara (Cali. Cada módulo utilizó emisores de riego diferente: microjet, autocompensados incorporados (Aqua-Traxx, Lyn y cinta de riego (Queen Gil. Los resultados mostraron que con este sistema de filtración los emisores de riego que alcanzaron los mejores coeficientes de uniformidad fueron: microjet (94,3% y Lyn (93,73%, en un periodo de 120 y 165 horas respectivamente. El sistema de riego que presentó un coeficiente de uniformidad más homogéneo durante la mayor duración de riego continuo (72 horas fue el correspondiente al módulo con los goteros Lyn que alcanzó valores de 91,5% (calificación buena, y el desempeño menos eficiente lo presentó la cinta de riego.Empregaram-se tecnologias de filtração não convencionais baseadas no fluxo ascendente da água através de filtros com camadas de materiais de diferente granulometria para avaliar os coeficientes de uniformidade em quatro módulos de irrigação de alta frequência, na planta piloto de tratamento de água do instituto de pesquisas Cinara (Cali. Cada módulo utilizou emissores de irrigação diferente: microjet, autocompensados incorporados (Aqua-Traxx, Lyn e fita de irrigação (Queen Gil. Os resultados mostraram que com este sistema de filtração os emissores de irrigação que atingiram os melhores coeficientes de uniformidade foram: microjet (94,3% e Lyn (93,73% em um periodo de 120 e 165 horas respetivamente. O sistema de irrigação que apresentou um coeficiente de uniformidade mais homogêneo durante a maior duração de irrigação continua (72 horas foi o correspondente ao modulo com os conta-gotas Lyn que atingiu valores de 91

  10. Langattomat asiakaspalautepäätteet : HOK-Elannon ravintolassa Stone's

    OpenAIRE

    Ahonen, Heikki

    2012-01-01

    Opinnäytetyö käsittelee langatonta asiakaspalautepäätettä ja sen käytettävyyttä HOK-Elannon ravintolassa Stone’s. Teoriapohjana on asiakaspalaute ja asiakaspalautteen merkitys yritykselle. Käsittelyvaiheessa keskitytään asiakaspalautteeseen ylipäätään Stone’sissa sekä erilaisiin asiakaspalauteväyliin, pääpainona asiakaspalautepääte. Työn myötä selvisi, että asiakaspalaute on yritykselle tärkeää, mutta Stone’sin tapauksessa kyseinen asiakaspalautepääte ei ole optimaalinen ratkaisu. Yrityks...

  11. Muovisten pakkausmateriaalien kierrätyksen ja hyötykäytön kehittäminen : case Alkon viinipussit ja lavasidosmuovit

    OpenAIRE

    Helle, Solja

    2012-01-01

    Muovi on paljon käytetty pakkausmateriaali ja sen käyttö on lisääntynyt räjähdysmäisesti viimeisten vuosikymmenien aikana. Muovien kierrätys on haasteellista erilaisten muovilaatujen suuren kirjon sekä hajanaisten jätevirtojen vuoksi. Muovit ovat yleisesti ottaen kestävää ja pitkäikäistä materiaalia, joten ne soveltuvat näiltä ominaisuuksiltaan hyvin kierrätettäväksi. Luontoon päätyessään muovijäte hajoaa erittäin heikosti ja aiheuttaa merkittäviä ympäristöhaittoja. Opinnäytetyössä selvit...

  12. Henkilöarvioinnin tehostaminen kohdeorganisaation rekrytoinnissa

    OpenAIRE

    Kytömaa, Johanna

    2013-01-01

    Tämä opinnäytetyön aihe on henkilöarvioinnin tehostamisen. Työn tavoite on luoda kohdeor-ganisaatiolle työhaastattelun rinnalle yksinkertaistettu arvioinnin väline, joka tehostaa henki-löarviointia työhönottotilanteessa. Työ käsittelee henkilöarviointia käsitteenä sekä siihen käy-tettäviä eri menetelmiä ja arviointiprosessia. Työ on luonteeltaan toiminnallinen, eli se on tehty projektimuotoisena. Työn kohdeorganisaatio, Nooa Säästöpankki, on suomalainen pääkaupunkiseudulla toimiva Säästöp...

  13. A personality trait-based interactionist model of job performance.

    Science.gov (United States)

    Tett, Robert P; Burnett, Dawn D

    2003-06-01

    Evidence for situational specificity of personality-job performance relations calls for better understanding of how personality is expressed as valued work behavior. On the basis of an interactionist principle of trait activation (R. P. Tett & H. A. Guterman, 2000), a model is proposed that distinguishes among 5 situational features relevant to trait expression (job demands, distracters, constraints, releasers, and facilitators), operating at task, social, and organizational levels. Trait-expressive work behavior is distinguished from (valued) job performance in clarifying the conditions favoring personality use in selection efforts. The model frames linkages between situational taxonomies (e.g., J. L. Holland's [1985] RIASEC model) and the Big Five and promotes useful discussion of critical issues, including situational specificity, personality-oriented job analysis, team building, and work motivation.

  14. The Grit in the Oyster – does an appreciation of threshold concepts in an adult literacies teaching qualification result in pearls of practice

    Directory of Open Access Journals (Sweden)

    David Wallace

    2010-08-01

    Full Text Available This paper draws from the experiences of a new adult literacies teaching qualification in Scotland that has been designed for experienced but unqualified adult literacies tutors.  Created to respond to an approach to adult literacies as social practices (Scottish Executive 2001, 2005, Tett et al 2006, the course team employs a sociocultural pedagogy that explicitly rejects transmission and seeks to build critical reflection through learning from experience, collaborative activities and the creation of an on-line community (Ackland and Wallace 2006.  Recognising that ‘moments of conflict and disjuncture may form the spaces in which learning occurs’ (Lewis, Enciso and Moje 2007:5 the paper explores whether ideas about liminality and threshold concepts (Cousin 2006:1, Land, Meyer and Smith 2008 illuminate the learning process.  It concludes that engagement with these concepts may assist adult literacies tutors to develop transformed practice (Cope and Kalantzis 2003:35.

  15. Android-sovelluksen toteutus opiskelijajärjestölle

    OpenAIRE

    Niemi, Iiro

    2017-01-01

    Android Studio on tällä hetkellä ainoa työkalu Android-sovellusten kehittämiseen. Tässä opinnäytetyössä perehdyn Android Studio -ohjelmointiympäristön toiminnallisuuksiin, työkaluihin ja itse ohjelmointiin. Android Studio tarjoaa monipuolisia työkaluja sovelluskehittäjän käyttöön ja onkin hyvä ymmärtää, mikä kaikki on mahdollista nykyaikaisella ohjelmointiympäristöllä. Ohessa toteutan myös sovelluksen opiskelijajärjestö SAMMAKKOlle. Opinnäytetyössäni tulen käymään läpi, miten RSS-syötett...

  16. Újraosztó fiskális politika nyitott gazdaságban

    OpenAIRE

    Szilágyi, Katalin

    2006-01-01

    A tanulmány az expanzív fiskális politika hatását vizsgálja egy kis, nyitott gazdaság kétszektoros reálmodelljében. A költségvetési politika a modellben újraosztja a forrásokat: költekezõ jellegű (expanzív) az állami költségvetés akkor, ha fokozza a redisztribúciót. Megmutatom, hogy ebben az esetben – az újraelosztás károsultjainak és kedvezményezettjeinek fogyasztási szerkezetére tett valószerű feltevések mellett – egy kétszektoros reálmodell számos, az irodalomban szokásosnak...

  17. Recognition in Britain for CERN personalities

    CERN Multimedia

    2001-01-01

    Sir Chris Llewellyn Smith Lyn Evans British CERN personalities were rewarded for their contribution to physics in this year's prestigious New Year Honours. Chris Llewellyn Smith, Director General from 1994 to 1998, was knighted for services to particle physics. 'The citation, 'for services to particle physics', obviously includes my period at CERN. The honour therefore recognises the work of everyone at CERN, including particularly the contributions of those who worked with me in the Directorate and the Management Board', said Sir Chris. Lyn Evans, Director of the LHC project, was awarded the CBE, Commander of the British Empire, for services to accelerator physics. Erwin Gabathuler, Director of Research from 1981 to 1983 was awarded the OBE, Officer of the British Empire, for services to physics.

  18. Signaling through intercellular adhesion molecule 1 (ICAM-1) in a B cell lymphoma line

    DEFF Research Database (Denmark)

    Holland, J; Owens, T

    1997-01-01

    Intercellular adhesion molecule 1 (ICAM-1) (CD54) is an adhesion molecule of the immunoglobulin superfamily. The interaction between ICAM-1 on B lymphocytes and leukocyte function-associated antigen 1 on T cells plays a major role in several aspects of the immune response, including T-dependent B...... cell activation. While it was originally believed that ICAM-1 played a purely adhesive role, recent evidence suggests that it can itself transduce biochemical signals. We demonstrate that cross-linking of ICAM-1 results in the up-regulation of class II major histocompatibility complex, and we...... investigate the biochemical mechanism for the signaling role of ICAM-1. We show that cross-linking of ICAM-1 on the B lymphoma line A20 induces an increase in tyrosine phosphorylation of several cellular proteins, including the Src family kinase p53/p56(lyn). In vitro kinase assays showed that Lyn kinase...

  19. LHC: seven golden suppliers

    CERN Multimedia

    2005-01-01

    The fourth CERN Golden Hadron awards saw seven of the LHC's best suppliers receive recognition for the high quality of their work, compliance with delivery deadlines, flexibility and adaptability to the demanding working conditions of the project. The representatives of the seven companies which received awards during the Golden Hadron ceremony, standing with Lyn Evans, LHC Project Leader. 'The Golden Hadron awards are a symbol of our appreciation of not only the quality and timely delivery of components but also the collaborative and flexible way the firms have contributed to this very difficult project,' said Lyn Evans, head of the LHC project. The awards went to Kemppi-Kempower (Finland), Metso Powdermet (Finland), Transtechnik (Germany), Babcock Noell Nuclear (Germany), Iniziative Industriali (Italy), ZTS VVU Kosice (Slovakia), and Jehier (France). Babock Noell Nuclear (BNN) successfully produced one-third (416 cold dipole masses) of the LHC's superconducting dipole magnets, one of the most critical an...

  20. Building bridges … and accelerators

    CERN Multimedia

    2009-01-01

    Lyn Evans, the LHC project leader, was awarded an honorary doctorate from the University of Geneva (UNIGE) to celebrate his role not just in building accelerators, but also in building bridges between nations. He was one of four notables honoured at the event on Friday 5 June, coinciding with the University’s 450th Anniversary. Lyn Evans arriving at the ceremony with Archbishop Desmond Tutu. "It was a big surprise when I found out I’d been nominated," recounts Evans, "but it was an even bigger surprise to find out with whom I’d been nominated". At the ceremony Evans was awarded the honorary doctorate along with three others: Archbishop Desmond Tutu, who was acclaimed for his fight against apartheid in South Africa, Mary Robinson, first woman president of Ireland and former United Nations’ high commissioner of human rights, and Pascal Lamy, Director-General of the World Trade Organization. The award ceremony, known as the �...

  1. Breaking through the tranfer tunnel

    CERN Document Server

    Laurent Guiraud

    2001-01-01

    This image shows the tunnel boring machine breaking through the transfer tunnel into the LHC tunnel. Proton beams will be transferred from the SPS pre-accelerator to the LHC at 450 GeV through two specially constructed transfer tunnels. From left to right: LHC Project Director, Lyn Evans; CERN Director-General (at the time), Luciano Maiani, and Director for Accelerators, Kurt Hubner.

  2. CERN recognizes LHC suppliers with Golden Hadron awards

    CERN Multimedia

    Patrice Loïez

    2002-01-01

    The recipients of CERN's first 'Golden Hadron' awards for outstanding supplier performance are the Russian institute BINP, the Belgian firm Cockerill-Sambre and the US company Wah-Chang. LHC project leader Lyn Evans (centre) with Santo Comel of Cockerill-Sambre (left) and Lynn Davis of Wah-Chang. The third recipient, Alexander Skrinsky of the Budker Institute, was unable to attend the ceremony and will collect the Institute's award in September.

  3. Kohti palveluliiketoimintaa, palvelumuotoilulla palvelua teollisuusyritykselle. : Tapaus KiiltoClean Oy

    OpenAIRE

    Turpeinen, Pekka

    2017-01-01

    Suuret muutokset maailmassa vaikuttavat suomalaiseen yrityselämään. Näitä muutoksia ovat muun muassa globalisaatio ja teknologioiden nopea kehittyminen. Muutokseen vaikuttavat digitalisaation tuomat mahdollisuudet liiketoiminnalle, kuten asioiden internet, Internet of Things (IoT) ja keinoälyn kehitys. Yrityksen kilpailuetuihin tulisi löytää uusia keinoja. Kehitys on antanut yrityksille mahdollisuuden luoda asiakkailleen entistä vaivattomammin palveluita. Useimmat asiakkaat eivät hae enää tuo...

  4. Dedication of Fermilab's LHC Remote Operations Center

    CERN Multimedia

    Claudia Marcelloni

    2007-01-01

    Fermilab's Remote Operations Center will be dedicated simultaneously at Fermilab in the U.S. and from CMS (Point 5) in Cessy, France. Speakers will include: from the U.S. DOE Undersecretary for Science Raymond Orbach and Fermilab Director Pier Oddone (U.S.); and from CERN Director General Robert Aymar, CMS Spokesperson Jim Virdee, LHC Project Leader Lyn Evans and US CMS Project Manager Joel Butler.

  5. Cataclysmic Variables from SDSS I. The First Results

    OpenAIRE

    Szkody, P.; Anderson, S. F.; Agueros, M.; Covarrubias, R.; Bentz, M.; Hawley, S.; Margon, B.; Voges, W.; Henden, A.; Knapp, G. R.; Berk, D. E. Vanden; Rest, A.; Miknaitis, G.; Magnier, E.; Brinkmann, J.

    2001-01-01

    The commissioning year of the Sloan Digital Sky Survey has demonstrated that many cataclysmic variables have been missed in previous surveys with brighter limits. We report the identification of 22 cataclysmic variables, of which 19 are new discoveries and 3 are known systems (SW UMa, BH Lyn and Vir4). A compendium of positions, colors and characteristics of these systems obtained from the SDSS photometry and spectroscopy is presented along with data obtained during follow-up studies with the...

  6. Kuulutati välja amatöörfilmide festivali võitjad

    Index Scriptorium Estoniae

    2006-01-01

    Eesti Filmiamatööride Liidu korraldatud Eesti 41. amatöörfilmide festivali võitis täiskasvanute osas Evelyn, Henry ja Madis Mäeoru mängufilm "Lendamise lummus". Auhinna sai ka Kristo Viidingu "Juko, Koko ja Lyn", Leeni Linna mängufilm "Personal Space", Martti Helde ja Laura Väliku eksperimentaalfilm "Null", alla 14-aastaste seas Elisabeth Sinipalu "Fucking Gravity". Anti välja 18 auhinda, viis eridiplomit ja 10 diplomit

  7. 59th Medical Wing Protection of Vulnerable Populations: Ombudsman Program

    Science.gov (United States)

    2018-04-20

    REPORT TYPE 20/04/2018 poster 4. TITLE AND SUBTITLE 59th Medical Wing Protection of Vulnerable Populations: Ombudsman Program 6. AUTHOR(S...13. SUPPLEMENTARY NOTES 2018 Annual AAHRPP Conference April 20-22, 2018 Denver, CO 14. ABSTRACT 1S. SUBJECT TERMS 16. SECURITY CLASSIFICATION OF...59th Medical Wing Protection of Vulnerable Populations: Ombudsman Program Wayne DeutschDDS1, MPH, Michele Tavish LYN, PMP, CCRC 1 Brenda

  8. Back to Essentials: Virtues and Character for Strategic Leaders

    Science.gov (United States)

    2012-03-20

    the exercise of virtues . 10 Virtues are acquired through intensive practice and they help avoid excesses.31 In that sense, Aristotle emphasized...2012). 31 Kreeft, Back to Virtue ; Havard, Virtuous Leadership. 32 Aristotle . 33 Robert Turknett, Lyn Turknett, and Chris McCusker, “Going First and...Leading Ethically .” Principal Leadership, (May 2008): 64. This study coincides with the tree virtues identified by Glanz - courage judgment and

  9. Successful test of SPS-to-LHC beamline

    CERN Multimedia

    Maximilien Brice

    2004-01-01

    On 23 October there was great excitement in the Prevessin control room when, on the first attempt, a beam passed over 2.5 km down the new SPS-to-LHC transfer line, TI8, to within a few metres of the LHC tunnel. Members of the AB, AT and TS departments involved in the beamline and its test, celebrate their success with the Director General, Robert Aymar, and the LHC Project Leader, Lyn Evans.

  10. Successful test of SPS-to-LHC beamline

    CERN Multimedia

    2004-01-01

    On 23 October there was great excitement in the Prevessin control room when, on the first attempt, a beam passed over 2.5 km down the new SPS-to-LHC transfer line, TI8, to within a few metres of the LHC tunnel. Above: members of the AB, AT and TS departments involved in the beamline and its test, celebrate their success with the Director General, Robert Aymar, and the LHC Project Leader, Lyn Evans.

  11. Light-Time Effect and Mass Transfer in the Triple Star SW Lyncis

    Directory of Open Access Journals (Sweden)

    Chun-Hwey Kim

    1999-06-01

    Full Text Available In this paper all the photoelectric times of minimum for the triple star SW Lyn have been analyzed in terms of light-time e ect due to the third-body and secular period decreases induced by mass transfer process. The light-time orbit determined recently by Ogloza et al.(1998 were modi ed and improved. And it is found that the orbital period of SW Lyn have been decreasing secularly. The third-body revolves around the mass center of triple stars every 5y.77 in a highly eccentric elliptical orbit(e=0.61. The third-body with a minimum mass of 1.13M may be a binary or a white dwarf. The rate of secular period-decrease were obtained as ¡âP/P = -12.45 x 10^-11, implying the mass-transfer from the massive primary star to the secondary. The mass losing rate from the primary were calculated as about 1.24 x 10^-8M /y. It is noticed that the mass-transfer in SW Lyn system is opposite in direction to that deduced from it's Roche geometry by previous investigators.

  12. Efficacy of ponatinib against ABL tyrosine kinase inhibitor-resistant leukemia cells

    International Nuclear Information System (INIS)

    Okabe, Seiichi; Tauchi, Tetsuzo; Tanaka, Yuko; Ohyashiki, Kazuma

    2013-01-01

    Highlights: •Efficacy of ponatinib against ABL tyrosine kinase inhibitor-resistant leukemia cells okabe et al. •Imatinib or nilotinib resistance was involved Src family kinase. •The BCR-ABL point mutation (E334V) was highly resistant to imatinib or nilotinib. •Ponatinib was a powerful strategy against imatinib or nilotinib resistant Ph-positive cells. -- Abstract: Because a substantial number of patients with chronic myeloid leukemia acquire resistance to ABL tyrosine kinase inhibitors (TKIs), their management remains a challenge. Ponatinib, also known as AP24534, is an oral multi-targeted TKI. Ponatinib is currently being investigated in a pivotal phase 2 clinical trial. In the present study, we analyzed the molecular and functional consequences of ponatinib against imatinib- or nilotinib-resistant (R) K562 and Ba/F3 cells. The proliferation of imatinib- or nilotinib-resistant K562 cells did not decrease after treatment with imatinib or nilotinib. Src family kinase Lyn was activated. Point mutation Ba/F3 cells (E334 V) were also highly resistant to imatinib and nilotinib. Treatment with ponatinib for 72 h inhibited the growth of imatinib- and nilotinib-resistant cells. The phosphorylation of BCR-ABL, Lyn, and Crk-L was reduced. This study demonstrates that ponatinib has an anti-leukemia effect by reducing ABL and Lyn kinase activity and this information may be of therapeutic relevance

  13. Photometry of the SW Sextantis-type nova-like BH Lyncis in high state

    Science.gov (United States)

    Stanishev, V.; Kraicheva, Z.; Genkov, V.

    2006-08-01

    Aims.We present a photometric study of the deeply eclipsing SW Sex-type nova-like cataclysmic variable star BH Lyn. Methods: .Time-resolved V-band CCD photometry was obtained for seven nights between 1999 and 2004. Results: .We determined 11 new eclipse timings of BH Lyn and derived a refined orbital ephemeris with an orbital period of 0.155875577(14) °. During the observations, BH Lyn was in high-state with V≃15.5 mag. The star presents ~1.5 mag deep eclipses with mean full-width at half-flux of 0.0683(±0.0054)P_orb. The eclipse shape is highly variable, even changing form cycle to cycle. This is most likely due to accretion disc surface brightness distribution variations, most probably caused by strong flickering. Time-dependent accretion disc self-occultation or variations of the hot spot(s) intensity are also possible explanations. Negative superhumps with period of ˜0.145 ° are detected in two long runs in 2000. A possible connection between SW Sex and negative superhump phenomena through the presence of tilted accretion disc is discussed, and a way to observationally test this is suggested.

  14. It’s no miracle...

    CERN Multimedia

    CERN Bulletin

    2012-01-01

    “The LHC has been a huge effort over more than 15 years. It’s not always been easy but today it is performing so spectacularly well that the people who built it should be very proud.” Lyn Evans, head of the LHC project since its beginning and until its commissioning in 2011, shares his recollections with us on the day of the long-awaited discovery.   Lyn Evans, former head of the LHC project, in the LHC tunnel, 2008. While you were building the LHC, were you expecting it to perform so well? Lyn Evans: I knew that the machine had been beautifully designed and was being built extremely well – but I could not have expected that such wonderful results could be achieved in so little time. What are the reasons for such a good performance? Evans: The LHC was designed to really push the limits; I think that the machine has got more than 30 years of accumulated experience in its design. The fact is the LHC has already exceeded the design luminosity at the en...

  15. Su Lyncis, a Hard X-Ray Bright M Giant: Clues Point to a Large Hidden Population of Symbiotic Stars

    Science.gov (United States)

    Mukai, K.; Luna, G. J. M.; Cusumano, G.; Segreto, A.; Munari, U.; Sokoloski, J. L.; Lucy, A. B.; Nelson, T.; Nunez, N. E.

    2016-01-01

    Symbiotic star surveys have traditionally relied almost exclusively on low resolution optical spectroscopy. However, we can obtain a more reliable estimate of their total Galactic population by using all available signatures of the symbiotic phenomenon. Here we report the discovery of a hard X-ray source, 4PBC J0642.9+5528, in the Swift hard X-ray all-sky survey, and identify it with a poorly studied red giant, SU Lyn, using pointed Swift observations and ground-based optical spectroscopy. The X-ray spectrum, the optical to UV spectrum, and the rapid UV variability of SU Lyn are all consistent with our interpretation that it is a symbiotic star containing an accreting white dwarf. The symbiotic nature of SU Lyn went unnoticed until now, because it does not exhibit emission lines strong enough to be obvious in low resolution spectra. We argue that symbiotic stars without shell-burning have weak emission lines, and that the current lists of symbiotic stars are biased in favor of shell-burning systems. We conclude that the true population of symbiotic stars has been underestimated, potentially by a large factor.

  16. Efficacy of ponatinib against ABL tyrosine kinase inhibitor-resistant leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Okabe, Seiichi, E-mail: okabe@tokyo-med.ac.jp; Tauchi, Tetsuzo; Tanaka, Yuko; Ohyashiki, Kazuma

    2013-06-07

    Highlights: •Efficacy of ponatinib against ABL tyrosine kinase inhibitor-resistant leukemia cells okabe et al. •Imatinib or nilotinib resistance was involved Src family kinase. •The BCR-ABL point mutation (E334V) was highly resistant to imatinib or nilotinib. •Ponatinib was a powerful strategy against imatinib or nilotinib resistant Ph-positive cells. -- Abstract: Because a substantial number of patients with chronic myeloid leukemia acquire resistance to ABL tyrosine kinase inhibitors (TKIs), their management remains a challenge. Ponatinib, also known as AP24534, is an oral multi-targeted TKI. Ponatinib is currently being investigated in a pivotal phase 2 clinical trial. In the present study, we analyzed the molecular and functional consequences of ponatinib against imatinib- or nilotinib-resistant (R) K562 and Ba/F3 cells. The proliferation of imatinib- or nilotinib-resistant K562 cells did not decrease after treatment with imatinib or nilotinib. Src family kinase Lyn was activated. Point mutation Ba/F3 cells (E334 V) were also highly resistant to imatinib and nilotinib. Treatment with ponatinib for 72 h inhibited the growth of imatinib- and nilotinib-resistant cells. The phosphorylation of BCR-ABL, Lyn, and Crk-L was reduced. This study demonstrates that ponatinib has an anti-leukemia effect by reducing ABL and Lyn kinase activity and this information may be of therapeutic relevance.

  17. Control of nuclear-cytoplasmic shuttling of Ankrd54 by PKCδ

    Institute of Scientific and Technical Information of China (English)

    Amy L Samuels; Alison Louw; Reza Zareie; Evan Ingley

    2017-01-01

    AIM To identify and characterize the effect of phosphorylation on the subcellular localization of Ankrd54.METHODS HEK293 T cells were treated with calyculin A, staurosporin or phorbol 12-myristate 13-acetate(PMA). Cells were transfected with eG FP-tagged Ankrd54 with or without Lyn tyrosine kinase(wild-type, Y397 F mutant, or Y508 F mutant). The subcellular localization was assessed by immunofluorescence imaging of cells, immunoblotting of subcellular fractionations. The phosphorylation of Ankrd54 was monitored using Phos-tagT M gel retardation. Phosphorylated peptides were analysed by multiplereaction-monitoring(MRM) proteomic analysis.RESULTS Activation of PKC kinases using PMA promoted nuclear export of Ankrd54 and correlated with increased Ankrd54 phosphorylation, assayed using Phos-tag TM gel retardation. Co-expression of an active form of the PKCδisoform specifically promoted both phosphorylation and cytoplasmic localization of Ankrd54, while PKCδ, Akt and PKA did not. Alanine mutation of several serine residues in the amino-terminal region of Ankrd54(Ser14, Ser17, Ser18, Ser19) reduced both PMA induced cytoplasmic localization and phosphorylation of Ankrd54. Using MRM proteomic analysis, phosphorylation of the Ser18 residue of Ankrd54 was readily detectable in response to PMA stimulation. PMA stimulation of cells co-expressing Ankrd54 and Lyn tyrosine kinase displayed increased coimmunoprecipitation and enhanced co-localization in the cytoplasm.CONCLUSION We identify phosphorylation by PKCδ as a major regulator of nuclear-cytoplasmic shuttling of Ankrd54, and its interaction with the tyrosine kinase Lyn.

  18. Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma

    Directory of Open Access Journals (Sweden)

    P. Balsas

    2017-03-01

    Full Text Available Abstract Background Pharmacological inhibition of B cell receptor (BCR signaling has recently emerged as an effective approach in a wide range of B lymphoid neoplasms. However, despite promising clinical activity of the first Bruton’s kinase (Btk and spleen tyrosine kinase (Syk inhibitors, a small fraction of patients tend to develop progressive disease after initial response to these agents. Methods We evaluated the antitumor activity of IQS019, a new BCR kinase inhibitor with increased affinity for Btk, Syk, and Lck/Yes novel tyrosine kinase (Lyn, in a set of 34 B lymphoid cell lines and primary cultures, including samples with acquired resistance to the first-in-class Btk inhibitor ibrutinib. Safety and efficacy of the compound were then evaluated in two xenograft mouse models of B cell lymphoma. Results IQS019 simultaneously engaged a rapid and dose-dependent de-phosphorylation of both constitutive and IgM-activated Syk, Lyn, and Btk, leading to impaired cell proliferation, reduced CXCL12-dependent cell migration, and induction of caspase-dependent apoptosis. Accordingly, B cell lymphoma-bearing mice receiving IQS019 presented a reduced tumor outgrowth characterized by a decreased mitotic index and a lower infiltration of malignant cells in the spleen, in tight correlation with downregulation of phospho-Syk, phospho-Lyn, and phospho-Btk. More interestingly, IQS019 showed improved efficacy in vitro and in vivo when compared to the first-in-class Btk inhibitor ibrutinib, and was active in cells with acquired resistance to this latest. Conclusions These results define IQS019 as a potential drug candidate for a variety of B lymphoid neoplasms, including cases with acquired resistance to current BCR-targeting therapies.

  19. House Dust Mite Allergen Regulates Constitutive Apoptosis of Normal and Asthmatic Neutrophils via Toll-Like Receptor 4.

