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Sample records for maclachlan lyn tett

  1. Four new species of Adicella MacLachlan (Trichoptera: Leptoceridae: Triaenodini) from Sabah, East Malaysia

    NARCIS (Netherlands)

    Huisman, J.; Andersen, T.

    1997-01-01

    Four new species of Adicella MacLachlan, 1877, A. anakpanah spec, nov., A. bavanga spec, nov., A. danumensis spec, nov., and A. gada spec, nov., from Sabah (Borneo), East Malaysia, are described and figured.

  2. 76 FR 19373 - Cathryn Lyn Chatman (also known as Cathryn Lyn Garcia): Debarment Order

    Science.gov (United States)

    2011-04-07

    ... HUMAN SERVICES Food and Drug Administration Cathryn Lyn Chatman (also known as Cathryn Lyn Garcia... ] Cathryn Lyn Chatman (also known as Cathryn Lyn Garcia) for 5 years from providing services in any capacity... Cathryn Lyn Garcia) pleaded guilty to a misdemeanor offense of misbranding a drug. On August 14, 2006,...

  3. 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...

  4. BINARY NATURE OF THE HADS STARS AN LYN & BE LYN

    Directory of Open Access Journals (Sweden)

    J. H. Peña

    2015-01-01

    Full Text Available A partir de los recién determinados tiempos de máximo en la fotometría CCD de las estrellas HADS AN Lyn & BE Lyn y de una recopilación de tiempos de máximo de la literatura, hemos sido capaces de determinar la naturaleza binaria de estas estrellas, así como los parámetros físicos, con la fotometría uvby — β .

  5. 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.

  6. Gain-of-function Lyn induces anemia: appropriate Lyn activity is essential for normal erythropoiesis and Epo receptor signaling.

    Science.gov (United States)

    Slavova-Azmanova, Neli S; Kucera, Nicole; Satiaputra, Jiulia; Stone, Leah; Magno, Aaron; Maxwell, Mhairi J; Quilici, Cathy; Erber, Wendy; Klinken, S Peter; Hibbs, Margaret L; Ingley, Evan

    2013-07-11

    Lyn is involved in erythropoietin (Epo)-receptor signaling and erythroid homeostasis. Downstream pathways influenced following Lyn activation and their significance to erythropoiesis remain unclear. To address this, we assessed a gain-of-function Lyn mutation (Lyn(up/up)) on erythropoiesis and Epo receptor signaling. Adult Lyn(up/up) mice were anemic, with dysmorphic red cells (spherocyte-like, acanthocytes) in their circulation, indicative of hemolytic anemia and resembling the human disorder chorea acanthocytosis. Heterozygous Lyn(+/up) mice became increasingly anemic with age, indicating that the mutation was dominant. In an attempt to overcome this anemia, extramedullary erythropoiesis was activated. As the mice aged, the levels of different immature erythroid populations changed, indicating compensatory mechanisms to produce more erythrocytes were dynamic. Changes in Epo signaling were observed in Lyn(+/up) erythroid cell lines and primary CD71(+) Lyn(up/up) erythroblasts, including significant alterations to the phosphorylation of Lyn, the Epo receptor, Janus kinase 2, Signal Transducer and Action of Transcription-5, GRB2-associated-binding protein-2, Akt, and Forkhead box O3. As a consequence of altered Lyn signaling, Lyn(+/up) cells remained viable in the absence of Epo but displayed delayed Epo-induced differentiation. These data demonstrate that Lyn gene dosage and activity are critical for normal erythropoiesis; constitutively active Lyn alters Epo signaling, which in turn produces erythroid defects.

  7. 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...

  8. Functions of the Lyn tyrosine kinase in health and disease

    Directory of Open Access Journals (Sweden)

    Ingley Evan

    2012-07-01

    Full Text Available Abstract Src family kinases such as Lyn are important signaling intermediaries, relaying and modulating different inputs to regulate various outputs, such as proliferation, differentiation, apoptosis, migration and metabolism. Intriguingly, Lyn can mediate both positive and negative signaling processes within the same or different cellular contexts. This duality is exemplified by the B-cell defect in Lyn−/− mice in which Lyn is essential for negative regulation of the B-cell receptor; conversely, B-cells expressing a dominant active mutant of Lyn (Lynup/up have elevated activities of positive regulators of the B-cell receptor due to this hyperactive kinase. Lyn has well-established functions in most haematopoietic cells, viz. progenitors via influencing c-kit signaling, through to mature cell receptor/integrin signaling, e.g. erythrocytes, platelets, mast cells and macrophages. Consequently, there is an important role for this kinase in regulating hematopoietic abnormalities. Lyn is an important regulator of autoimmune diseases such as asthma and psoriasis, due to its profound ability to influence immune cell signaling. Lyn has also been found to be important for maintaining the leukemic phenotype of many different liquid cancers including acute myeloid leukaemia (AML, chronic myeloid leukaemia (CML and B-cell lymphocytic leukaemia (BCLL. Lyn is also expressed in some solid tumors and here too it is establishing itself as a potential therapeutic target for prostate, glioblastoma, colon and more aggressive subtypes of breast cancer. Lay Abstract To relay information, a cell uses enzymes that put molecular markers on specific proteins so they interact with other proteins or move to specific parts of the cell to have particular functions. A protein called Lyn is one of these enzymes that regulate information transfer within cells to modulate cell growth, survival and movement. Depending on which type of cell and the source of the information

  9. LYN-activating mutations mediate antiestrogen resistance in estrogen receptor-positive breast cancer.

    Science.gov (United States)

    Schwarz, Luis J; Fox, Emily M; Balko, Justin M; Garrett, Joan T; Kuba, María Gabriela; Estrada, Mónica Valeria; González-Angulo, Ana María; Mills, Gordon B; Red-Brewer, Monica; Mayer, Ingrid A; Abramson, Vandana; Rizzo, Monica; Kelley, Mark C; Meszoely, Ingrid M; Arteaga, Carlos L

    2014-12-01

    Estrogen receptor-positive (ER(+)) breast cancers adapt to hormone deprivation and become resistant to antiestrogen therapy. Here, we performed deep sequencing on ER(+) tumors that remained highly proliferative after treatment with the aromatase inhibitor letrozole and identified a D189Y mutation in the inhibitory SH2 domain of the SRC family kinase (SFK) LYN. Evaluation of 463 breast tumors in The Cancer Genome Atlas revealed four LYN mutations, two of which affected the SH2 domain. In addition, LYN was upregulated in multiple ER(+) breast cancer lines resistant to long-term estrogen deprivation (LTED). An RNAi-based kinome screen revealed that LYN is required for growth of ER(+) LTED breast cancer cells. Kinase assays and immunoblot analyses of SRC substrates in transfected cells indicated that LYN(D189Y) has higher catalytic activity than WT protein. Further, LYN(D189Y) exhibited reduced phosphorylation at the inhibitory Y507 site compared with LYN(WT). Other SH2 domain LYN mutants, E159K and K209N, also exhibited higher catalytic activity and reduced inhibitory site phosphorylation. LYN(D189Y) overexpression abrogated growth inhibition by fulvestrant and/or the PI3K inhibitor BKM120 in 3 ER(+) breast cancer cell lines. The SFK inhibitor dasatinib enhanced the antitumor effect of BKM120 and fulvestrant against estrogen-deprived ER(+) xenografts but not LYN(D189Y)-expressing xenografts. These results suggest that LYN mutations mediate escape from antiestrogens in a subset of ER(+) breast cancers.

  10. Lyn kinase represses mucus hypersecretion by regulating IL-13-induced endoplasmic reticulum stress in asthma.

    Science.gov (United States)

    Wang, Xing; Yang, Xiaoqiong; Li, Yin; Wang, Xiaoyun; Zhang, Yun; Dai, Xi; Niu, Bin; Wu, Juan; Yuan, Xiefang; Xiong, Anjie; Liu, Zhigang; Zhong, Nanshan; Wu, Min; Li, Guoping

    2017-02-01

    In asthma, mucus hypersecretion is thought to be a prominent pathological feature associated with widespread mucus plugging. However, the current treatments for mucus hypersecretion are often ineffective or temporary. The potential therapeutic targets of mucus hypersecretion in asthma remain unknown. Here, we show that Lyn is a central effector of endoplasmic reticulum stress (ER stress) and mucous hypersecretion in asthma. In Lyn-transgenic mice (Lyn-TG) and wild-type (WT) C57BL/6J mice exposed to ovalbumin (OVA), Lyn overexpression attenuates mucus hypersecretion and ER stress. Interleukin 13 (IL-13) induced MUC5AC expression by enhancing ER stress in vitro. Lyn serves as a negative regulator of IL-13-induced ER stress and MUC5AC expression. We further find that an inhibitor of ER stress, which is likely involved in the PI3K p85α/Akt pathway and NFκB activity, blocked MUC5AC expression in Lyn-knockdown cells. Furthermore, PI3K/Akt signaling is required for IL-13-induced ER stress and MUC5AC expression in airway epithelial cells. The ER stress regulation of MUC5AC expression depends on NFκB in Lyn-knockdown airway epithelial cells. Our studies indicate not only a concept of mucus hypersecretion in asthma that involves Lyn kinase but also an important therapeutic candidate for asthma.

  11. Lyn kinase represses mucus hypersecretion by regulating IL-13-induced endoplasmic reticulum stress in asthma

    Directory of Open Access Journals (Sweden)

    Xing Wang

    2017-02-01

    Full Text Available In asthma, mucus hypersecretion is thought to be a prominent pathological feature associated with widespread mucus plugging. However, the current treatments for mucus hypersecretion are often ineffective or temporary. The potential therapeutic targets of mucus hypersecretion in asthma remain unknown. Here, we show that Lyn is a central effector of endoplasmic reticulum stress (ER stress and mucous hypersecretion in asthma. In Lyn-transgenic mice (Lyn-TG and wild-type (WT C57BL/6J mice exposed to ovalbumin (OVA, Lyn overexpression attenuates mucus hypersecretion and ER stress. Interleukin 13 (IL-13 induced MUC5AC expression by enhancing ER stress in vitro. Lyn serves as a negative regulator of IL-13-induced ER stress and MUC5AC expression. We further find that an inhibitor of ER stress, which is likely involved in the PI3K p85α/Akt pathway and NFκB activity, blocked MUC5AC expression in Lyn-knockdown cells. Furthermore, PI3K/Akt signaling is required for IL-13-induced ER stress and MUC5AC expression in airway epithelial cells. The ER stress regulation of MUC5AC expression depends on NFκB in Lyn-knockdown airway epithelial cells. Our studies indicate not only a concept of mucus hypersecretion in asthma that involves Lyn kinase but also an important therapeutic candidate for asthma.

  12. LYN-activating mutations mediate antiestrogen resistance in estrogen receptor–positive breast cancer

    Science.gov (United States)

    Schwarz, Luis J.; Fox, Emily M.; Balko, Justin M.; Garrett, Joan T.; Kuba, María Gabriela; Estrada, Mónica Valeria; González-Angulo, Ana María; Mills, Gordon B.; Red-Brewer, Monica; Mayer, Ingrid A.; Abramson, Vandana; Rizzo, Monica; Kelley, Mark C.; Meszoely, Ingrid M.; Arteaga, Carlos L.

    2014-01-01

    Estrogen receptor–positive (ER+) breast cancers adapt to hormone deprivation and become resistant to antiestrogen therapy. Here, we performed deep sequencing on ER+ tumors that remained highly proliferative after treatment with the aromatase inhibitor letrozole and identified a D189Y mutation in the inhibitory SH2 domain of the SRC family kinase (SFK) LYN. Evaluation of 463 breast tumors in The Cancer Genome Atlas revealed four LYN mutations, two of which affected the SH2 domain. In addition, LYN was upregulated in multiple ER+ breast cancer lines resistant to long-term estrogen deprivation (LTED). An RNAi-based kinome screen revealed that LYN is required for growth of ER+ LTED breast cancer cells. Kinase assays and immunoblot analyses of SRC substrates in transfected cells indicated that LYND189Y has higher catalytic activity than WT protein. Further, LYND189Y exhibited reduced phosphorylation at the inhibitory Y507 site compared with LYNWT. Other SH2 domain LYN mutants, E159K and K209N, also exhibited higher catalytic activity and reduced inhibitory site phosphorylation. LYND189Y overexpression abrogated growth inhibition by fulvestrant and/or the PI3K inhibitor BKM120 in 3 ER+ breast cancer cell lines. The SFK inhibitor dasatinib enhanced the antitumor effect of BKM120 and fulvestrant against estrogen-deprived ER+ xenografts but not LYND189Y-expressing xenografts. These results suggest that LYN mutations mediate escape from antiestrogens in a subset of ER+ breast cancers. PMID:25401474

  13. Lyn Delivers Bacteria to Lysosomes for Eradication through TLR2-Initiated Autophagy Related Phagocytosis.

    Directory of Open Access Journals (Sweden)

    Xuefeng Li

    2016-01-01

    Full Text Available Extracellular bacteria, such as Pseudomonas aeruginosa and Klebsiella pneumoniae, have been reported to induce autophagy; however, the role and machinery of infection-induced autophagy remain elusive. We show that the pleiotropic Src kinase Lyn mediates phagocytosis and autophagosome maturation in alveolar macrophages (AM, which facilitates eventual bacterial eradication. We report that Lyn is required for bacterial infection-induced recruitment of autophagic components to pathogen-containing phagosomes. When we blocked autophagy with 3-methyladenine (3-MA or by depleting Lyn, we observed less phagocytosis and subsequent bacterial clearance by AM. Both morphological and biological evidence demonstrated that Lyn delivered bacteria to lysosomes through xenophagy. TLR2 initiated the phagocytic process and activated Lyn following infection. Cytoskeletal trafficking proteins, such as Rab5 and Rab7, critically facilitated early phagosome formation, autophagosome maturation, and eventual autophagy-mediated bacterial degradation. These findings reveal that Lyn, TLR2 and Rab modulate autophagy related phagocytosis and augment bactericidal activity, which may offer insight into novel therapeutic strategies to control lung infection.

  14. Astaxanthin Improves Human Sperm Capacitation by Inducing Lyn Displacement and Activation

    Science.gov (United States)

    Andrisani, Alessandra; Donà, Gabriella; Tibaldi, Elena; Brunati, Anna Maria; Sabbadin, Chiara; Armanini, Decio; Alvisi, Gualtiero; Gizzo, Salvatore; Ambrosini, Guido; Ragazzi, Eugenio; Bordin, Luciana

    2015-01-01

    Astaxanthin (Asta), a photo-protective red pigment of the carotenoid family, is known for its multiple beneficial properties. In this study, the effects of Asta on isolated human sperm were evaluated. Capacitation involves a series of transformations to let sperm acquire the correct features for potential oocyte fertilization, including the generation of a controlled amount of reactive oxygen species (ROS), cholesterol depletion of the sperm outer membrane, and protein tyrosine phosphorylation (Tyr-P) process in the head region. Volunteers, with normal spermiogram values, were divided in two separate groups on the basis of their ability to generate the correct content of endogenous ROS. Both patient group (PG) and control group (CG) were analysed for Tyr-phosphorylation (Tyr-P) pattern and percentages of acrosome-reacted cells (ARC) and non-viable cells (NVC), in the presence or absence of Asta. In addition, the involvement of ROS on membrane reorganization and the presence of Lyn, a Src family kinase associated with lipid rafts, were investigated. Results show that Lyn is present in the membranes of human sperm, mainly confined in midpiece in resting conditions. Following capacitation, Lyn translocated to the head concomitantly with raft relocation, thus allowing the Tyr-P of head proteins. Asta succeeded to trigger Lyn translocation in PG sperm thus bypassing the impaired ROS-related mechanism for rafts and Lyn translocation. In this study, we showed an interdependence between ROS generation and lipid rafts and Lyn relocation leading the cells to undergo the successive acrosome reaction (AR). Asta, by ameliorating PG sperm functioning, may be utilised to decrease male idiopathic infertility. PMID:26308013

  15. Astaxanthin Improves Human Sperm Capacitation by Inducing Lyn Displacement and Activation

    Directory of Open Access Journals (Sweden)

    Alessandra Andrisani

    2015-08-01

    Full Text Available Astaxanthin (Asta, a photo-protective red pigment of the carotenoid family, is known for its multiple beneficial properties. In this study, the effects of Asta on isolated human sperm were evaluated. Capacitation involves a series of transformations to let sperm acquire the correct features for potential oocyte fertilization, including the generation of a controlled amount of reactive oxygen species (ROS, cholesterol depletion of the sperm outer membrane, and protein tyrosine phosphorylation (Tyr-P process in the head region. Volunteers, with normal spermiogram values, were divided in two separate groups on the basis of their ability to generate the correct content of endogenous ROS. Both patient group (PG and control group (CG were analysed for Tyr-phosphorylation (Tyr-P pattern and percentages of acrosome-reacted cells (ARC and non-viable cells (NVC, in the presence or absence of Asta. In addition, the involvement of ROS on membrane reorganization and the presence of Lyn, a Src family kinase associated with lipid rafts, were investigated. Results show that Lyn is present in the membranes of human sperm, mainly confined in midpiece in resting conditions. Following capacitation, Lyn translocated to the head concomitantly with raft relocation, thus allowing the Tyr-P of head proteins. Asta succeeded to trigger Lyn translocation in PG sperm thus bypassing the impaired ROS-related mechanism for rafts and Lyn translocation. In this study, we showed an interdependence between ROS generation and lipid rafts and Lyn relocation leading the cells to undergo the successive acrosome reaction (AR. Asta, by ameliorating PG sperm functioning, may be utilised to decrease male idiopathic infertility.

  16. Lyn regulates inflammatory responses in Klebsiella pneumoniae infection via the p38/NF-κB pathway.

    Science.gov (United States)

    Li, Xuefeng; Zhou, Xikun; Ye, Yan; Li, Yi; Li, Jiaxin; Privratsky, Breanna; Wu, Erxi; Gao, Hongwei; Huang, Canhua; Wu, Min

    2014-03-01

    Klebsiella pneumoniae (Kp) is one of the most common pathogens in nosocomial infections and is becoming increasingly multidrug resistant. However, the underlying molecular pathogenesis of this bacterium remains elusive, limiting the therapeutic options. Understanding the mechanism of its pathogenesis may facilitate the development of anti-bacterial therapeutics. Here, we show that Lyn, a pleiotropic Src tyrosine kinase, is involved in host defense against Kp by regulating phagocytosis process and simultaneously downregulating inflammatory responses. Using acute infection mouse models, we observed that lyn(-/-) mice were more susceptible to Kp with increased mortality and severe lung injury compared with WT mice. Kp infected-lyn(-/-) mice exhibited elevated inflammatory cytokines (IL-6 and TNF-α), and increased superoxide in the lung and other organs. In addition, the phosphorylation of p38 and NF-κB p65 subunit increased markedly in response to Kp infection in lyn(-/-) mice. We also demonstrated that the translocation of p65 from cytoplasm to nuclei increased in cultured murine lung epithelial cells by Lyn siRNA knockdown. Furthermore, lipid rafts clustered with activated Lyn and accumulated in the site of Kp invasion. Taken together, these findings revealed that Lyn may participate in host defense against Kp infection through the negative modulation of inflammatory cytokines.

  17. 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.

  18. 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

  19. Yes and Lyn play a role in nuclear translocation of the epidermal growth factor receptor.

    Science.gov (United States)

    Iida, M; Brand, T M; Campbell, D A; Li, C; Wheeler, D L

    2013-02-07

    The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in human cancers. Cetuximab is an anti-EGFR antibody that has been approved for use in oncology. Previously we investigated mechanisms of resistance to cetuximab using a model derived from the non-small cell lung cancer line NCI-H226. We demonstrated that cetuximab-resistant clones (Ctx(R)) had increased nuclear localization of the EGFR. This process was mediated by Src family kinases (SFKs), and nuclear EGFR had a role in resistance to cetuximab. To better understand SFK-mediated nuclear translocation of EGFR, we investigated which SFK member(s) controlled this process as well as the EGFR tyrosine residues that are involved. Analyses of mRNA and protein expression indicated upregulation of the SFK members Yes (v-Yes-1 yamaguchi sarcoma viral oncogene) and Lyn (v-yes-1 Yamaguchi sarcoma viral-related oncogene homolog) in all Ctx(R) clones. Further, immunoprecipitation analysis revealed that EGFR interacts with Yes and Lyn in Ctx(R) clones, but not in cetuximab-sensitive (Ctx(S)) parental cells. Using RNAi interference, we found that knockdown of either Yes or Lyn led to loss of EGFR translocation to the nucleus. Conversely, overexpression of Yes or Lyn in low nuclear EGFR-expressing Ctx(S) parental cells led to increased nuclear EGFR. Chromatin immunoprecipitation (ChIP) assays confirmed nuclear EGFR complexes associated with the promoter of the known EGFR target genes B-Myb and iNOS. Further, all Ctx(R) clones exhibited upregulation of B-Myb and iNOS at the mRNA and protein levels. siRNAs directed at Yes or Lyn led to decreased binding of EGFR complexes to the B-Myb and iNOS promoters based on ChIP analyses. SFKs have been shown to phosphorylate EGFR on tyrosines 845 and 1101 (Y845 and Y1101), and mutation of Y1101, but not Y845, impaired nuclear entry of the EGFR. Taken together, our findings demonstrate that Yes and Lyn phosphorylate EGFR at Y1101, which influences EGFR

  20. GPI-anchored receptor clusters transiently recruit Lyn and Gα for temporary cluster immobilization and Lyn activation: single-molecule tracking study 1

    OpenAIRE

    2007-01-01

    The signaling mechanisms for glycosylphosphatidylinositol-anchored receptors (GPI-ARs) have been investigated by tracking single molecules in living cells. Upon the engagement or colloidal gold–induced cross-linking of CD59 (and other GPI-ARs) at physiological levels, CD59 clusters containing three to nine CD59 molecules were formed, and single molecules of Gαi2 or Lyn (GFP conjugates) exhibited the frequent but transient (133 and 200 ms, respectively) recruitment to CD59 clusters, via both p...

  1. DZ Lyn: a contact binary with components in poor thermal contact

    Institute of Scientific and Technical Information of China (English)

    Massirniliano Martignoni; Francesco Acerbi; Carlo Barani

    2009-01-01

    CCD photometric observations of the short-period eclipsing binary DZ Lyn were obtained during seven nights in March-April 2008 in the B,V,R_c and I_c bands;these observations confirm the short-period (P=0.378 d) of the system.The presented light curves are analyzed by means of the 2003 version of the Wilson-Devinney (WD)program.A grid of solutions for several fixed values of mass ratio was calculated.The best fitting possible is for a mass ratio of q = 0.885,a degree of contact f = 0.18 and a low orbital inclination of i = 57.6°.The results show that DZ Lyn is an A-subtype W Ursae Majoris contact binary in poor thermal contact; in fact the difference between the mean temperatures of the components is about 1800 K.The star DZ Lyn seems to be another member of the class of poorly understood close binaries in or near geometrical contact but far from thermal contact.The absolute dimensions are estimated and its dynamical evolution is inferred.

  2. LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity.

    Science.gov (United States)

    Proekt, Irina; Miller, Corey N; Jeanne, Marion; Fasano, Kayla J; Moon, James J; Lowell, Clifford A; Gould, Douglas B; Anderson, Mark S; DeFranco, Anthony L

    2016-10-03

    Studies of the genetic factors associated with human autoimmune disease suggest a multigenic origin of susceptibility; however, how these factors interact and through which tolerance pathways they operate generally remain to be defined. One key checkpoint occurs through the activity of the autoimmune regulator AIRE, which promotes central T cell tolerance. Recent reports have described a variety of dominant-negative AIRE mutations that likely contribute to human autoimmunity to a greater extent than previously thought. In families with these mutations, the penetrance of autoimmunity is incomplete, suggesting that other checkpoints play a role in preventing autoimmunity. Here, we tested whether a defect in LYN, an inhibitory protein tyrosine kinase that is implicated in systemic autoimmunity, could combine with an Aire mutation to provoke organ-specific autoimmunity. Indeed, mice with a dominant-negative allele of Aire and deficiency in LYN spontaneously developed organ-specific autoimmunity in the eye. We further determined that a small pool of retinal protein-specific T cells escaped thymic deletion as a result of the hypomorphic Aire function and that these cells also escaped peripheral tolerance in the presence of LYN-deficient dendritic cells, leading to highly destructive autoimmune attack. These findings demonstrate how 2 distinct tolerance pathways can synergize to unleash autoimmunity and have implications for the genetic susceptibility of autoimmune disease.

  3. Lyn modulates Claudin-2 expression and is a therapeutic target for breast cancer liver metastasis.

    Science.gov (United States)

    Tabariès, Sébastien; Annis, Matthew G; Hsu, Brian E; Tam, Christine E; Savage, Paul; Park, Morag; Siegel, Peter M

    2015-04-20

    Claudin-2 enhances breast cancer liver metastasis and promotes the development of colorectal cancers. The objective of our current study is to define the regulatory mechanisms controlling Claudin-2 expression in breast cancer cells. We evaluated the effect of several Src Family Kinase (SFK) inhibitors or knockdown of individual SFK members on Claudin-2 expression in breast cancer cells. We also assessed the potential effects of pan-SFK and SFK-selective inhibitors on the formation of breast cancer liver metastases. This study reveals that pan inhibition of SFK signaling pathways significantly elevated Claudin-2 expression levels in breast cancer cells. In addition, our data demonstrate that pan-SFK inhibitors can enhance breast cancer metastasis to the liver. Knockdown of individual SFK members reveals that loss of Yes or Fyn induces Claudin-2 expression; whereas, diminished Lyn levels impairs Claudin-2 expression in breast cancer cells. The Lyn-selective kinase inhibitor, Bafetinib (INNO-406), acts to reduce Claudin-2 expression and suppress breast cancer liver metastasis. Our findings may have major clinical implications and advise against the treatment of breast cancer patients with broad-acting SFK inhibitors and support the use of Lyn-specific inhibitors.