    Directory of Open Access Journals (Sweden)

    Do Hyung Kim

    Full Text Available House dust mites (HDMs induce allergic diseases such as asthma. Neutrophil apoptosis is an important process of innate immunity, and its dysregulation is associated with asthma. In this study, we examined the effects of HDM on constitutive apoptosis of normal and asthmatic neutrophils. Extract of Dermatophagoides pteronissinus (DP inhibited neutrophil apoptosis, but Dermatophagoides farinae extract had no effect. Anti-apoptotic signaling mediated by DP involves in TLR4, Lyn, PI3K, Akt, ERK, and NF-κB in normal neutrophils. DP delayed cleavage of procaspase 9 and procaspase 3 and the decrease in Mcl-1 expression. Supernatant collected from DP-treated normal neutrophils inhibited the constitutive apoptosis of normal neutrophils, and S100A8 and S100A9 were identified as anti-apoptotic proteins in the supernatant. S100A8 and S100A9 transduced the anti-apoptotic signal via TLR4, Lyn, PI3K, Akt, ERK, and NF-κB. DP also suppressed asthmatic neutrophil apoptosis and induced secretion of S100A8 and S100A9, which delayed the constitutive apoptosis. The anti-apoptotic effects of DP, S100A8 and S100A9 in asthmatic neutrophils are associated with TLR4, Lyn, PI3K, Akt, ERK, and NF-κB. The concentrations of S100A8 and S100A9 were significantly elevated in asthmatic bronchoalveolar lavage fluid (BALF when compared to normal BALF (p<0.01, but not in serum. S100A8 concentration in BALF was positively correlated with the number of BALF neutrophils and negatively correlated with FEV1(%. These findings improve our understanding of the role of HDM in regulation of neutrophil apoptosis in normal individuals and asthmatics and will enable elucidation of asthma pathogenesis.

  20. Pathway and network-based analysis of genome-wide association studies and RT-PCR validation in polycystic ovary syndrome.

    Science.gov (United States)

    Shen, Haoran; Liang, Zhou; Zheng, Saihua; Li, Xuelian

    2017-11-01

    The purpose of this study was to identify promising candidate genes and pathways in polycystic ovary syndrome (PCOS). Microarray dataset GSE345269 obtained from the Gene Expression Omnibus database includes 7 granulosa cell samples from PCOS patients, and 3 normal granulosa cell samples. Differentially expressed genes (DEGs) were screened between PCOS and normal samples. Pathway enrichment analysis was conducted for DEGs using ClueGO and CluePedia plugin of Cytoscape. A Reactome functional interaction (FI) network of the DEGs was built using ReactomeFIViz, and then network modules were extracted, followed by pathway enrichment analysis for the modules. Expression of DEGs in granulosa cell samples was measured using quantitative RT-PCR. A total of 674 DEGs were retained, which were significantly enriched with inflammation and immune-related pathways. Eight modules were extracted from the Reactome FI network. Pathway enrichment analysis revealed significant pathways of each module: module 0, Regulation of RhoA activity and Signaling by Rho GTPases pathways shared ARHGAP4 and ARHGAP9; module 2, GlycoProtein VI-mediated activation cascade pathway was enriched with RHOG; module 3, Thromboxane A2 receptor signaling, Chemokine signaling pathway, CXCR4-mediated signaling events pathways were enriched with LYN, the hub gene of module 3. Results of RT-PCR confirmed the finding of the bioinformatic analysis that ARHGAP4, ARHGAP9, RHOG and LYN were significantly upregulated in PCOS. RhoA-related pathways, GlycoProtein VI-mediated activation cascade pathway, ARHGAP4, ARHGAP9, RHOG and LYN may be involved in the pathogenesis of PCOS.

  1. Tunneälyjohtaminen asiantuntijaorganisaation muutoksessa

    OpenAIRE

    Kolari, Pirjo

    2010-01-01

    Väitöstutkimuksen kohteena on johtamisen yhteys henkilöstön emotionaalisiin rakenteisiin, motivaatioon, toimintastrategioihin ja osaamisen kehittymiseen jatkuvassa muutoksessa elävän teknologia-alan asiantuntijaorganisaatiossa. Pääosin kysymyksessä on kvalitatiivinen tutkimus, jossa tietoa on haettu sekä haastattelujen mutta myös kyselytutkimuksen avulla. Kyselytutkimuksessa kohdeorganisaation henkilöstö (N=313) arvioi lähimmän esimiehensä johtamis- ja tunneälyn kompetensseja. Myös esimie...

  2. CERN Academic Training Programme 2008/2009

    CERN Multimedia

    HR Department

    2009-01-01

    LECTURE SERIES 8, 9, 10 11 & 12 June 2009 11:00-12:00 - BE Auditorium Meyrin, Bldg. 6-2-024 Scenarios and Technological Challenges for a LHC Luminosity Upgrade: Introduction to the LHC Upgrade Program and Summary of Physics Motivations Lyn Evans / DG Projects Office, Michelangelo Mangano / PH Department After a general introduction to the motivations for a LHC upgrade, the lectures will discuss the beam dynamics and technological challenges of the increase of the LHC luminosity, and the possible scenarios. Items such as a stronger final focus with larger aperture magnets, crab cavities, electron cloud issues, beam-beam interaction, machine protection and collimation will be discussed.

  3. Blessed with song

    CERN Multimedia

    2008-01-01

    The Morriston Orpheus Choir from Swansea sing in the CERN control center.The Morriston Orpheus Choir from Swansea were joined by the Welsh First Minister Rhodri Morgan at the LHC control room on Sunday 12 October. Lyn Evans, a fellow Welshman, was excited to have them here at CERN. "The control room has been somewhat quieter recently than on the 10 September," he said later in his speech at the LHC inauguration ceremony, "but last week, some fellow countrymen of mine, the wonderful Morriston Orpheus choir from Wales, paid us a visit and blessed the LHC with song."

  4. Informaatiotulvan hallitseminen tekoälyllä

    OpenAIRE

    Kostiainen, Matias

    2017-01-01

    Tässä kandidaatintutkielmassa selvitetään kirjallisuuskatsauksena, miten infor- maatioähkyä voidaan hallita tekoälyn avulla. Tutkielmassa käydään yksityiskohtaisesti läpi mitä informaatioähky tarkoittaa, miten se ilmenee ja syntyy, sekä millaisia vaikutuksia sil- lä voi olla. Tutkimusongelmaa lähestytään valikoivan tarkkaavaisuuden näkökulmasta, sekä kartoitetaan, miten tekoäly pystyy mallintamaan ihmisille ominaista valikoivaa tarkkaavai- suutta. Keinotekoinen valikoiva tarkkaavaisuuden agen...

  5. Raman-atomic force microscopy of the ommatidial surfaces of Dipteran compound eyes

    Science.gov (United States)

    Anderson, Mark S.; Gaimari, Stephen D.

    2003-01-01

    The ommatidial lens surfaces of the compound eyes in several species of files (Insecta: Diptera) and a related order (Mecoptera) were analyzed using a recently developed Raman-atomic force microscope. We demonstrate in this work that the atomic force microscope (AFM) is a potentially useful instrument for gathering phylogenetic data and that the newly developed Raman-AFM may extend this application by revealing nanometer-scale surface chemistry. This is the first demonstration of apertureless near-field Raman spectroscopy on an intact biological surface. For Chrysopilus testaceipes Bigot (Rhagionidae), this reveals unique cerebral cortex-like surface ridges with periodic variation in height and surface chemistry. Most other Brachyceran flies, and the "Nematoceran" Sylvicola fenestralis (Scopoli) (Anisopodidae), displayed the same morphology, while other taxa displayed various other characteristics, such as a nodule-like (Tipula (Triplicitipula) sp. (Tipulidae)) or coalescing nodule-like (Tabanus punctifer Osten Sacken (Tabanidae)) morphology, a smooth morphology with distinct pits and grooves (Dilophus orbatus (Say) (Bibionidae)), or an entirely smooth surface (Bittacus chlorostigma MacLachlan (Mecoptera: Bittacidae)). The variation in submicrometer structure and surface chemistry provides a new information source of potential phylogenetic importance, suggesting the Raman-atomic force microscope could provide a new tool useful to systematic and evolutionary inquiry.

  6. Simulations of Merging Helion Bunches on the AGS Injection Porch

    Energy Technology Data Exchange (ETDEWEB)

    Gardner, C. J. [Brookhaven National Lab. (BNL), Upton, NY (United States). Collider-Accelerator Dept.

    2014-08-29

    During the setup of helions for the FY2014 RHIC run it was discovered that the standard scheme for merging bunches on the AGS injection porch required an injection kicker pulse shorter than what was available. To overcome this difficulty, K. Zeno proposed and developed an interesting and unusual alternative which uses RF harmonic numbers 12, 4, 2 (rather than the standard 8, 4, 2) to merge 8 helion bunches into 2. In this note we carry out simulations that illustrate how the alternative scheme works and how it compares with the standard scheme. This is done in Sections 13 and 14. A scheme in which 6 bunches are merged into 1 is simulated in Section 15. This may be useful if more helions per merged bunch are needed in future runs. General formulae for the simulations are given in Sections 9 through 12. For completeness, Sections 1 through 8 give a derivation of the turn-by-turn equations of longitudinal motion at constant magnetic field. The derivation is based on the work of MacLachlan. The reader may wish to skip over these Sections and start with Section 9.

  7. Simulations of Merging Helion Bunches on the AGS Injection Porch

    International Nuclear Information System (INIS)

    Gardner, C. J.

    2014-01-01

    During the setup of helions for the FY2014 RHIC run it was discovered that the standard scheme for merging bunches on the AGS injection porch required an injection kicker pulse shorter than what was available. To overcome this difficulty, K. Zeno proposed and developed an interesting and unusual alternative which uses RF harmonic numbers 12, 4, 2 (rather than the standard 8, 4, 2) to merge 8 helion bunches into 2. In this note we carry out simulations that illustrate how the alternative scheme works and how it compares with the standard scheme. This is done in Sections 13 and 14. A scheme in which 6 bunches are merged into 1 is simulated in Section 15. This may be useful if more helions per merged bunch are needed in future runs. General formulae for the simulations are given in Sections 9 through 12. For completeness, Sections 1 through 8 give a derivation of the turn-by-turn equations of longitudinal motion at constant magnetic field. The derivation is based on the work of MacLachlan. The reader may wish to skip over these Sections and start with Section 9.

  8. Occurrence and Diversity of Tetracycline Resistance Genes in Lagoons and Groundwater Underlying Two Swine Production Facilities

    Science.gov (United States)

    Chee-Sanford, J. C.; Aminov, R.I.; Krapac, I.J.; Garrigues-Jeanjean, N.; Mackie, R.I.

    2001-01-01

    In this study, we used PCR typing methods to assess the presence of tetracycline resistance determinants conferring ribosomal protection in waste lagoons and in groundwater underlying two swine farms. All eight classes of genes encoding this mechanism of resistance [tet(O), tet(Q), tet(W), tet(M), tetB(P), tet(S), tet(T), and otrA] were found in total DNA extracted from water of two lagoons. These determinants were found to be seeping into the underlying groundwater and could be detected as far as 250 m downstream from the lagoons. The identities and origin of these genes in groundwater were confirmed by PCR-denaturing gradient gel electrophoresis and sequence analyses. Tetracycline-resistant bacterial isolates from groundwater harbored the tet(M) gene, which was not predominant in the environmental samples and was identical to tet(M) from the lagoons. The presence of this gene in some typical soil inhabitants suggests that the vector of antibiotic resistance gene dissemination is not limited to strains of gastrointestinal origin carrying the gene but can be mobilized into the indigenous soil microbiota. This study demonstrated that tet genes occur in the environment as a direct result of agriculture and suggested that groundwater may be a potential source of antibiotic resistance in the food chain.

  9. Læring av erfaring?

    DEFF Research Database (Denmark)

    Ramvi, Ellen

    Hva skal til for å lære av erfaring? Denne avhandlingen er en empirisk baseret undersøkelse av ungdosmskolelæreres muligheter og betingelser for å "lære av erfaring" i den særlige betydning av begrepet  W. Bion gir i sin psykoanalytiske teori. Undersøgelsen baserer seg på et feltarbeid som strekker...... seg over ett skoleår. Datamaterialet ble samlet inn via observerasjoner og mer eller mindre strukturerte samtaler med lærere ved to forskellige norske ungdsomsskoler. Analysen av materialet foregår i to trinn: først en fenomenologisk analyse, tett på lærernes egne beskrivelser og refleksjoner av...... lærerarbeidet, dets udfordringer og vanskeligheter, og deretter en psykoanalytisk perspektivering av de fenomenologiske analyseresultatene. Analysen viser en almindelig lærerhverdag og en skoleorganisation, hvor lærernes "læring av erfaring" i stor utstrekning blokkeres i et vekselspill mellem lærernes flukt...

  10. A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells.

    Science.gov (United States)

    Rix, U; Remsing Rix, L L; Terker, A S; Fernbach, N V; Hantschel, O; Planyavsky, M; Breitwieser, F P; Herrmann, H; Colinge, J; Bennett, K L; Augustin, M; Till, J H; Heinrich, M C; Valent, P; Superti-Furga, G

    2010-01-01

    Resistance to the BCR-ABL tyrosine kinase inhibitor imatinib poses a pressing challenge in treating chronic myeloid leukemia (CML). This resistance is often caused by point mutations in the ABL kinase domain or by overexpression of LYN. The second-generation BCR-ABL inhibitor INNO-406 is known to inhibit most BCR-ABL mutants and LYN efficiently. Knowledge of its full target spectrum would provide the molecular basis for potential side effects or suggest novel therapeutic applications and possible combination therapies. We have performed an unbiased chemical proteomics native target profile of INNO-406 in CML cells combined with functional assays using 272 recombinant kinases thereby identifying several new INNO-406 targets. These include the kinases ZAK, DDR1/2 and various ephrin receptors. The oxidoreductase NQO2, inhibited by both imatinib and nilotinib, is not a relevant target of INNO-406. Overall, INNO-406 has an improved activity over imatinib but a slightly broader target profile than both imatinib and nilotinib. In contrast to dasatinib and bosutinib, INNO-406 does not inhibit all SRC kinases and most TEC family kinases and is therefore expected to elicit fewer side effects. Altogether, these properties may make INNO-406 a valuable component in the drug arsenal against CML.

  11. The long road to the LHC

    CERN Multimedia

    CERN. Geneva; Jenni, Peter; Evans, Lyn

    2014-01-01

    Lecture by Lyn Evans Abstract The key to the discovery of the Higgs boson has been the development of particle accelerators at CERN through the years. I will explain how a particle accelerator works and will follow the path from the construction of the Proton Synchrotron in the 1950s to the world’s most powerful colliding beam machine, the Large Hadron Collider. Biography Born in 1945, Lyn Evans has spent his whole career in the field of high energy physics and particle accelerators, participating in all the great projects of CERN. From 1993 he led the team that designed, built and commissioned the LHC. He is presently a visiting professor at Imperial College London and Director of the Linear Collider Collaboration. Among his many honours he is a Fellow of the American Physical Society and a Fellow of the Royal Society. He was awarded a Special Fundamental Physics Prize in 2013 for his contribution to the discovery of the Higgs boson. “Some aspects of physics at CERN (and elsewhere...

  12. Radotinib Induces Apoptosis of CD11b+ Cells Differentiated from Acute Myeloid Leukemia Cells.

    Directory of Open Access Journals (Sweden)

    Sook-Kyoung Heo

    Full Text Available Radotinib, developed as a BCR/ABL tyrosine kinase inhibitor (TKI, is approved for the second-line treatment of chronic myeloid leukemia (CML in South Korea. However, therapeutic effects of radotinib in acute myeloid leukemia (AML are unknown. In the present study, we demonstrate that radotinib significantly decreases the viability of AML cells in a dose-dependent manner. Kasumi-1 cells were more sensitive to radotinib than NB4, HL60, or THP-1 cell lines. Furthermore, radotinib induced CD11b expression in NB4, THP-1, and Kasumi-1 cells either in presence or absence of all trans-retinoic acid (ATRA. We found that radotinib promoted differentiation and induced CD11b expression in AML cells by downregulating LYN. However, CD11b expression induced by ATRA in HL60 cells was decreased by radotinib through upregulation of LYN. Furthermore, radotinib mainly induced apoptosis of CD11b+ cells in the total population of AML cells. Radotinib also increased apoptosis of CD11b+ HL60 cells when they were differentiated by ATRA/dasatinib treatment. We show that radotinib induced apoptosis via caspase-3 activation and the loss of mitochondrial membrane potential (ΔΨm in CD11b+ cells differentiated from AML cells. Our results suggest that radotinib may be used as a candidate drug in AML or a chemosensitizer for treatment of AML by other therapeutics.

  13. Comparative evaluation of extracellular β-D-fructofuranosidase in submerged and solid-state fermentation produced by newly identified Bacillus subtilis strain.

    Science.gov (United States)

    Lincoln, Lynette; More, Sunil S

    2018-04-17

    To screen and identify a potential extracellular β-D-fructofuranosidase or invertase producing bacterium from soil, and comparatively evaluate the enzyme biosynthesis under submerged and solid-state fermentation. Extracellular invertase producing bacteria were screened from soil. Identification of the potent bacterium was performed based on microscopic examinations and 16S rDNA molecular sequencing. Bacillus subtilis LYN12 invertase secretion was surplus with wheat bran humidified with molasses medium (70%), with elevated activity at 48 h and 37 °C under solid-state fermentation, whereas under submerged conditions increased activity was observed at 24 h and 45 °C in the molasses medium. The study revealed a simple fermentative medium for elevated production of extracellular invertase from a fast growing Bacillus strain. Bacterial invertases are scarce and limited reports are available. By far, this is the first report on the comparative analysis of optimization of extracellular invertase synthesis from Bacillus subtilis strain by submerged and solid-state fermentation. The use of agricultural residues increased yields resulting in development of a cost-effective and stable approach. Bacillus subtilis LYN12 invertase possesses excellent fermenting capability to utilize agro-industrial residues under submerged and solid-state conditions. This could be a beneficial candidate in food and beverage processing industries. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  14. Last cast for the LHC

    CERN Multimedia

    2005-01-01

    The first major contract signed for the LHC is drawing to a close. Belgian firm Cockerill Sambre (a member of the Arcelor Group) has just completed production of 50,000 tonnes of steel sheets for the accelerator's superconducting magnet yokes, in what has proved to be an exemplary partnership with CERN. Philippe Lebrun, Head of the AT Department, Lyn Evans, LHC Project Leader, and Lucio Rossi, Head of the AT-MAS Group, in front of the last batch of steel for the LHC at Cockerill Sambre. It was a bright red-letter day at the end of May, when Belgian firm Cockerill Sambre of the Arcelor Group marked the completion of one of the largest contracts for the LHC machine by casting the last batch of steel sheets for the LHC superconducting magnet yokes in the presence of LHC Project Leader Lyn Evans, AT Department Head Philippe Lebrun, Magnets and Superconductors (AT-MAS) Group Leader Lucio Rossi and Head of the AT-MAS Group's components centre Francesco Bertinelli. The yokes constitute approximately 80% of the acc...

  15. Hydrogen inhalation ameliorated mast cell mediated brain injury after ICH in mice

    Science.gov (United States)

    Manaenko, Anatol; Lekic, Tim; Ma, Qingyi; Zhang, John H.; Tang, Jiping

    2012-01-01

    OBJECTIVE Hydrogen inhalation was neuroprotective in several brain injury models. Its mechanisms are believed to be related to anti-oxidative stress. We investigated the potential neurovascular protective effect of hydrogen inhalation especially effect on mast cell activation in a mouse model of intracerebral hemorrhage (ICH). DESIGN Controlled in vivo laboratory study. SETTING Animal research laboratory SUBJECTS 171, 8 weeks old male CD-1 mice were used. INTERVENTIONS Collagenase-induced ICH model in 8 weeks old, male, CD-1 mice was used. Hydrogen was administrated via spontaneous inhalation. The blood-brain barrier (BBB) permeability and neurological deficits were investigated at 24 and 72 hours after ICH. Mast cell activation was evaluated by Western blot and immuno-staining. The effects of hydrogen inhalation on mast cell activation were confirmed in an autologous blood injection model ICH. MEASURMENT AND MAIN RESULTS At 24 and 72 hours post-ICH, animals showed BBB disruption, brain edema, neurological deficits, accompanied with phosphorylation of Lyn kinase and release of tryptase, indicating mast cell activation. Hydrogen treatment diminished phosphorylation of Lyn kinase and release of tryptase, decreased accumulation and degranulation of mast cells, attenuated BBB disruption and improved neurobehavioral function. CONCLUSION Activation of mast cells following ICH contributed to increase of BBB permeability and brain edema. Hydrogen inhalation preserved BBB disruption by prevention of mast cell activation after ICH. PMID:23388512

  16. DFB component production at IHEP complete

    CERN Multimedia

    2007-01-01

    The last of the components for the 42 DFBs (electrical distribution boxes feeding the strings of superconducting magnets in the LHC) produced for CERN by IHEP Protvino (Russia) were delivered to CERN in January 2007. The DFBs will provide the electrical supply for the superconducting magnets for the LHC, making possible the transition from room temperature down to -268ºC (4.5 K) (see Bulletin No. 37/2006). This important achievement was celebrated on the 14th February 2007 at the IHEP House of Scientists in Protvino in the presence of all the IHEP personnel who contributed to the DFB components production, and with the participation of eight delegates from CERN Management and CERN engineers involved in DFB production. Lyn Evans handed over a present symbolizing the IHEP-CERN collaboration to Nikolaj Tyurin, who offered to Lyn Evans a model of a DFB. Since August 2005, when the components for the first two boxes arrived at CERN, a total of 360 tonnes of raw materials were transported to IHEP on 19 lorries...

  17. Erythropoietin Receptor Signaling Is Membrane Raft Dependent

    Science.gov (United States)

    McGraw, Kathy L.; Fuhler, Gwenny M.; Johnson, Joseph O.; Clark, Justine A.; Caceres, Gisela C.; Sokol, Lubomir; List, Alan F.

    2012-01-01

    Upon erythropoietin (Epo) engagement, Epo-receptor (R) homodimerizes to activate JAK2 and Lyn, which phosphorylate STAT5. Although recent investigations have identified key negative regulators of Epo-R signaling, little is known about the role of membrane localization in controlling receptor signal fidelity. Here we show a critical role for membrane raft (MR) microdomains in creation of discrete signaling platforms essential for Epo-R signaling. Treatment of UT7 cells with Epo induced MR assembly and coalescence. Confocal microscopy showed that raft aggregates significantly increased after Epo stimulation (mean, 4.3±1.4(SE) vs. 25.6±3.2 aggregates/cell; p≤0.001), accompanied by a >3-fold increase in cluster size (p≤0.001). Raft fraction immunoblotting showed Epo-R translocation to MR after Epo stimulation and was confirmed by fluorescence microscopy in Epo stimulated UT7 cells and primary erythroid bursts. Receptor recruitment into MR was accompanied by incorporation of JAK2, Lyn, and STAT5 and their activated forms. Raft disruption by cholesterol depletion extinguished Epo induced Jak2, STAT5, Akt and MAPK phosphorylation in UT7 cells and erythroid progenitors. Furthermore, inhibition of the Rho GTPases Rac1 or RhoA blocked receptor recruitment into raft fractions, indicating a role for these GTPases in receptor trafficking. These data establish a critical role for MR in recruitment and assembly of Epo-R and signal intermediates into discrete membrane signaling units. PMID:22509308

  18. The benefits of management training

    CERN Multimedia

    2002-01-01

    After six years an unusual management course remains very popular. Participants in the most recent session of 3CM course, with the external course leader Ton Bastiaans (left back), Lyn Evans, LHC project leader (3rd from the right) and Sudeshna Datta Cockerill (far right) who organises the management and communication courses. In 1996 a sceptical Lyn Evans agreed to act as the 'sponsor' from CERN's senior management for a new course on 'Introduction to management', aimed at young professionals at CERN who may in the near future have supervisory roles. CERN's LHC Project Leader quickly discovered that it is a 'remarkable course' and six years later he remains enthusiastic about its value. His role is to attend at the end of the last day and to listen to the reactions of the participants - how they have benefited and how they see the benefits to CERN. The session also gives the participants the opportunity to discuss with one of the Directorate their views on problems at CERN. Code-named 3CM, and run by an ex...

  19. India and CERN: a collaboration in good shape

    CERN Multimedia

    2002-01-01

    The addenda were signed by the director of India's Centre for Advanced Technology, Dilip Bhawalkar, and LHC project leader, Lyn Evans. Back row, from left to right: P.J. Bryant, Ph. Lebrun, V.C. Sahni, M. Karmarkar, S. Bhave, G. Govindarajan. The director of India's Centre for Advanced Technology, Dilip Bhawalkar, and LHC project leader Lyn Evans have just signed the final addenda for the first Indian contribution to the LHC at a meeting of the Indian Department of Atomic Energy (DAE) - CERN joint committee. The main component of this contribution covers the superconducting corrector magnets for the accelerator's main dipoles and quadrupoles. During their visit, members of the DAE delegation visited the assembly laboratory where Indian engineers working at CERN under the CERN-India co-operation agreement are involved in the warm and cold magnet measurements of the LHC magnets. The Indian collaboration with CERN started in 1991, when India signed a co-operation Agreement with CERN with a view to participatin...

  20. Retirement postponed!

    CERN Multimedia

    Joannah Caborn Wengler

    2012-01-01

    As the LHC celebrates a highly successful year so far, the world accelerator community is already looking ahead to the next collider. It has appointed a CERN past master of accelerator building to coordinate the development of future linear collider efforts.   Lyn Evans at SM-18. Lyn Evans, former LHC project leader, has just been appointed director of the new Linear Collider organisation which brings together the two existing linear collider programmes under one roof. “We will initially continue to work in parallel on both CLIC and the ILC,” says Evans. The two proposed accelerators have a number of elements in common, from the damping rings to the final focus systems. Both have very similar detector designs, with the exception of the data acquisition systems as the machines have very different time structures. “The technologies for the two accelerators are at very different levels of maturity,” summarises Evans. When the time comes to make t...

  1. Globalizing rehabilitation psychology: Application of foundational principles to global health and rehabilitation challenges.

    Science.gov (United States)

    Bentley, Jacob A; Bruyère, Susanne M; LeBlanc, Jeanne; MacLachlan, Malcolm

    2016-02-01

    This article reviewed foundational principles in rehabilitation psychology and explored their application to global health imperatives as outlined in the World Report on Disability (World Health Organization & World Bank, 2011). Historical theories and perspectives are used to assist with conceptual formulation as applied to emerging international rehabilitation psychology topics. According to the World Report on Disability (World Health Organization & World Bank, 2011), there are approximately 1 billion individuals living with some form of disability globally. An estimated 80% of persons with disabilities live in low- to middle-income countries (WHO, 2006). The primary messages and recommendations of the World Report on Disability have been previously summarized as it relates to potential opportunities for contribution within the field of rehabilitation psychology (MacLachlan & Mannan, 2014). Yet, undeniable barriers remain to realizing the full potential for contributions in low- to middle-income country settings. A vision for engaging in international capacity building and public health efforts is needed within the field of rehabilitation psychology. Foundational rehabilitation psychology principles have application to the service of individuals with disabilities in areas of the world facing complex socioeconomic and sociopolitical challenges. Foundational principles of person-environment interaction, importance of social context, and need for involvement of persons with disabilities can provide guidance to the field as it relates to global health and rehabilitation efforts. The authors illustrate the application of rehabilitation psychology foundational principles through case examples and description of ongoing work, and link foundational principles to discreet domains of intervention going forward. (c) 2016 APA, all rights reserved).

  2. Effects of wind turbines on area use and behaviour of semi-domestic reindeer in enclosures

    Directory of Open Access Journals (Sweden)

    Kjetil Flydal

    2004-04-01

    effekt på arealbruk, aktivitetsskifter, vaktsomhetsatferd, og rastløshetsatferd i form av løp, gange og ståing for tamrein i innhegning. I en 450 m lang innhegning på 8 hektar som var plassert tett opp til en vindmølle, ble fem forskjellig grupper av reinsdyr manipulert ved å slå vindmøllerotoren av og på. Reinsdyrene i innhegningen ved vindmøllen ble sammenlignet med reinsdyr i en kontrollinnhegning som var uten påvirkning fra vindmøller. Når reinsdyrene ble utsatt for vindmøllerotoren i bevegelse, viste to grupper av dyr et skifte i arealbruk til områder av innhegningen som var lenger unna møllen, to grupper av dyr viste ikke noe skifte i arealbruk, mens en gruppe dyr beveget seg nærmere vindmøllen. Sammenligning av atferden hos reinsdyrene i vindmølleinnhegningen og kontrollinnhegningen viste ingen systematisk forskjell som kunne indikere frykt eller stress som en effekt av vindmøllen eller rotorbevegelsen. Vi konkluderer med at tamrein i innhegning ikke viser negative atferdsresponser og viser lite eller ingen reduksjon i arealbruken tett opp til en vindmølle. Muligheten for at det skjer en rask tilvenning i en liten innhegning der dyrene er i kontinuerlig påvirkning av vindmøllen betyr at effekter på arealbruk bør studeres i et større arealperspektiv eller på frittgående rein.

  3. A Comprehensive Analysis on Spread and Distribution Characteristic of Antibiotic Resistance Genes in Livestock Farms of Southeastern China.

    Directory of Open Access Journals (Sweden)

    Na Wang

    Full Text Available The pollution of antibiotic resistance genes (ARGs in livestock farms is a problem which need to be paid more attention to, due to the severe resistance dissemination and the further human health risk. In this study, all the relevant exposure matrices (manure, soil and water of sixteen animal farms in Southeastern China were sampled to determine twenty-two ARGs conferring resistance to five major classes of antibiotics including tetracyclines, sulfonamides, quinolones, aminoglycosides, and macrolides. The results showed that the spread property of sul genes was most extensive and strong, followed by tet and erm genes. The abundance of tet genes expressing ribosomal protection proteins (tetM, tetO, tetQ, tetT and tetW was higher than that expressing efflux pump proteins (tetA, tetC, tetE and tetG in each type of samples. The high abundance and frequency of ermB gene in the matrices should be paid more attention, because macrolides is a major medicine for human use. For manures, it was found that the similar ARGs distribution rules were existing in poultry manure or porcine manure samples, despite of the different origins of these two types of livestock farms. Meanwhile, it was interesting that the distribution rule of tet genes in animal manure was nearly the same as all the ARGs. For soils, the result of nonmetric multi-dimensional scaling (NMDS analysis showed that the pollution of ARGs in the soils fertilized by poultry and cattle manures were more substantial in northern Jiangsu, but no significant ARGs diversity was observed among porcine manured soils of five different regions. Furthermore, most ARGs showed significant positive relationships with environmental variables such as concentration of sulfonamides, tetracyclines, Cu, Zn and total organic carbon (TOC. The pollution profile and characteristics of so many ARGs in livestock farms can provide significative foundation for the regulation and legislation of antibiotics in China.

  4. Global warming: it's not only size that matters

    Science.gov (United States)

    Hegerl, Gabriele C.

    2011-09-01

    Observed and model simulated warming is particularly large in high latitudes, and hence the Arctic is often seen as the posterchild of vulnerability to global warming. However, Mahlstein et al (2011) point out that the signal of climate change is emerging locally from that of climate variability earliest in regions of low climate variability, based on climate model data, and in agreement with observations. This is because high latitude regions are not only regions of strong feedbacks that enhance the global warming signal, but also regions of substantial climate variability, driven by strong dynamics and enhanced by feedbacks (Hall 2004). Hence the spatial pattern of both observed warming and simulated warming for the 20th century shows strong warming in high latitudes, but this warming occurs against a backdrop of strong variability. Thus, the ratio of the warming to internal variability is not necessarily highest in the regions that warm fastest—and Mahlstein et al illustrate that it is actually the low-variability regions where the signal of local warming emerges first from that of climate variability. Thus, regions with strongest warming are neither the most important to diagnose that forcing changes climate, nor are they the regions which will necessarily experience the strongest impact. The importance of the signal-to-noise ratio has been known to the detection and attribution community, but has been buried in technical 'optimal fingerprinting' literature (e.g., Hasselmann 1979, Allen and Tett 1999), where it was used for an earlier detection of climate change by emphasizing aspects of the fingerprint of global warming associated with low variability in estimates of the observed warming. What, however, was not discussed was that the local signal-to-noise ratio is of interest also for local climate change: where temperatures emerge from the range visited by internal climate variability, it is reasonable to assume that changes in climate will also cause more

  5. Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines.

    Science.gov (United States)

    Deguchi, Yasuyuki; Kimura, Shinya; Ashihara, Eishi; Niwa, Tomoko; Hodohara, Keiko; Fujiyama, Yoshihide; Maekawa, Taira

    2008-06-01

    We compared the growth-inhibitory effects and inhibition profile of the SRC family kinases (SFKs) of imatinib, dasatinib, nilotinib and INNO-406. Dasatinib exhibited the strongest potency against BCR-ABL with little selectivity over SFKs. Nilotinib exhibited a weaker affinity than the other inhibitors, but was highly specific for ABL and may be useful for the treatment of P-glycoprotein overexpressing leukemic cells. INNO-406 had an intermediate affinity for BCR-ABL between that of dasatinib and nilotinib, and inhibited only SFKs LCK and LYN among SFKs. Both nilotinib and INNO-406 were potent inhibitors of the dasatinib-resistant T315A, F317L and F317V BCR-ABL mutations.

  6. The BINP receives its Golden Hadron award

    CERN Multimedia

    2002-01-01

    On Thursday, 14 September, the LHC Project Leader, Lyn Evans, handed over a Golden Hadron award to Alexander Skrinsky of Russia's Budker Institute of Nuclear Physics (BINP). The prize is awarded in recognition of exceptional performances by suppliers and this year prizes were awarded to two firms, Cockerill-Sambre (Belgium) and Wah-Chang (United States), and to the Budker Institute, which was unable to receive the award at the same time as the two other recipients (see Bulletin No 34/2002, of 19 August 2002). The Russian institute has been rewarded for the particularly high-quality production of 360 dipole magnets and 185 quadrupole magnets for the LHC proton beam transfer lines.

  7. First Kepler results on compact pulsators - II. KIC 010139564, a new pulsating subdwarf B (V361 Hya) star with an additional low-frequency mode

    DEFF Research Database (Denmark)

    Kawaler, Stephen; Reed, M.D.; Quint, A.C.

    2010-01-01

    We present the discovery of non-radial pulsations in a hot subdwarf B star based on 30.5 d of nearly continuous time series photometry using the Kepler spacecraft. KIC 010139564 is found to be a short-period pulsator of the V361 Hya (EC 14026) class with more than 10 independent pulsation modes...... whose periods range from 130 to 190 s. It also shows one periodicity at a period of 3165 s. If this periodicity is a high-order g-mode, then this star may be the hottest member of the hybrid DW Lyn stars. In addition to the resolved pulsation frequencies, additional periodic variations in the light...... are independent stellar oscillation modes. We find that most of the identified periodicities are indeed stable in phase and amplitude, suggesting a rotation period of 2-3 weeks for this star, but further observations are needed to confirm this suspicion....

  8. Neoliberal ideology, global capitalism, and science education: engaging the question of subjectivity

    Science.gov (United States)

    Bazzul, Jesse

    2012-12-01

    This paper attempts to add to the multifaceted discussion concerning neoliberalism and globalization out of two Cultural Studies of Science Education journal issues along with the recent Journal of Research in Science Teaching devoted to these topics. However, confronting the phenomena of globalization and neoliberalism will demand greater engagement with relevant sociopolitical thought in fields typically outside the purview of science education. Drawing from thinkers Michel Foucault, Jean Baudrillard, Judith Butler, and Louis Althusser this paper attempts to extend some key ideas coming from Ken Tobin, Larry Bencze, and Lyn Carter and advocates science educators taking up notions of ideology, discourse, and subjectivity to engage globalization and neoliberalism. Subjectivity (and its constitution in science education) is considered alongside two relevant textbook examples and also in terms of its importance in formulating political and culturally relevant questions in science education.

  9. Journalismin uudet vuorovaikutuskeinot : Eli kuinka joukkoälyä käytetään osana toimituksellista työprosessia

    OpenAIRE

    Riihinen, Eleonoora

    2012-01-01

    Joukkoäly journalistisessa prosessissa on vielä vähän kokeiltu toimitustyökalu, joka yhdistää yleisön hyödyntämisen, tutkivan journalismin ja verkon datasovellukset. Joukkoälyllä tarkoitetaan jonkin tehtävän ulkoistamista ennalta nimeämättömälle joukolle ihmisiä. Tutkielmassani selvitän, millainen prosessi joukkoälyn käyttö on journalistisessa työprosessissa ja kuinka kiinnostuneita pienemmän levikkialueen maakuntalehdet ovat käyttämään yleisöä osana journalistista prosessia uusia toimitu...

  10. Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways

    International Nuclear Information System (INIS)

    Heizmann, Beate; Sellars, MacLean; Macias-Garcia, Alejandra; Chan, Susan; Kastner, Philippe

    2016-01-01

    The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation.

  11. NO, nitrosonium ions, nitroxide ions, nitrosothiols and iron-nitrosyls in biology: a chemist's perspective.

    Science.gov (United States)

    Butler, A R; Flitney, F W; Williams, D L

    1995-01-01

    The multiplicity of biological functions thus far attributed to NO has led to suggestions that some effects might be mediated by other, related species instead. The radical nature of NO cannot account for its cytotoxicity, but its reaction with superoxide to form peroxynitite and highly reactive hydroxyl radicals may be important in this context. The ease with which NO can react with and destroy Fe-S clusters is also an important factor. Nitrosonium and nitroxide ions can be produced in vivo and will react under conditions that are physiologically relevant. Both could, in theory, serve in cell signalling or as cytotoxic agents. More direct experimental evidence for their involvement is needed before we can confidently assign them specific biological roles. In this article, Anthony Butler, Frederick Flitney and Lyn Williams discuss the chemistry of NO and related species.

  12. Worldwide U.S. Active Duty Military Deaths. Alphabetical Index by Name, 1 October 1979 Through 30 September 1994

    Science.gov (United States)

    1994-09-30

    DE LME NDO G E R A R D O MAR I GZA A I R F O R C E D E LMUNDO L I LY F E D E R I S NAVY D E LOACH B O B B Y D E A N A I R F ORCE D E LOGE B...YAN LAMON EAR LE JAME S ARTHUR EAR LEY KEN W EAR LEY R OB E R T WI L L IAM J R EAR LS M I CHAE L G EAR LS OMAR DALE EAR LY BE N JAMIN J R...8 9 B R OOK LYN E 0 4 2 2 F e b 8 2 KEN TON E 0 7 14 D e c 9 1 R OCKH I L L 0 0 2 1 4 J u l 8 1 T E XAS C I T Y E 0 6 24 Oc t 7 9

  13. Epistatic interactions on chromosome 14 influencing stillbirth in Fleckvieh cattle

    Directory of Open Access Journals (Sweden)

    Gábor Mészáros

    2016-09-01

    Full Text Available Single nucleotide polymorphism (SNP data of 7384 Fleckvieh bulls was analyzed to identify epistatic interactions influencing stillbirth. Deregressed breeding values were used as phenotypes. The epistatic effects were identified as significant interaction terms from pairwise linear regressions performed for each SNP after accounting for multiple testing. Majority of the detected epistatic effects were located in the 9-31Mb region of chromosome 14, corresponding to the most significant region from the genome wide association. Additional epistatic SNPs at 50.5Mb and 80.5 Mb at the same chromosome were detected. The region around 25 Mb contained genes connected to height and body size such as PLAG1, CHCHD7, LYN, RDHE2 (SDR16C5 and PENK. The other interesting region at 50.5Mb contained the TRPS1 gene influencing bone malformations. Both regions have been identified as candidates influencing stillbirth.

  14. Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Heizmann, Beate [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Sellars, MacLean [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Macias-Garcia, Alejandra [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Institute for Medical Engineering and Science at MIT, Cambridge, MA 02139 (United States); Chan, Susan, E-mail: scpk@igbmc.fr [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Kastner, Philippe, E-mail: scpk@igbmc.fr [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Faculté de Médecine, Université de Strasbourg, Strasbourg (France)

    2016-02-12

    The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation.

  15. Laboratory and field temperature preference and avoidance data of fish related to the establishment of standards

    International Nuclear Information System (INIS)

    Stauffer, J.R.; Cherry, D.S.; Dickson, K.L.; Cairns, J. Jr.

    1975-01-01

    Temperature preferences for important fish species in the New River in the vicinity of Appalachian Power Company's Glen Lyn, Virginia plant were determined independently by both field and laboratory studies. A relationship was demonstrated between the temperature preference data generated by the two approaches. Based on the temperature preference data the responses of fish to the thermal discharges can be predicted. From these data and from other data on the fish community structure, it was possible to determine that the thermal discharge was causing no appreciable harm to the fish community. Based on these studies it was concluded that the most reasonable approach to establishing thermal standards is to couple temperature preference studies with site specific studies. (U.S.)

  16. The LHC inauguration in pictures - LHCfest

    CERN Multimedia

    2008-01-01

    After the VIPs had left, 3000 other ‘very important people’ turned up to celebrate at the LHCfest. The party for CERN personnel involved in the LHC was a huge success and very popular. At the mention of food the crowd moved into SM18 where the buffet was being served. Some of the equipment in SM18 served as useful tables. AlpineKat performed the now notorious LHC rap, with a little help from Lyn Evans who joined her on stage as a backing dancer. You can watch a video of the rap at http://www.cern.ch/project-tv/LHCFest.html Even when most people thought that the last shuttles had left, the party was still going strong with the Canettes blues band.

  17. Signal transduction by FcεRI: Analysis of the early molecular events

    Directory of Open Access Journals (Sweden)

    Henry Metzger

    1999-01-01

    Full Text Available We are analysing the initial molecular events stimulated by the high-affinity receptor for IgE, FcεRI. Earlier studies have shown that the first response when the receptor-bound IgE interacts with a multivalent antigen is a transphosphorylation of receptor tyrosines, induced by the approximation of two or more receptors by a constitutively associated src-family kinase (Lyn. The amount of weakly associated kinase regulates the intensity of the response. Several aspects are being analyzed: (i the sites on Lyn and the receptor that account for the constitutive interaction; (ii how the intrinsic affinity of a ligand for the receptor-bound IgE influences the responses; and (iii the mechanism(s by which low-affinity ligands can act as antagonists. In the latter studies, mast cell responses were followed by monitoring the phosphorylation of tyrosines on several proteins and secretion. At equivalent levels of receptor phosphorylation, a ligand with high affinity stimulated vigorous phosphorylation of downstream components, whereas a low-affinity ligand was unable to stimulate phosphorylation of the same components effectively. Cells stimulated with a mixture of high- and low-affinity ligands, under a protocol where simple displacement of one by the other was prevented, remarkably showed that excess low-affinity ligand inhibited the phosphorylation as well as degranulation by the high-affinity ligand. This antagonism results from a competition for the limiting amount of the constitutive initiating kinase. Related receptors that depend on recruitment of initiating kinases may be subject to similar regulatory mechanisms.

  18. Slides with no attached paper

    International Nuclear Information System (INIS)

    Warin, Dominique; Wallenius, Janne; Ouzounian, Gerald; Wikberg, Peter; Todd, Terry A.; Kormilitsyn, Mikhael V.; Osipenko, Alexander G.; Mayorshin, A.A.; McLachlan, Fiona; Nash, Ken L.; Nilsson, M.; Grimes, T.; Braley, J.C.; TAKESHITA, Kenji; Babain, Vasiliy A.; Spendlikova, I.; Distler, P.; John, J.; Sebesta, F.; VU, Trong-Hung; SIMONIN, Jean-Pierre; PAULENOVA, Alena; PRECEK, Martin; HARTIG, Kyle; KNAPP, Nathan; Vidick, Geoffrey; Bouslimani, Nouri; Desreux, Jean F.; Lewis, F.W.; Hudson, M.J.; Harwood, L.M.; Nunez, Ana; Nagarajan, K.; Vasudeva Rao, P.R.; Raj, Baldev; Ignatiev, Victor; Surenkov, Alexander; Pouchon, Manuel A.; Skarnemark, Gunnar; Allard, Stefan; Ekberg, Christian; Retegan, Teodora; Nordlund, Anders; John, Jan; Maershin, Alexander; Zakirov, R.; Panov, A.; Toropov, Andrey

    2010-01-01

    This document brings together the different presentations (slides) given at the workshop but with no attached paper. These slides refer to the following presentations: - Presentation of ITN (Instituto Tecnologico e Nuclear); - Minor Actinide Partitioning (Dominique Warin); - Transmutation (Janne Wallenius); - Radioactive Waste Management, IGD-TP (Gerald Ouzounian); - Present status of the Swedish nuclear waste management programme (Peter Wikberg); - The U.S. Fuel Cycle Research and Development Program - Separations Research and Development (Terry Todd); - Strategies and national programs of closed fuel cycles - Russian Expert Vision (Mikhael Kormilitsyn) - Extraction Studies Of Potential Solvent Formulations For The GANEX Process (Fiona MacLachlan); - Investigations of The Fundamental Chemistry of the TALSPEAK Process (Ken Nash); - Extraction Separation of Trivalent Minor Actinides and Lanthanides by Hexa-dentate Nitrogen-donor Extractant, TPEN, and its Analogs (Kenji Takeshita); - Fluorinated Diluents for HLW Processing - technological point of view (Vasiliy Babain); - Extraction properties of some new pyridine molecules and search for better diluents (Irena Spendlikova); - Kinetics of extraction of Eu 3+ ion by TODGA and CyMe 4 -BTBP studied using the RMC technique (Trong Hung Vu); - Redox Chemistry of Neptunium in Solutions of Nitric Acid (Alena Paulenova); - NMR applied to actinide ions and their complexes. In search of covalency effects (Geoffrey Vidick); - Towards 'Stability Rules' for Radiolysis of bis-DGA compounds (Ana Nunez); - Pyroprocess Research Activities at IGCAR, Kalpakkam, India (K. Nagarajan); - Critical issues of nuclear energy systems employing molten salt fluorides: from ISTC No. 1606 to No. 3749 (1. year of project activity) and MARS/EVOL cooperation (Victor Ignatiev); - Conversion processes: Internal Gelation and the Sphere-pac concept (Manuel Pouchon); - A Combined Nuclear Technology and Nuclear Chemistry Master. A Unique

  19. COPD exacerbations by disease severity in England

    Directory of Open Access Journals (Sweden)

    Merinopoulou E

    2016-04-01

    Full Text Available Evie Merinopoulou,1 Mireia Raluy-Callado,1 Sreeram Ramagopalan,1 Sharon MacLachlan,1 Javaria Mona Khalid2 1Real-World Evidence, Evidera, 2Takeda Development Centre Europe Ltd, London, UK Objectives: Exacerbations of chronic obstructive pulmonary disease (COPD are associated with accelerated disease progression and are important drivers of health care resource utilization. The study aimed to quantify the rates of COPD exacerbations in England and assess health care resource utilization by severity categories according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD 2013.Methods: Data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics were used to identify patients with a COPD diagnosis aged ≥40 years. Those with complete spirometric, modified Medical Research Council Dyspnea Scale information, and exacerbation history 12 months prior to January 1, 2011 (index date were classified into GOLD severity groups. Study outcomes over follow-up (up to December 31, 2013 were exacerbation rates and resource utilization (general practitioner visits, hospital admissions.Results: From the 44,201 patients in the study cohort, 83.5% were classified into severity levels GOLD A: 33.8%, GOLD B: 21.0%, GOLD C: 18.1%, and GOLD D: 27.0%. Mean age at diagnosis was 66 years and 52.0% were male. Annual exacerbation rates per person-year increased with severity, from 0.83 (95% confidence interval [CI]: 0.81–0.85 for GOLD A to 2.51 (95% CI: 2.47–2.55 for GOLD D. General practitioner visit rates per person-year also increased with severity, from 4.82 (95% CI: 4.74–4.93 for GOLD A to 7.44 (95% CI: 7.31–7.61 for GOLD D. COPD-related hospitalization rates per person-year increased from less symptoms (GOLD A: 0.28, GOLD C: 0.39 to more symptoms (GOLD B: 0.52, GOLD D: 0.84.Conclusion: Patients in the most severe category (GOLD D experienced nearly three times the number of exacerbations and COPD

  20. Oculocerebrorenal syndrome of Lowe: magnetic resonance imaging findings in the first six years of life

    Energy Technology Data Exchange (ETDEWEB)

    Carvalho-Neto, Arnolfo de; Ono, Sergio Eiji; Cardoso, Georgina de Melo; Santos, Mara Lucia Schmitz Ferreira; Celidonio, Izabela [Hospital Pequeno Principe, Curitiba, PR (Brazil)], e-mail: ono.sergio@gmail.com

    2009-06-15

    The oculocerebrorenal syndrome of Lowe (OCRL), was first recognized as a distinct disease in 1952 by Drs. Lowe, Terrey and MacLachlan at Massachusetts General Hospital, in Boston, USA, describing three male children with organic aciduria, decreased renal ammonia production, hydrophtalmos and mental retardation. The X-linked recessive inheritance pattern was recognized first by LeFebvre. It is present in all races, with a predominance in those of Caucasian and Asian ancestries. Rarely females are affected. It is a very rare disease, with estimated prevalence in the general population of 1 in 500,000. In USA the Lowe Syndrome Association (LSA) documented 190 living patients in the year 2000 (0.67 x million inhabitants). It is caused by a mutation in the gene encoding oculocerebrorenal- Lowe protein (OCRL1), isolated in 1992, linked to the Xq24-q26 region of the X chromosome,4-6. Approximately 60% of OCRL patients demonstrate a loss of OCRL gene expression, and the definitive laboratory test, that can be used for prenatal diagnosis, is the biochemical assay for deficiency of phosphatidylinositol 4,5-biphosphate 5-phosphate in cultured fibroblasts. The classic triad of eye, central nervous system, and kidney involvement are required for the diagnosis of Lowe's syndrome. Cataract is present at birth in all patients and glaucoma is detected within the first year of life. Hypotonia compromises suction and causes serious respiratory problems in the first period of life. Motor development is retarded and mental retardation is moderate or severe in almost all cases. Obsessive-compulsive behavior is typical. Seizure is seen in approximately 50% of the patients over 18 years old. Renal disease is primarily characterized by renal Fanconi syndrome but many children are asymptomatic at birth. Renal involvement is initially related to bicarbonate, salt and water wasting, causing failure to thrive. Later, a significant number of patients develop chronic renal failure. The

  1. Calibration and application of the IP25 biomarker for Arctic sea ice reconstructions

    Science.gov (United States)

    Cabedo Sanz, P.; Navarro Rodriguez, A.; Belt, S. T.; Brown, T. A.; Knies, J.; Husum, K.; Giraudeau, J.; Andrews, J.

    2012-04-01

    The presence of the sea ice diatom biomarker IP25 in Arctic marine sediments has been used in previous studies as a proxy for past spring sea ice occurrence and as an indicator of wider palaeoenvironmental conditions for different regions of the Arctic over various timescales [e.g. 1, 3]. In addition, measurement of IP25 has also been applied as a sea ice origin tracer for studying the transfer of organic carbon through Arctic food-webs [2]. The current study focuses on three main areas: (1) In order to improve on the quantitative analytical aspects of IP25 based research, we present here the results of a large scale extraction, purification and identification procedure for IP25 from marine sediments. This has confirmed the structure of IP25 in sediments and enabled more robust quantitative measurements by gas chromatography - mass spectrometry (GC-MS) to be established. (2) Quantitative measurements of IP25 from a sediment core from Andfjord (continental shelf, Tromsø, Norway) have been determined for the period 6.3 to 14.3 ka BP. The results of this study add significant further information to that reported previously from other biomarker studies for this core (e.g. brassicasterol) [4]. (3) Analytical detection issues (GC-MS) regarding the occurrence of IP25 in other sub-Arctic regions (e.g. East Greenland - North Iceland area) will be presented and discussed with relation to other proxy data (e.g. IRD). Belt, S. T., Vare, L. L., Massé, G., Manners, H. R., Price, J. C., MacLachlan, S. E., Andrews, J. T. & Schmidt, S. (2010) 'Striking similarities in temporal changes to spring sea ice occurrence across the central Canadian Arctic Archipelago over the last 7000 years', Quaternary Science Reviews, 29 (25-26), pp. 3489-3504. Brown, T. A. & Belt, S. T. (2012) 'Identification of the sea ice diatom biomarker IP25 in Arctic benthic macrofauna: direct evidence for a sea ice diatom diet in Arctic heterotrophs', Polar Biology, 35, pp. 131-137. Müller, J., Massé, G

  2. Oculocerebrorenal syndrome of Lowe: magnetic resonance imaging findings in the first six years of life

    International Nuclear Information System (INIS)

    Carvalho-Neto, Arnolfo de; Ono, Sergio Eiji; Cardoso, Georgina de Melo; Santos, Mara Lucia Schmitz Ferreira; Celidonio, Izabela

    2009-01-01

    The oculocerebrorenal syndrome of Lowe (OCRL), was first recognized as a distinct disease in 1952 by Drs. Lowe, Terrey and MacLachlan at Massachusetts General Hospital, in Boston, USA, describing three male children with organic aciduria, decreased renal ammonia production, hydrophtalmos and mental retardation. The X-linked recessive inheritance pattern was recognized first by LeFebvre. It is present in all races, with a predominance in those of Caucasian and Asian ancestries. Rarely females are affected. It is a very rare disease, with estimated prevalence in the general population of 1 in 500,000. In USA the Lowe Syndrome Association (LSA) documented 190 living patients in the year 2000 (0.67 x million inhabitants). It is caused by a mutation in the gene encoding oculocerebrorenal- Lowe protein (OCRL1), isolated in 1992, linked to the Xq24-q26 region of the X chromosome,4-6. Approximately 60% of OCRL patients demonstrate a loss of OCRL gene expression, and the definitive laboratory test, that can be used for prenatal diagnosis, is the biochemical assay for deficiency of phosphatidylinositol 4,5-biphosphate 5-phosphate in cultured fibroblasts. The classic triad of eye, central nervous system, and kidney involvement are required for the diagnosis of Lowe's syndrome. Cataract is present at birth in all patients and glaucoma is detected within the first year of life. Hypotonia compromises suction and causes serious respiratory problems in the first period of life. Motor development is retarded and mental retardation is moderate or severe in almost all cases. Obsessive-compulsive behavior is typical. Seizure is seen in approximately 50% of the patients over 18 years old. Renal disease is primarily characterized by renal Fanconi syndrome but many children are asymptomatic at birth. Renal involvement is initially related to bicarbonate, salt and water wasting, causing failure to thrive. Later, a significant number of patients develop chronic renal failure. The treatment

  3. Prevalence and proliferation of antibiotic resistance genes in two municipal wastewater treatment plants.

    Science.gov (United States)

    Mao, Daqing; Yu, Shuai; Rysz, Michal; Luo, Yi; Yang, Fengxia; Li, Fengxiang; Hou, Jie; Mu, Quanhua; Alvarez, P J J

    2015-11-15

    The propagation of antibiotic resistance genes (ARGs) is an emerging health concern worldwide. Thus, it is important to understand and mitigate their occurrence in different systems. In this study, 30 ARGs that confer resistance to tetracyclines, sulfonamides, quinolones or macrolides were detected in two activated sludge wastewater treatment plants (WWTPs) in northern China. Bacteria harboring ARGs persisted through all treatment units, and survived disinfection by chlorination in greater percentages than total Bacteria (assessed by 16S rRNA genes). Although the absolute abundances of ARGs were reduced from the raw influent to the effluent by 89.0%-99.8%, considerable ARG levels [(1.0 ± 0.2) × 10(3) to (9.5 ± 1.8) × 10(5) copies/mL)] were found in WWTP effluent samples. ARGs were concentrated in the waste sludge (through settling of bacteria and sludge dewatering) at (1.5 ± 2.3) × 10(9) to (2.2 ± 2.8) × 10(11) copies/g dry weight. Twelve ARGs (tetA, tetB, tetE, tetG, tetH, tetS, tetT, tetX, sul1, sul2, qnrB, ermC) were discharged through the dewatered sludge and plant effluent at higher rates than influent values, indicating overall proliferation of resistant bacteria. Significant antibiotic concentrations (2%-50% of raw influent concentrations) remained throughout all treatment units. This apparently contributed selective pressure for ARG replication since the relative abundance of resistant bacteria (assessed by ARG/16S rRNA gene ratios) was significantly correlated to the corresponding effluent antibiotic concentrations. Similarly, the concentrations of various heavy metals (which induce a similar bacterial resistance mechanism as antibiotics - efflux pumps) were also correlated to the enrichment of some ARGs. Thus, curtailing the release of antibiotics and heavy metals to sewage systems (or enhancing their removal in pre-treatment units) may alleviate their selective pressure and mitigate ARG proliferation in WWTPs. Copyright © 2015 Elsevier Ltd. All

  4. E-Læring som pedagogisk virkemiddel for innlæring av anatomi, fysiologi og biokjemi i sykepleierutdanningen

    Directory of Open Access Journals (Sweden)

    Mona Elisabeth Meyer

    2014-02-01

    Full Text Available Utgangspunktet for studien er at naturvitenskaplige fag, særlig anatomi, fysiologi og biokjemi (AFB, oppleves som vanskelig for sykepleierstudentene. Hensikten var å undersøke om læringsverktøyet e-læring, i form av nettester, kan være et effektivt virkemiddel til innlæring av og påvirke læringsutbyttet i AFB.Førsteårsstudentene i bachelorutdanningen i sykepleie ved Høgskolen i Akershus fikk et spørreskjema med 23 spørsmål som ble besvart anonymt.Resultatet av studentundersøkelsen viste at nettoppgavene ble mye brukt, og at studentene mente de ga et godt læringsutbytte. Nettoppgaver med umiddelbar feedback gir stor studentaktivitet og «time-on-task». Testene kan tette hullet mellom det studentene forventes å kunne og det de faktisk kan, og egner seg til faktafag som m å pugges og forstås. E-læring kan gi god hjelp til studenters strukturering av tid, læringsstrategier og selvregulering.Læringsutbyttet av nettester diskuteres i lys av nytten av umiddelbar feedback i et pedagogisk perspektiv.AbstractThe starting point of the study is that the natural sciences, particularly anatomy, physiology and biochemistry (collectively known as APB, are often difficult subjects for nursing students. The aim was to investigate whether e-learning tools, in terms of web services, can be an effective educational tool and affect learning outcomes in APB.First year students in the Bachelor's degree program in nursing at Akershus University College of Applied Sciences received a questionnaire with 23 questions, which were answered anonymously.The results of the student survey showed that online tasks were widely used, and that students felt they resulted in good learning outcomes. Online training with immediate feedback shows great student activity and “time-on-task.” These tests can close the gap between what the students are expected to know and what they actually do, and is suitable for factual subjects requiring both memorization and

  5. Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics

    Science.gov (United States)

    Robles, Eloy F.; Mena-Varas, Maria; Barrio, Laura; Merino-Cortes, Sara V.; Balogh, Péter; Du, Ming-Qing; Akasaka, Takashi; Parker, Anton; Roa, Sergio; Panizo, Carlos; Martin-Guerrero, Idoia; Siebert, Reiner; Segura, Victor; Agirre, Xabier; Macri-Pellizeri, Laura; Aldaz, Beatriz; Vilas-Zornoza, Amaia; Zhang, Shaowei; Moody, Sarah; Calasanz, Maria Jose; Tousseyn, Thomas; Broccardo, Cyril; Brousset, Pierre; Campos-Sanchez, Elena; Cobaleda, Cesar; Sanchez-Garcia, Isidro; Fernandez-Luna, Jose Luis; Garcia-Muñoz, Ricardo; Pena, Esther; Bellosillo, Beatriz; Salar, Antonio; Baptista, Maria Joao; Hernandez-Rivas, Jesús Maria; Gonzalez, Marcos; Terol, Maria Jose; Climent, Joan; Ferrandez, Antonio; Sagaert, Xavier; Melnick, Ari M.; Prosper, Felipe; Oscier, David G.; Carrasco, Yolanda R.; Dyer, Martin J. S.; Martinez-Climent, Jose A.