  4. NS-187 (INNO-406, a Bcr-Abl/Lyn Dual Tyrosine Kinase Inhibitor

    Directory of Open Access Journals (Sweden)

    Tomoko Niwa

    2007-01-01

    Full Text Available Protein kinases catalyze the transfer of the γ-phosphoryl group of adenosine triphosphate (ATP to the hydroxyl groups of protein side chains, and they play critical roles in regulating cellular signal transduction and other biochemical processes. They are attractive targets for today’s drug discovery and development, and many pharmaceutical companies are intensively developing various kinds of protein kinase inhibitors. A good example is the recent success with the Bcr-Abl tyrosine kinase inhibitor imatinib mesylate (GleevecTM in the treatment of chronic myeloid leukemia. Though imatinib has dramatically improved the treatment of Bcr-Abl-positive chronic myeloid leukemia, resistance is often found in patients with advanced-stage disease. Several mechanisms have been proposed to explain this resistance, including point mutations within the Abl kinase domain, amplification of the bcr-abl gene, overexpression of the corresponding mRNA, increased drug efflux mediated by P-glycoprotein, and activation of the Src-family kinase (SFK Lyn. We set out to develop a novel drug whose affinity for Abl is higher than that of imatinib and whose specifi city in inhibiting Lyn is higher than that of SFK/Abl inhibitors such as dasatinib (SprycelTM or bosutinib (SKI-606. Our work has led to the development of NS-187 (INNO-406, a novel Abl/Lyn dual tyrosine kinase inhibitor with clinical prospects. To provide an overview of how a selective kinase inhibitor has been developed, this review presents chemical-modification studies carried out with the guidance of molecular modeling, the structural basis for the high potency and selectivity of NS-187 based on the X-ray structure of the NS-187/Abl complex, and the biological profi ling of NS-187, including site-directed mutagenesis experiments.

  5. Neuroblastoma tyrosine kinase signaling networks involve FYN and LYN in endosomes and lipid rafts.

    Directory of Open Access Journals (Sweden)

    Juan Palacios-Moreno

    2015-04-01

    Full Text Available Protein phosphorylation plays a central role in creating a highly dynamic network of interacting proteins that reads and responds to signals from growth factors in the cellular microenvironment. Cells of the neural crest employ multiple signaling mechanisms to control migration and differentiation during development. It is known that defects in these mechanisms cause neuroblastoma, but how multiple signaling pathways interact to govern cell behavior is unknown. In a phosphoproteomic study of neuroblastoma cell lines and cell fractions, including endosomes and detergent-resistant membranes, 1622 phosphorylated proteins were detected, including more than half of the receptor tyrosine kinases in the human genome. Data were analyzed using a combination of graph theory and pattern recognition techniques that resolve data structure into networks that incorporate statistical relationships and protein-protein interaction data. Clusters of proteins in these networks are indicative of functional signaling pathways. The analysis indicates that receptor tyrosine kinases are functionally compartmentalized into distinct collaborative groups distinguished by activation and intracellular localization of SRC-family kinases, especially FYN and LYN. Changes in intracellular localization of activated FYN and LYN were observed in response to stimulation of the receptor tyrosine kinases, ALK and KIT. The results suggest a mechanism to distinguish signaling responses to activation of different receptors, or combinations of receptors, that govern the behavior of the neural crest, which gives rise to neuroblastoma.

  6. Lyn- and PLC-beta3-dependent regulation of SHP-1 phosphorylation controls Stat5 activity and myelomonocytic leukemia-like disease.

    Science.gov (United States)

    Xiao, Wenbin; Ando, Tomoaki; Wang, Huan-You; Kawakami, Yuko; Kawakami, Toshiaki

    2010-12-23

    Hyperactivation of the transcription factor Stat5 leads to various leukemias. Stat5 activity is regulated by the protein phosphatase SHP-1 in a phospholipase C (PLC)-β3-dependent manner. Thus, PLC-β3-deficient mice develop myeloproliferative neoplasm, like Lyn (Src family kinase)- deficient mice. Here we show that Lyn/PLC-β3 doubly deficient lyn(-/-);PLC-β3(-/-) mice develop a Stat5-dependent, fatal myelodysplastic/myeloproliferative neoplasm, similar to human chronic myelomonocytic leukemia (CMML). In hematopoietic stem cells of lyn(-/-);PLC-β3(-/-) mice that cause the CMML-like disease, phosphorylation of SHP-1 at Tyr(536) and Tyr(564) is abrogated, resulting in reduced phosphatase activity and constitutive activation of Stat5. Furthermore, SHP-1 phosphorylation at Tyr(564) by Lyn is indispensable for maximal phosphatase activity and for suppression of the CMML-like disease in these mice. On the other hand, Tyr(536) in SHP-1 can be phosphorylated by Lyn and another kinase(s) and is necessary for efficient interaction with Stat5. Therefore, we identify a novel Lyn/PLC-β3-mediated regulatory mechanism of SHP-1 and Stat5 activities.

  7. IL-21 promotes the production of anti-DNA IgG but is dispensable for kidney damage in lyn-/- mice.

    Science.gov (United States)

    Gutierrez, Toni; Mayeux, Jessica M; Ortega, Sterling B; Karandikar, Nitin J; Li, Quan-Zhen; Rakheja, Dinesh; Zhou, Xin J; Satterthwaite, Anne B

    2013-02-01

    The autoimmune disease systemic lupus erythematosus is characterized by loss of tolerance to nuclear Ags and a heightened inflammatory environment, which together result in end organ damage. Lyn-deficient mice, a model of systemic lupus erythematosus, lack an inhibitor of B-cell and myeloid cell activation. This results in B-cell hyper-responsiveness, plasma cell accumulation, autoantibodies, and glomerulonephritis (GN). IL-21 is associated with autoimmunity in mice and humans and promotes B-cell differentiation and class switching. Here, we explore the role of IL-21 in the autoimmune phenotypes of lyn(-/-) mice. We find that IL-21 mRNA is reduced in the spleens of lyn(-/-) IL-6(-/-) and lyn(-/-) Btk(lo) mice, neither of which produce pathogenic autoantibodies or develop significant GN. While IL-21 is dispensable for plasma cell accumulation and IgM autoantibodies in lyn(-/-) mice, it is required for anti-DNA IgG antibodies and some aspects of T-cell activation. Surprisingly, GN still develops in lyn(-/-) IL-21(-/-) mice. This likely results from the presence of IgG autoantibodies against a limited set of non-DNA Ags. These studies identify a specific role for IL-21 in the class switching of anti-DNA B cells and demonstrate that neither IL-21 nor anti-DNA IgG is required for kidney damage in lyn(-/-) mice.

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

    CERN Multimedia

    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 ...

  9. Differential mitotic activation of endogenous c-Src, c-Yes, and Lyn in HeLa cells.

    Science.gov (United States)

    Kuga, Takahisa; Nakayama, Yuji; Hoshino, Masaki; Higashiyama, Yukihiro; Obata, Yuuki; Matsuda, Daisuke; Kasahara, Kousuke; Fukumoto, Yasunori; Yamaguchi, Naoto

    2007-10-01

    Src-family tyrosine kinases (SFKs) play an important role in mitosis. Despite overlapping expression of multiple SFK members, little is known about how individual SFK members are activated in M phase. Here, we examined mitotic activation of endogenous c-Src, c-Yes, and Lyn, which are co-expressed in HeLa cells. c-Src, c-Yes, and Lyn were activated at different levels in M phase, and the activation was inhibited by Cdc2 inactivation. Mitotic c-Src and c-Yes exhibited normal- and retarded-electrophoretic-mobility forms on SDS-polyacrylamide gels, whereas Lyn did not show mobility retardation. Like c-Src, the retardation of electrophoretic mobility of c-Yes was caused by Cdc2-mediated phosphorylation. The normal- and retarded-mobility forms of c-Src were comparably activated, but activation of the retarded-mobility form of c-Yes was higher than that of the normal-mobility form of c-Yes. Thus, these results suggest that endogenous c-Src, c-Yes, and Lyn are differentially activated through Cdc2 activation during M phase.

  10. 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....... In particular, protein substrates between 50 and 140 kDa appeared to be selectively phosphorylated by TPO. We demonstrated that Jak2, Stat3 and Shc were activated in B1647 cells after TPO, as already shown for different cell lines by other authors. Moreover, Lyn kinase activation was detected. Grb2 co...... 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...

  11. Direct interaction of Syk and Lyn protein tyrosine kinases in rat basophilic leukemia cells activated via type I Fc epsilon receptors.

    Science.gov (United States)

    Amoui, M; Dráberová, L; Tolar, P; Dráber, P

    1997-01-01

    Activation of rat mast cells through the receptor with high affinity for IgE (Fc epsilonRI) requires a complex set of interactions involving transmembrane subunits of the Fc epsilonRI and two classes of nonreceptor protein tyrosine kinase (PTK). the Src family PTK p53/p56(lyn) (Lyn) and the Syk/ZAP-family PTK p72(syk) (Syk). Early activation events involve increased activity of Lyn and Syk kinases and their translocation into membrane domains containing aggregated Fc epsilonRI, but the molecular mechanisms responsible for these changes have remained largely unclear. To determine the role of Fc epsilonRI subunits in this process, we have analyzed Syk- and Lyn-associated proteins in activated rat basophilic leukemia (RBL) cells and their variants deficient in the expression of Fc epsilonRI beta or gamma subunits. Sepharose 4B gel chromatography of postnuclear supernatants from Nonidet-P40-solubilized antigen (Ag)- or pervanadate-activated RBL cells revealed extensive changes in the size of complexes formed by Lyn and Syk kinases and other cellular components. A fusion protein containing Src homology 2 (SH2) and SH3 domains of Lyn bound Syk from lysates of nonactivated RBL cells; an increased binding was observed when lysates from Ag- or pervanadate-activated cells were used. A similar amount of Syk was bound when lysates from pervanadate-activated variant cells deficient in the expression of Fc epsilonRI beta or gamma subunits were used, suggesting that Fc epsilonRI does not function as the only intermediate in the formation of the Syk-Lyn complexes. Further experiments have indicated that Syk-Lyn interactions occur in Ag-activated RBL cells under in vivo conditions and that these interactions could involve direct binding of the Lyn SH2 domain with phosphorylated tyrosine of Syk. The physical association of Lyn and Syk during mast-like cell activation supports the recently proposed functional cooperation of these two tyrosine kinases in Fc epsilonRI signaling.

  12. Differential trafficking of Src, Lyn, Yes and Fyn is specified by the state of palmitoylation in the SH4 domain.

    Science.gov (United States)

    Sato, Izumi; Obata, Yuuki; Kasahara, Kousuke; Nakayama, Yuji; Fukumoto, Yasunori; Yamasaki, Takahito; Yokoyama, Kazunari K; Saito, Takashi; Yamaguchi, Naoto

    2009-04-01

    Src-family tyrosine kinases (SFKs), which participate in a variety of signal transduction events, are known to localize to the cytoplasmic face of the plasma membrane through lipid modification. Recently, we showed that Lyn, an SFK member, is exocytosed to the plasma membrane via the Golgi region along the secretory pathway. We show here that SFK trafficking is specified by the palmitoylation state. Yes is also a monopalmitoylated SFK and is biosynthetically transported from the Golgi pool of caveolin to the plasma membrane. This pathway can be inhibited in the trans-Golgi network (TGN)-to-cell surface delivery by temperature block at 19 degrees C or dominant-negative Rab11 GTPase. A large fraction of Fyn, a dually palmitoylated SFK, is directly targeted to the plasma membrane irrespective of temperature block of TGN exit. Fyn(C6S), which lacks the second palmitoylation site, is able to traffic in the same way as Lyn and Yes. Moreover, construction of Yes(S6C) and chimeric Lyn or Yes with the Fyn N-terminus further substantiates the importance of the dual palmitoylation site for plasma membrane targeting. Taken together with our recent finding that Src, a nonpalmitoylated SFK, is rapidly exchanged between the plasma membrane and late endosomes/lysosomes, these results suggest that SFK trafficking is specified by the palmitoylation state in the SH4 domain.

  13. The cysteine-cluster motif of c-Yes, Lyn and FAK as a suppressive module for the kinases.

    Science.gov (United States)

    Rahman, Mohammad Aminur; Senga, Takeshi; Oo, Myat Lin; Hasegawa, Hitoki; Biswas, Md Helal Uddin; Mon, Naing Naing; Huang, Pengyu; Ito, Satoko; Yamamoto, Tadashi; Hamaguchi, Michinari

    2008-04-01

    The Src family of non-receptor protein tyrosine kinases plays a critical role in the progression of human cancers so that the development of its specific inhibitors is important as a therapeutic tool. We previously reported that cysteine residues in the cysteine-cluster (CC) motif of v-Src were critical for the kinase inactivation by the SH-alkylating agents such as N-(9-acridinyl) maleimide (NAM), whereas other cysteine residues were dispensable. We found similar CC-motifs in other Src-family kinases and a non-Src-family kinase, FAK. In this study, we explored the function of the CC-motif in Yes, Lyn and FAK. While Src has four cysteines in the CC-motif, c-Yes and Lyn have three and two of the four cysteines, respectively. Two conserved cysteines of the Src family kinases, corresponding to Cys487 and Cys498 of Src, were essential for the resistance to the inactivation of the kinase activity by NAM, whereas the first cysteine of c-Yes, which is absent in Lyn, was less important. FAK has similar CC-motifs with two cysteines and both cysteines were again essential for the resistance to the inactivation of the kinase activity by NAM. Taken together, modification of cysteine residues of the CC-motif causes a repressor effect on the catalytic activity of the Src family kinases and FAK.

  14. Lyn- and PLC-β3–dependent regulation of SHP-1 phosphorylation controls Stat5 activity and myelomonocytic leukemia-like disease

    Science.gov (United States)

    Xiao, Wenbin; Ando, Tomoaki; Wang, Huan-You; Kawakami, Yuko

    2010-01-01

    Hyperactivation of the transcription factor Stat5 leads to various leukemias. Stat5 activity is regulated by the protein phosphatase SHP-1 in a phospholipase C (PLC)–β3-dependent manner. Thus, PLC-β3–deficient mice develop myeloproliferative neoplasm, like Lyn (Src family kinase)– deficient mice. Here we show that Lyn/PLC-β3 doubly deficient lyn−/−;PLC-β3−/− mice develop a Stat5-dependent, fatal myelodysplastic/myeloproliferative neoplasm, similar to human chronic myelomonocytic leukemia (CMML). In hematopoietic stem cells of lyn−/−;PLC-β3−/− mice that cause the CMML-like disease, phosphorylation of SHP-1 at Tyr536 and Tyr564 is abrogated, resulting in reduced phosphatase activity and constitutive activation of Stat5. Furthermore, SHP-1 phosphorylation at Tyr564 by Lyn is indispensable for maximal phosphatase activity and for suppression of the CMML-like disease in these mice. On the other hand, Tyr536 in SHP-1 can be phosphorylated by Lyn and another kinase(s) and is necessary for efficient interaction with Stat5. Therefore, we identify a novel Lyn/PLC-β3–mediated regulatory mechanism of SHP-1 and Stat5 activities. PMID:20858858

  15. 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

    2011-07-01

    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 G(i)-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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Fukumoto, Yasunori, E-mail: fukumoto@faculty.chiba-u.jp; Kuki, Kazumasa; Morii, Mariko; Miura, Takahito; Honda, Takuya; Ishibashi, Kenichi; Hasegawa, Hitomi; Kubota, Sho; Ide, Yudai; Yamaguchi, Noritaka; Nakayama, Yuji; Yamaguchi, Naoto, E-mail: nyama@faculty.chiba-u.jp

    2014-09-26

    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.

  18. 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

  19. 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.

  20. MD-2 interacts with Lyn kinase and is tyrosine phosphorylated following LPS-induced activation of the Toll-like receptor 4 signaling pathway

    Science.gov (United States)

    Gray, Pearl; Dagvadorj, Jargalsaikhan; Michelsen, Kathrin S.; Brikos, Constantinos; Rentsendorj, Altan; Town, Terrence; Crother, Timothy R.; Arditi, Moshe

    2011-01-01

    Stimulation with LPS induces tyrosine phosphorylation of numerous proteins involved in the TLR signaling pathway. In this study, we demonstrate that MD-2 is also tyrosine phosphorylated following LPS stimulation. LPS-induced tyrosine phosphorylation of MD-2 is specific, it is blocked by the tyrosine kinase inhibitor, Herbimycin A, and by an inhibitor of endocytosis, Cytochalsin-D, suggesting that MD-2 phosphorylation occurs during trafficking of MD2 and not on cell surface. Furthermore, we identify two possible phospho-accepting tyrosine residues at positions 22 and 131. Mutant proteins in which these tyrosines were changed to phenylalanine have reduced phosphorylation and significantly diminished ability to activate NF-κB in response to LPS. In addition, MD2 co-precipitates and colocalizes with Lyn kinase, most likely in ER. A Lyn-binding peptide inhibitor abolished MD2 tyrosine phosphorylation, suggesting that Lyn is a likely candidate to be the kinase required for MD-2 tyrosine phophorylation. Our study demonstrates that tyrosine phosphorylation of MD-2 is important for signaling following exposure to LPS and underscores the importance of this event in mediating an efficient and prompt immune response. PMID:21918188

  1. Myeloid differentiation factor-2 interacts with Lyn kinase and is tyrosine phosphorylated following lipopolysaccharide-induced activation of the TLR4 signaling pathway.

    Science.gov (United States)

    Gray, Pearl; Dagvadorj, Jargalsaikhan; Michelsen, Kathrin S; Brikos, Constantinos; Rentsendorj, Altan; Town, Terrence; Crother, Timothy R; Arditi, Moshe

    2011-10-15

    Stimulation with LPS induces tyrosine phosphorylation of numerous proteins involved in the TLR signaling pathway. In this study, we demonstrated that myeloid differentiation factor-2 (MD-2) is also tyrosine phosphorylated following LPS stimulation. LPS-induced tyrosine phosphorylation of MD-2 is specific; it is blocked by the tyrosine kinase inhibitor, herbimycin A, as well as by an inhibitor of endocytosis, cytochalasin D, suggesting that MD-2 phosphorylation occurs during trafficking of MD-2 and not on the cell surface. Furthermore, we identified two possible phospho-accepting tyrosine residues at positions 22 and 131. Mutant proteins in which these tyrosines were changed to phenylalanine had reduced phosphorylation and significantly diminished ability to activate NF-κB in response to LPS. In addition, MD-2 coprecipitated and colocalized with Lyn kinase, most likely in the endoplasmic reticulum. A Lyn-binding peptide inhibitor abolished MD-2 tyrosine phosphorylation, suggesting that Lyn is a likely candidate to be the kinase required for MD-2 tyrosine phosphorylation. Our study demonstrated that tyrosine phosphorylation of MD-2 is important for signaling following exposure to LPS and underscores the importance of this event in mediating an efficient and prompt immune response.

  2. A novel Lyn-protein kinase Cδ/ε-protein kinase D axis is activated in B cells by signalosome-independent alternate pathway BCR signaling.

    Science.gov (United States)

    Guo, Benchang; Rothstein, Thomas L

    2013-06-01

    BCR signaling initiates multiple activities critical for B-cell function. Recently, we identified an alternate BCR signaling pathway, induced by IL-4, that is signalosome-independent, unlike the classical signalosome-dependent pathway, and that leads to activation of the MAP kinase, ERK. Here we questioned whether alternate pathway signaling extends to other key downstream events, especially protein kinase D (PKD) activation. We found that in murine spleen-derived B cells the IL-4-induced alternate pathway for BCR signaling results in PKD and PKD substrate phosphorylation, and that alternate pathway phosphorylation of HDAC5/7 and other key substrates requires PKD. Furthermore, we found that tyrosine phosphorylation of PKCδ/ε occurs as a result of alternate but not classical pathway signaling and is required for phosphorylation of PKD and PKD substrates. This result identifies PKCδ/ε tyrosine phosphorylation as a unique outcome of the alternate pathway. The alternate pathway is mediated by Lyn that is not required for classical pathway signaling and we found that Lyn associates directly with PKCδ/ε and is required for phosphorylation of PKCδ/ε and of PKD. These findings indicate that IL-4 influences B-cell activation by inducing a novel signaling pathway from BCR to Lyn to PKCδ/ε to PKD.

  3. A PrP(C)-caveolin-Lyn complex negatively controls neuronal GSK3β and serotonin 1B receptor.

    Science.gov (United States)

    Hernandez-Rapp, Julia; Martin-Lannerée, Séverine; Hirsch, Théo Z; Pradines, Elodie; Alleaume-Butaux, Aurélie; Schneider, Benoît; Baudry, Anne; Launay, Jean-Marie; Mouillet-Richard, Sophie

    2014-05-08

    The cellular prion protein, PrP(C), is a glycosylphosphatidylinositol-anchored protein, abundant in lipid rafts and highly expressed in the brain. While PrP(C) is much studied for its involvement under its abnormal PrP(Sc) isoform in Transmissible Spongiform Encephalopathies, its physiological role remains unclear. Here, we report that GSK3β, a multifunctional kinase whose inhibition is neuroprotective, is a downstream target of PrP(C) signalling in serotonergic neuronal cells. We show that the PrP(C)-dependent inactivation of GSK3β is relayed by a caveolin-Lyn platform located on neuronal cell bodies. Furthermore, the coupling of PrP(C) to GSK3β potentiates serotonergic signalling by altering the distribution and activity of the serotonin 1B receptor (5-HT1BR), a receptor that limits neurotransmitter release. In vivo, our data reveal an increased GSK3β kinase activity in PrP-deficient mouse brain, as well as sustained 5-HT1BR activity, whose inhibition promotes an anxiogenic behavioural response. Collectively, our data unveil a new facet of PrP(C) signalling that strengthens neurotransmission.

  4. Leukaemic cells from chronic lymphocytic leukaemia patients undergo apoptosis following microtubule depolymerization and Lyn inhibition by nocodazole.

    Science.gov (United States)

    Frezzato, Federica; Trimarco, Valentina; Martini, Veronica; Gattazzo, Cristina; Ave, Elisa; Visentin, Andrea; Cabrelle, Anna; Olivieri, Valeria; Zambello, Renato; Facco, Monica; Zonta, Francesca; Cristiani, Andrea; Brunati, Anna Maria; Moro, Stefano; Semenzato, Gianpietro; Trentin, Livio

    2014-06-01

    Functional abnormalities of chronic lymphocytic leukaemia (CLL) cells may be related to the microtubular network of cell cytoskeleton; specifically tubulin involvement in cells after B-cell receptor engagement. As microtubule inhibitors could represent a therapeutic strategy for CLL, this study investigated the capability of nocodazole, a synthetic depolymerizing agent, to kill CLL leukaemic cells. We demonstrated that nocodazole was highly specific for the in vitro induction of apoptosis in leukaemic cells from 90 CLL patients, without affecting the viability of T-cells and/or mesenchymal stromal cells (MSCs) recovered from the same patients. Nocodazole was observed to overcome the pro-survival signals provided by MSCs. Competing with ATP for the nucleotide-binding site, nocodazole has been observed to turn off the high basal tyrosine phosphorylation of leukaemic cells mediated by the Src-kinase Lyn. Considering that most anti-microtubule drugs have limited clinical use because of their strong toxic effects, the high selectivity of nocodazole for leukaemic cells in CLL and its capability to bypass microenvironmental pro-survival stimuli, suggests the use of this inhibitor for designing new therapeutic strategies in CLL treatment.

  5. 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.

  6. 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, highlightin

  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

    Crosslinking of major histocompatibility complex class I (MHC-I) molecules on the surface of human B lymphoma cells was shown to induce protein tyrosine phosphorylation and mobilization of intracellular free calcium. Immunoprecipitations indicated that the protein tyrosine kinases p53/56lyn and p72...... and the results indicate that these two kinases have different substrate specificity and regulate intracellular free calcium differently in response to MHC-I crosslinking. In addition MHC-I crosslinking of a sIgM-negative DT40 chicken B cell variant results in less activity of tyrosine kinases and less...... 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. First analysis of eight Algol-type binaries: EI Aur, XY Dra, BP Dra, DD Her, VX Lac, WX Lib, RZ Lyn, and TY Tri

    CERN Document Server

    Zasche, P

    2015-01-01

    The available photometry from the online databases were used for the first light curve analysis of eight eclipsing binary systems EI Aur, XY Dra, BP Dra, DD Her, VX Lac, WX Lib, RZ Lyn, and TY Tri. All these stars are of Algol-type, having the detached components and the orbital periods from 0.92 to 6.8 days. For the systems EI Aur and BP Dra the large amount of the third light was detected during the light curve solution. Moreover, 468 new times of minima for these binaries were derived, trying to identify the period variations. For the systems XY Dra and VX Lac the third bodies were detected with the periods 17.7, and 49.3 years, respectively.