    2016-01-01

    NKX2 homeobox family proteins have a role in cancer development. Here we show that NKX2-3 is overexpressed in tumour cells from a subset of patients with marginal-zone lymphomas, but not with other B-cell malignancies. While Nkx2-3-deficient mice exhibit the absence of marginal-zone B cells, transgenic mice with expression of NKX2-3 in B cells show marginal-zone expansion that leads to the development of tumours, faithfully recapitulating the principal clinical and biological features of human marginal-zone lymphomas. NKX2-3 induces B-cell receptor signalling by phosphorylating Lyn/Syk kinases, which in turn activate multiple integrins (LFA-1, VLA-4), adhesion molecules (ICAM-1, MadCAM-1) and the chemokine receptor CXCR4. These molecules enhance migration, polarization and homing of B cells to splenic and extranodal tissues, eventually driving malignant transformation through triggering NF-κB and PI3K-AKT pathways. This study implicates oncogenic NKX2-3 in lymphomagenesis, and provides a valid experimental mouse model for studying the biology and therapy of human marginal-zone B-cell lymphomas. PMID:27297662

  6. GSL-enriched membrane microdomains in innate immune responses.

    Science.gov (United States)

    Nakayama, Hitoshi; Ogawa, Hideoki; Takamori, Kenji; Iwabuchi, Kazuhisa

    2013-06-01

    Many pathogens target glycosphingolipids (GSLs), which, together with cholesterol, GPI-anchored proteins, and various signaling molecules, cluster on host cell membranes to form GSL-enriched membrane microdomains (lipid rafts). These GSL-enriched membrane microdomains may therefore be involved in host-pathogen interactions. Innate immune responses are triggered by the association of pathogens with phagocytes, such as neutrophils, macrophages and dendritic cells. Phagocytes express a diverse array of pattern-recognition receptors (PRRs), which sense invading microorganisms and trigger pathogen-specific signaling. PRRs can recognize highly conserved pathogen-associated molecular patterns expressed on microorganisms. The GSL lactosylceramide (LacCer, CDw17), which binds to various microorganisms, including Candida albicans, is expressed predominantly on the plasma membranes of human mature neutrophils and forms membrane microdomains together with the Src family tyrosine kinase Lyn. These LacCer-enriched membrane microdomains can mediate superoxide generation, migration, and phagocytosis, indicating that LacCer functions as a PRR in innate immunity. Moreover, the interactions of GSL-enriched membrane microdomains with membrane proteins, such as growth factor receptors, are important in mediating the physiological properties of these proteins. Similarly, we recently found that interactions between LacCer-enriched membrane microdomains and CD11b/CD18 (Mac-1, CR3, or αMβ2-integrin) are significant for neutrophil phagocytosis of non-opsonized microorganisms. This review describes the functional role of LacCer-enriched membrane microdomains and their interactions with CD11b/CD18.

  7. Involvement of glycosphingolipid-enriched lipid rafts in inflammatory responses.

    Science.gov (United States)

    Iwabuchi, Kazuhisa

    2015-01-01

    Glycosphingolipids (GSLs) are membrane components consisting of hydrophobic ceramide and hydrophilic sugar moieties. GSLs cluster with cholesterol in cell membranes to form GSL-enriched lipid rafts. Biochemical analyses have demonstrated that GSL-enriched lipid rafts contain several kinds of transducer molecules, including Src family kinases. Among the GSLs, lactosylceramide (LacCer, CDw17) can bind to various microorganisms, is highly expressed on the plasma membranes of human phagocytes, and forms lipid rafts containing the Src family tyrosine kinase Lyn. LacCer-enriched lipid rafts mediate immunological and inflammatory reactions, including superoxide generation, chemotaxis, and non-opsonic phagocytosis. Therefore, LacCer-enriched membrane microdomains are thought to function as pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) expressed on microorganisms. LacCer also serves as a signal transduction molecule for functions mediated by CD11b/CD18-integrin (αM/β2-integrin, CR3, Mac-1), as well as being associated with several key cellular processes. LacCer recruits PCKα/ε and phospholipase A2 to stimulate PECAM-1 expression in human monocytes and their adhesion to endothelial cells, as well as regulating β1-integrin clustering and endocytosis on cell surfaces. This review describes the organizational and inflammation-related functions of LacCer-enriched lipid rafts.

  8. Bafetinib (INNO-406) reverses multidrug resistance by inhibiting the efflux function of ABCB1 and ABCG2 transporters

    Science.gov (United States)

    Zhang, Yun-Kai; Zhang, Guan-Nan; Wang, Yi-Jun; Patel, Bhargav A.; Talele, Tanaji T.; Yang, Dong-Hua; Chen, Zhe-Sheng

    2016-05-01

    ATP-Binding Cassette transporters are involved in the efflux of xenobiotic compounds and are responsible for decreasing drug accumulation in multidrug resistant (MDR) cells. Discovered by structure-based virtual screening algorithms, bafetinib, a Bcr-Abl/Lyn tyrosine kinase inhibitor, was found to have inhibitory effects on both ABCB1- and ABCG2-mediated MDR in this in-vitro investigation. Bafetinib significantly sensitized ABCB1 and ABCG2 overexpressing MDR cells to their anticancer substrates and increased the intracellular accumulation of anticancer drugs, particularly doxorubicin and [3H]-paclitaxel in ABCB1 overexpressing cells; mitoxantrone and [3H]-mitoxantrone in ABCG2 overexpressing cells, respectively. Bafetinib stimulated ABCB1 ATPase activities while inhibited ABCG2 ATPase activities. There were no significant changes in the expression level or the subcellular distribution of ABCB1 and ABCG2 in the cells exposed to 3 μM of bafetinib. Overall, our study indicated that bafetinib reversed ABCB1- and ABCG2-mediated MDR by blocking the drug efflux function of these transporters. These findings might be useful in developing combination therapy for MDR cancer treatment.

  9. The effects of erythropoietin signaling on telomerase regulation in non-erythroid malignant and non-malignant cells

    International Nuclear Information System (INIS)

    Uziel, Orit; Kanfer, Gil; Beery, Einat; Yelin, Dana; Shepshelovich, Daniel; Bakhanashvili, Mary; Nordenberg, Jardena; Lahav, Meir

    2014-01-01

    Highlights: • We assumed that some of erythropoietin adverse effects may be mediated by telomerase activity. • EPO administration increased telomerase activity, cells proliferation and migration. • The inhibition of telomerase modestly repressed the proliferative effect of erythropoietin. • Telomere shortening caused by long term inhibition of the enzyme totally abolished that effect. • This effect was mediated via the Lyn–AKT axis and not by the canonical JAK2–STAT pathway. - Abstract: Treatment with erythropoietin (EPO) in several cancers is associated with decreased survival due to cancer progression. Due to the major importance of telomerase in cancer biology we hypothesized that some of these effects may be mediated through EPO effect on telomerase. For this aim we explored the possible effects of EPO on telomerase regulation, cell migration and chemosensitivity in non-erythroid malignant and non-malignant cells. Cell proliferation, telomerase activity (TA) and cell migration increased in response to EPO. EPO had no effect on cancer cells sensitivity to cisplatinum and on the cell cycle status. The inhibition of telomerase modestly repressed the proliferative effect of EPO. Telomere shortening caused by long term inhibition of the enzyme abolished the effect of EPO, suggesting that EPO effects on cancer cells are related to telomere dynamics. TA was correlated with the levels of Epo-R. The increase in TA was mediated post-translationally through the Lyn-Src and not the canonical JAK2 pathway

  10. The first American magnet has arrived!

    CERN Multimedia

    2003-01-01

    On 21 January the first US-built LHC magnet arrived at CERN, after a journey of 6000 km by land and sea, an event hailed on both sides of the Atlantic. This 10-m long, 4.7-tonne dipole magnet was manufactured over a period of nine months by Brookhaven National Laboratory (BNL). Single-aperture magnets of this type will be installed on either side of the ALICE and LHCb experiments and will deviate the beams in order to provoke their interaction and subsequent separation. Brookhaven will be supplying 19 other dipoles for the insertion regions, including four of the same type as the one which has just arrived. «These magnets are based on a technology developed by Brookhaven Laboratory for its own RHIC accelerator,» explains Ranko Ostojic. LHC Project Leader Lyn Evans adds «our Brookhaven colleagues have done a fantastic job in completing the USA's first superconducting magnet for the LHC to specification and on schedule. Other deliveries will shortly be arriving from Brookhaven but also from Fermilab and the ...

  11. A word from Steve Myers: The Operational Performance Marathon is just starting

    CERN Multimedia

    2008-01-01

    In the previous Bulletin, Lyn (Evans) referred to the construction phase of the LHC as a marathon that is now almost completed. This is absolutely true and thanks to the hard work and dedication of all the construction staff, CERN now has a superb accelerator ready to be operated and driven to its maximum potential performance. However, for many of us, the next phase of operation and exploitation of the LHC is a second marathon and the firing pistol has just been fired. My first encounter with the LHC was in the very early 1980s, when many of us were fully occupied with LEP construction. Through a chance invitation by CERN director Herwig Schopper I participated in a discussion in the US about future proton colliders. Following this meeting, in April 1983, my boss (the late Wolfgang Schnell) and I published "LEP note 440", which gave preliminary estimates of the possible performance of a proton collider in the LEP tunnel. After the controversial de...

  12. The necrotic signal induced by mycophenolic acid overcomes apoptosis-resistance in tumor cells.

    Directory of Open Access Journals (Sweden)

    Gwendaline Guidicelli

    Full Text Available BACKGROUND: The amount of inosine monophosphate dehydrogenase (IMPDH, a pivotal enzyme for the biosynthesis of the guanosine tri-phosphate (GTP, is frequently increased in tumor cells. The anti-viral agent ribavirin and the immunosuppressant mycophenolic acid (MPA are potent inhibitors of IMPDH. We recently showed that IMPDH inhibition led to a necrotic signal requiring the activation of Cdc42. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we strengthened the essential role played by this small GTPase in the necrotic signal by silencing Cdc42 and by the ectopic expression of a constitutive active mutant of Cdc42. Since resistance to apoptosis is an essential step for the tumorigenesis process, we next examined the effect of the MPA-mediated necrotic signal on different tumor cells demonstrating various mechanisms of resistance to apoptosis (Bcl2-, HSP70-, Lyn-, BCR-ABL-overexpressing cells. All tested cells remained sensitive to MPA-mediated necrotic signal. Furthermore, inhibition of IMPDH activity in Chronic Lymphocytic Leukemia cells was significantly more efficient at eliminating malignant cells than apoptotic inducers. CONCLUSIONS/SIGNIFICANCE: These findings indicate that necrosis and apoptosis are split signals that share few if any common hub of signaling. In addition, the necrotic signaling pathway induced by depletion of the cellular amount of GTP/GDP would be of great interest to eliminate apoptotic-resistant tumor cells.

  13. Engineering of kinase-based protein interacting devices: active expression of tyrosine kinase domains

    KAUST Repository

    Diaz Galicia, Miriam Escarlet

    2018-05-01

    Protein-protein interactions modulate cellular processes in health and disease. However, tracing weak or rare associations or dissociations of proteins is not a trivial task. Kinases are often regulated through interaction partners and, at the same time, themselves regulate cellular interaction networks. The use of kinase domains for creating a synthetic sensor device that reads low concentration protein-protein interactions and amplifies them to a higher concentration interaction which is then translated into a FRET (Fluorescence Resonance Energy Transfer) signal is here proposed. To this end, DNA constructs for interaction amplification (split kinases), positive controls (intact kinase domains), scaffolding proteins and phosphopeptide - SH2-domain modules for the reading of kinase activity were assembled and expression protocols for fusion proteins containing Lyn, Src, and Fak kinase domains in bacterial and in cell-free systems were optimized. Also, two non-overlapping methods for measuring the kinase activity of these proteins were stablished and, finally, a protein-fragment complementation assay with the split-kinase constructs was tested. In conclusion, it has been demonstrated that features such as codon optimization, vector design and expression conditions have an impact on the expression yield and activity of kinase-based proteins. Furthermore, it has been found that the defined PURE cell-free system is insufficient for the active expression of catalytic kinase domains. In contrast, the bacterial co-expression with phosphatases produced active kinase fusion proteins for two out of the three tested Tyrosine kinase domains.

  14. A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation.

    Science.gov (United States)

    Dikic, I; Tokiwa, G; Lev, S; Courtneidge, S A; Schlessinger, J

    1996-10-10

    The mechanisms by which mitogenic G-protein-coupled receptors activate the MAP kinase signalling pathway are poorly understood. Candidate protein tyrosine kinases that link G-protein-coupled receptors with MAP kinase include Src family kinases, the epidermal growth factor receptor, Lyn and Syk. Here we show that lysophosphatidic acid (LPA) and bradykinin induce tyrosine phosphorylation of Pyk2 and complex formation between Pyk2 and activated Src. Moreover, tyrosine phosphorylation of Pyk2 leads to binding of the SH2 domain of Src to tyrosine 402 of Pyk2 and activation of Src. Transient overexpression of a dominant interfering mutant of Pyk2 or the protein tyrosine kinase Csk reduces LPA- or bradykinin-induced activation of MAP kinase. LPA- or bradykinin-induced MAP kinase activation was also inhibited by overexpression of dominant interfering mutants of Grb2 and Sos. We propose that Pyk2 acts with Src to link Gi- and Gq-coupled receptors with Grb2 and Sos to activate the MAP kinase signalling pathway in PC12 cells.

  15. Identification of a new adapter protein that may link the common beta subunit of the receptor for granulocyte/macrophage colony-stimulating factor, interleukin (IL)-3, and IL-5 to phosphatidylinositol 3-kinase.

    Science.gov (United States)

    Jücker, M; Feldman, R A

    1995-11-17

    Binding of human granulocyte/macrophage colony-stimulating factor (hGM-CSF) to its receptor induces the rapid activation of phosphatidylinositol-3 kinase (PI 3-kinase). As hGM-CSF receptor (hGMR) does not contain a consensus sequence for binding of PI 3-kinase, hGMR must use a distinct mechanism for its association with and activation of PI 3-kinase. Here, we describe the identification of a tyrosine-phosphorylated protein of 76-85 kDa (p80) that associates with the common beta subunit of hGMR and with the SH2 domains of the p85 subunit of PI 3-kinase in hGM-CSF-stimulated cells. Src/Yes and Lyn were tightly associated with the p80.PI 3-kinase complex, suggesting that p80 and other phosphotyrosyl proteins present in the complex were phosphorylated by Src family kinases. Tyrosine phosphorylation of p80 was only detected in hGM-CSF or human interleukin-3-stimulated cells, suggesting that activation of p80 might be specific for signaling via the common beta subunit. We postulate that p80 functions as an adapter protein that may participate in linking the hGM-CSF receptor to the PI 3-kinase signaling pathway.

  16. A word from the DG: LHC commissionning 
enters the home straight

    CERN Multimedia

    2007-01-01

    In an age of blogs there are seemingly no secrets, so by the time Lyn Evans gave his talk on the status of LHC commissioning on 13 September, everyone seemed to know about plug-in modules, beam position monitors and transmitters embedded in ping-pong balls. All the on-line speculation made for interesting reading, and is a clear sign of the growing interest there is in CERN as we approach LHC start-up. We are now entering the final phase of commissioning, and things are going well given the unprecedented complexity of the task in hand. Following the cool-down, powering and warm-up of Sector 7-8 earlier this year, we have learned a great deal about what it means to commission the LHC. There have inevitably been hitches, including the plug-in modules, or PIMs. When the LHC is cooled down, each sector shrinks by about 10 metres in length, and this has to be absorbed by bellows between components and a system of sliding copper fingers (PIM) that ensure electrical connectivity ar...

  17. Switched on!

    CERN Multimedia

    2008-01-01

    Like a star arriving on stage, impatiently followed by each member of CERN personnel and by millions of eyes around the world, the first beam of protons has circulated in the LHC. After years in the making and months of increasing anticipation, today the work of hundreds of people has borne fruit. WELL DONE to all! Successfully steered around the 27 kilometres of the world’s most powerful particle accelerator at 10:28 this morning, this first beam of protons circulating in the ring marks a key moment in the transition from over two decades of preparation to a new era of scientific discovery. "It’s a fantastic moment," said the LHC project leader Lyn Evans, "we can now look forward to a new era of understanding about the origins and evolution of the universe". Starting up a major new particle accelerator takes much more than flipping a switch. Thousands of individual elements have to work in harmony, timings have to be synchronize...

  18. Mesenchymal stromal cells of osteosarcoma patients do not show evidence of neoplastic changes during long-term culture.

    Science.gov (United States)

    Buddingh, Emilie P; Ruslan, S Eriaty N; Reijnders, Christianne M A; Szuhai, Karoly; Kuijjer, Marieke L; Roelofs, Helene; Hogendoorn, Pancras C W; Maarten Egeler, R; Cleton-Jansen, Anne-Marie; Lankester, Arjan C

    2015-01-01

    In vitro expanded mesenchymal stromal cells (MSCs) are increasingly used as experimental cellular therapy. However, there have been concerns regarding the safety of their use, particularly with regard to possible oncogenic transformation. MSCs are the hypothesized precursor cells of high-grade osteosarcoma, a tumor with often complex karyotypes occurring mainly in adolescents and young adults. To determine if MSCs from osteosarcoma patients could be predisposed to malignant transformation we cultured MSCs of nine osteosarcoma patients and five healthy donors for an average of 649 days (range 601-679 days). Also, we compared MSCs derived from osteosarcoma patients at diagnosis and from healthy donors using genome wide gene expression profiling. Upon increasing passage, increasing frequencies of binucleate cells were detected, but no increase in proliferation suggestive of malignant transformation occurred in MSCs from either patients or donors. Hematopoietic cell specific Lyn substrate 1 (HLCS1) was differentially expressed (fold change 0.25, P value 0.0005) between MSCs of osteosarcoma patients (n = 14) and healthy donors (n = 9). This study shows that although HCLS1 expression was downregulated in MSCs of osteosarcoma patients and binucleate cells were present in both patient and donor derived MSCs, there was no evidence of neoplastic changes to occur during long-term culture.

  19. The first LHC sector is fully interconnected

    CERN Multimedia

    2006-01-01

    Sector 7-8 is the first sector of the LHC to become fully operational. All the magnets, cryogenic line, vacuum chambers and services are interconnected. The cool down of this sector can soon commence. LHC project leader Lyn Evans, the teams from CERN's AT/MCS, AT/VAC and AT/MEL groups, and the members of the IEG consortium celebrate the completion of the first LHC sector. The 10th of November was a red letter day for the LHC accelerator teams, marking the completion of the first sector of the machine. The magnets of sector 7-8, together with the cryogenic line, the vacuum chambers and the distribution feedboxes (DFBs) are now all completely interconnected. Sector 7-8 has thus been closed and is the first LHC sector to become operational. The interconnection work required several thousand electrical, cryogenic and insulating connections to be made on the 210 interfaces between the magnets in the arc, the 30 interfaces between the special magnets and the interfaces with the cryogenic line. 'This represent...

  20. Fully transparent LHC

    CERN Multimedia

    2008-01-01

    Thanks to the first real signals received from the LHC while in operation before the incident, the experiments are now set to make the best use of the data they have collected. Report from the LHCC open session.The September open session of the LHCC (LHC Experiments Committee) came just a few days after the incident that occurred at the LHC. The packed auditorium was a testament to the huge interest raised by Lyn Evans’ talk about the status of the machine and the plans for the future. After being told that the actual consequences of the incident will be clear only once Sector 3-4 has been warmed up, the audience focussed on the reports from the experiments. For the first time, the reports showed performance results of the various detectors with particles coming from the machine and not just from cosmic rays or tests and simulations. "The first days of LHC beam exceeded all expectations and the experiments made extensive and rapid use of the data they collected", says ...

  1. IgE in lupus pathogenesis: Friends or foes?

    Science.gov (United States)

    Augusto, Jean-François; Truchetet, Marie-Elise; Charles, Nicolas; Blanco, Patrick; Richez, Christophe

    2018-04-01

    Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving multiple immunological pathways. Recently, several studies have suggested an implication of Immunoglobulin E (IgE) in the pathophysiology of SLE. In the Lyn -/- and FcγIIB -/- .Yaa lupus mouse models, autoreactive IgE activate basophils, and promote a Th2 environment with, subsequently, production of autoantibodies by plasma cells. Autoreactive IgE has been also shown to play a role in the activation of human plasmacytoid dendritic cells (pDCs), in synergy with IgG, which results in an increase of interferon-alpha (IFN-α) production. In contrast, a protective effect of total non-autoreactive IgE has also been suggested, through a decreased ability of FcεRI-triggered pDCs to secrete IFN-α. This review summarizes in a comprehensive manner the emerging recent literature in the field, and propose new concepts to reconcile the observations. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. Antiallergic Activity of Ethanol Extracts of Arctium lappa L. Undried Roots and Its Active Compound, Oleamide, in Regulating FcεRI-Mediated and MAPK Signaling in RBL-2H3 Cells.

    Science.gov (United States)

    Yang, Woong-Suk; Lee, Sung Ryul; Jeong, Yong Joon; Park, Dae Won; Cho, Young Mi; Joo, Hae Mi; Kim, Inhye; Seu, Young-Bae; Sohn, Eun-Hwa; Kang, Se Chan

    2016-05-11

    The antiallergic potential of Arctium lappa L. was investigated in Sprague-Dawley rats, ICR mice, and RBL-2H3 cells. Ethanol extract (90%) of A. lappa (ALE, 100 μg/mL) inhibited the degranulation rate by 52.9%, determined by the level of β-hexosaminidase. ALE suppressed passive cutaneous anaphylaxis (PCA) in rats and attenuated anaphylaxis and histamine release in mice. To identify the active compound of ALE, we subsequently fractionated and determined the level of β-hexosaminidase in all subfractions. Oleamide was identified as an active compound of ALE, which attenuated the secretion of histamine and the production of tumor necrosis factor (TNF)-α and interleukin-4 (IL-4) in cells treated with compound 48/80 or A23187/phorbol myristate acetate (PMA). Oleamide suppressed FcεRI-tyrosine kinase Lyn-mediated pathway, c-Jun N-terminal kinases (JNK/SAPK), and p38 mitogen-activated protein kinases (p38-MAPKs). These results showed that ALE and oleamide attenuated allergic reactions and should serve as a platform to search for compounds with antiallergic activity.

  3. CERN honours Carlo Rubbia

    CERN Multimedia

    2009-01-01

    On 7 April CERN will be holding a symposium to mark the 75th birthday of Carlo Rubbia, who shared the 1984 Nobel Prize for Physics with Simon van der Meer for contributions to the discovery of the W and Z bosons, carriers of the weak interaction. Following a presentation by Rolf Heuer, lectures will be given by eminent speakers on areas of science to which Carlo Rubbia has made decisive contributions. Michel Spiro, Director of the French National Institute of Nuclear and Particle Physics (IN2P3) of the CNRS, Lyn Evans, sLHC Project Leader, and Alan Astbury of the TRIUMF Laboratory will talk about the physics of the weak interaction and the discovery of the W and Z bosons. Former CERN Director-General Herwig Schopper will lecture on CERN’s accelerators from LEP to the LHC. Giovanni Bignami, former President of the Italian Space Agency and Professor at the IUSS School for Advanced Studies in Pavia will speak about his work with Carlo Rubbia. Finally, Hans Joachim Sch...

  4. CERN honours Carlo Rubbia

    CERN Multimedia

    2009-01-01

    On 7 April CERN will be holding a symposium to mark the 75th birthday of Carlo Rubbia, who shared the 1984 Nobel Prize for Physics with Simon van der Meer for contributions to the discovery of the W and Z bosons, carriers of the weak interaction. Following a presentation by Rolf Heuer, lectures will be given by eminent speakers on areas of science to which Carlo Rubbia has made decisive contributions. Michel Spiro, Director of the French National Institute of Nuclear and Particle Physics (IN2P3) of the CNRS, Lyn Evans, sLHC Project Leader, and Alan Astbury of the TRIUMF Laboratory will talk about the physics of the weak interaction and the discovery of the W and Z bosons. Former CERN Director-General Herwig Schopper will lecture on CERN’s accelerators from LEP to the LHC. Giovanni Bignami, former President of the Italian Space Agency, will speak about his work with Carlo Rubbia. Finally, Hans Joachim Schellnhuber of the Potsdam Institute for Climate Research and Sven Kul...

  5. Luteolin, a flavonoid, inhibits AP-1 activation by basophils

    International Nuclear Information System (INIS)

    Hirano, Toru; Higa, Shinji; Arimitsu, Junsuke; Naka, Tetsuji; Ogata, Atsushi; Shima, Yoshihito; Fujimoto, Minoru; Yamadori, Tomoki; Ohkawara, Tomoharu; Kuwabara, Yusuke; Kawai, Mari; Matsuda, Hisashi; Yoshikawa, Masayuki; Maezaki, Naoyoshi; Tanaka, Tetsuaki; Kawase, Ichiro; Tanaka, Toshio

    2006-01-01

    Flavonoids including luteolin, apigenin, and fisetin are inhibitors of IL-4 synthesis and CD40 ligand expression by basophils. This study was done to search for compounds with greater inhibitory activity of IL-4 expression and to clarify the molecular mechanisms through which flavonoids inhibit their expression. Of the 37 flavonoids and related compounds examined, ayanin, luteolin, and apigenin were the strongest inhibitors of IL-4 production by purified basophils in response to anti-IgE antibody plus IL-3. Luteolin did not suppress Syk or Lyn phosphorylation in basophils, nor did suppress p54/46 SAPK/JNK, p38 MAPK, and p44/42 MAPK activation by a basophilic cell line, KU812 cells, stimulated with A23187 and PMA. However, luteolin did inhibit phosphorylation of c-Jun and DNA binding activity of AP-1 in nuclear lysates from stimulated KU812 cells. These results provide a fundamental structure of flavonoids for IL-4 inhibition and demonstrate a novel action of flavonoids that suppresses the activation of AP-1

  6. Volume-activated trimethylamine oxide efflux in red blood cells of spiny dogfish (Squalus acanthias).

    Science.gov (United States)

    Koomoa, D L; Musch, M W; MacLean, A V; Goldstein, L

    2001-09-01

    The aims of this study were to determine the pathway of swelling-activated trimethylamine oxide (TMAO) efflux and its regulation in spiny dogfish (Squalus acanthias) red blood cells and compare the characteristics of this efflux pathway with the volume-activated osmolyte (taurine) channel present in erythrocytes of fishes. The characteristics of the TMAO efflux pathway were similar to those of the taurine efflux pathway. The swelling-activated effluxes of both TMAO and taurine were significantly inhibited by known anion transport inhibitors (DIDS and niflumic acid) and by the general channel inhibitor quinine. Volume expansion by hypotonicity, ethylene glycol, and diethyl urea activated both TMAO and taurine effluxes similarly. Volume expansion by hypotonicity, ethylene glycol, and diethyl urea also stimulated the activity of tyrosine kinases p72syk and p56lyn, although the stimulations by the latter two treatments were less than by hypotonicity. The volume activations of both TMAO and taurine effluxes were inhibited by tyrosine kinase inhibitors, suggesting that activation of tyrosine kinases may play a role in activating the osmolyte effluxes. These results indicate that the volume-activated TMAO efflux occurs via the organic osmolyte (taurine) channel and may be regulated by the volume activation of tyrosine kinases.