  9. Platelet Activation and Thrombus Formation over IgG Immune Complexes Requires Integrin αIIbβ3 and Lyn Kinase.

    Science.gov (United States)

    Zhi, Huiying; Dai, Jing; Liu, Junling; Zhu, Jieqing; Newman, Debra K; Gao, Cunji; Newman, Peter J

    2015-01-01

    IgG immune complexes contribute to the etiology and pathogenesis of numerous autoimmune disorders, including heparin-induced thrombocytopenia, systemic lupus erythematosus, rheumatoid- and collagen-induced arthritis, and chronic glomerulonephritis. Patients suffering from immune complex-related disorders are known to be susceptible to platelet-mediated thrombotic events. Though the role of the Fc receptor, FcγRIIa, in initiating platelet activation is well understood, the role of the major platelet adhesion receptor, integrin αIIbβ3, in amplifying platelet activation and mediating adhesion and aggregation downstream of encountering IgG immune complexes is poorly understood. The goal of this investigation was to gain a better understanding of the relative roles of these two receptor systems in immune complex-mediated thrombotic complications. Human platelets, and mouse platelets genetically engineered to differentially express FcγRIIa and αIIbβ3, were allowed to interact with IgG-coated surfaces under both static and flow conditions, and their ability to spread and form thrombi evaluated in the presence and absence of clinically-used fibrinogen receptor antagonists. Although binding of IgG immune complexes to FcγRIIa was sufficient for platelet adhesion and initial signal transduction events, platelet spreading and thrombus formation over IgG-coated surfaces showed an absolute requirement for αIIbβ3 and its ligands. Tyrosine kinases Lyn and Syk were found to play key roles in IgG-induced platelet activation events. Taken together, our data suggest a complex functional interplay between FcγRIIa, Lyn, and αIIbβ3 in immune complex-induced platelet activation. Future studies may be warranted to determine whether patients suffering from immune complex disorders might benefit from treatment with anti-αIIbβ3-directed therapeutics.

  10. Platelet Activation and Thrombus Formation over IgG Immune Complexes Requires Integrin αIIbβ3 and Lyn Kinase.

    Directory of Open Access Journals (Sweden)

    Huiying Zhi

    Full Text Available IgG immune complexes contribute to the etiology and pathogenesis of numerous autoimmune disorders, including heparin-induced thrombocytopenia, systemic lupus erythematosus, rheumatoid- and collagen-induced arthritis, and chronic glomerulonephritis. Patients suffering from immune complex-related disorders are known to be susceptible to platelet-mediated thrombotic events. Though the role of the Fc receptor, FcγRIIa, in initiating platelet activation is well understood, the role of the major platelet adhesion receptor, integrin αIIbβ3, in amplifying platelet activation and mediating adhesion and aggregation downstream of encountering IgG immune complexes is poorly understood. The goal of this investigation was to gain a better understanding of the relative roles of these two receptor systems in immune complex-mediated thrombotic complications. Human platelets, and mouse platelets genetically engineered to differentially express FcγRIIa and αIIbβ3, were allowed to interact with IgG-coated surfaces under both static and flow conditions, and their ability to spread and form thrombi evaluated in the presence and absence of clinically-used fibrinogen receptor antagonists. Although binding of IgG immune complexes to FcγRIIa was sufficient for platelet adhesion and initial signal transduction events, platelet spreading and thrombus formation over IgG-coated surfaces showed an absolute requirement for αIIbβ3 and its ligands. Tyrosine kinases Lyn and Syk were found to play key roles in IgG-induced platelet activation events. Taken together, our data suggest a complex functional interplay between FcγRIIa, Lyn, and αIIbβ3 in immune complex-induced platelet activation. Future studies may be warranted to determine whether patients suffering from immune complex disorders might benefit from treatment with anti-αIIbβ3-directed therapeutics.

  11. Evidence for the involvement of p59fyn and p53/56lyn in collagen receptor signalling in human platelets.

    Science.gov (United States)

    Briddon, S J; Watson, S P

    1999-02-15

    The binding of collagen to platelet glycoprotein VI (GPVI) leads to the subsequent activation of phospholipase Cgamma2 through a pathway that is dependent on the Fc receptor gamma (FcR gamma) chain and the tyrosine kinase p72syk. We have investigated the role of platelet Src-family kinases in this signalling pathway. The selective Src-family kinase inhibitor PP1 prevented collagen-stimulated increases in whole-cell tyrosine phosphorylation and tyrosine phosphorylation of the FcR gamma chain and p72syk. A similar set of observations was made for a collagen-related peptide (CRP), which binds to GPVI but not to the integrin alpha2beta1 (GPIa/IIa). These effects were seen at a concentration of PP1 that inhibited platelet aggregation, dense granule release and Ca2+ mobilization induced by CRP, but not aggregation and Ca2+ mobilization mediated by the G-protein-coupled receptor agonist thrombin. After stimulation by CRP or collagen, the Src-family kinases p59fyn and p53/56lyn became associated with several tyrosine-phosphorylated proteins including the FcR gamma chain. This was not true of the other platelet Src-family kinases. The association between the FcR gamma chain and p59fyn was also seen under basal conditions, and was stable only in the weak detergent Brij96 but not in Nonidet P40, suggesting a non-SH2-dependent interaction. These results provide strong evidence for the involvement of p59fyn and p53/56lyn in signalling via GPVI, with p59fyn possibly acting upstream of FcR gamma chain phosphorylation.

  12. 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

  13. “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.

  14. Physical and functional association of the Src family kinases Fyn and Lyn with the collagen receptor glycoprotein VI-Fc receptor gamma chain complex on human platelets.

    Science.gov (United States)

    Ezumi, Y; Shindoh, K; Tsuji, M; Takayama, H

    1998-07-20

    We have previously shown that uncharacterized glycoprotein VI (GPVI), which is constitutively associated and coexpressed with Fc receptor gamma chain (FcRgamma) in human platelets, is essential for collagen-stimulated tyrosine phosphorylation of FcRgamma, Syk, and phospholipase Cgamma2 (PLCgamma2), leading to platelet activation. Here we investigated involvement of the Src family in the proximal signals through the GPVI-FcRgamma complex, using the snake venom convulxin from Crotalus durissus terrificus, which specifically recognizes GPVI and activates platelets through cross-linking GPVI. Convulxin-coupled beads precipitated the GPVI-FcRgamma complex from platelet lysates. Collagen and convulxin induced tyrosine phosphorylation of FcRgamma, Syk, and PLCgamma2 and recruited tyrosine-phosphorylated Syk to the GPVI-FcRgamma complex. Using coprecipitation methods with convulxin-coupled beads and antibodies against FcRgamma and the Src family, we showed that Fyn and Lyn, but not Yes, Src, Fgr, Hck, and Lck, were physically associated with the GPVI-FcRgamma complex irrespective of stimulation. Furthermore, Fyn was rapidly activated by collagen or cross-linking GPVI. The Src family-specific inhibitor PP1 dose-dependently inhibited collagen- or convulxin-induced tyrosine phosphorylation of proteins including FcRgamma, Syk, and PLCgamma2, accompanied by a loss of aggregation and ATP release reaction. These results indicate that the Src family plays a critical role in platelet activation via the collagen receptor GPVI-FcRgamma complex.

  15. Physical and Functional Association of the Src Family Kinases Fyn and Lyn with the Collagen Receptor Glycoprotein VI-Fc Receptor γ Chain Complex on Human Platelets

    Science.gov (United States)

    Ezumi, Yasuharu; Shindoh, Keisuke; Tsuji, Masaaki; Takayama, Hiroshi

    1998-01-01

    We have previously shown that uncharacterized glycoprotein VI (GPVI), which is constitutively associated and coexpressed with Fc receptor γ chain (FcRγ) in human platelets, is essential for collagen-stimulated tyrosine phosphorylation of FcRγ, Syk, and phospholipase Cγ2 (PLCγ2), leading to platelet activation. Here we investigated involvement of the Src family in the proximal signals through the GPVI–FcRγ complex, using the snake venom convulxin from Crotalus durissus terrificus, which specifically recognizes GPVI and activates platelets through cross-linking GPVI. Convulxin-coupled beads precipitated the GPVI–FcRγ complex from platelet lysates. Collagen and convulxin induced tyrosine phosphorylation of FcRγ, Syk, and PLCγ2 and recruited tyrosine-phosphorylated Syk to the GPVI–FcRγ complex. Using coprecipitation methods with convulxin-coupled beads and antibodies against FcRγ and the Src family, we showed that Fyn and Lyn, but not Yes, Src, Fgr, Hck, and Lck, were physically associated with the GPVI–FcRγ complex irrespective of stimulation. Furthermore, Fyn was rapidly activated by collagen or cross-linking GPVI. The Src family–specific inhibitor PP1 dose-dependently inhibited collagen- or convulxin-induced tyrosine phosphorylation of proteins including FcRγ, Syk, and PLCγ2, accompanied by a loss of aggregation and ATP release reaction. These results indicate that the Src family plays a critical role in platelet activation via the collagen receptor GPVI–FcRγ complex. PMID:9670039

  16. Kaposi's Sarcoma Associated Herpesvirus Induces LYN Overexpression in Kaposis Sarcoma%Kaposi肉瘤相关疱疹病毒感染诱导LYN表达在其发病中的作用

    Institute of Scientific and Technical Information of China (English)

    张芳; 陈颖; 郭峰; 徐益明; 谭晓华; 杨磊; 李锋; 姬玉; 李冬妹

    2016-01-01

    Objective To analyze the function of Kaposi's Sarcoma associated herpesvirus (KSHV) infection in the expression of v-yes-1 Yamaguchi sarcoma viral related oncogene homolog (lyn) and reveal the mechanism in Kaposis Sarcoma (KS).Methods Primary human umbilical vein endothelial cells (HUVECs) were cultivated by enzyme infusion method and immunocytochemistry (ICC) was used to detect CD31 and CD34 to verify HUVECs.KSHV were extracted from BCBL-1 cells, then used to infect HUVECs.We observed the cell morphology variation using microscope and recorded imagines.PCR was used to amplificate KS330233 fragment to verify the infection.Western blot was used to detect the level of LYN, p-PI3K and p-AKT.Results HUVECs were cytomembrane staining for CD31 and cytoplasmic staining for CD34, which verified that the primary cultivated cells were HUVECs.After KSHV infected HUVECs, the cells showed long spindle morphology.The expression of LYN was increase and the expression of p-PI3K and p-AKT was also increased.Conclusion KSHV promoted overexpression of LYN in KSHV de novo infected HUVECs and increased the level of p-PI3K as well as p-AKT in PI3K/AKT signaling pathway.%目的 探讨Kaposi肉瘤相关疱疹病毒(kaposi's sarcoma associated herpesvirus,KSHV)感染对v-yes-1 Yamaguchi肉瘤病毒相关同源癌基因(v-yes-1 Yamaguchi sarcoma viral related oncogene homolog,LYN)表达的影响,及其在卡波氏肉瘤(kaposi's sarcoma,KS)发病机制中的作用.方法 采用酶灌注法原代培养脐静脉内皮细胞(human umbilical vein endothelial cells,HUVECs),运用免疫细胞化学检测CD34和CD31以验证HUVECs.从BCBL-1中提取KSHV病毒感染HUVECs,显微镜下观察细胞形态并拍照,PCR扩增KS330233证实感染成功.采用Western blot检测LYN表达及p-PI3K和p-AKT水平.结果 HUVECs中CD 31胞膜阳性和CD 34胞浆阳性,说明酶灌注法取得的细胞为HUVECs.KSHV感染HUVECs后细胞变为长梭形,LYN表达增高,同时p-PI3K

  17. 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 .

  18. Role of Lyn kinase and endoplasmic reticulum stress in allergic bronchial asthma%Lyn激酶和内质网应激在过敏性支气管哮喘中的作用

    Institute of Scientific and Technical Information of China (English)

    伍娟; 杨小琼

    2016-01-01

    Bronchial asthma is an airway inflammatory disease which many kinds of cells and cellular compo-nents are involved in. It is characterized by airway inflammation, airway remodeling and airway hyperresponsiveness. However, the pathogenesis of bronchial asthma is very complex. Therefore in this paper, the important roles of Lyn ki-nase and endoplasmic reticulum stress in the pathogenesis of bronchial asthma are reviewed.%支气管哮喘是多种细胞及细胞组分参与的气道炎症性疾病,主要以气道炎症和气道重塑、气道高反应性为特征;然而其发病机制十分复杂,本文对Lyn激酶和内质网应激在支气管哮喘的发病机制中的重要作用进行综述.

  19. 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.

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

    CERN Multimedia

    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...

  1. Erythrocyte membrane changes of chorea-acanthocytosis are the result of altered Lyn kinase activity

    NARCIS (Netherlands)

    Franceschi, L. de; Tomelleri, C.; Matte, A.; Brunati, A.M.; Bovee-Geurts, P.H.M.; Bertoldi, M.; Lasonder, E.; Tibaldi, E.; Danek, A.; Walker, R.H.; Jung, H.H.; Bader, B.; Siciliano, A.; Ferru, E.; Mohandas, N.; Bosman, G.J.C.G.M.

    2011-01-01

    Acanthocytic RBCs are a peculiar diagnostic feature of chorea-acanthocytosis (ChAc), a rare autosomal recessive neurodegenerative disorder. Although recent years have witnessed some progress in the molecular characterization of ChAc, the mechanism(s) responsible for generation of acanthocytes in ChA

  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......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 V......-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...

  3. 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 ...

  4. Folic acid-conjugated MnO nanoparticles as a T1 contrast agent for magnetic resonance imaging of tiny brain gliomas.

    Science.gov (United States)

    Chen, Ning; Shao, Chen; Qu, Yanming; Li, Shuai; Gu, Wei; Zheng, Tingting; Ye, Ling; Yu, Chunjiang

    2014-11-26

    Detection of brain gliomas at the earliest stage is of great importance to improve outcomes, but it remains a most challenging task. In this study, oleic acid capped manganese oxide (MnO) nanoparticles (NPs) were prepared by the thermal decomposition of manganese oleate precursors and then transformed to water-dispersible MnO NPs by replacing oleic acid with N-(trimethoxysilylpropyl) ethylene diamine triacetic acid (TETT) silane. The covalently bonded TETT silane offers MnO NPs colloidal stability and abundant carboxylic functional groups allowing the further conjugation of the glioma-specific moiety, folic acid (FA). Moreover, the thin layer of TETT silane ensures a short distance between external Mn ion and water proton, which endows the FA-conjugated, TETT modified MnO (MnO-TETT-FA) NPs a longitudinal relaxivity as high as 4.83 mM(-1) s(-1). Accordingly, the in vivo magnetic resonance (MR) images demonstrated that MnO-TETT-FA NPs could efficiently enhance the MRI contrast for tiny brain gliomas. More importantly, due to the specificity of FA, MnO-TETT-FA NPs led to a clearer margin of the tiny glioma. This together with the good biocompatibility discloses the great potential of MnO-TETT-FA NPs as effective MRI contrast agents for the early diagnosis of brain gliomas.

  5. 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)

  6. Op loop met ’n lyn: T.T. Cloete se “toepassings van dante” ikonies en intertekstueel gelees

    Directory of Open Access Journals (Sweden)

    H.J.G. Du Plooy

    2008-07-01

    Full Text Available Taking a line for a walk: an iconic and intertextual reading of T.T. Cloete’s “toepassings van dante” (“applications of dante” The cycle of poems in T.T. Cloete’s “toepassings van dante” (“applications of dante” has iconic characteristics but also resonates within wider intertextual and cultural spheres. The interpretation of the poems presented in this article attempts to incorporate textual aspects such as iconicity, referentiality, selfreferentiality and representation as well as the intertextual and cultural meanings generated by the texts. The poems refer directly to Dante’s “Paradiso”, activating the codes of chivalry which informed medieval poetry, but the strong visual nature of the poems also leads the reader to Paul Klee’s esthetic and visual principles and Bachelard’s views on form and space. The coherence as well as the development of themes are discussed. Line, movement and form are depicted as dynamic aspects of creativity but ultimately the paradoxical relation between beauty and functionality is thematised. Nevertheless, it is emphasised that even in the interpretation of the multilayered meanings of the texts, the referential nature of language and the iconic nature of the text are basic and therefore essential aspects of the generation of meaning.

  7. 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

  8. 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...

  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. [Clinical burden of multi-cause and pneumococcal pneumonia, meningitis, and septicemia in Hungary. Results of a retrospective study (2006-2011)].

    Science.gov (United States)

    Ludwig, Endre; Jorgensen, Lindsay; Gray, Sharon; Munson, Samantha; Chou, Kathy; Gutterman, Elane M

    2014-09-07

    Bevezetés: Kevés adat áll rendelkezésre a konjugált pneumococcusvakcináknak a pneumonia, meningitis és septikaemia előfordulására gyakorolt hatásáról Magyarországon. Célkitűzés: A szerzők retrospektív vizsgálattal kívánták felmérni a 2006–2011 között Magyarországon minden korosztályban előforduló, kórházi kezelést igénylő, bármely kórokú és pneumococcus okozta pneumonia-, meningitis- és septikaemiaeseteket. Módszer: Összesített adatokat gyűjtöttek az Országos Egészségbiztosítási Pénztár adatbázisából előre meghatározott BNO-10-kódok segítségével. Az összehasonlítás χ2-próba segítségével készült a következők alapján: átlagos arány a védőoltás bevezetését megelőzően (2006–2007) versus átlagos arány a védőoltás bevezetését követően (2010–2011). Eredmények: A 0–4 éves korú gyermekeknél a kórházi kezelést igénylő esetek aránya jelentősen csökkent a bármely kórokú tüdőgyulladás és agyhártyagyulladás esetében, de nőtt a septikaemia esetében. A többi korcsoportnál jelentősen növekedett a bármely kórokú pneumonia- és septikaemiaesetek száma. A kórházi halálozás aránya az életkorral emelkedett. A pneumococcusspecifikus kódok korlátozott alkalmazása miatt nem állapítottak meg egyértelmű eredményeket a pneumococcus okozta betegségeket illetően. Következtetések: A bármely kórokú tüdőgyulladás és agyhártyagyulladás csökkenése a 0–4 éves korosztálynál a konjugált pneumococcusvakcinációnak a kórházi kezelés arányára gyakorolt közvetlen hatására utal. Orv. Hetil., 2014, 155(36), 1426–1436.

  11. 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...

  12. 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.

  13. Dysregulation of Src family kinases in mast cells from epilepsy-resistant ASK versus epilepsy-prone EL mice.

    Science.gov (United States)

    Kitaura, Jiro; Kawakami, Yuko; Maeda-Yamamoto, Mari; Horejsi, Vaclav; Kawakami, Toshiaki

    2007-01-01

    EL mice have been used as a model of epilepsy, whereas ASK mice are an epilepsy-resistant variant originating from a colony of EL mice. Mast cell-dependent anaphylaxis is easily inducible by stimulation with IgE and Ag in ASK mice, whereas EL mice are resistant to such stimuli. In this study we have characterized mast cells derived from these two strains. ASK mast cells proliferated more vigorously than EL cells in response to IL-3 and stem cell factor. Although ASK mast cells degranulated less vigorously than EL mast cells upon stimulation with IgE and Ag, ASK cells produced and secreted several-fold more TNF-alpha and IL-2 than EL cells. Consistent with the similarities of these ASK and EL mast cell responses with phenotypes of lyn(-/-) and wild-type mast cells, respectively, Lyn activity was reduced in ASK cells. In addition to the impaired Lyn activity, ASK cells just like lyn(-/-) cells exhibited reduced Syk activity, prolonged activation of ERK and JNK, and enhanced activation of Akt. Furthermore, the lipid raft-resident transmembrane adaptor protein Cbp/PAG that associates with Lyn was hypophosphorylated in ASK cells. Importantly, similar to lyn(-/-) cells, Fyn was hyperactivated in ASK cells. Therefore, these results are consistent with the notion that Lyn-dependent phosphorylation of Cbp/PAG negatively regulates Src family kinases. This study also suggests that reduced activity of Lyn, a negative regulator of mast cell activation, underlies the susceptibility of ASK mice to anaphylaxis and implies that dysregulation of Lyn and other Src family kinases contributes to epileptogenesis.

  14. NEO Personality Inventory-Revised Normative Data that Distinguish U.S. Air Force AC-130 Gunship Sensor Operators from Enlisted Airmen Who Fail Training and Peers in the General Population

    Science.gov (United States)

    2011-08-01

    strongly agree”). The reliability coefficients for the 30 facets are reported in the test manual and range from .56 to .81 (Ref 22). The normative...Psychology, 96(1), Jan 2011, pp. 113-33. 5. Tett RP, Christiansen ND, “Personality Tests at the Crossroads: A Response to Morgeson, Campion...Hillsdale, NJ, 1988. 24. Cascio WF, Aguinis H, “The Federal Uniform Guidelines on Employee Selection Procedures (1978): An Update on Selected Issues

  15. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2006-01-05

    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.

  17. The Large Hadron Collider

    CERN Multimedia

    CERN Audiovisual Unit

    2005-01-01

    With Mike Struik (LHC Magnets Interconnection), Pascal Ponsot (LHC Magnet Transport), André Jacquemod (LHC Magnets Interconnection), Jean-Marc Balaguer (Ultrasound Welding), Davide Bozzini (Testing) and Lyn Evans (LHC Project Leader)

  18. Immunomodulation by Proteins of Bordetella Pertussis

    Science.gov (United States)

    1985-08-30

    York, NT 10016 Dr. Alvin L. Winters Lyn Yaffe, M.D. Department of Microbiology Research Support Center University of Alabama Naval Medical Research Inst. University, AL 35486 National Naval Medical Center Bethesda, MD 20814

  19. 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.

  20. Blessed with song: the Morriston Orpheus Choir from Swansea sing in the CERN control center.

    CERN Multimedia

    2008-01-01

    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.

  1. 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

  2. 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

  3. Annual parallax measurements of a Mira variable star, U Lyncis

    Science.gov (United States)

    Kamezaki, Tatsuya; Nakagawa, Akiharu; Omodaka, Toshihiro; Handa, Toshihiro; Inoue, Kan-ichiro; Kurayama, Tomoharu; Kobayashi, Hideyuki; Nagayama, Takumi; Ueno, Yuji

    2016-10-01

    We have measured the annual parallax of the water maser around a Mira star, U Lyncis (U Lyn) with VLBI Exploration of Radio Astrometry (VERA). The value of the parallax is 1.27 ± 0.06 mas, corresponding to a distance of 786^{+40}_{-36}pc. This is the first VLBI measurement of the parallax of U Lyn. We obtained the period and the apparent magnitude of U Lyn based on near-infrared observations with the Kagoshima University 1 m telescope. The period and the mean magnitude of the K' band are 437.9 day and +1.15 ± 0.09 mag, respectively. Using our measured parallax and period, we find that the location of U Lyn on the period-luminosity plane is consistent with its nature as a Mira variable fundamental mode pulsator. Also, we estimated the distance using the period-luminosity relationship, our period and apparent magnitude and this gave a difference of about 100 pc between our parallactic distance and the distance estimated by using the period-luminosity relationship. We estimated the luminosity, radius, and mass of U Lyn to be 10100 ± 420 L⊙, 391 ± 34 R⊙, and 1.9 ± 0.7 M⊙, respectively. We found 50 water maser spots with a distribution ˜ 13 au around the star and the motion implies the existence of an outflow.

  4. A történeti személynévföldrajz mint a nyelvföldrajz egyik kutatási területe I. A nyelvföldrajzi módszer a névtani kutatásokban [The geography of historical personal names as a research area of Geolinguistics I. Name geographic methods in name studies

    Directory of Open Access Journals (Sweden)

    N. Fodor, János

    2014-08-01

    Full Text Available Spatial distribution of proper names – similarly to that of common nouns – is a natural consequence of language change; as a result, the geography of personal (especially family names has recently become an important field of study in international and Hungarian Onomastics. The paper first outlines the history of previous Hungarian name geographical research, focusing on terminological questions. The author then discusses the relationship between Geolinguistics and name geographical research, using examples from ‘Történeti magyar családnévatlasz’ (Atlas of Hungarian Historical Family Names. Relations between the frequency of Christian names and that of family names are illustrated in the paper by the 15th–18th-century geography of the family name Benkő: the outstanding historical or contemporary frequency of family names derived from the same Christian name in an area is determined by the previous frequency of the base Christian name in the territory. Christian names can also be used to demonstrate the ethnic composition of the Carpathian Basin: the 18th-century expansion of the southern Slavic and German ethnic groups is illustrated by the appearance of the names Jován and Fridericus (and their variants, respectively.

  5. 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...

  6. 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...

  7. Asbesti bitumikatteissa ja sen aiheuttamat riskit bitumikatteiden kierrätyksessä

    OpenAIRE

    Savioja, Pyry

    2016-01-01

    Tarpaper Recycling Finland Oy on kierrätysalan yritys, joka kerää bitumikatejätettä purkutyömailta ja bitumikatteen valmistajilta, minkä jälkeen valmistaa siitä raaka-ainetta asfalttiteollisuudelle. Bitumikatteiden hyödyntämisessä on nähty ongelmana asbesti, jota käytettiin niiden yhtenä raaka-aineena menneinä vuosikymmeninä. Tiedot asbestin käytöstä ovat kuitenkin hajanaisia, minkä vuoksi on ollut tarvetta tarkemmille tiedoille siitä, kuinka yleisiä asbestipitoiset bitumikatteet ovat ja aihe...