  7. The new heart of the PS is beating strongly

    CERN Multimedia

    Corinne Pralavorio

    2011-01-01

    The PS has resumed operation with a brand new electrical power system called POPS; this enormous system comprising power electronics and capacitors is crucial because if it broke down practically no particles would be able to circulate at CERN. As soon as it started, POPS passed all the tests with flying colours and is now pulsing at full power.   The new PS power system is made up of 6 containers, each with 60 tonnes of capacitors and 8 power converters. The date 11/02/11 will always be remembered with affection by the engineers in the Electrical Power Converters Group. At 11:11 in the morning (no joke), the first beams powered by the new system began to circulate in the PS. The cutely-named POPS (POwer for PS) took over from the old rotating machine that had been working since 1968. From now on it will be POPS that supplies the PS main magnets with the electrical pulses needed to accelerate the beams for the LHC and all CERN's other facilities. The system is crucial as the PS is one of the lyn...

  8. Installation of the LHC transfer lines begins

    CERN Multimedia

    Patrice Loïez

    2003-01-01

    The first of 700 magnets has been installed in one of the two transfer tunnels built to transfer the SPS beam into the LHC. The start of this first installation phase of the LHC transfer lines provides the opportunity to launch a new and highly original modular system for transporting and installing all kinds of magnets in very narrow tunnels. The system is based on very compact bogies, up to four of which can be coupled together to form a convoy. The wheels are fitted with individual motors enabling them to swivel through an angle of 90° and the convoy to move laterally. In this way the magnet is delivered directly to its installation point, but beneath the beamline. It is then raised into its final position in the beamline using air cushions, which form an integrated part of the transport system.Photos 01, 02: Pictured with the newly installed magnet and transport system in the transfer line tunnel are LHC project leader Lyn Evans (second left, white helmet); Volker Mertens, responsible for the LHC injecti...

  9. LHC: forwards and onwards

    CERN Multimedia

    2008-01-01

    Following the recent incident in Sector 3-4, which has brought the start-up of the LHC to a halt, the various teams are working hard to establish the cause, evaluate the situation and plan the necessary repairs. The LHC will be started up again in spring 2009 following the winter shutdown for the maintenance of all the CERN installations. The LHC teams are at work on warming up Sector 3-4 and establishing the cause of the serious incident that occurred on Friday, 19 September. Preliminary investigations suggest that the likely cause of the problem was a faulty electrical connection between two magnets. The connections probably melted, leading to a mechanical failure and a large leak of helium into the tunnel. However, the teams will not be able to carry out a full evaluation and assess the repairs needed until the sector has been warmed up again and inspected. "We are not worried about repairing the magnets as spare parts are available", said Lyn Evans, the LHC Project Leade...

  10. Medical approach to the treatment of feline injection site sarcoma with masitinib: a case report

    Directory of Open Access Journals (Sweden)

    Ledoux JM

    2014-09-01

    Full Text Available Jean-Marie Ledoux,1 Pascal Brun,2 Tom Chapuis,2 Paul Dumas,3 Jean Guillotin41Veterinary Surgery, Lys-Lez-Lannoy, 2AB Science, Paris, 3Laboratoire de Pathologie Vétérinaire du Nord, Annœullin, 4Laboratoire Départemental Public, Villeneuve d'Ascq, FranceAbstract: Feline injection site sarcoma is a common tumor among cats, for which existing medical treatments do not prove to be entirely satisfactory. In this tumor, the platelet-derived growth factor receptor, a tyrosine kinase receptor, is frequently hyperactivated. In the past, clinical case reports with imatinib, a tyrosine kinase inhibitor (TKI, have demonstrated tumoral stabilization. Here we describe the use of another TKI, masitinib, which specifically inhibits c-Kit, platelet-derived growth factor receptor, and Lyn, and is currently licensed for veterinary use in canine mast cell tumors. The therapeutic results were initially satisfactory, with regression of the tumor followed by tumoral recurrence which was stabilized and moderately reduced. Further studies are suggested, in order to evaluate the relevance of TKIs in the treatment and prevention of recurrences of feline injection site sarcoma. Tumoral stabilization by means of an inexpensive and reasonably well tolerated treatment would prove to be of true therapeutic relevance, in particular for inoperable feline injection site sarcomas. Another indication for such TKIs could be in preoperative treatment as a means of facilitating surgical excision by reduction of adhesions.Keywords: fibrosarcoma, imatinib, platelet-derived growth factor receptor, tyrosine kinase receptor

  11. ATLAS looks forward to having beams!

    CERN Multimedia

    Hans von der Schmitt

    Lyn Evans, head of the LHC project at CERN, brought very good news: all problems are now solved or understood, and barring a disaster, the LHC should see beams in July 2008. The ATLAS overview week (8-12 October) showed impressively that the experiment is getting ready for beams on all fronts. Perhaps that is best seen in the recent runs with cosmic events, which are integrating all ATLAS subsystems. The integration milestone M4 ended just a month ago (see the article in the September issue of ATLAS e-news), exercising for one week the complete chain from detectors - trigger and data acquisition - reconstruction at Tier0 - shipment of data worldwide to Tier1s. Event displays and histograms, available both online and offline, were shown throughout the overview week and are proof that the entire chain is actually working. The integration milestones give an enormous boost to the experiment - next time during M5 end of October. During the week we learned about successes and remaining issues along this ent...

  12. Highlights from past and future physics

    CERN Multimedia

    Daisy Yuhas

    2009-01-01

    A two-day symposium was held at CERN on 3 and 4 December in celebration of the fiftieth anniversary of the Proton Synchrotron and the twentieth anniversary of LEP. The symposium, entitled “From the Proton Synchrotron to the Large Hadron Collider- 50 Years of Nobel Memories in High-Energy Physics”, included a series of seminars reflecting on the past fifty years in particle physics and an exhibition highlighting CERN’s research over this period.   Lyn Evans, LHC project leader, addressing the audience gathered in the Main Auditorium during the symposium that celebrated the 50 years of the PS and the 20 years of LEP.  The events were well attended on both days. Thursday’s reception, to which the Director-General invited everyone working at CERN, attracted over 1200 people. The seminars drew about 500 people to the Main Auditorium and the Council Chamber each day, with at least as many on-line attendees. The symposium speakers, including thirteen No...

  13. LHC Report: Boost in bunches brings record luminosity

    CERN Multimedia

    2011-01-01

    Having hit a luminosity of around 8.4x1032 cm-2 s-1 with 768 bunches per beam, the LHC went into a 5-day machine development (MD) program on Wednesday 4 May. Operators are now working on increasing the number of particle bunches in the machine towards a 2011 maximum of around 1380 bunches. The team is already hitting major milestones, recording another record-breaking peak luminosity on Monday 23 May.   Former LHC Project Leader Lyn Evans (to the right) and Laurette Ponce, the engineer-in-charge when the recent luminosity record was achieved. The MD periods improve our understanding of the machine, with the aim of increasing its short- and long-term performance. This one also included tests of the machine’s configurations for special physics runs and a future high luminosity LHC. It was an intense program and overall it went very well, with most measurements carried out successfully. Highlights included: commissioning a dedicated machine setup for TOTEM and ALFA; succe...

  14. Cloning and Sequencing of Protein Kinase cDNA from Harbor Seal (Phoca vitulina Lymphocytes

    Directory of Open Access Journals (Sweden)

    Jennifer C. C. Neale

    2004-01-01

    Full Text Available Protein kinases (PKs play critical roles in signal transduction and activation of lymphocytes. The identification of PK genes provides a tool for understanding mechanisms of immunotoxic xenobiotics. As part of a larger study investigating persistent organic pollutants in the harbor seal and their possible immunomodulatory actions, we sequenced harbor seal cDNA fragments encoding PKs. The procedure, using degenerate primers based on conserved motifs of human protein tyrosine kinases (PTKs, successfully amplified nine phocid PK gene fragments with high homology to human and rodent orthologs. We identified eight PTKs and one dual (serine/threonine and tyrosine kinase. Among these were several PKs important in early signaling events through the B- and T-cell receptors (FYN, LYN, ITK and SYK and a MAP kinase involved in downstream signal transduction. V-FGR, RET and DDR2 were also expressed. Sequential activation of protein kinases ultimately induces gene transcription leading to the proliferation and differentiation of lymphocytes critical to adaptive immunity. PKs are potential targets of bioactive xenobiotics, including persistent organic pollutants of the marine environment; characterization of these molecules in the harbor seal provides a foundation for further research illuminating mechanisms of action of contaminants speculated to contribute to large-scale die-offs of marine mammals via immunosuppression.

  15. Tyrosol Suppresses Allergic Inflammation by Inhibiting the Activation of Phosphoinositide 3-Kinase in Mast Cells.

    Directory of Open Access Journals (Sweden)

    In-Gyu Je

    Full Text Available Allergic diseases such as atopic dermatitis, rhinitis, asthma, and anaphylaxis are attractive research areas. Tyrosol (2-(4-hydroxyphenylethanol is a polyphenolic compound with diverse biological activities. In this study, we investigated whether tyrosol has anti-allergic inflammatory effects. Ovalbumin-induced active systemic anaphylaxis and immunoglobulin E-mediated passive cutaneous anaphylaxis models were used for the immediate-type allergic responses. Oral administration of tyrosol reduced the allergic symptoms of hypothermia and pigmentation in both animal models. Mast cells that secrete allergic mediators are key regulators on allergic inflammation. Tyrosol dose-dependently decreased mast cell degranulation and expression of inflammatory cytokines. Intracellular calcium levels and activation of inhibitor of κB kinase (IKK regulate cytokine expression and degranulation. Tyrosol blocked calcium influx and phosphorylation of the IKK complex. To define the molecular target for tyrosol, various signaling proteins involved in mast cell activation such as Lyn, Syk, phosphoinositide 3-kinase (PI3K, and Akt were examined. Our results showed that PI3K could be a molecular target for tyrosol in mast cells. Taken together, these findings indicated that tyrosol has anti-allergic inflammatory effects by inhibiting the degranulation of mast cells and expression of inflammatory cytokines; these effects are mediated via PI3K. Therefore, we expect tyrosol become a potential therapeutic candidate for allergic inflammatory disorders.

  16. Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan

    International Nuclear Information System (INIS)

    Imamura, T; Kiyokawa, N; Kato, M; Imai, C; Okamoto, Y

    2016-01-01

    Recent studies revealed that a substantial proportion of patients with high-risk B-cell precursor acute lymphoblastic leukemia (BCP-ALL) harbor fusions involving tyrosine kinase and cytokine receptors, such as ABL1, PDGFRB, JAK2 and CRLF2, which are targeted by tyrosine kinase inhibitors (TKIs). In the present study, transcriptome analysis or multiplex reverse transcriptase–PCR analysis of 373 BCP-ALL patients without recurrent genetic abnormalities identified 29 patients with kinase fusions. Clinically, male predominance (male/female: 22/7), older age at onset (mean age at onset: 8.8 years) and a high white blood cell count at diagnosis (mean: 94 200/μl) reflected the predominance of National Cancer Institute high-risk (NCI-HR) patients (NCI-standard risk/HR: 8/21). Genetic analysis identified three patients with ABL1 rearrangements, eight with PDGFRB rearrangements, two with JAK2 rearrangements, three with IgH-EPOR and one with NCOR1-LYN. Of the 14 patients with CRLF2 rearrangements, two harbored IgH-EPOR and PDGFRB rearrangements. IKZF1 deletion was present in 16 of the 22 patients. The 5-year event-free and overall survival rates were 48.6±9.7% and 73.5±8.6%, respectively. The outcome was not satisfactory without sophisticated minimal residual disease-based stratification. Furthermore, the efficacy of TKIs combined with conventional chemotherapy without allogeneic hematopoietic stem cell transplantation in this cohort should be determined

  17. Small-scale structure in the diffuse interstellar medium

    International Nuclear Information System (INIS)

    Meyer, D.M.

    1990-01-01

    The initial results of a study to probe the small-scale structure in the diffuse interstellar medium (ISM) through IUE and optical observations of interstellar absorption lines toward both components of resolvable binary stars is reported. The binaries (Kappa CrA, 57 Aql, 59 And, HR 1609/10, 19 Lyn, and Theta Ser) observed with IUE have projected linear separations ranging from 5700 to 700 Au. Except for Kappa CrA, the strengths of the interstellar absorption lines toward both components of these binaries agree to within 10 percent. In the case of Kappa CrA, the optically thin interstellar Mg I and Mn II lines are about 50 percent stronger toward Kappa-2 CrA than Kappa-1 CrA. Higher resolution observations of interstellar Ca II show that this difference is concentrated in the main interstellar component at V(LSR) = 9 + or - 2 km/s. Interestingly, this velocity corresponds to an intervening cloud that may be associated with the prominent Loop I shell in the local ISM. Given the separation (23 arcsec) and distance (120 pc) of Kappa CrA, the line strength variations indicate that this cloud has structure on scales of 2800 AU or less. 21 refs

  18. A special broadcast of CERN's Video news

    CERN Multimedia

    2003-01-01

    A special edition of CERN's video news giving a complete update on the LHC project is to be broadcast in the Main Auditorium. After your lunch make a small detour to the Main Auditorium, where you see the big picture. On 14, 15 and 16 May, between 12:30 and 14:00, a special edition of CERN's video news bulletin will be broadcast in the Main Auditorium. You will have the chance get up-to-date on the LHC project and its experiments. With four years to go before the first collisions in the LHC, the LHC Project Leader Lyn Evans will present a status report on the construction of the accelerator. The spokesmen of the five LHC experiments (ALICE, ATLAS, CMS, LHCb and TOTEM) will explain how the work is going and what the state of play will be in four years' time. This special video news broadcast is the result of collaboration between the CERN Audiovisual Service, the Photo Service and the External communication section. The broadcast will begin with a brand-new programme title sequence. And just as in the real c...

  19. Targeting the TAM Receptors in Leukemia.

    Science.gov (United States)

    Huey, Madeline G; Minson, Katherine A; Earp, H Shelton; DeRyckere, Deborah; Graham, Douglas K

    2016-11-08

    Targeted inhibition of members of the TAM (TYRO-3, AXL, MERTK) family of receptor tyrosine kinases has recently been investigated as a novel strategy for treatment of hematologic malignancies. The physiologic functions of the TAM receptors in innate immune control, natural killer (NK) cell differentiation, efferocytosis, clearance of apoptotic debris, and hemostasis have previously been described and more recent data implicate TAM kinases as important regulators of erythropoiesis and megakaryopoiesis. The TAM receptors are aberrantly or ectopically expressed in many hematologic malignancies including acute myeloid leukemia, B- and T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma. TAM receptors contribute to leukemic phenotypes through activation of pro-survival signaling pathways and interplay with other oncogenic proteins such as FLT3, LYN, and FGFR3. The TAM receptors also contribute to resistance to both cytotoxic chemotherapeutics and targeted agents, making them attractive therapeutic targets. A number of translational strategies for TAM inhibition are in development, including small molecule inhibitors, ligand traps, and monoclonal antibodies. Emerging areas of research include modulation of TAM receptors to enhance anti-tumor immunity, potential roles for TYRO-3 in leukemogenesis, and the function of the bone marrow microenvironment in mediating resistance to TAM inhibition.

  20. A side-effect free method for identifying cancer drug targets.

    Science.gov (United States)

    Ashraf, Md Izhar; Ong, Seng-Kai; Mujawar, Shama; Pawar, Shrikant; More, Pallavi; Paul, Somnath; Lahiri, Chandrajit

    2018-04-27

    Identifying effective drug targets, with little or no side effects, remains an ever challenging task. A potential pitfall of failing to uncover the correct drug targets, due to side effect of pleiotropic genes, might lead the potential drugs to be illicit and withdrawn. Simplifying disease complexity, for the investigation of the mechanistic aspects and identification of effective drug targets, have been done through several approaches of protein interactome analysis. Of these, centrality measures have always gained importance in identifying candidate drug targets. Here, we put forward an integrated method of analysing a complex network of cancer and depict the importance of k-core, functional connectivity and centrality (KFC) for identifying effective drug targets. Essentially, we have extracted the proteins involved in the pathways leading to cancer from the pathway databases which enlist real experimental datasets. The interactions between these proteins were mapped to build an interactome. Integrative analyses of the interactome enabled us to unearth plausible reasons for drugs being rendered withdrawn, thereby giving future scope to pharmaceutical industries to potentially avoid them (e.g. ESR1, HDAC2, F2, PLG, PPARA, RXRA, etc). Based upon our KFC criteria, we have shortlisted ten proteins (GRB2, FYN, PIK3R1, CBL, JAK2, LCK, LYN, SYK, JAK1 and SOCS3) as effective candidates for drug development.

  1. MBNL142 and MBNL143 gene isoforms, overexpressed in DM1-patient muscle, encode for nuclear proteins interacting with Src family kinases.

    Science.gov (United States)

    Botta, A; Malena, A; Tibaldi, E; Rocchi, L; Loro, E; Pena, E; Cenci, L; Ambrosi, E; Bellocchi, M C; Pagano, M A; Novelli, G; Rossi, G; Monaco, H L; Gianazza, E; Pantic, B; Romeo, V; Marin, O; Brunati, A M; Vergani, L

    2013-08-15

    Myotonic dystrophy type-1 (DM1) is the most prevalent form of muscular dystrophy in adults. This disorder is an RNA-dominant disease, caused by expansion of a CTG repeat in the DMPK gene that leads to a misregulation in the alternative splicing of pre-mRNAs. The longer muscleblind-like-1 (MBNL1) transcripts containing exon 5 and the respective protein isoforms (MBNL142-43) were found to be overexpressed in DM1 muscle and localized exclusively in the nuclei. In vitro assays showed that MBNL142-43 bind the Src-homology 3 domain of Src family kinases (SFKs) via their proline-rich motifs, enhancing the SFK activity. Notably, this association was also confirmed in DM1 muscle and myotubes. The recovery, mediated by an siRNA target to Ex5-MBNL142-43, succeeded in reducing the nuclear localization of both Lyn and MBNL142-43 proteins and in decreasing the level of tyrosine phosphorylated proteins. Our results suggest an additional molecular mechanism in the DM1 pathogenesis, based on an altered phosphotyrosine signalling pathway.

  2. Golden Hadrons 2004: and the winners are …

    CERN Multimedia

    2004-01-01

    For the third year running, CERN has awarded a prize to its best LHC suppliers. Three companies were presented with the Golden Hadron 2004. On Friday 30 July, three of the two hundred suppliers for the LHC were presented with Golden Hadron awards by Lyn Evans. This is the third year that the awards have been presented. This year it was the turn of Alstom-MSA (France), Ernesto Malvestiti S.p.A. (Italy) and Simic S.p.A. (Italy) to receive awards, not only for their technical and financial achievements but also for their compliance with contractual deadlines. From left to right: Sandro Ferraris (SIMIC), Guiseppi Ginola (SIMIC), Gérard Grunblatt (ALSTOM), Phillippe Mocaer (ALSTOM), Gianfranco Malvestiti (ERNESTO MALVESTITI), Ernesto Malvestiti (ERNESTO MALVESTITI) Alstom-MSA was awarded the prize for manufacturing superconducting cable for the LHC's main magnets, the dipoles designed to steer the particles round the accelerator and the quadrupoles designed to focus the particle beams. Seven thousand kilometres ...

  3. The LHC's suppliers come up trumps

    CERN Multimedia

    2006-01-01

    Four of the LHC Project's most exceptional suppliers have just been honoured in the fifth Golden Hadron awards ceremony. For the first time, a CERN team was among the prize-winners. The CERN main workshop (Mechanical and Materials Engineering group, TS/MME) received the Golden Hadron Award at the prize-giving ceremony held at the Globe. From left to right, Saïd Atieh (TS/MME), Vincent Vuillemin (TS/MME group leader), Michel Caccioppoli (TS/MME), Lyn Evans (LHC Project Leader), Marc Polini (TS/MME-MS section leader), Jean-Luc Gayraud (Cegelec), Jean-Paul Bacher (TS/MME-AS section leader) and Paolo Ciriani (head of the TS Department). Flexible, responsive, committed... all fitting adjectives to describe the recipients of the fifth Golden Hadron awards. The prizes, designed to honour the LHC Project's best suppliers, were awarded to a total of four suppliers, including two that are involved in the final accelerator assembly work: proof, if it were needed, that the project has now entered its final phase. Drak...

  4. KNOWLEDGE-BASED ROBOT VISION SYSTEM FOR AUTOMATED PART HANDLING

    Directory of Open Access Journals (Sweden)

    J. Wang

    2012-01-01

    Full Text Available

    ENGLISH ABSTRACT: This paper discusses an algorithm incorporating a knowledge-based vision system into an industrial robot system for handling parts intelligently. A continuous fuzzy controller was employed to extract boundary information in a computationally efficient way. The developed algorithm for on-line part recognition using fuzzy logic is shown to be an effective solution to extract the geometric features of objects. The proposed edge vector representation method provides enough geometric information and facilitates the object geometric reconstruction for gripping planning. Furthermore, a part-handling model was created by extracting the grasp features from the geometric features.

    AFRIKAANSE OPSOMMING: Hierdie artikel beskryf ‘n kennis-gebaseerde visiesisteemalgoritme wat in ’n industriёle robotsisteem ingesluit word om sodoende intelligente komponenthantering te bewerkstellig. ’n Kontinue wasige beheerder is gebruik om allerlei objekinligting deur middel van ’n effektiewe berekeningsmetode te bepaal. Die ontwikkelde algoritme vir aan-lyn komponentherkenning maak gebruik van wasige logika en word bewys as ’n effektiewe metode om geometriese inligting van objekte te bepaal. Die voorgestelde grensvektormetode verskaf voldoende inligting en maak geometriese rekonstruksie van die objek moontlik om greepbeplanning te kan doen. Voorts is ’n komponenthanteringsmodel ontwikkel deur die grypkenmerke af te lei uit die geometriese eienskappe.

  5. Pan-SRC kinase inhibition blocks B-cell receptor oncogenic signaling in non-Hodgkin lymphoma.

    Science.gov (United States)

    Battistello, Elena; Katanayeva, Natalya; Dheilly, Elie; Tavernari, Daniele; Donaldson, Maria C; Bonsignore, Luca; Thome, Margot; Christie, Amanda L; Murakami, Mark A; Michielin, Olivier; Ciriello, Giovanni; Zoete, Vincent; Oricchio, Elisa

    2018-05-24

    In diffuse large B-cell lymphoma (DLBCL), activation of the B-cell receptor (BCR) promotes multiple oncogenic signals, which are essential for tumor proliferation. Inhibition of the Bruton's tyrosine kinase (BTK), a BCR downstream target, is therapeutically effective only in a subgroup of patients with DLBCL. Here, we used lymphoma cells isolated from patients with DLBCL to measure the effects of targeted therapies on BCR signaling and to anticipate response. In lymphomas resistant to BTK inhibition, we show that blocking BTK activity enhanced tumor dependencies from alternative oncogenic signals downstream of the BCR, converging on MYC upregulation. To completely ablate the activity of the BCR, we genetically and pharmacologically repressed the activity of the SRC kinases LYN, FYN, and BLK, which are responsible for the propagation of the BCR signal. Inhibition of these kinases strongly reduced tumor growth in xenografts and cell lines derived from patients with DLBCL independent of their molecular subtype, advancing the possibility to be relevant therapeutic targets in broad and diverse groups of DLBCL patients. © 2018 by The American Society of Hematology.

  6. Elaeocarpusin Inhibits Mast Cell-Mediated Allergic Inflammation

    Directory of Open Access Journals (Sweden)

    Min-Jong Kim

    2018-06-01

    Full Text Available Mast cells are major effector cells for allergic responses that act by releasing inflammatory mediators, such as histamine and pro-inflammatory cytokines. Accordingly, different strategies have been pursued to develop anti-allergic and anti-inflammatory candidates by regulating the function of mast cells. The purpose of this study was to determine the effectiveness of elaeocarpusin (EL on mast cell-mediated allergic inflammation. We isolated EL from Elaeocarpus sylvestris L. (Elaeocarpaceae, which is known to possess anti-inflammatory properties. For this study, various sources of mast cells and mouse anaphylaxis models were used. EL suppressed the induction of markers for mast cell degranulation, such as histamine and β-hexosaminidase, by reducing intracellular calcium levels. Expression of pro-inflammatory cytokines, such as tumor necrosis factor-α and IL-4, was significantly decreased in activated mast cells by EL. This inhibitory effect was related to inhibition of the phosphorylation of Fyn, Lyn, Syk, and Akt, and the nuclear translocation of nuclear factor-κB. To confirm the effect of EL in vivo, immunoglobulin E-mediated passive cutaneous anaphylaxis (PCA and ovalbumin-induced active systemic anaphylaxis (ASA models were induced. EL reduced the PCA reaction in a dose dependent manner. In addition, EL attenuated ASA reactions such as hypothemia, histamine release, and IgE production. Our results suggest that EL is a potential therapeutic candidate for allergic inflammatory diseases that acts via the inhibition of mast cell degranulation and expression of proinflammatory cytokines.

  7. DNA Methylation and Gene Expression Profiling of Ewing Sarcoma Primary Tumors Reveal Genes That Are Potential Targets of Epigenetic Inactivation

    Directory of Open Access Journals (Sweden)

    Nikul Patel

    2012-01-01

    Full Text Available The role of aberrant DNA methylation in Ewing sarcoma is not completely understood. The methylation status of 503 genes in 52 formalin-fixed paraffin-embedded EWS tumors and 3 EWS cell lines was compared to human mesenchymal stem cell primary cultures (hMSCs using bead chip methylation analysis. Relative expression of methylated genes was assessed in 5-Aza-2-deoxycytidine-(5-AZA-treated EWS cell lines and in a cohort of primary EWS samples and hMSCs by gene expression and quantitative RT-PCR. 129 genes demonstrated statistically significant hypermethylation in EWS tumors compared to hMSCs. Thirty-six genes were profoundly methylated in EWS and unmethylated in hMSCs. 5-AZA treatment of EWS cell lines resulted in upregulation of expression of hundreds of genes including 162 that were increased by at least 2-fold. The expression of 19 of 36 candidate hypermethylated genes was increased following 5-AZA. Analysis of gene expression from an independent cohort of tumors confirmed decreased expression of six of nineteen hypermethylated genes (AXL, COL1A1, CYP1B1, LYN, SERPINE1, and VCAN. Comparing gene expression and DNA methylation analyses proved to be an effective way to identify genes epigenetically regulated in EWS. Further investigation is ongoing to elucidate the role of these epigenetic alterations in EWS pathogenesis.

  8. The effects of erythropoietin signaling on telomerase regulation in non-erythroid malignant and non-malignant cells

    Energy Technology Data Exchange (ETDEWEB)

    Uziel, Orit, E-mail: Oritu@clalit.org.il [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Kanfer, Gil [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Dep. of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Beery, Einat [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Yelin, Dana; Shepshelovich, Daniel [Medicine A, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Bakhanashvili, Mary [Unit of Infectious Diseases, Sheba Medical Center, Tel-Hashomer (Israel); Nordenberg, Jardena [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Dep. of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Endocrinology Laboratory, Beilinson Medical Center, Petah-Tikva (Israel); Lahav, Meir [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Medicine A, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel)

    2014-07-18

    Highlights: • We assumed that some of erythropoietin adverse effects may be mediated by telomerase activity. • EPO administration increased telomerase activity, cells proliferation and migration. • The inhibition of telomerase modestly repressed the proliferative effect of erythropoietin. • Telomere shortening caused by long term inhibition of the enzyme totally abolished that effect. • This effect was mediated via the Lyn–AKT axis and not by the canonical JAK2–STAT pathway. - Abstract: Treatment with erythropoietin (EPO) in several cancers is associated with decreased survival due to cancer progression. Due to the major importance of telomerase in cancer biology we hypothesized that some of these effects may be mediated through EPO effect on telomerase. For this aim we explored the possible effects of EPO on telomerase regulation, cell migration and chemosensitivity in non-erythroid malignant and non-malignant cells. Cell proliferation, telomerase activity (TA) and cell migration increased in response to EPO. EPO had no effect on cancer cells sensitivity to cisplatinum and on the cell cycle status. The inhibition of telomerase modestly repressed the proliferative effect of EPO. Telomere shortening caused by long term inhibition of the enzyme abolished the effect of EPO, suggesting that EPO effects on cancer cells are related to telomere dynamics. TA was correlated with the levels of Epo-R. The increase in TA was mediated post-translationally through the Lyn-Src and not the canonical JAK2 pathway.