  8. The DODO Survey: Imaging Planets around White Dwarfs

    Science.gov (United States)

    Hogan, E.; Burleigh, M. R.; Clarke, F. J.

    2007-09-01

    The aim of the Degenerate Objects around Degenerate Objects (DODO) survey is to directly image very low mass (⪆2 MJup) common proper motion companions in wide orbits around nearby white dwarfs. These proceedings contribution presents detailed results for three interesting white dwarfs from this survey and briefly describes the results from 19 other northern hemisphere and equatorial white dwarfs. So far, these results are consistent with the conclusions of tet{t40_mz2004}, that no more than ˜3% of stars harbour 5 - 10 MJup planets in wide orbits.

  9. Effects of Reinforcement Configuration on Reserve Capacity of Concrete Slabs

    Science.gov (United States)

    1985-08-01

    Reinforced concreted Tensile membrane,, Buried shelters/ Shelters/ ..i, Civil defense, Slab capacity, 120. A34TlRACT rCcnhma in~ r aidit noe..era aad...CHAPTER 1 I XTPODLCT, CI At the- iiti it io., of this Study civil d~efense plwlgcalled for the .;evacuation of nonessenrt*I51 pezrsonnel to safe (lower...lqbal and Derecho (Reference 10). The reinforcement ratio, p , was 0.0062 in "Christianscn’s te,;tts and varied from 0.0023 to 0.0093 in Roberts’ tests

  10. Dragonflies and damselflies (Insecta: Odonata of the northeastern region of Bangladesh with five new additions to the Odonata fauna of Bangladesh

    Directory of Open Access Journals (Sweden)

    M. Kawsar Khan

    2015-09-01

    Full Text Available Odonata were surveyed in one reserve forest, two national parks, one Eco Park, one lake and one University campus in the northeastern region of Bangladesh from March 2014 to March 2015.  A total of 64 species of Anisoptera and Zygoptera belonging to 41 genera under seven families were recorded.  Among them 45 species and 19 genera were new records for the study area.  Two species of Anisoptera, i.e., Anax indicus Lieftinck, 1942 and Gynacantha khasiaca MacLachlan, 1896, and three species of Zygoptera i.e., Matrona nigripectus Selys, 1879, Agriocnemis kalinga Nair & Subramanian, 2014, and Prodasineura laidlawii Forster, 1907 were recorded for the first time from Bangladesh.  

  11. Phase i and pharmacological study of the broad-spectrum tyrosine kinase inhibitor JNJ-26483327 in patients with advanced solid tumours

    NARCIS (Netherlands)

    I.R.H.M. Konings (Inge); M.J.A. de Jonge (Maja); H. Burger (Herman); A. van der Gaast (Ate); L.E.C. van Beijsterveldt (Ludy); H. Winkler; J. Verweij (Jaap); Z. Yuan; P. Hellemans; F.A.L.M. Eskens (Ferry)

    2010-01-01

    textabstractBackground:JNJ-26483327 is an oral, potent, multi-targeted tyrosine kinase inhibitor, inhibiting kinases of epidermal growth factor receptor (EGFR)-1,-2 and-4, rearranged during transfection (RET) receptor, vascular endothelial growth factor receptor (VEGFR)-3 and Src family (Lyn, Fyn,

  12. 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.

  13. 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…

  14. Structural analysis of leader peptide binding enables leader-free cyanobactin processing.

    Science.gov (United States)

    Koehnke, Jesko; Mann, Greg; Bent, Andrew F; Ludewig, Hannes; Shirran, Sally; Botting, Catherine; Lebl, Tomas; Houssen, Wael E; Jaspars, Marcel; Naismith, James H

    2015-08-01

    Regioselective modification of amino acids within the context of a peptide is common to a number of biosynthetic pathways, and many of the resulting products have potential as therapeutics. The ATP-dependent enzyme LynD heterocyclizes multiple cysteine residues to thiazolines within a peptide substrate. The enzyme requires the substrate to have a conserved N-terminal leader for full activity. Catalysis is almost insensitive to immediately flanking residues in the substrate, suggesting that recognition occurs distant from the active site. Nucleotide and peptide substrate co-complex structures of LynD reveal that the substrate leader peptide binds to and extends the β-sheet of a conserved domain of LynD, whereas catalysis is accomplished in another conserved domain. The spatial segregation of catalysis from recognition combines seemingly contradictory properties of regioselectivity and promiscuity, and it appears to be a conserved strategy in other peptide-modifying enzymes. A variant of LynD that efficiently processes substrates without a leader peptide has been engineered.

  15. Structural analysis of leader peptide binding enables leader-free cyanobactin processing

    Science.gov (United States)

    Ludewig, Hannes; Shirran, Sally; Botting, Catherine; Lebl, Tomas; Houssen, Wael; Jaspars, Marcel; Naismith, James H

    2015-01-01

    Regioselective modification of amino acids within the context of a peptide is common to a number of biosynthetic pathways and many such products have potential as therapeutics. The ATP dependent enzyme LynD heterocyclizes multiple cysteine residues to thiazolines within a peptide substrate. The enzyme requires the substrate to have conserved N-terminal leader for full activity. Catalysis is almost insensitive to immediately flanking residues in the substrate suggesting recognition occurs distant from the active site. Nucleotide and peptide substrate co-complex structures of LynD reveal the substrate leader peptide binds to and extends the β-sheet of a conserved domain of LynD, whilst catalysis is accomplished in another conserved domain. The spatial segregation of catalysis from recognition combines seemingly contradictory properties of regioselectivity and promiscuity; it appears to be a conserved strategy in other peptide modifying enzymes. A variant of LynD that efficiently processes substrates without a leader peptide has been engineered. PMID:26098679

  16. 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.

  17. colonial worldview in African literature: an overview and the case of ...

    African Journals Online (AJOL)

    with such characters' position in society and the roles they play and value a .... female characters or femalehood as such in a very negative light in this text. It is ... Early in a chapter entitled “African Writing and Gender” (1997), Lyn Innes and.

  18. Population dynamics of the spionid polychaete Pygospio elegans in Isefjord and Roskilde Fjord

    DEFF Research Database (Denmark)

    Thonig, Anne; Banta, Gary Thomas; Kesäniemi, Jenni;

    We sampled populations of Pygospio elegans at four locations (Lynæs, Lammefjord, Vellerup, Herslev) in the Isefjord - Roskilde Fjord estuary complex with approximately monthly intervals from March to November 2014. The goal of this study is to compare the population dynamics, with special focus o...

  19. 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.

  20. Development Approaches Coupled with Verification and Validation Methodologies for Agent-Based Mission-Level Analytical Combat Simulations

    Science.gov (United States)

    2004-03-01

    Where Computers Meet Biology, Vintage Books, a division of Random House, Inc.: New York NY. 117. Liu, Bing, Siew-Hwee Choo , Shee-Ling Lok, Sing-Meng...Simpkins, Scott D., Eugene P. Paulo, , and Lyn R. Whitaker (2001) “Case Study in Modeling and Simulation Validation Methodology”. Proceedings of

  1. Schooling Ophelia: Hysteria, Memory and Adolescent Femininity

    Science.gov (United States)

    Marshall, Elizabeth

    2007-01-01

    In this paper, I analyze the theorization of adolescent femininity within three popular cultural texts about girls and schooling written by women and published in the United States during the 1990s. The books, referred to as "Ophelia narratives," include Lyn Mikel Brown and Carol Gilligan's (1992) "Meeting at the Crossroads," Mary Pipher's (1994)…

  2. 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.

  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. 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 rece

  5. 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.

  6. AcEST: DK960689 [AcEST

    Lifescience Database Archive (English)

    Full Text Available p|Q9LYN2|FRI3_ARATH Ferritin-3, chloroplastic OS=Arabidopsis th... 203 6e-53 sp|Q94FY2|FRI_MALXI Ferritin, chloroplastic OS=Malus xia...DLQLQG 582 KGHG +HFD +L G Sbjct: 243 KGHGTWHFDQELLG 256 >sp|Q94FY2|FRI_MALXI Ferritin, chloroplastic OS=Malus xiao

  7. A trendy approach to education!

    CERN Multimedia

    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...

  8. 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.

  9. A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling.

    Science.gov (United States)

    Patterson, Heide Christine; Gerbeth, Carolin; Thiru, Prathapan; Vögtle, Nora F; Knoll, Marko; Shahsafaei, Aliakbar; Samocha, Kaitlin E; Huang, Cher X; Harden, Mark Michael; Song, Rui; Chen, Cynthia; Kao, Jennifer; Shi, Jiahai; Salmon, Wendy; Shaul, Yoav D; Stokes, Matthew P; Silva, Jeffrey C; Bell, George W; MacArthur, Daniel G; Ruland, Jürgen; Meisinger, Chris; Lodish, Harvey F

    2015-10-20

    Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) govern cellular homeostasis by inducing signaling. H2O2 modulates the activity of phosphatases and many other signaling molecules through oxidation of critical cysteine residues, which led to the notion that initiation of ROS signaling is broad and nonspecific, and thus fundamentally distinct from other signaling pathways. Here, we report that H2O2 signaling bears hallmarks of a regular signal transduction cascade. It is controlled by hierarchical signaling events resulting in a focused response as the results place the mitochondrial respiratory chain upstream of tyrosine-protein kinase Lyn, Lyn upstream of tyrosine-protein kinase SYK (Syk), and Syk upstream of numerous targets involved in signaling, transcription, translation, metabolism, and cell cycle regulation. The active mediators of H2O2 signaling colocalize as H2O2 induces mitochondria-associated Lyn and Syk phosphorylation, and a pool of Lyn and Syk reside in the mitochondrial intermembrane space. Finally, the same intermediaries control the signaling response in tissues and species responsive to H2O2 as the respiratory chain, Lyn, and Syk were similarly required for H2O2 signaling in mouse B cells, fibroblasts, and chicken DT40 B cells. Consistent with a broad role, the Syk pathway is coexpressed across tissues, is of early metazoan origin, and displays evidence of evolutionary constraint in the human. These results suggest that H2O2 signaling is under control of a signal transduction pathway that links the respiratory chain to the mitochondrial intermembrane space-localized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells.

  10. 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.

  11. Széchenyi, Kinga: "Megbélyegzettek. A kitelepítések tragédiája" [Stigmatized. The Tragedy of the Dislocations]; Hantó, Zsuzsa: "Kitiltott családok" [Banished Families

    Directory of Open Access Journals (Sweden)

    Katalin Fenyves

    2011-01-01

    Full Text Available Széchenyi, Kinga. 2007. “Megbélyegzettek. A kitelepítések tragédiája” [Stigmatized:The Tragedy of the Dislocations]. Pomáz: Kráter Műhely Egyesület. 614 pp., illus. Hantó, Zsuzsa. 2010. “Kitiltott családok” [Banished Families]. Második, javított és bővített kiadás (Second, corrected and extended edition. Budapest: Magyar Ház Könyvek. 475 pp., illus. + CD. Reviewed by Katalin Fenyves, Budapesti Kommunikációs és Üzleti Főiskola

  12. Organically modified sols as pseudostationary phases for microchip electrophoresis.

    Science.gov (United States)

    Pumera, Martin; Wang, Joseph; Grushka, Eli; Lev, Ovadia

    2007-04-30

    We demonstrate that the selectivity of microchip electrophoresis separations is greatly improved by the presence of organically modified silica (Ormosil) sols in the run buffer. A negatively-charged N-(trimethoxysilylpropyl)ethylenediamine triacetic-acid (TETT)-based sol is used for improving the selectivity between nitroaromatic explosives and a methyltrimethoxysilane (MTMOS)-based sol is employed for enhancing the microchip separation of environmental pollutants, aminophenols. These sols are added to the run buffer and act as pseudostationary phases. Their presence in the run buffer changes the apparent mobility of studied solutes, and leads to a higher resolution. The observed mobilities changes reflect the interactions between the Ormosil sols and the solutes. Relevant experimental variables have been characterized and optimized. The diverse chemistry of Ormosil sols should be extremely useful for tailoring the selectivity of a wide range of electrophoresis microchip separations.

  13. 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.

  14. Elintarvikealan yrityksissÀ kertyvÀ biojÀte ja sen hyödyntÀminen EtelÀ-Savon ja Satakunnan alueella

    OpenAIRE

    2014-01-01

    BiojÀte on elintarvike-, ruoka- tai puutarhajÀtettÀ, joka on monella tapaa hyödynnettÀvissÀ. Silti osa biojÀtteestÀ pÀÀtyy edelleen kaatopaikalle aiheuttaen ympÀristölle haitallisia pÀÀstöjÀ ja valumia. TÀmÀ tutkimus toteutettiin osana EtelÀ- Savon ja Satakunnan alueella tehtyÀ JaloJÀte- tutkimushanketta, jossa pyrkimyksenÀ oli yhteiskuntavastuullisten liiketoimintamallien kehittÀminen elintarvikeketjun eloperÀisten jÀtteiden jalostamiseen energiaksi, kierrÀtysla...