  9. Anti-allergic activity of sesquiterpenes from the rhizomes of Cyperus rotundus.

    Science.gov (United States)

    Jin, Jeong Ho; Lee, Dong-Ung; Kim, Yeong Shik; Kim, Hyun Pyo

    2011-02-01

    From the 70% ethanol extract of the rhizomes of Cyperus rotundus (CRE), several major constituents including the sesquiterpene derivatives (valencene, nootkatone, and caryophyllene α-oxide), monoterpenes (β-pinene, 1,8-cineole, and limonene) and 4-cymene were isolated and examined for their anti-allergic activity in vitro and in vivo. In rat basophilic leukemia (RBL)-1 cells, the sesquiterpenes strongly inhibited 5-lipoxygenase-catalyzed leukotrienes production. In addition, they inhibited β-hexosaminidase release by antigen-stimulated RBL-2H3 cells, with valencene having the highest inhibitory effect. CRE inhibited leukotrienes production and β-hexosaminidase release at 300 μg/mL. It was also found that the most active sesquiterpene (valencene) and CRE inhibited β-hexosaminidase degranulation by inhibiting the initial activation reaction, Lyn phosphorylation, in IgE-stimulated RBL-2H3 cells. Moreover, CRE, valencene and nootkatone significantly inhibited the delayed-type hypersensitivity reaction in mice when administered orally at 50-300 mg/kg. In conclusion, C. rotundus and its constituents, valencene, nootkatone, and caryophyllene α-oxide, exert anti-allergic activity in vitro and in vivo. These sesquiterpenes, but not monoterpenes, certainly contribute to the anti-allergic activity of the rhizomes of C. rotundus.

  10. Targeting the TAM Receptors in Leukemia

    Directory of Open Access Journals (Sweden)

    Madeline G. Huey

    2016-11-01

    Full Text Available Targeted inhibition of members of the TAM (TYRO-3, AXL, MERTK family of receptor tyrosine kinases has recently been investigated as a novel strategy for treatment of hematologic malignancies. The physiologic functions of the TAM receptors in innate immune control, natural killer (NK cell differentiation, efferocytosis, clearance of apoptotic debris, and hemostasis have previously been described and more recent data implicate TAM kinases as important regulators of erythropoiesis and megakaryopoiesis. The TAM receptors are aberrantly or ectopically expressed in many hematologic malignancies including acute myeloid leukemia, B- and T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma. TAM receptors contribute to leukemic phenotypes through activation of pro-survival signaling pathways and interplay with other oncogenic proteins such as FLT3, LYN, and FGFR3. The TAM receptors also contribute to resistance to both cytotoxic chemotherapeutics and targeted agents, making them attractive therapeutic targets. A number of translational strategies for TAM inhibition are in development, including small molecule inhibitors, ligand traps, and monoclonal antibodies. Emerging areas of research include modulation of TAM receptors to enhance anti-tumor immunity, potential roles for TYRO-3 in leukemogenesis, and the function of the bone marrow microenvironment in mediating resistance to TAM inhibition.

  11. 10 September: the LHC’s first circulating beam

    CERN Multimedia

    On 10 September, a first beam of protons will circulate in the LHC. The first moments in the life of the LHC will be an exciting time for the CERN staff, and will be captured by more than 250 media organizations from all over the world. The first injection of the beam into the machine will be between 9:00 and 10:00 a. m. At 9:15 the LHC project leader, Lyn Evans, will give a brief explanation of the day’s proceedings in French followed by some words from Robert Aymar, CERN Director general. CERN personnel are invited to follow the first beam day events, which will be shown in the following rooms around CERN: All day: Council Chamber, Main Auditorium, IT Auditorium, AB Auditorium Prévessin, Conference Room 40-S2-A01, Conference Room 40-S2-C01. Afternoon: AB Auditorium Meyrin, AT Auditorium. Please note that the event will also be webcast but, given the limited number of connections, this option is intended for use of the public outside CERN. CERN personnel are encouraged to follow the event from the confe...

  12. Start-up date announced

    CERN Multimedia

    7th August 2008. CERN has announced that the first attempt to circulate the beam in the LHC will be made on the 10th September. This news comes as the cool down phase of commissioning the accelerator reaches a successful conclusion.The next phase is the synchronization of the LHC with the SPS accelerator, the last link in the LHC’s injector chain. A first synchronization test is scheduled for the 9th August, for the clockwise circulating beam, with the second to follow over the coming weeks.Once stable circulating beams have been established in September they will be brought to collision, and the final step will be to commission the LHC’s acceleration system to boost the energy to 5 TeV, the target energy for 2008.“We’re finishing a marathon with a sprint”, said LHC project leader Lyn Evans. “It’s been a long haul, and we’re all eager to get the LHC research programme underway.”For more information, please see the recent press release at: http://press.web.cern.ch/press/PressReleases/Rele...

  13. Differential sensitivity of Src-family kinases to activation by SH3 domain displacement.

    Directory of Open Access Journals (Sweden)

    Jamie A Moroco

    Full Text Available Src-family kinases (SFKs are non-receptor protein-tyrosine kinases involved in a variety of signaling pathways in virtually every cell type. The SFKs share a common negative regulatory mechanism that involves intramolecular interactions of the SH3 domain with the PPII helix formed by the SH2-kinase linker as well as the SH2 domain with a conserved phosphotyrosine residue in the C-terminal tail. Growing evidence suggests that individual SFKs may exhibit distinct activation mechanisms dictated by the relative strengths of these intramolecular interactions. To elucidate the role of the SH3:linker interaction in the regulation of individual SFKs, we used a synthetic SH3 domain-binding peptide (VSL12 to probe the sensitivity of downregulated c-Src, Hck, Lyn and Fyn to SH3-based activation in a kinetic kinase assay. All four SFKs responded to VSL12 binding with enhanced kinase activity, demonstrating a conserved role for SH3:linker interaction in the control of catalytic function. However, the sensitivity and extent of SH3-based activation varied over a wide range. In addition, autophosphorylation of the activation loops of c-Src and Hck did not override regulatory control by SH3:linker displacement, demonstrating that these modes of activation are independent. Our results show that despite the similarity of their downregulated conformations, individual Src-family members show diverse responses to activation by domain displacement which may reflect their adaptation to specific signaling environments in vivo.

  14. 1754 Days to the LHC and counting!

    CERN Multimedia

    2001-01-01

    At the 118th session of CERN Council, held on Friday 15 June under the chairmanship of Professor Maurice Bourquin of Switzerland, Director-General, Luciano Maiani, presented the commissioning schedule for the Large Hadron Collider (LHC) for the first time. The LHC will collide its first beams in a pilot run starting on 1 April 2006. 'We are 1754 days from the LHC', said Professor Maiani. A full seven-month physics run will begin in August 2006, and the LHC's heavy-ion programme will start in February 2007. Left to right: Lyn Evans, Luciano Maiani, Alexander Skrinsky, and Kurt Hubner with the magnets from Novosibirsk. Professor Maiani underlined to Council that the LHC is now CERN's most important single activity, accounting for over 70% of the Laboratory's resources. Moreover, with some 70% of the total LHC cost adjudicated and 30% paid, the project is very far advanced. With the adjudication this Autumn of the contracts for the 1236 fifteen metre superconducting dipole magnets, the placing of major contrac...

  15. An Orbital Stability Study of the Proposed Companions of SW Lyncis

    Directory of Open Access Journals (Sweden)

    T. C. Hinse

    2014-09-01

    Full Text Available We have investigated the dynamical stability of the proposed companions orbiting the Algol type short-period eclipsing binary SW Lyncis (Kim et al. 2010. The two candidate companions are of stellar to substellar nature, and were inferred from timing measurements of the system’s primary and secondary eclipses. We applied well-tested numerical techniques to accurately integrate the orbits of the two companions and to test for chaotic dynamical behavior. We carried out the stability analysis within a systematic parameter survey varying both the geometries and orientation of the orbits of the companions, as well as their masses. In all our numerical integrations we found that the proposed SW Lyn multi-body system is highly unstable on time-scales on the order of 1000 years. Our results cast doubt on the interpretation that the timing variations are caused by two companions. This work demonstrates that a straightforward dynamical analysis can help to test whether a best-fit companion-based model is a physically viable explanation for measured eclipse timing variations. We conclude that dynamical considerations reveal that the proposed SW Lyncis multi-body system most likely does not exist or the companions have significantly different orbital properties from those conjectured in Kim et al. (2010.

  16. Identification of contrasting seasonal sea ice conditions during the Younger Dryas

    Science.gov (United States)

    Cabedo-Sanz, P.; Belt, S. T.; Knies, J.

    2012-12-01

    through a comparison of the concentrations of IP25 with those of another highly branched isoprenoid (HBI) alkene that is di-unsaturated and believed to also be produced by sea ice diatoms. The ratio of the HBI diene to IP25, termed DIP25, is believed to provide a useful indicator of stability or variability in sea ice conditions and complements the outcomes from the IP25 and PBIP25 index data. 1. Belt, S.T., Vare, L.L., Massé, G., Manners, H.R., Price, J.C., MacLachlan, S.E., Andrews, J.T. , Schmidt, S., 2010. Striking similarities in temporal changes to spring sea ice occurrence across the central Canadian Arctic Archipelago over the last 7000 years. Quaternary Science Reviews 29, 3489-3504. 2. Müller, J., Massé, G., Stein, R., Belt, S.T., 2009. Variability of sea-ice conditions in the Fram Strait over the past 30,000 years. Nature Geoscience 2, 772-776.

  17. Residence times in a hypersaline lagoon: Using salinity as a tracer

    Science.gov (United States)

    Mudge, Stephen M.; Icely, John D.; Newton, Alice

    2008-04-01

    Generally the waters of the Ria Formosa Lagoon, Portugal have a short residence time, in the order of 0.5 days (Tett, P., Gilpin, L., Svendsen, H., Erlandsson, C.P., Larsson, U., Kratzer, S., Fouilland, E., Janzen, C., Lee, J., Grenz, C., Newton, A., Ferreira, J.G., Fernandes, T., Scory, S., 2003. Eutrophication and some European waters of restricted exchange. Continental Shelf Research 23, 1635-1671). This estimation is based on the measurements of currents and the modelling of water exchange at the outlets to the ocean. However, observations of the temperature and salinity in the inner channels imply that residence time is greater in these regions of the lagoon. To resolve this apparent contradiction, spatial measurements of the temperature and salinity were made with a meter for conductivity, temperature and depth along the principal channels of the western portion of the lagoon, with a sampling frequency of two per second. Evaporation rates of 5.4 mm day -1 were measured in a salt extraction pond adjacent to the lagoon and used to determine the residence time through salinity differences with the incoming seawater. In June 2004, the water flooding in from the ocean had an average salinity of 36.07 which contrasted with a maximum of 37.82 at mid ebb on a spring tide, corresponding to a residence time of >7 days; the mean residence time was 2.4 days. As the tide flooded into the channels, the existing water was advected back into the lagoon. Although there was a small amount of mixing with water from another inlet, the water body from the inner lagoon essentially remained distinct with respect to temperature and salinity characteristics. The residence time of the water was further prolonged at the junction between the main channels, where distinct boundaries were observed between the different water masses. As the water ebbed out, the shallow Western Channel was essentially isolated from the rest of the outer lagoon, and the water from this channel was forced

  18. KIT polymorphisms and mutations determine responses of neoplastic mast cells to bafetinib (INNO-406).

    Science.gov (United States)

    Peter, Barbara; Hadzijusufovic, Emir; Blatt, Katharina; Gleixner, Karoline V; Pickl, Winfried F; Thaiwong, Tuddow; Yuzbasiyan-Gurkan, Vilma; Willmann, Michael; Valent, Peter

    2010-09-01

    Advanced systemic mastocytosis (SM) is characterized by uncontrolled growth of neoplastic mast cells (MC) and drug resistance. The tyrosine kinase receptor KIT is often mutated and activated and thus contributes to malignant growth of MC. Therefore, KIT-targeting drugs are currently tested for their ability to block growth of malignant MC. We determined the effects of the multikinase inhibitor INNO-406 (bafetinib) on primary neoplastic MC, the canine mastocytoma cell line C2, the human MC leukemia cell line HMC-1.1 bearing the KIT mutant V560G, and HMC-1.2 cells harboring KIT V560G and KIT D816V. INNO-406 was found to inhibit proliferation in HMC-1.1 cells (IC(50): 30-40 nM), but not in HMC-1.2 cells or primary neoplastic cells in patients with KIT D816V-positive SM. In canines, growth-inhibitory effects of INNO-406 were seen in C2 cells (IC(50): 50-100 nM) exhibiting a KIT exon 11 internal tandem-duplication and in primary neoplastic MC harboring wild-type exon 11, whereas no effects were seen in MC exhibiting a polymorphism at amino acid 581 in exon 11. INNO-406 was found to block KIT phosphorylation and expression in HMC-1.1 cells and C2 cells, but not in HMC-1.2 cells, whereas Lyn-phosphorylation was blocked by INNO-406 in all types of MC. In neoplastic MC, the major target of INNO-406 appears to be KIT. Drug responses may depend on the presence and type of KIT mutation. In human MC, the KIT D816V mutant introduces resistance, and in canine mastocytomas, an exon 11 polymorphism may be indicative of resistance against INNO-406.

  19. Selective Targeting of SH2 Domain–Phosphotyrosine Interactions of Src Family Tyrosine Kinases with Monobodies

    Energy Technology Data Exchange (ETDEWEB)

    Kükenshöner, Tim; Schmit, Nadine Eliane; Bouda, Emilie; Sha, Fern; Pojer, Florence; Koide, Akiko; Seeliger, Markus; Koide, Shohei; Hantschel, Oliver

    2017-05-01

    The binding of Src-homology 2 (SH2) domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the eight Src family kinases (SFKs). The high sequence conservation of the 120 human SH2 domains poses a significant challenge to selectively perturb the interactions of even the SFK SH2 family against the rest of the SH2 domains. We have developed synthetic binding proteins, termed monobodies, for six of the SFK SH2 domains with nanomolar affinity. Most of these monobodies competed with pY ligand binding and showed strong selectivity for either the SrcA (Yes, Src, Fyn, Fgr) or SrcB subgroup (Lck, Lyn, Blk, Hck). Interactome analysis of intracellularly expressed monobodies revealed that they bind SFKs but no other SH2-containing proteins. Three crystal structures of monobody–SH2 complexes unveiled different and only partly overlapping binding modes, which rationalized the observed selectivity and enabled structure-based mutagenesis to modulate inhibition mode and selectivity. In line with the critical roles of SFK SH2 domains in kinase autoinhibition and T-cell receptor signaling, monobodies binding the Src and Hck SH2 domains selectively activated respective recombinant kinases, whereas an Lck SH2-binding monobody inhibited proximal signaling events downstream of the T-cell receptor complex. Our results show that SFK SH2 domains can be targeted with unprecedented potency and selectivity using monobodies. They are excellent tools for dissecting SFK functions in normal development and signaling and to interfere with aberrant SFK signaling networks in cancer cells.

  20. Role of focal adhesion tyrosine kinases in GPVI-dependent platelet activation and reactive oxygen species formation.

    Directory of Open Access Journals (Sweden)

    Naadiya Carrim

    Full Text Available We have previously shown the presence of a TRAF4/p47phox/Hic5/Pyk2 complex associated with the platelet collagen receptor, GPVI, consistent with a potential role of this complex in GPVI-dependent ROS formation. In other cell systems, NOX-dependent ROS formation is facilitated by Pyk2, which along with its closely related homologue FAK are known to be activated and phosphorylated downstream of ligand binding to GPVI.To evaluate the relative roles of Pyk2 and FAK in GPVI-dependent ROS formation and to determine their location within the GPVI signaling pathway.Human and mouse washed platelets (from WT or Pyk2 KO mice were pre-treated with pharmacological inhibitors targeting FAK or Pyk2 (PF-228 and Tyrphostin A9, respectively and stimulated with the GPVI-specific agonist, CRP. FAK, but not Pyk2, was found to be essential for GPVI-dependent ROS production and aggregation. Subsequent human platelet studies with PF-228 confirmed FAK is essential for GPVI-mediated phosphatidylserine exposure, α-granule secretion (P-selectin (CD62P surface expression and integrin αIIbβ3 activation. To determine the precise location of FAK within the GPVI pathway, we analyzed the effect of PF-228 inhibition in CRP-stimulated platelets in conjunction with immunoprecipitation and pulldown analysis to show that FAK is downstream of Lyn, Spleen tyrosine kinase (Syk, PI3-K and Bruton's tyrosine kinase (Btk and upstream of Rac1, PLCγ2, Ca2+ release, PKC, Hic-5, NOX1 and αIIbβ3 activation.Overall, these data suggest a novel role for FAK in GPVI-dependent ROS formation and platelet activation and elucidate a proximal signaling role for FAK within the GPVI pathway.

  1. Rational redesign of neutral endopeptidase binding to merlin and moesin proteins

    Science.gov (United States)

    Niv, Masha Y; Iida, Katsuyuki; Zheng, Rong; Horiguchi, Akio; Shen, Ruoqian; Nanus, David M

    2009-01-01

    Neutral endopeptidase (NEP) is a 90- to 110-kDa cell-surface peptidase that is normally expressed by numerous tissues but whose expression is lost or reduced in a variety of malignancies. The anti-tumorigenic function of NEP is mediated not only by its catalytic activity but also through direct protein–protein interactions of its cytosolic region with several binding partners, including Lyn kinase, PTEN, and ezrin/radixin/moesin (ERM) proteins. We have previously shown that mutation of the K19K20K21 basic cluster in NEPs' cytosolic region to residues QNI disrupts binding to the ERM proteins. Here we show that the ERM-related protein merlin (NF2) does not bind NEP or its cytosolic region. Using experimental data, threading, and sequence analysis, we predicted the involvement of moesin residues E159Q160 in binding to the NEP cytosolic domain. Mutation of these residues to NL (to mimic the corresponding N159L160 residues in the nonbinder merlin) disrupted moesin binding to NEP. Mutation of residues N159L160Y161K162M163 in merlin to the corresponding moesin residues resulted in NEP binding to merlin. This engineered NEP peptide–merlin interaction was diminished by the QNI mutation in NEP, supporting the role of the NEP basic cluster in binding. We thus identified the region of interaction between NEP and moesin, and engineered merlin into a NEP-binding protein. These data form the basis for further exploration of the details of NEP-ERM binding and function. PMID:19388049

  2. Pulsations and period variations of the δ Scuti star AN Lyncis in a possible three-body system

    Science.gov (United States)

    Li, Gang; Fu, Jianning; Su, Jie; Fox-Machado, Lester; Michel, Raul; Guo, Zhen; Liu, Jinzhong; Feng, Guojie

    2018-01-01

    Observations for the δ Scuti star AN Lyn have been made between 2008 and 2016 with the 85-cm telescope at Xinglong station of National Astronomical Observatories of China, the 84-cm telescope at SPM Observatory of Mexico and the Nanshan One metre Wide field Telescope of Xinjiang Observatory of China. Data in V in 50 nights and in R in 34 nights are obtained in total. The bi-site observations from both Xinglong Station and SPM Observatory in 2014 are analysed with Fourier Decomposition to detect pulsation frequencies. Two independent frequencies are resolved, including one non-radial mode. A number of stellar model tracks are constructed with the MESA code and the fit of frequencies leads to the best-fitting model with the stellar mass of M = 1.70 ± 0.05 M⊙, the metallicity abundance of Z = 0.020 ± 0.001, the age of 1.33 ± 0.01 billion years and the period change rate 1/P · dP/dt = 1.06 × 10-9 yr-1, locating the star at the evolutionary stage close to the terminal age main sequence. The O-C diagram provides the period change rate of (1/P)(dP/dt) = 4.5(8) × 10-7 yr-1. However, the period change rate calculated from the models is smaller in two orders than the one derived from the O-C diagram. Together with the sinusoidal function signature, the period variations are regarded to be dominated by the light-travel time effect of the orbital motion of a three-body system with two low-luminosity components, rather than the stellar evolutionary effect.

  3. Mejoramiento de la calidad del agua de riego por filtración en múltiples etapas (FiME

    Directory of Open Access Journals (Sweden)

    Sánchez Luis Darío

    2009-12-01

    Full Text Available

    El presente experimento, conducido a escala piloto, evaluó algunas técnicas de filtración en múltiples etapas (FiME para mejorar la calidad de agua en sistemas de riego con el fin de disminuir el riesgo de obturación en los emisores de riego localizado de alta frecuencia (RLAF. Cuatro configuraciones FiME fueron estudiadas en términos de su efecto sobre algunos parámetros fisicoquímicos y microbiológicos del agua que inciden en la obturación de los emisores de riego. El efluente de cada una de dichas tecnologías alimentó cuatro tipos de sistemas RLAF. De acuerdo con los resultados, el filtro lento de arena mostró el mejor desempeño, mientras que el filtro de anillos tuvo el comportamiento más deficiente, presentando parámetros de calidad de agua con riesgo medio de obturación. Habiendo llegado al punto de uniformidad de irrigación mínima admisible después de 4,7 meses de operación, los goteros lyn y autocompensado alcanzaron los mejores tiempos de riego. Se propone una matriz preliminar de selección de tecnología, que define el esquema FiME-RLAF en función del tiempo de operación de riego y la calidad del agua cruda. Se identificó la necesidad de profundizar en la medición del tamaño de partículas como posible causa de obturación de los emisores.

  4. Lenalidomide induces lipid raft assembly to enhance erythropoietin receptor signaling in myelodysplastic syndrome progenitors.

    Science.gov (United States)

    McGraw, Kathy L; Basiorka, Ashley A; Johnson, Joseph O; Clark, Justine; Caceres, Gisela; Padron, Eric; Heaton, Ruth; Ozawa, Yukiyasu; Wei, Sheng; Sokol, Lubomir; List, Alan F

    2014-01-01

    Anemia remains the principal management challenge for patients with lower risk Myelodysplastic Syndromes (MDS). Despite appropriate cytokine production and cellular receptor display, erythropoietin receptor (EpoR) signaling is impaired. We reported that EpoR signaling is dependent upon receptor localization within lipid raft microdomains, and that disruption of raft integrity abolishes signaling capacity. Here, we show that MDS erythroid progenitors display markedly diminished raft assembly and smaller raft aggregates compared to normal controls (p = 0.005, raft number; p = 0.023, raft size). Because lenalidomide triggers raft coalescence in T-lymphocytes promoting immune synapse formation, we assessed effects of lenalidomide on raft assembly in MDS erythroid precursors and UT7 cells. Lenalidomide treatment rapidly induced lipid raft formation accompanied by EpoR recruitment into raft fractions together with STAT5, JAK2, and Lyn kinase. The JAK2 phosphatase, CD45, a key negative regulator of EpoR signaling, was displaced from raft fractions. Lenalidomide treatment prior to Epo stimulation enhanced both JAK2 and STAT5 phosphorylation in UT7 and primary MDS erythroid progenitors, accompanied by increased STAT5 DNA binding in UT7 cells, and increased erythroid colony forming capacity in both UT7 and primary cells. Raft induction was associated with F-actin polymerization, which was blocked by Rho kinase inhibition. These data indicate that deficient raft integrity impairs EpoR signaling, and provides a novel strategy to enhance EpoR signal fidelity in non-del(5q) MDS.

  5. 4-Chlorotetrazolo[1,5-a]quinoxaline inhibits activation of Syk kinase to suppress mast cells in vitro and mast cell-mediated passive cutaneous anaphylaxis in mice

    Energy Technology Data Exchange (ETDEWEB)

    Park, Kui Lea [Center for Drug Development Assistance, National Institute of Food Drug Safety Evaluation (NIFDS), KFDA, Cheongwon-gun (Korea, Republic of); Ko, Na Young; Lee, Jun Ho; Kim, Do Kyun; Kim, Hyuk Soon; Kim, A-Ram; Her, Erk; Kim, Bokyung [Department of Immunology and physiology, College of Medicine, Konkuk University, Chungju (Korea, Republic of); Kim, Hyung Sik [College of Pharmacy, Pusan National University, Busan (Korea, Republic of); Moon, Eun-Yi [Department of Bioscience and Biotechnology, College of Biological Science, Sejong University, Seoul (Korea, Republic of); Kim, Young Mi [College of Pharmacy, Duksung Women' s University, Seoul (Korea, Republic of); Kim, Hang-Rae, E-mail: hangrae2@snu.ac.kr [Department of Anatomy, Seoul National University College of Medicine, Seoul (Korea, Republic of); Choi, Wahn Soo, E-mail: wahnchoi@kku.ac.kr [Department of Immunology and physiology, College of Medicine, Konkuk University, Chungju (Korea, Republic of)

    2011-12-15

    4-Chlorotetrazolo[1,5-a]quinoxaline is a quinoxaline derivative. We aimed to study the effects of 4-chlorotetrazolo[1,5-a]quinoxaline on activation of mast cells in vitro and in mice. 4-Chlorotetrazolo[1,5-a]quinoxaline reversibly inhibited degranulation of mast cells in a dose-dependent manner, and also suppressed the expression and secretion of TNF-{alpha} and IL-4 in mast cells. Mechanistically, 4-chlorotetrazolo[1,5-a]quinoxaline inhibited activating phosphorylation of Syk and LAT, which are crucial for early Fc{epsilon}RI-mediated signaling events, as well as Akt and MAP kinases, which play essential roles in the production of various pro-inflammatory cytokines in mast cells. Notably, although 4-chlorotetrazolo[1,5-a]quinoxaline inhibited the activation of Fyn and Syk, minimal inhibition was observed in mast cells in the case of Lyn. Furthermore, consistent with its in vitro activity, 4-chlorotetrazolo[1,5-a]quinoxaline significantly suppressed mast cell-mediated passive cutaneous anaphylaxis in mice. In summary, the results from this study demonstrate that 4-chlorotetrazolo[1,5-a]quinoxaline shows an inhibitory effect on mast cells in vitro and in vivo, and that this is mediated by inhibiting the activation of Syk in mast cells. Therefore, 4-chlorotetrazolo[1,5-a]quinoxaline could be useful in the treatment of mast cell-mediated allergic diseases. -- Highlights: Black-Right-Pointing-Pointer 4-chlorotetrazolo[1,5-a]quinoxaline is a quinoxaline derivative. Black-Right-Pointing-Pointer The effect of 4-chlorotetrazolo[1,5-a]quinoxaline on mast cells was investigated. Black-Right-Pointing-Pointer 4-chlorotetrazolo[1,5-a]quinoxaline reversibly inhibited Syk activation. Black-Right-Pointing-Pointer 4-chlorotetrazolo[1,5-a]quinoxaline could be useful for IgE-mediated allergy.

  6. Type I collagen synergistically enhances PDGF-induced smooth muscle cell proliferation through pp60src-dependent crosstalk between the α2β1 integrin and PDGFβ receptor

    International Nuclear Information System (INIS)

    Hollenbeck, Scott T.; Itoh, Hiroyuki; Louie, Otway; Faries, Peter L.; Liu Bo; Kent, K. Craig

    2004-01-01

    Smooth muscle cells (SMCs) are exposed to both platelet-derived growth factor (PDGF) and type I collagen (CNI) at the time of arterial injury. In these studies we explore the individual and combined effects of these agonists on human saphenous vein SMC proliferation. PDGF-BB produced a 5.5-fold increase in SMC DNA synthesis whereas CNI stimulated DNA synthesis to a much lesser extent (1.6-fold increase). Alternatively, we observed an 8.3-fold increase in DNA synthesis when SMCs were co-incubated with CNI and PDGF-BB. Furthermore, stimulation of SMCs with PDGF-BB produced a significant increase in ERK-2 activity whereas CNI alone had no effect. Co-incubation of SMCs with PDGF-BB and CNI resulted in ERK-2 activity that was markedly greater than that produced by PDGF-BB alone. In a similar fashion, PDGF-BB induced phosphorylation of the PDGF receptor β (PDGFRβ) and CNI did not, whereas concurrent agonist stimulation produced a synergistic increase in receptor activity. Blocking antibodies to the α2 and β1 subunits eliminated this synergistic interaction, implicating the α2β1 integrin as the mediator of this effect. Immunoprecipitation of the α2β1 integrin in unstimulated SMCs followed by immunoblotting for the PDGFRβ as well as Src family members, pp60 src , Fyn, Lyn, and Yes demonstrated coassociation of α2β1 and the PDGFRβ as well as pp60 src . Incubation of cells with CNI and/or PDGF-BB did not change the degree of association. Finally, inhibition of Src activity with SU6656 eliminated the synergistic effect of CNI on PDGF-induced PDGFRβ phosphorylation suggesting an important role for pp60 src in the observed receptor crosstalk. Together, these data demonstrate that CNI synergistically enhances PDGF-induced SMC proliferation through Src-dependent crosstalk between the α2β1 integrin and the PDGFRβ

  7. SH2-catalytic domain linker heterogeneity influences allosteric coupling across the SFK family.

    Science.gov (United States)

    Register, A C; Leonard, Stephen E; Maly, Dustin J

    2014-11-11

    Src-family kinases (SFKs) make up a family of nine homologous multidomain tyrosine kinases whose misregulation is responsible for human disease (cancer, diabetes, inflammation, etc.). Despite overall sequence homology and identical domain architecture, differences in SH3 and SH2 regulatory domain accessibility and ability to allosterically autoinhibit the ATP-binding site have been observed for the prototypical SFKs Src and Hck. Biochemical and structural studies indicate that the SH2-catalytic domain (SH2-CD) linker, the intramolecular binding epitope for SFK SH3 domains, is responsible for allosterically coupling SH3 domain engagement to autoinhibition of the ATP-binding site through the conformation of the αC helix. As a relatively unconserved region between SFK family members, SH2-CD linker sequence variability across the SFK family is likely a source of nonredundant cellular functions between individual SFKs via its effect on the availability of SH3 and SH2 domains for intermolecular interactions and post-translational modification. Using a combination of SFKs engineered with enhanced or weakened regulatory domain intramolecular interactions and conformation-selective inhibitors that report αC helix conformation, this study explores how SH2-CD sequence heterogeneity affects allosteric coupling across the SFK family by examining Lyn, Fyn1, and Fyn2. Analyses of Fyn1 and Fyn2, isoforms that are identical but for a 50-residue sequence spanning the SH2-CD linker, demonstrate that SH2-CD linker sequence differences can have profound effects on allosteric coupling between otherwise identical kinases. Most notably, a dampened allosteric connection between the SH3 domain and αC helix leads to greater autoinhibitory phosphorylation by Csk, illustrating the complex effects of SH2-CD linker sequence on cellular function.

  8. Selective Targeting of SH2 Domain-Phosphotyrosine Interactions of Src Family Tyrosine Kinases with Monobodies.

    Science.gov (United States)

    Kükenshöner, Tim; Schmit, Nadine Eliane; Bouda, Emilie; Sha, Fern; Pojer, Florence; Koide, Akiko; Seeliger, Markus; Koide, Shohei; Hantschel, Oliver

    2017-05-05

    The binding of Src-homology 2 (SH2) domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the eight Src family kinases (SFKs). The high sequence conservation of the 120 human SH2 domains poses a significant challenge to selectively perturb the interactions of even the SFK SH2 family against the rest of the SH2 domains. We have developed synthetic binding proteins, termed monobodies, for six of the SFK SH2 domains with nanomolar affinity. Most of these monobodies competed with pY ligand binding and showed strong selectivity for either the SrcA (Yes, Src, Fyn, Fgr) or SrcB subgroup (Lck, Lyn, Blk, Hck). Interactome analysis of intracellularly expressed monobodies revealed that they bind SFKs but no other SH2-containing proteins. Three crystal structures of monobody-SH2 complexes unveiled different and only partly overlapping binding modes, which rationalized the observed selectivity and enabled structure-based mutagenesis to modulate inhibition mode and selectivity. In line with the critical roles of SFK SH2 domains in kinase autoinhibition and T-cell receptor signaling, monobodies binding the Src and Hck SH2 domains selectively activated respective recombinant kinases, whereas an Lck SH2-binding monobody inhibited proximal signaling events downstream of the T-cell receptor complex. Our results show that SFK SH2 domains can be targeted with unprecedented potency and selectivity using monobodies. They are excellent tools for dissecting SFK functions in normal development and signaling and to interfere with aberrant SFK signaling networks in cancer cells. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  9. Structural analysis of the Csk homologous kinase CHK

    International Nuclear Information System (INIS)

    Mulhern, T.; Chong, Y.-P.; Cheng, H.-C.

    2003-01-01

    Full text: CHK (Csk homologous kinase) is an intracellular protein tyrosine kinase, which is highly expressed in the haematopoietic system and the brain. The in vivo role of CHK is to specifically phosphorylate and deactivate the Src family of protein tyrosine kinases. The members of the Src family: Src, Blk, Fyn, Fgr, Hck, Lck, Lyn, Yes and Yrk are major players in numerous cell signalling pathways and exquisitely tuned control of Src family activity is fundamental to many processes in normal cells (reviewed in Lowell and Soriano, 1996). For example, the Src family kinase Fyn is highly expressed in the brain and its activity is vital for memory and learning. In the haematopoietic system, the Src family kinase Hck controls cytoskeletal reorganization, cell motility and immunologic activation. While the Csk family enzymes are closely related to the Src proteins (∼37% identity), the x-ray crystal structures of Src (Xu et al., 1997) and Csk (Ogawa et al., 2002) do display several important differences. Unlike Src, the Csk the SH2 and SH3 domains do not bind intramolecular ligands and they adopt a strikingly different disposition to that observed in Src. Another interesting feature is that the linkers between the SH3 and SH2 domains and between the SH2 and kinase domains, are in intimate contact with the N-lobe of kinase and both appear to play important roles in regulation of the kinase activity. However, the structural and functional basis of how this can be altered is still unclear. We describe the results of biochemical analyses of CHK mediated deactivation of Hck, which suggest that in addition to direct tail-phosphorylation, protein-protein interactions are important. We also describe heteronuclear NMR studies of the structure and ligand binding properties of the CHK SH2 and SH3 domains with a particular emphasis on the transmission of regulatory signals from the ligand binding sites to the interdomain linkers

  10. Contributions of F-BAR and SH2 domains of Fes protein tyrosine kinase for coupling to the FcepsilonRI pathway in mast cells.

    Science.gov (United States)

    McPherson, Victor A; Everingham, Stephanie; Karisch, Robert; Smith, Julie A; Udell, Christian M; Zheng, Jimin; Jia, Zongchao; Craig, Andrew W B

    2009-01-01

    This study investigates the roles of Fer-CIP4 homology (FCH)-Bin/amphiphysin/Rvs (F-BAR) and SH2 domains of Fes protein tyrosine kinase in regulating its activation and signaling downstream of the high-affinity immunoglobulin G (IgE) receptor (FcepsilonRI) in mast cells. Homology modeling of the Fes F-BAR domain revealed conservation of some basic residues implicated in phosphoinositide binding (R113/K114). The Fes F-BAR can bind phosphoinositides and induce tubulation of liposomes in vitro. Mutation of R113/K114 to uncharged residues (RK/QQ) caused a significant reduction in phosphoinositide binding in vitro and a more diffuse cytoplasmic localization in transfected COS-7 cells. RBL-2H3 mast cells expressing full-length Fes carrying the RK/QQ mutation show defects in FcepsilonRI-induced Fes tyrosine phosphorylation and degranulation compared to cells expressing wild-type Fes. This correlated with reduced localization to Lyn kinase-containing membrane fractions for the RK/QQ mutant compared to wild-type Fes in mast cells. The Fes SH2 domain also contributes to Fes signaling in mast cells, via interactions with the phosphorylated FcepsilonRI beta chain and the actin regulatory protein HS1. We show that Fes phosphorylates C-terminal tyrosine residues in HS1 implicated in actin stabilization. Thus, coordinated actions of the F-BAR and SH2 domains of Fes allow for coupling to FcepsilonRI signaling and potential regulation the actin reorganization in mast cells.

  11. [Effects of PCI-32765 and Dasatinib on the Acute Lymphoblastic Leukemic Cells and Their Mechanisms].

    Science.gov (United States)

    Deng, Yuan; Tao, Shan-Dong; Zhang, Xin; Ma, Jing-Jing; He, Zheng-Mei; Chen, Yue; Deng, Zhi-Kui; Yu, Liang

    2017-02-01

    To investigate the effects of Btk inhibitor (PCI-32765) and BCR-ABL tyrosine kinase inhibitor (Dasatinib) on proliferation and apoptosis of acute lymphoblastic leukemia (ALL) cell lines (Sup-B15, RS4;11) and the possible mechanism. RS4;11 and Sup-B15 cells were treated with PCI-32765 and Dasatinib, the cell proliferation and apoptosis were detected by CCK-8, the Btk and other apoptotic proteins were detected by Western blot. PCI-32765 could inhibit the proliferation of RS4;11 and Sup-B15 cells in a dose-dependent manner, Sup-B15 cells were more sensitive to PCI-32765 than RS4;11 cells, their IC 50 were 3 µmol/L and 8 µmol/L respectively, the difference between them was statistically significant (PPCI-32765(PPCI-32765 or Dasatinib alone group and the combination group at the different time-point (8, 12, 24, 36, 48 and 72 h), the 2 drugs showed a synergistic effect on cells in a time-dependent manner. After being treated with PCI-32765 and Dasatinib, the RS4;11 and Sup-B15 cells showed that cell shrinkage, increase of cytoplasmic density, nuclear pyknosis, deviation and karyorrhexis, and increase of the apoptotic cells in the combination group, while the promotive effect of low dosage dasatinib on apoptosis of RS4;11 cells was not strong. PCI-32765 and Dasatinib could decrease the expression and activity of BCR-ABL, Btk, Lyn, Src in Sup-B15 and RS4;11 cells. PCI-32765 or Dasatinib can inhibit the proliferation and induce the apoptosis of Sup-B15 and RS4;11 cells, PCI-32765 and Dasatinib displayed the synergistic effects. The possible mechanism may be related with the blocking of B cell receptor(BCR) signal pathway, thereby inhibiting the cell proliferation and promoting the cell apoptosis.

  12. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine

    Science.gov (United States)

    Okazaki, Taku; Maeda, Akito; Nishimura, Hiroyuki; Kurosaki, Tomohiro; Honjo, Tasuku

    2001-01-01

    PD-1 is an immunoreceptor that belongs to the immunoglobulin (Ig) superfamily and contains two tyrosine residues in the cytoplasmic region. Studies on PD-1-deficient mice have shown that PD-1 plays critical roles in establishment and/or maintenance of peripheral tolerance, but the mode of action is totally unknown. To study the molecular mechanism for negative regulation of lymphocytes through the PD-1 receptor, we generated chimeric molecules composed of the IgG Fc receptor type IIB (FcγRIIB) extracellular region and the PD-1 cytoplasmic region and expressed them in a B lymphoma cell line, IIA1.6. Coligation of the cytoplasmic region of PD-1 with the B cell receptor (BCR) in IIA1.6 transformants inhibited BCR-mediated growth retardation, Ca2+ mobilization, and tyrosine phosphorylation of effector molecules, including Igβ, Syk, phospholipase C-γ2 (PLCγ2), and ERK1/2, whereas phosphorylation of Lyn and Dok was not affected. Mutagenesis studies indicated that these inhibitory effects do not require the N-terminal tyrosine in the immunoreceptor tyrosine-based inhibitory motif-like sequence, but do require the other tyrosine residue in the C-terminal tail. This tyrosine was phosphorylated and recruited src homology 2-domain-containing tyrosine phosphatase 2 (SHP-2) on coligation of PD-1 with BCR. These results show that PD-1 can inhibit BCR signaling by recruiting SHP-2 to its phosphotyrosine and dephosphorylating key signal transducers of BCR signaling. PMID:11698646

  13. Microbial products activate monocytic cells through detergent-resistant membrane microdomains.

    Science.gov (United States)

    Epelman, Slava; Berenger, Byron; Stack, Danuta; Neely, Graham G; Ma, Ling Ling; Mody, Christopher H

    2008-12-01

    Patients with cystic fibrosis suffer recurrent pulmonary infections that are characterized by an overactive yet ineffective and destructive inflammatory response that is associated with respiratory infections by Pseudomonas aeruginosa, a pathogen that produces a number of phlogistic molecules. To better understand this process, we used exoenzyme S (ExoS), one of the key P. aeruginosa-secreted exoproducts, which is known to stimulate cells via the Toll-like receptor (TLR) pathway. We found that ExoS induced proinflammatory cytokine production via the NF-kappaB, Erk1/2, and Src kinase pathways. Because Src kinases are concentrated within cholesterol-containing, detergent-resistant membrane microdomains (DRM) (also called lipid rafts) and DRM act as signaling platforms and amplifiers on the surface of cells, we addressed the role of DRM in ExoS signaling. ExoS bound directly to a subset of DRM and induced the phosphorylation of multiple proteins within DRM, including Src kinases. Disruption of DRM by cholesterol extraction prevented NF-kappaB and Erk 1/2 activation and TNF-alpha production in response to ExoS. Activation of monocytic cells by other TLR and Nod-like receptor agonists, such as lipoteichoic acid, lipopolysaccharide, and peptidoglycan, were also dependent on DRM, and disruption prevented TNF-alpha production. Disruption of DRM did not prevent ExoS binding but did release the Src kinase, Lyn, from the DRM fraction into the detergent-soluble fraction, a site in which Src kinases are not active. These studies show that ExoS, a TLR agonist, requires direct binding to DRM for optimal signaling, which suggests that DRM are possible therapeutic targets in cystic fibrosis.

  14. 4-Chlorotetrazolo[1,5-a]quinoxaline inhibits activation of Syk kinase to suppress mast cells in vitro and mast cell-mediated passive cutaneous anaphylaxis in mice

    International Nuclear Information System (INIS)

    Park, Kui Lea; Ko, Na Young; Lee, Jun Ho; Kim, Do Kyun; Kim, Hyuk Soon; Kim, A-Ram; Her, Erk; Kim, Bokyung; Kim, Hyung Sik; Moon, Eun-Yi; Kim, Young Mi; Kim, Hang-Rae; Choi, Wahn Soo

    2011-01-01

    4-Chlorotetrazolo[1,5-a]quinoxaline is a quinoxaline derivative. We aimed to study the effects of 4-chlorotetrazolo[1,5-a]quinoxaline on activation of mast cells in vitro and in mice. 4-Chlorotetrazolo[1,5-a]quinoxaline reversibly inhibited degranulation of mast cells in a dose-dependent manner, and also suppressed the expression and secretion of TNF-α and IL-4 in mast cells. Mechanistically, 4-chlorotetrazolo[1,5-a]quinoxaline inhibited activating phosphorylation of Syk and LAT, which are crucial for early FcεRI-mediated signaling events, as well as Akt and MAP kinases, which play essential roles in the production of various pro-inflammatory cytokines in mast cells. Notably, although 4-chlorotetrazolo[1,5-a]quinoxaline inhibited the activation of Fyn and Syk, minimal inhibition was observed in mast cells in the case of Lyn. Furthermore, consistent with its in vitro activity, 4-chlorotetrazolo[1,5-a]quinoxaline significantly suppressed mast cell-mediated passive cutaneous anaphylaxis in mice. In summary, the results from this study demonstrate that 4-chlorotetrazolo[1,5-a]quinoxaline shows an inhibitory effect on mast cells in vitro and in vivo, and that this is mediated by inhibiting the activation of Syk in mast cells. Therefore, 4-chlorotetrazolo[1,5-a]quinoxaline could be useful in the treatment of mast cell-mediated allergic diseases. -- Highlights: ► 4-chlorotetrazolo[1,5-a]quinoxaline is a quinoxaline derivative. ► The effect of 4-chlorotetrazolo[1,5-a]quinoxaline on mast cells was investigated. ► 4-chlorotetrazolo[1,5-a]quinoxaline reversibly inhibited Syk activation. ► 4-chlorotetrazolo[1,5-a]quinoxaline could be useful for IgE-mediated allergy.

  15. Davallia mariesii Moore Improves FcεRI-Mediated Allergic Responses in the Rat Basophilic Leukemia Mast Cell Line RBL-2H3 and Passive Cutaneous Anaphylaxis in Mice

    Directory of Open Access Journals (Sweden)

    Hyun Ju Do

    2017-01-01

    Full Text Available Davallia mariesii Moore (Drynaria rhizome extract (DRE is widely known for its efficacy in treating inflammation, arteriosclerosis, and bone injuries. This study evaluated whether treatment with DRE inhibited FcɛRI-mediated allergic responses in the RBL-2H3 mast cells and investigated the early- and late-phase mechanisms by which DRE exerts its antiallergic effects. IgE anti-DNP/DNP-HSA-sensitized RBL-2H3 mast cells were tested for cytotoxicity to DRE, followed by the assessment of β-hexosaminidase release. We measured the amounts of inflammatory mediators (e.g., histamine, PGD2, TNF-α, IL-4, and IL-6 and examined the expression of genes involved in arachidonate and FcεRI signaling pathways. In addition, we confirmed the antiallergic effects of DRE on passive cutaneous anaphylaxis (PCA in mice. DRE inhibited RBL-2H3 mast cell degranulation and production of allergic mediators in them. In early allergic responses, DRE reduced expression of FcεRI signaling-related genes (e.g., Syk, Lyn, and Fyn and extracellular signal-regulated kinase phosphorylation in mast cells. In late allergic responses, DRE reduced PGD2 release and COX-2 expression and cPLA2 phosphorylation in FcɛRI-mediated mast cells. Lastly, 250–500 mg/kg DRE significantly attenuated the IgE-induced PCA reaction in mice. These findings provide novel information on the molecular mechanisms underlying the antiallergic effects of DRE in FcɛRI-mediated allergic responses.

  16. Inhibition of Src kinase activity attenuates amyloid associated microgliosis in a murine model of Alzheimer’s disease

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    Dhawan Gunjan

    2012-07-01

    Full Text Available Abstract Background Microglial activation is an important histologic characteristic of the pathology of Alzheimer’s disease (AD. One hypothesis is that amyloid beta (Aβ peptide serves as a specific stimulus for tyrosine kinase-based microglial activation leading to pro-inflammatory changes that contribute to disease. Therefore, inhibiting Aβ stimulation of microglia may prove to be an important therapeutic strategy for AD. Methods Primary murine microglia cultures and the murine microglia cell line, BV2, were used for stimulation with fibrillar Aβ1-42. The non-receptor tyrosine kinase inhibitor, dasatinib, was used to treat the cells to determine whether Src family kinase activity was required for the Aβ stimulated signaling response and subsequent increase in TNFα secretion using Western blot analysis and enzyme-linked immunosorbent assay (ELISA, respectively. A histologic longitudinal analysis was performed using an AD transgenic mouse model, APP/PS1, to determine an age at which microglial protein tyrosine kinase levels increased in order to administer dasatinib via mini osmotic pump diffusion. Effects of dasatinib administration on microglial and astroglial activation, protein phosphotyrosine levels, active Src kinase levels, Aβ plaque deposition, and spatial working memory were assessed via immunohistochemistry, Western blot, and T maze analysis. Results Aβ fibrils stimulated primary murine microglia via a tyrosine kinase pathway involving Src kinase that was attenuated by dasatinib. Dasatinib administration to APP/PS1 mice decreased protein phosphotyrosine, active Src, reactive microglia, and TNFα levels in the hippocampus and temporal cortex. The drug had no effect on GFAP levels, Aβ plaque load, or the related tyrosine kinase, Lyn. These anti-inflammatory changes correlated with improved performance on the T maze test in dasatinib infused animals compared to control animals. Conclusions These data suggest that amyloid

  17. Deciphering signature of selection affecting beef quality traits in Angus cattle.

    Science.gov (United States)

    Taye, Mengistie; Yoon, Joon; Dessie, Tadelle; Cho, Seoae; Oh, Sung Jong; Lee, Hak-Kyo; Kim, Heebal

    2018-01-01

    Artificial selection towards a desired phenotype/trait has modified the genomes of livestock dramatically that generated breeds that greatly differ in morphology, production and environmental adaptation traits. Angus cattle are among the famous cattle breeds developed for superior beef quality. This paper aimed at exploring genomic regions under selection in Angus cattle that are associated with meat quality traits and other associated phenotypes. The whole genome of 10 Angus cattle was compared with 11 Hanwoo (A-H) and 9 Jersey (A-J) cattle breeds using a cross-population composite likelihood ratio (XP-CLR) statistical method. The top 1% of the empirical distribution was taken as significant and annotated using UMD3.1. As a result, 255 and 210 genes were revealed under selection from A-H and A-J comparisons, respectively. The WebGestalt gene ontology analysis resulted in sixteen (A-H) and five (A-J) significantly enriched KEGG pathways. Several pathways associated with meat quality traits (insulin signaling, type II diabetes mellitus pathway, focal adhesion pathway, and ECM-receptor interaction), and feeding efficiency (olfactory transduction, tight junction, and metabolic pathways) were enriched. Genes affecting beef quality traits (e.g., FABP3, FTO, DGAT2, ACS, ACAA2, CPE, TNNI1), stature and body size (e.g., PLAG1, LYN, CHCHD7, RPS20), fertility and dystocia (e.g., ESR1, RPS20, PPP2R1A, GHRL, PLAG1), feeding efficiency (e.g., PIK3CD, DNAJC28, DNAJC3, GHRL, PLAG1), coat color (e.g., MC1-R) and genetic disorders (e.g., ITGB6, PLAG1) were found to be under positive selection in Angus cattle. The study identified genes and pathways that are related to meat quality traits and other phenotypes of Angus cattle. The findings in this study, after validation using additional or independent dataset, will provide useful information for the study of Angus cattle in particular and beef cattle in general.

  18. A randomized controlled trial of telephone-mentoring with home-based walking preceding rehabilitation in COPD

    Directory of Open Access Journals (Sweden)

    Cameron-Tucker HL

    2016-08-01

    Full Text Available Helen Laura Cameron-Tucker,1 Richard Wood-Baker,1 Lyn Joseph,1 Julia A Walters,1 Natalie Schüz,2 E Haydn Walters1 1Centre of Research Excellence for Chronic Respiratory Disease and Lung Aging, School of Medicine, 2School of Health Sciences, Faculty of Health, University of Tasmania, Hobart, Tasmania, Australia Purpose: With the limited reach of pulmonary rehabilitation (PR and low levels of daily physical activity in chronic obstructive pulmonary disease (COPD, a need exists to increase daily exercise. This study evaluated telephone health-mentoring targeting home-based walking (tele-rehab compared to usual waiting time (usual care followed by group PR. Patients and methods: People with COPD were randomized to tele-rehab (intervention or usual care (controls. Tele-rehab delivered by trained nurse health-mentors supported participants’ home-based walking over 8–12 weeks. PR, delivered to both groups simultaneously, included 8 weeks of once-weekly education and self-management skills, with separate supervised exercise. Data were collected at three time-points: baseline (TP1, before (TP2, and after (TP3 PR. The primary outcome was change in physical capacity measured by 6-minute walk distance (6MWD with two tests performed at each time-point. Secondary outcomes included changes in self-reported home-based walking, health-related quality of life, and health behaviors. Results: Of 65 recruits, 25 withdrew before completing PR. Forty attended a median of 6 (4 education sessions. Seventeen attended supervised exercise (5±2 sessions. Between TP1 and TP2, there was a statistically significant increase in the median 6MWD of 12 (39.1 m in controls, but no change in the tele-rehab group. There were no significant changes in 6MWD between other time-points or groups, or significant change in any secondary outcomes. Participants attending supervised exercise showed a nonsignificant improvement in 6MWD, 12.3 (71 m, while others showed no change, 0 (33 m

  19. South Africa's New African Language Dictionaries and their Use for the African Speech Communities

    Directory of Open Access Journals (Sweden)

    Juliane Klein

    2011-10-01

    Full Text Available

    Abstract: During the last 15 years, the lexicographic scene in South Africa changed drastically as many new dictionaries for the African languages were compiled. The different dictionary types and publication modes discussed in this article are: general dictionaries, restricted dictionaries, printed dictionaries, electronic dictionaries, online and cell phone dictionaries. Although there are different dictionary types, they all have three major uses for the speech communities. Dictionaries are useful tools for language documentation and standardization, as they try to cover and document the general vocabulary (general dictionaries or the spe-cialized vocabulary (technical dictionaries. They empower the language users because they help to improve communication by providing users with the necessary vocabulary they need. In addition, dictionaries have a high symbolic value for a language. Having dictionaries, and especially technical, online or cell phone dic-tionaries, is the visible proof that a language is standardized and modern, and can be used in all domains of life.

    Keywords: LEXICOGRAPHY, GENERAL DICTIONARIES, RESTRICTED DICTIONARIES, ONLINE DICTIONARIES, CELL PHONE DICTIONARIES, LANGUAGE DOCUMENTATION, LANGUAGE STANDARDIZATION, EMPOWERMENT, COMMUNICATION, PSYCHOLOGI-CAL FACTOR, SOCIOLINGUISTICS, LANGUAGE PLANNING

    Opsomming: Suid-Afrika se nuwe Afrikataalwoordeboeke en hul gebruik vir die Afrikataalgemeenskappe. Gedurende die afgelope 15 jaar het die leksikografiese toneel in Suid-Afrika ingrypend verander deurdat baie nuwe woordeboeke vir die Afrikatale saamgestel is. Die verskillende woordeboeksoorte en publikasievorme wat in hierdie artikel bespreek word, is: algemene woordeboeke, beperkte woordeboeke, gedrukte woordeboeke, aan-lyn- en selfoonwoordeboeke. Alhoewel daar verskillende woordeboeksoorte is, het hulle almal drie hoofgebruike vir die taalgemeenskappe. Woordeboeke is nuttige werktuie vir taaldokumentasie en

  20. New approaches to the modulation of inflammatory processes in airway disease models: ATS 2001, May 18-23, San Francisco

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    Hele David J

    2001-07-01

    Full Text Available Abstract The 97th American Thoracic Society meeting proved to be an excellent meeting, providing a wealth of new information on inflammatory diseases of the airways. Once again there appeared to be an increased emphasis on chronic obstructive pulmonary disease (COPD with most of the major drug companies concentrating a large part of their efforts in this field. An assessment of the new British Thoracic Society guidelines, which are designed to promote better management of COPD, was also presented at the meeting. Potential new treatments for inflammatory diseases of the airways including COPD were described, ranging from phase III trial data with GlaxoSmithKline's PDE4 inhibitor, Cilomilast (Ariflo® to the development of AstraZeneca's novel dual dopamine D2-receptor/β2-adrenoreceptor agonist, Viozan™. Of particular interest was Byk Gulden's Ciclesonide, a new corticosteroid with equivalent efficacy to the market leaders but with an improved safety profile. The same company also presented data on their PDE4 inhibitor, Roflumilast, which is now in phase II/III. Bayer presented data on their PDE4 inhibitor, BAY 19-8004, in a smoking animal model and claimed greater anti-inflammatory efficacy than with a steroid. Asta Medica (now known as Elbion also described a new potent PDE4 inhibitor, AWD 12-281, with anti-inflammatory activity. In the bronchodilator field, an analysis of data from a one-year trial with Boehringer Ingelheim's Tiotropium revealed a possible improvement in lung function in COPD patients; this needs to be confirmed in a specifically designed study. Inhibitors of p38 (c-Jun NH2-terminal kinase and syk kinase were also discussed as anti-inflammatory agents with potential in the treatment of COPD and asthma. GlaxoSmithKline's p38 kinase inhibitor, SB 239063, appeared to be the most advanced of these with clinical data expected in two to three years. Lyn kinase was also discussed as a novel target for inflammatory airway diseases.

  1. Activation/Inhibition of mast cells by supra-optimal antigen concentrations.

    Science.gov (United States)

    Huber, Michael

    2013-01-22

    Mast cells (MCs) are tissue resident cells of hemopoietic origin and are critically involved in allergic diseases. MCs bind IgE by means of their high-affinity receptor for IgE (FcεRI). The FcεRI belongs to a family of multi-chain immune recognition receptors and is activated by cross-linking in response to multivalent antigens (Ags)/allergens. Activation of the FcεRI results in immediate release of preformed granular substances (e.g. histamine, heparin, and proteases), generation of arachidonic acid metabolites, and production of pro-inflammatory cytokines. The FcεRI shows a remarkable, bell-shaped dose-response behavior with weak induction of effector responses at both low and high (so-called supra-optimal) Ag concentrations. This is significantly different from many other receptors, which reach a plateau phase in response to high ligand concentrations. To explain this unusual dose-response behavior of the FcεRI, scientists in the past have drawn parallels to so-called precipitin curves resulting from titration of Ag against a fixed concentration of antibody (Ab) in solution (a.k.a. Heidelberger curves). Thus, for high, supra-optimal Ag concentrations one could assume that every IgE-bound FcεRI formed a monovalent complex with "its own Ag", thus resulting in marginal induction of effector functions due to absence of receptor cross-linking. However, this was never proven to be the case. More recently, careful studies of FcεRI activation and signaling events in MCs in response to supra-optimal Ag concentrations have suggested a molecular explanation for the descending part of this bell-shaped curve. It is obvious now that extensive FcεRI/IgE/Ag clusters are formed and inhibitory molecules and signalosomes are engaged in response to supra-optimal cross-linking (amongst them the Src family kinase Lyn and the inositol-5'-phosphatase SHIP1) and they actively down-regulate MC effector responses. Thus, the analysis of MC signaling triggered by supra

  2. Instabilities in Interacting Binary Stars

    Science.gov (United States)

    Andronov, I. L.; Andrych, K. D.; Antoniuk, K. A.; Baklanov, A. V.; Beringer, P.; Breus, V. V.; Burwitz, V.; Chinarova, L. L.; Chochol, D.; Cook, L. M.; Cook, M.; Dubovský, P.; Godlowski, W.; Hegedüs, T.; Hoňková, K.; Hric, L.; Jeon, Y.-B.; Juryšek, J.; Kim, C.-H.; Kim, Y.; Kim, Y.-H.; Kolesnikov, S. V.; Kudashkina, L. S.; Kusakin, A. V.; Marsakova, V. I.; Mason, P. A.; Mašek, M.; Mishevskiy, N.; Nelson, R. H.; Oksanen, A.; Parimucha, S.; Park, J.-W.; Petrík, K.; Quiñones, C.; Reinsch, K.; Robertson, J. W.; Sergey, I. M.; Szpanko, M.; Tkachenko, M. G.; Tkachuk, L. G.; Traulsen, I.; Tremko, J.; Tsehmeystrenko, V. S.; Yoon, J.-N.; Zola, S.; Shakhovskoy, N. M.

    2017-07-01

    The types of instability in the interacting binary stars are briefly reviewed. The project “Inter-Longitude Astronomy” is a series of smaller projects on concrete stars or groups of stars. It has no special funds, and is supported from resources and grants of participating organizations, when informal working groups are created. This “ILA” project is in some kind similar and complementary to other projects like WET, CBA, UkrVO, VSOLJ, BRNO, MEDUZA, AstroStatistics, where many of us collaborate. Totally we studied 1900+ variable stars of different types, including newly discovered variables. The characteristic timescale is from seconds to decades and (extrapolating) even more. The monitoring of the first star of our sample AM Her was initiated by Prof. V.P. Tsesevich (1907-1983). Since more than 358 ADS papers were published. In this short review, we present some highlights of our photometric and photo-polarimetric monitoring and mathematical modeling of interacting binary stars of different types: classical (AM Her, QQ Vul, V808 Aur = CSS 081231:071126+440405, FL Cet), asynchronous (BY Cam, V1432 Aql), intermediate (V405 Aql, BG CMi, MU Cam, V1343 Her, FO Aqr, AO Psc, RXJ 2123, 2133, 0636, 0704) polars and magnetic dwarf novae (DO Dra) with 25 timescales corresponding to different physical mechanisms and their combinations (part “Polar”); negative and positive superhumpers in nova-like (TT Ari, MV Lyr, V603 Aql, V795 Her) and many dwarf novae stars (“Superhumper”); eclipsing “non-magnetic” cataclysmic variables(BH Lyn, DW UMa, EM Cyg; PX And); symbiotic systems (“Symbiosis”); super-soft sources (SSS, QR And); spotted (and not spotted) eclipsing variables with (and without) evidence for a current mass transfer (“Eclipser”) with a special emphasis on systems with a direct impact of the stream into the gainer star's atmosphere, which we propose to call “Impactor” (short from “Extreme Direct Impactor”), or V361 Lyr-type stars. Other

  3. New Gene Markers for Metabolic Processes and Homeostasis in Porcine Buccal Pouch Mucosa during Cells Long Term-Cultivation—A Primary Culture Approach

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    Marta Dyszkiewicz-Konwińska

    2018-03-01

    Full Text Available The oral mucosal tissue is a compound structure composed of morphologically and physiologically different cell types. The morphological modification involves genetically determined lifespan, which may be recognized as the balance between cell survival and apoptosis. Although the biochemical processes and pathways in oral mucosa, with special regards to drug transport, delivery, and metabolism, are well known, the cellular physiological homeostasis in this tissue requires further investigation. The porcine buccal pouch mucosal cells (BPMCs collected from 20 pubertal crossbred Landrace gilts, were used in this study. Immediately after recovery, the oral mucosa was separated micro-surgically, and treated enzymatically. The dispersed cells were transferred into primary in vitro culture systems for a long-term cultivation of 30 days. After each step of in vitro culture (IVC, the cells were collected for isolation of total RNA at 24 h, 7, 15, and 30 days of IVC. While the expression was analyzed for days 7, 15, and 30, the 24th hour was used as a reference for outcome calibration. The gene expression profile was determined using Affymetrix microarray assays and necessary procedures. In results, we observed significant up-regulation of SCARB1, PTGS2, DUSP5, ITGB3, PLK2, CCL2, TGFB1, CCL8, RFC4, LYN, ETS1, REL, LIF, SPP1, and FGER1G genes, belonging to two ontological groups, namely “positive regulation of metabolic process”, and “regulation of homeostatic process” at 7 day of IVC as compared to down-regulation at days 15 and 30. These findings suggest that the metabolic processes and homeostatic regulations are much more intense in porcine mucosal cells at day 7 of IVC. Moreover, the increased expression of marker genes, for both of these ontological groups, may suggest the existence of not only “morphological lifespan” during tissue keratinization, but also “physiological checkpoint” dedicated to metabolic processes in oral mucosa

  4. Purification, characterization and allergenicity assessment of 26kDa protein, a major allergen from Cicer arietinum.

    Science.gov (United States)

    Verma, Alok Kumar; Sharma, Akanksha; Kumar, Sandeep; Gupta, Rinkesh Kumar; Kumar, Dinesh; Gupta, Kriti; Giridhar, B H; Das, Mukul; Dwivedi, Premendra D

    2016-06-01

    Chickpea (CP), a legume of the family Fabaceae, is an important nutrient-rich food providing protein, essential amino acids, vitamins, dietary fibre, and minerals. Unfortunately, several IgE-binding proteins in CP have been detected that are responsible for allergic manifestations in sensitized population. Therefore, the prevalence of CP induced allergy prompted us towards purification, characterization and allergenicity assessment of a major ∼26kDa protein from chickpea crude protein extract (CP-CPE). Purification of CP 26kDa protein was done using a combination of fractionation and anion exchange chromatography. This protein was further characterized as "Chain A, crystal structure of a plant albumin" from Cicer arietinum with Mol wt 25.8kDa by Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Further, allergenic potential of purified 25.8kDa protein was assessed using in vivo and in vitro model. Purified protein showed IgE-binding capacity with sensitized BALB/c mice and CP allergic patient's sera. Enhanced levels of specific and total IgE, MCP-1, MCPT-1, myeloperoxidase, histamine, prostaglandin D2, and cysteinyl leukotriene were found in sera of mice treated with CP ∼26kDa protein. Further, expressions of Th2 cytokines (i.e. IL-4, IL-5, IL-13), transcription factors (i.e. GATA-3, STAT-6, SOCS-3) and mast cell signaling proteins (Lyn, cFgr, Syk, PLC-γ2, PI-3K, PKC) were also found increased at mRNA and protein levels in the intestines of mice treated with CP ∼26kDa protein. In addition, enhanced release of β-hexosaminidase, histamine, cysteinyl leukotriene and prostaglandin D2 were observed in RBL2H3 cell line when treated (125μg) with CP 26kDa protein. Conclusively, in vivo and in vitro studies revealed the allergenic potential of purified CP 26kDa protein. Being a potential allergen, plant albumin may play a pivotal role in CP induced allergenicity. Current study will be helpful for better development of therapeutic approaches to

  5. Inhibitory effect of fermented Arctium lappa fruit extract on the IgE-mediated allergic response in RBL‑2H3 cells.

    Science.gov (United States)

    Yoo, Jae-Myung; Yang, Ju Hye; Yang, Hye Jin; Cho, Won-Kyung; Ma, Jin Yeul

    2016-02-01

    Arctium lappa fruit has been used in traditional medicine, and it is known to exert beneficial effects, such as antioxidant, anti-inflammatory and anticancer effects. However, the effects of the Arctium lappa fruit on the allergic response remain unknown. In this study, we evaluated the anti-allergic effects of Arctium lappa fruit extract (AFE) and its fermented form (F-AFE) using immunoglobulin E (IgE)-activated RBL‑2H3 cells. To investigate the anti-allergic effects of AFE or F-AFE, we examined the release of β-hexosaminidase, a key biomarker of degranulation during an allergic reaction, and the production of pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) in the cells treated with or without the above-mentioned extracts. AFE weakly inhibited the release of β-hexosaminidase, whereas F-AFE significantly suppressed the release of β-hexosaminidase in a dose-dependent manner. Consistently, F-AFE suppressed the production of TNF-α and PGE2 in a dose-dependent manner. F-AFE exerted an inhibitory effect on the production of β-hexosaminidase, TNF-α and PGE2 with an IC50 value of 30.73, 46.96 and 36.27 µg/ml, respectively. Furthermore, F-AFE inhibited the phosphorylation of Lyn, Fyn and Syk, which are involved in the FcεRI signaling pathway, that of phosphoinositide phospholipase C (PLC)γ1/2 and protein kinase C (PKC)δ, which are associated with the degranulation process, as well as that of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase 1/2 (JNK), p38 and Akt, which are associated with cytokine expression. In the late phase, F-AFE partially suppressed the phosphorylation of cytosolic phospholipase A2 (cPLA2), but not the expression of cyclooxygenase (COX)-2. To compare and identify the major components of the two extracts, we used high-performance liquid chromatography. The levels of arctigenin, one of the major compounds, were elevated 6-fold in F-AFE compared with AFE, whereas the

  6. Transcriptomic variation of locally-infected skin of Epinephelus coioides reveals the mucosal immune mechanism against Cryptocaryon irritans.

    Science.gov (United States)

    Hu, Yazhou; Li, Anxing; Xu, Yang; Jiang, Biao; Lu, Geling; Luo, Xiaochun

    2017-07-01

    , cathepsin and complement components were significantly up-regulated (fold-change ranged from 3.3 to 12,944) in infected skin compared with control skin. The up-regulation of chemokines and chemokine receptors and activation of the leukocyte transendothelial migration pathway suggested that leucocytes intensively migrated to the local infected sites to mount a local immune defense. Toll-like receptors (TLRs) 1, 2, 5 and 5S were most significantly up-regulated in the infected skin, suggesting that these TLRs may be involved in parasite pathogen-associated molecular pattern (PAMPs) recognition. Up-regulation of the dendritic cell markers CD209 and CD83 and other antigen presentation pathway molecules provided evidence for skin local antigen presentation. Up-regulation of the T cell markers CD4 and CD48, B cell markers CD22 and CD81 and B cell receptor signaling kinase Lyn, showed the presence and population expansion of T/B cells at locally-infected sites, which suggested possible activation of a local specific immune response in the skin. Our results will facilitate in-depth understanding of local immune defense mechanisms in fish skin against ectoparasite infection. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Low rate of human papillomavirus vaccination among schoolgirls in Lebanon: barriers to vaccination with a focus on mothers’ knowledge about available vaccines

    Directory of Open Access Journals (Sweden)

    Abou El-Ola MJ

    2018-03-01

    Full Text Available Maria J Abou El-Ola,1 Mariam A Rajab,2 Dania I Abdallah,3 Ismail A Fawaz,4 Lyn S Awad,5 Hani M Tamim,6 Ahmad O Ibrahim,7 Anas M Mugharbil,7 Rima A Moghnieh8 1Department of Obstetrics and Gynaecology, Makassed General Hospital, Beirut, Lebanon; 2Department of Pediatrics, Makassed General Hospital, Beirut, Lebanon; 3Department of Pharmacy, Makassed General Hospital, Beirut, Lebanon; 4Department of Internal Medicine, Iklim Health Foundation Hospital, Mazboud, Mount Lebanon, Chouf, Lebanon; 5Department of Pharmacy, Makassed General Hospital, Beirut, Lebanon; 6Department of Internal Medicine, American University of Beirut, Beirut, Lebanon; 7Division of Hematology/Oncology, Department of Internal Medicine, Makassed General Hospital, Beirut, Lebanon; 8Division of Infectious Diseases, Department of Internal Medicine, Makassed General Hospital, Beirut, Lebanon Background: Human papillomavirus (HPV infection is an established predisposing factor of cervical cancer. In this study, we assessed the awareness about genital warts, cervical cancer, and HPV vaccine among mothers having girls who are at the age of primary HPV vaccination attending a group of schools in Lebanon. We also assessed the rate of HPV vaccination among these girls and the barriers to vaccination in this community. Subjects and methods: This is a cross-sectional, school-based survey. A 23-item, self-administered, anonymous, pretested, structured questionnaire with closed-ended questions was used to obtain data. The questionnaire was sent to the mothers through their student girls, and they were asked to return it within a week. Data were analyzed using the Statistical Package for Social Sciences version 21.0. Bivariate analysis was performed using the chi-square test to compare categorical variables, whereas continuous variables were compared using the Student’s t-test. Fisher’s exact test was used when chi-square test could not be employed. Results: The response rate in our survey

  8. Mobile Breast Cancer e-Support Program for Chinese Women With Breast Cancer Undergoing Chemotherapy (Part 1): Qualitative Study of Women's Perceptions.

    Science.gov (United States)

    Zhu, Jiemin; Ebert, Lyn; Guo, Dongmei; Yang, Sumei; Han, Qiuying; Chan, Sally Wai-Chi

    2018-04-11

    . Physical or psychological health status, stigma related with breast cancer, and app instability were mentioned as the challenges to engagement. Suggestions for improvement included adding message reminders to prompt instant communication and search engine to locate information quickly, supplementing more interesting and practical knowledge, updating the information more often, and quickening the responses to women's questions. The participants recommended the Breast Cancer e-Support program to be incorporated as routine care to support women during chemotherapy. This study demonstrates the potential of the Breast Cancer e-Support program to support women during chemotherapy. Future app-based programs should apply a family-centered approach and provide more support on stigma associated with the disease to encourage engagement with the app. Suggestions of improvement regarding the design, content, and operation of the app-based intervention should be addressed in future studies. It is promising to incorporate the Breast Cancer e-Support program into routine care to generalize the benefits. Australian New Zealand Clinical Trials Registry ACTRN12616000639426; http://www.ANZCTR.org.au/ ACTRN12616000639426.aspx (Archived by WebCite at http://www.webcitation.org/6v1n9hGZq). ©Jiemin Zhu, Lyn Ebert, Dongmei Guo, Sumei Yang, Qiuying Han, Sally Wai-Chi Chan. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 11.04.2018.

  9. Mobile Breast Cancer e-Support Program for Chinese Women With Breast Cancer Undergoing Chemotherapy (Part 2): Multicenter Randomized Controlled Trial.

    Science.gov (United States)

    Zhu, Jiemin; Ebert, Lyn; Liu, Xiangyu; Wei, Di; Chan, Sally Wai-Chi

    2018-04-30

    duration ranged from 0 to 9371 min (mean 1072.3; SD 2359.5; median 100; IQR 27-279). Repeated measures multivariate analysis of covariance (intention-to-treat) found that breast cancer e-support + care as usual participants had significant better health outcomes at 3 months regarding self-efficacy (21.05; 95% CI 1.87-40.22; P=.03; d=0.53), symptom interference (-0.73; 95% CI -1.35 to -.11; P=.02; d=-0.51), and quality of life (6.64; 95% CI 0.77-12.50; P=.03, d=0.46) but not regarding social support, symptom severity, anxiety, and depression compared with care as usual participants. These beneficial effects were not sustained at 6 months. Spearman rank-order correlation showed that the breast cancer e-support usage duration was positively correlated with self-efficacy (r=.290, P=.03), social support (r=.320, P=.02), and quality of life (r=.273, P=.04) at 3 months. The breast cancer e-support program demonstrated its potential as an effective and easily accessible intervention to promote women's self-efficacy, symptom interference, and quality of life during chemotherapy. Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12616000639426; www.ANZCTR.org.au/ACTRN12616000639426.aspx (Archived by Webcite at http://www.webcitation.org/6v1n9hGZq). ©Jiemin Zhu, Lyn Ebert, Xiangyu Liu, Di Wei, Sally Wai-Chi Chan. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 30.04.2018.

  10. Building Yolŋu Skills, Knowledge, and Priorities into Early Childhood Assessment and Support: Protocol for a Qualitative Study.

    Science.gov (United States)

    Lowell, Anne; Maypilama, Elaine Lawurrpa; Fasoli, Lyn; Gundjarranbuy, Rosemary; Godwin-Thompson, Jenine; Guyula, Abbey; Yunupiŋu, Megan; Armstrong, Emily; Garrutju, Jane; McEldowney, Rose

    2018-03-07

    support optimal child development. The study findings are guiding the development of a Web-based educational resource for staff working with Aboriginal communities and families in the field of early child development. This website will also function as a community-developed tool for strengthening and maintaining Aboriginal knowledge and practice related to child development and child rearing. It will be widely accessible to community members through a range of platforms (eg, mobile phones and tablets) and will provide a model for other cultural contexts. This project will facilitate wider recognition and reflection of cultural knowledge and practice in early childhood programs and policies and will support strengthening and maintenance of cultural knowledge. The culturally responsive and highly collaborative approach to community-based research on which this project is based will also inform future research through sharing knowledge about the research process as well as research findings. ©Anne Lowell, Elaine Lawurrpa Maypilama, Lyn Fasoli, Rosemary Gundjarranbuy, Jenine Godwin-Thompson, Abbey Guyula, Megan Yunupiŋu, Emily Armstrong, Jane Garrutju, Rose McEldowney. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 07.03.2018.

  11. Increased Serotonin Signaling Contributes to the Warburg Effect in Pancreatic Tumor Cells Under Metabolic Stress and Promotes Growth of Pancreatic Tumors in Mice.

    Science.gov (United States)

    Jiang, Shu-Heng; Li, Jun; Dong, Fang-Yuan; Yang, Jian-Yu; Liu, De-Jun; Yang, Xiao-Mei; Wang, Ya-Hui; Yang, Min-Wei; Fu, Xue-Liang; Zhang, Xiao-Xin; Li, Qing; Pang, Xiu-Feng; Huo, Yan-Miao; Li, Jiao; Zhang, Jun-Feng; Lee, Ho-Young; Lee, Su-Jae; Qin, Wen-Xin; Gu, Jian-Ren; Sun, Yong-Wei; Zhang, Zhi-Gang

    2017-07-01

    of 5-HT to be increased in human PDAC tissues compared with non-tumor pancreatic tissues, and PDAC cell lines compared with non-transformed pancreatic cells. Incubation of PDAC cell lines with 5-HT increased proliferation and prevented apoptosis. Agonists of HTR2B, but not other 5-HT receptors, promoted proliferation and prevented apoptosis of PDAC cells. Knockdown of HTR2B in PDAC cells, or incubation of cells with HTR2B inhibitors, reduced their growth as xenograft tumors in mice. We observed a correlation between 5-HT and glycolytic flux in PDAC cells; levels of metabolic enzymes involved in glycolysis, the phosphate pentose pathway, and hexosamine biosynthesis pathway increased significantly in PDAC cells following 5-HT stimulation. 5-HT stimulation led to formation of the HTR2B-LYN-p85 complex, which increased PI3K-Akt-mTOR signaling and the Warburg effect by increasing protein levels of MYC and HIF1A. Administration of SB204741 to KPC mice slowed growth and metabolism of established pancreatic tumors and prolonged survival of the mice. Human PDACs have increased levels of 5-HT, and PDAC cells increase expression of its receptor, HTR2B. These increases allow for tumor glycolysis under metabolic stress and promote growth of pancreatic tumors and PDAC xenograft tumors in mice. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  12. Quantum Field Theory in Curved Spacetime

    Science.gov (United States)

    Reynolds, Sally C.; Gallagher, Andrew

    2012-03-01

    ; 19. Assimilation and modern human origins in the African peripheries Fred H. Smith, Vance T. Hutchinson and Ivor Janković; 20. Patterns of Middle Pleistocene hominin evolution in Africa and the emergence of modern humans Emma Mbua and Günter Bräuer; 21. Integration of the genetic, anatomical, and archaeological data for the African origin of modern humans: problems and prospects Osbjorn M. Pearson; Part IV. In Search of Context: Hominin Environments, Behaviour and Lithic Cultures: 22. Animal palaeocommunity variability and habitat preference of robust australopiths in South Africa Darryl J. de Ruiter, Matt Sponheimer and Julia Lee-Thorp; 23. Impacts of environmental change and community ecology on the composition and diversity of the southern African monkey fauna from the Plio-Pleistocene to the present Sarah Elton; 24. African genesis revisited: reflections on Raymond Dart and the 'Predatory Transition from Ape(-Man) to Man' Travis R. Pickering; 25. Shared intention in early artefacts: an exploration of deep structure and implications for communication and language John A. J. Gowlett; 26. Sibudu Cave: recent archaeological work on the Middle Stone Age Lyn Wadley; 27. The oldest burials and their significance Avraham Ronen; Index.

  13. Book Reviews

    Directory of Open Access Journals (Sweden)

    Redactie KITLV

    2004-07-01

    , and modernity in Dominican history. Stanford CA: Stanford University Press, 2003. x + 384 pp. -Eric Paul Roorda, Bernardo Vega, Almoina, Galíndez y otros crímenes de Trujillo en el extranjero. Santo Domingo: Fundación Cultural Dominicana, 2001. 147 pp.''Diario de una misión en Washington. Santo Domingo: Fundación Cultural Dominicana, 2002. 526 pp. -Gerben Nooteboom, Aspha Bijnaar, Kasmoni: Een spaartraditie in Suriname en Nederland. Amsterdam: Uitgeverij Bert Bakker, 2002. 378 pp. -Dirk H.A. Kolff, Chan E.S. Choenni ,Hindostanen: Van Brits-Indische emigranten via Suriname tot burgers van Nederland. The Hague: Communicatiebureau Sampreshan, 2003. 224 pp., Kanta Sh. Adhin (eds -Dirk H.A. Kolff, Sandew Hira, Het dagboek van Munshi Rahman Khan. The Hague: Amrit/Paramaribo: NSHI, 2003. x + 370 pp. -William H. Fisher, Neil L. Whitehead, Dark Shamans: Kanaimà and the poetics of violent death. Durham NC: Duke University Press, 2002. 309 pp. -David Scott, A.J. Simoes da Silva, The luxury of nationalist despair: George Lamming's fiction as decolonizing project. Amsterdam: Rodopi, 2000. 217 pp. -Lyn Innes, Maria Cristina Fumagalli, The flight of the vernacular. Amsterdam: Rodopi, 2001. xvi + 303 pp. -Maria Cristina Fumagalli, Tobias Döring, Caribbean-English passages: Intertextuality in a postcolonial tradition. London: Routledge, 2002. xii + 236 pp. -A. James Arnold, Celia Britton, Race and the unconscious: Freudianism in French Caribbean thought. Oxford: Legenda, 2002. 115 pp. -Nicole Roberts, Dorothy E. Mosby, Place, language, and identity in Afro-Costa Rican literature. Columbia: University of Missouri Press, 2003. xiii + 248 pp. -Stephen Steumpfle, Philip W. Scher, Carnival and the formation of a Caribbean transnation. Gainesville: University Press of Florida, 2003. xvi + 215 pp. -Peter Manuel, Frances R. Aparicho ,Musical migrations: transnationalism and cultural hybridity in Latin/o America, Volume 1. With Maria Elena Cepeda. New York: Palgrave Macmillan, 2003. 216

  14. Editorial volume 3 - issue 3: The future of the Learning Management System

    Directory of Open Access Journals (Sweden)

    Yngve Nordkvelle

    2007-12-01

    participation and reflexivity in the social construction of the development of educational technology”. Larsen, Hole and Fahlvik demonstrate how this is a dynamic developmental process. The last paper has a different topic, but relates to the first article in the sense that if the technology is the same, different users approach it differently. The authors: Neil Anderson, Carolyn Timms and Lyn Courtney of James Cook University address the rural/urban distinction in a complex project, investigated in several aspects. If the difference is systematic and in conflict with educational and political aims, the alarm goes off. In this case the troubling news are that students in rural areas are less interested in adopting new technologies. References:Brown, D. (2007 Mashing up the Once and Future CMS. Educause Review. March/April (s.7-8 McInnis, C. (2001 Inaugural proffesorial lecture. Signs of disengagement? The changing undergraduate experience in Australian universities. http://eprints.unimelb.edu.au/archive /00000094/01/InaugLec23_8_01.pdf Zemsky, R. & Massy, W.F (2004 Thwarted Innovation. What happened to e-learning and why? http://www.irhe.upenn.edu/Docs/Jun2004/ThwartedInnovation.pdf

  15. Algunas reflexiones sobre Gaia, evolución y cultura

    Directory of Open Access Journals (Sweden)

    Pou Royo, Antonio

    2002-05-01

    Full Text Available Not available

    Durante los viajes que James Lovelock realizó por todo el mundo, rastreando el DDT y otros componentes traza con su invento del detector de captura de electrones, le llamó la atención la interconectividad química de toda la atmósfera con los seres vivos y su gran estabilidad, lo que le llevó a la concepción de una nueva teoría, la hipótesis Gaia, que él define como «Una nueva visión de las interacciones entre las partes vivas e inorgánicas del planeta. De ahí ha surgido la hipótesis, el modelo, en el cual la materia viva, el aire, los océanos y la superficie terrestre forman un sistema complejo que puede ser visto como un único organismo y que tiene la capacidad de mantener nuestro planeta como un lugar apto para la vida». Lyn Margulis, la conocida bióloga, dotó a la hipótesis de una base científica que la dio credibilidad, pero en mi parecer el éxito de la teoría entre el gran público radica más en la elección del nombre «Gaia», la antigua madre-diosa griega, y su posible connotación religiosa, que no en su aportación científica. El mismo Lovelock da pie a esa interpretación cuando afirma «... para mí, Gaia es un concepto religioso y científico a la vez, y es manejable en ambas esferas», aunque en otros momentos ha intentado matizar «De ningún modo veo a Gaia como un ser consciente, un Dios alternativo. Para mí Gaia está viva y es parte del universo inefable y yo soy una parte de ella». Desde el mundo científico se acepta mal esa ambivalencia y todavía hay quienes arquean las cejas al oír hablar de Gaia. Sin embargo la hipótesis ha facilitado un nuevo marco de referencia en el que ahora caben perspectivas más amplias e interesantes, como la simbiogénesis que propone Margulis. En el continuo debate sobre la evolución, y desde el punto de vista de su éxito social, es casi inevitable tratar de comparar Gaia con el evolucionismo de Darwin, aunque Lovelock se declara cien por

  16. Hubble Observes Surface of Titan

    Science.gov (United States)

    1994-01-01

    's first flyby of Titan, the spacecraft is to release the European Space Agency's Huygens Probe to parachute to Titan's surface. Images like Smith's team has taken of Titan can be used to identify choice landing spots - - and help engineers and scientists understand how Titan's winds will blow the parachute through the satellite's atmosphere.UA scientists play major roles in the Cassini mission: Carolyn C. Porco, an associate professor at the Lunar and Planetary Laboratory, leads the 14-member Cassini Imaging Team. Jonathan I. Lunine, also an associate professor at the lab, is the only American selected by the European Space Agency to be on the three-member Huygens Probe interdisciplinary science team. Smith is a member of research professor Martin G. Tomasko's international team of scientists who will image the surface of Titan in visible light and in color with the Descent Imager/Spectral Radiometer, one of five instruments in the Huygens Probe's French, German, Italian and U.S. experiment payload. Senior research associate Lyn R. Doose is also on Tomasko's team. Lunine and LPL professor Donald M. Hunten are members of the science team for another U.S. instrument on that payload, the gas chromatograph mass spectrometer. Hunten was on the original Cassini mission science definition team back in 1983.PHOTO CAPTION: Four global projections of the HST Titan data, separated in longitude by 90 degrees. Upper left: hemisphere facing Saturn. Upper right: leading hemisphere (brightest region). Lower left: the hemisphere which never faces Saturn. Lower right: trailing hemisphere. Not that these assignments assume that the rotation is synchronous. The imaging team says its data strongly support this assumption -- a longer time baseline is needed for proof. The surface near the poles is never visible to an observer in Titan's equatorial plane because of the large optical path.The Wide Field/Planetary Camera 2 was developed by the Jet Propulsion Laboratory and managed by the Goddard

  17. PERSPECTIVE: Climate change: seeking balance in media reports

    Science.gov (United States)

    Huntingford, Chris; Fowler, David

    2008-06-01

    Intergovernmental Panel on Climate Change ed J T Houghton, Y Ding, D J Griggs, M Noguer, P J van der Linden, X Dai, K Maskell and C A Johnson (Cambridge: Cambridge University Press) IPCC 2007 Climate Change 2007: The Physical Basis. Contribution of Working Group I to the Fourth Assessment Report of the Intergovernmental Panel on Climate Change ed S Solomon, D Qin, M Manning, Z Chen, M Marquis, K B Averyt, M Tignor, and H L Miller (Cambridge: Cambridge University Press) Lawson N 2008 An Appeal to Reason: a Cool Look at Global Warming (London: Duckworth Overlook) Michaels P J 2004 Meltdown: The Predictable Distortion of Global Warming by Scientists, Politicians, and the Media (Washington: CATO Institute) Michaels P J (ed) 2005 Shattered Consensus: The True State of Global Warming (Lanham: Rowman and Littlefield) Parker D E 2006 A demonstration that large-scale warming is not urban J. Climate 19 2882 95 Pearce F 2007 The Last Generation: How Nature Will Take Her Revenge for Climate Change (London: Eden Project Books) Schellnhuber H J, Cramer W, Nakicenovic N, Wigley T and Yohe G (ed) 2006 Avoiding Dangerous Climate Change (Cambridge: Cambridge University Press) Sloan T and Wolfendale A W 2008 Testing the proposed causal link between cosmic rays and cloud cover Environ. Res. Lett. 3 024001 Smith D M, Cusack S, Colman A W, Folland C K, Harris G R and Murphy J M 2007 Improved surface temperature prediction for the coming decade from a global climate model Science 317 796 9 Spencer C 2008 Climate Confusion: How Global Warming Hysteria Leads to Bad Science, Pandering Politicians and Misguided Policies that Hurt the Poor (New York: Encounter Books) Stott P A, Tett S F B, Jones G S, Allen M R, Mitchell J F B and Jenkins G J 2000 External control of twentieth century temperature variations by natural and anthropogenic forcings Science 290 2133 7 Photo of Chris Huntingford Dr Chris Huntingford has a degree in mathematics from Cambridge University, and a PhD in fluid dynamics from the