  15. A Corpus- based Research on Language Features and Textual Analysis of Tourism Promotional Texts%基于语料库的旅游文本语言特征及语篇分析

    Institute of Scientific and Technical Information of China (English)

    侯晋荣

    2011-01-01

    So far, most of the studies on tourism texts are based on cross - culture, text type and skopos, which are not comprehensive. The research based on the comparable corpus found that original English tourism texts (OETY) are more vocative, more variable in words and easier to understand. On th English tourism texts (TETY) display some hints of Chinese, such as strikingly frequent use e one hand, translated of numerals and feces- sive cohesion. On the other hand, TETT exaggerate features of target language, such as overuse of articles and rela- tive pronouns. Considering that, TETT should strengthen the vocative function, enhance textual cohesion and im- prove translation quality to ensure communication and publicity.%目前,旅游文本的研究多从跨文化、文本类型、目的论等角度入手,缺乏深入细致全面的分析。基于类比语料库的研究表明,源语文本注重呼唤功能,用词平易、丰富,通俗易懂;翻译文本依然存留汉语文本的某些特征,表现为数量表达使用过于频繁,常用隐性衔接,有时过度突现目的语英语的特征,如冠词、关系代词使用偏多等。因此,在汉语旅游文本英译时需要强化呼唤功能,加强语篇衔接,同时要注意语言运用质量,以实现旅游推介的目的。

  16. Using Collaborate Writing Groups in Undergraduate Courses to Improve Scientific Writing Skills and Confidence

    Science.gov (United States)

    Maclachlan, J. C.; Feist, S.

    2016-12-01

    Communication of primary scientific research is an aspect of undergraduate teaching that rarely researches platforms outside of the classroom. One method to encourage the dissemination of scientific findings to an international audience is the implementation of Collaborative Writing Groups (CWG). This paper will discuss the development, implementation and successful results of two Collaborative Writing Group creating within two different senior undergraduate classes offered at McMaster University in Hamilton, Ontario, Canada through discussion of the implementation of the assignment coupled with challenges and opportunities the process provided. A key to the successful implementation of the CWG is a detailed timeline for the students to follow with achievable goals throughout the process. The eight-week process began with students creating groups and choosing a topic of interest. As groups form it became apparent the diversity of academic skills and interest within the classroom made selecting a research project all group members could agree on difficult. Throughout the course students were given time to not only review their colleagues writing but also have discussions on particularly challenging aspects of their research and help in providing solutions. While the timeline for this project was ambitious it was necessary to allow time for effective feedback on the scientific writing from both the students and the instructional team. Overall this process has produced 11 peer-reviewed undergraduate student written papers within two special editions of the journal Cartographica published by the University of Toronto Press (Maclachlan and Lee, 2015). The papers topics are quite diverse including: the modelling of glacier melt in Iceland; a look into the effects of urban sprawl; and an exploration of the spatial characteristics of dunes in southern Ontario. This encouragement of dissemination to an international audience will create an experience that promotes self

  17. Physical parameters of components in close binary systems: V

    CERN Document Server

    Zola, S; Zakrzewski, B; Kjurkchieva, D P; Marchev, D V; Baran, A; Rucinski, S M; Ogloza, W; Siwak, M; Koziel, D; Drozdz, M; Pokrzywka, B

    2009-01-01

    The paper presents combined spectroscopic and photometric orbital solutions for ten close binary systems: CN And, V776 Cas, FU Dra, UV Lyn, BB Peg, V592 Per, OU Ser, EQ Tau, HN UMa and HT Vir. The photometric data consist of new multicolor light curves, while the spectroscopy has been recently obtained within the radial velocity program at the David Dunlap Observatory (DDO). Absolute parameters of the components for these binary systems are derived. Our results confirm that CN And is not a contact system. Its configuration is semi-detached with the secondary component filling its Roche lobe. The configuration of nine other systems is contact. Three systems (V776 Cas, V592 Per and OU Ser) have high (44-77%) and six (FU Dra, UV Lyn, BB Peg, EQ Tau, HN UMa and HT Vir) low or intermediate (8-32%) fill-out factors. The absolute physical parameters are derived.

  18. 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.

  19. An observational study of the eclipsing nova-like variable BH Lyncis (= PG 0818 + 513)

    Science.gov (United States)

    Dhillon, V. S.; Jones, D. H. P.; Marsh, T. R.; Smith, R. C.

    1992-09-01

    We present photometric and spectroscopic observations of the novalike variable BH Lyn. The continuum and line light curves exhibit deep eclipses which recur with a period of 3.74 hr. The spectra have single-peaked Balmer and He I emission lines which exhibit a double-peaked structure near the inferior conjunction of the emission-line source. Radial velocity measurements show large phase shifts in all the emission lines. We construct light-center and Doppler maps of the system which suggest that the line emission is largely nondisk in origin. We compare and contrast BH Lyn with a number of other eclipsing novalike variables. The objects show basically the same behavior, and we conclude that the emission lines must be produced by a similar (unknown) mechanism.

  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. 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...

  2. Applied Warfighter Ergonomics: A Research Method for Evaluating Military Individual Equipment

    Science.gov (United States)

    2005-09-01

    and dedication. Professors Robert Koyak and Lyn Whitaker reviewed my statistics, offering valuable suggestions and guidance in coaxing a coherent...not consent to be persuaded to.” People are persuaded (by other people) based in part on “liking” and “authority” ( Cialdini , 1993). Within...Topology field experiments at Camp Roberts , interviews and focus groups were conducted to determine how users perceive the usability of military PDAs

  3. 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.

  4. 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.

  5. 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.

  6. Breaking through the tranfer tunnel

    CERN Multimedia

    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.

  7. 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.

  8. Evaluating and Improving the SAMA (Segmentation Analysis and Market Assessment) Recruiting Model

    Science.gov (United States)

    2015-06-01

    IMPROVING THE SAMA ( SEGMENTATION ANALYSIS AND MARKET ASSESSMENT) RECRUITING MODEL by William N. Marmion June 2015 Thesis Advisor: Lyn...REPORT TYPE AND DATES COVERED Master’s Thesis 4. TITLE AND SUBTITLE EVALUATING AND IMPROVING THE SAMA ( SEGMENTATION ANALYSIS AND MARKET ...and potential within their areas of responsibility. One of the tools used by USAREC is the Segmentation Analysis and Market Assessment (SAMA) tool

  9. 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

  10. 用模拟仿真技术补充WinCC的显示功能%Studies on the Application of Simulation Technology to Supplement WinCC's Display Function

    Institute of Scientific and Technical Information of China (English)

    王辉

    2010-01-01

    通过介绍WinCC,Creator,LynX,Vega等软件的功能以及使用这些软件传送数据的方法,创建了三维场景Vega应用程序定义文件,最终调用Vega API函数实时操纵三维场景中模型的运动,补充了WinCC的显示功能.

  11. Vega Prime之路径导航程序设计

    Institute of Scientific and Technical Information of China (English)

    赵常寿; 张鹏; 韦宏强

    2013-01-01

    针对Vega Prime中的路径导航运动方式,使用LynX Prime和Path Tool,结合实例讨论路径导航程序设计的基本方法.优点是界面友好、操作方便,可以快速定义出复杂的运动路径.

  12. The Delivery of an Effective Collective Security Mechanism in West Africa: It Is Long Overdue

    Science.gov (United States)

    2014-06-13

    regional standby brigades. Conflict Trends no. 3 (30 October): 34-38. Ambert, Anne Marie, Patricia A. Adler , Peter Adler , and Daniel F. Detzner F...Nations: The struggle for power and peace. New York: Alfred E. Knopf. Morse, Janice, and Lyn Richards. 2002. Read me first for a user’s guide to...tracking-the-stabilization-of-somalia/ (accessed April 26, 2014). Nhema, Alfred , and Paul Tiyambe Zeleza. 2008. Roots of African conflicts: The

  13. Professor Andrzej Budzanowski, Director General, Henryk Niewodniczanski Institute of Nuclear Physics (HNINP) Poland. Dr. Grzegorz Polok, Deputy Director

    CERN Multimedia

    Maximilien Brice

    2003-01-01

    Andrzej Budzanowski, Director-General of the Cracow Institute of Nuclear Physics (HNINP) and Lyn Evans, LHC Project Leader, signing the collaboration agreement. In the background, from leftto right : Grzegorz Polok, Deputy Director-General of the Cracow Institute of Nuclear Physics, Blazej Skoczen, in charge of the LHC cryomagnet interconnections, Claude Détraz, Director for Fixed Target and Future Programmes, Alain Poncet, AT/CRI Group Leader.

  14. 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

  15. Early redox, Src family kinase, and calcium signaling integrate wound responses and tissue regeneration in zebrafish

    OpenAIRE

    Yoo, Sa Kan; Freisinger, Christina M.; LeBert, Danny C.; Huttenlocher, Anna

    2012-01-01

    Tissue injury can lead to scar formation or tissue regeneration. How regenerative animals sense initial tissue injury and transform wound signals into regenerative growth is an unresolved question. Previously, we found that the Src family kinase (SFK) Lyn functions as a redox sensor in leukocytes that detects H2O2 at wounds in zebrafish larvae. In this paper, using zebrafish larval tail fins as a model, we find that wounding rapidly activated SFK and calcium signaling in epithelia. The immedi...

  16. Analysis of Regional Effects on Market Segment Production

    Science.gov (United States)

    2016-06-01

    customers (Nielsen, 2016). Nielsen assigns every household in America to a PRIZM NE market segment based on demographics , credit card spending...REGIONAL EFFECTS ON MARKET SEGMENT PRODUCTION by James D. Moffitt June 2016 Thesis Advisor: Lyn R. Whitaker Co-Advisor: Jonathan K. Alt...REPORT TYPE AND DATES COVERED Master’s thesis 4. TITLE AND SUBTITLE ANALYSIS OF REGIONAL EFFECTS ON MARKET SEGMENT PRODUCTION 5. FUNDING NUMBERS 6

  17. Visualizing Mixed Variable-Type Multidimensional Data Using Tree Distances

    Science.gov (United States)

    2015-09-01

    VARIABLE-TYPE MULTIDIMENSIONAL DATA USING TREE DISTANCES by Yoav Shaham September 2015 Thesis Advisor: Lyn R. Whitaker Second Reader...TYPE AND DATES COVERED Master’s thesis 4. TITLE AND SUBTITLE VISUALIZING MIXED VARIABLE-TYPE MULTIDIMENSIONAL DATA USING TREE DISTANCES 5...public release; distribution is unlimited 12b. DISTRIBUTION CODE 13. ABSTRACT (maximum 200 words) This research explores the use of the tree

  18. A Photometric Study of the Near Contact Binary UU Lyncis

    Institute of Scientific and Technical Information of China (English)

    Li-Ying Zhu; Sheng-Bang Qian; Soonthornthum Boonrucksar; Jia-Jia He; Jin-Zhao Yuan

    2007-01-01

    The near-contact binary UU Lyn with an F3V-type primary was observed in 2005 and 2006. With the latest version of the Wilson-Devinney code, the photometric elements were computed. The results reveal that UU Lyn is a marginal contact system with a large temperature difference of about 1900K between the primary and secondary components.All available eclipse times, including new ones, were used in the analysis. The results show that the orbital period of this system undergoes a continuous decrease at a rate of dP/dt =-1.84 × 10-8 d yr-1. With the period decrease, UU Lyn may evolve from the present short-period marginal contact system into a contact system with true thermal contact. This target might just be undergoing the cycles predicted by the theory of thermal relaxation oscillations (TRO). It is an interesting example resembling BL And, GW Tau, ZZ Aur, KQ Gem, CN And and AD Cnc, that lie in the key evolutionary stage.

  19. 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...

  20. A balance between B cell receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining optimal Ets1 levels.

    Science.gov (United States)

    Luo, Wei; Mayeux, Jessica; Gutierrez, Toni; Russell, Lisa; Getahun, Andrew; Müller, Jennifer; Tedder, Thomas; Parnes, Jane; Rickert, Robert; Nitschke, Lars; Cambier, John; Satterthwaite, Anne B; Garrett-Sinha, Lee Ann

    2014-07-15

    Signaling through the BCR can drive B cell activation and contribute to B cell differentiation into Ab-secreting plasma cells. The positive BCR signal is counterbalanced by a number of membrane-localized inhibitory receptors that limit B cell activation and plasma cell differentiation. Deficiencies in these negative signaling pathways may cause autoantibody generation and autoimmune disease in both animal models and human patients. We have previously shown that the transcription factor Ets1 can restrain B cell differentiation into plasma cells. In this study, we tested the roles of the BCR and inhibitory receptors in controlling the expression of Ets1 in mouse B cells. We found that Ets1 is downregulated in B cells by BCR or TLR signaling through a pathway dependent on PI3K, Btk, IKK2, and JNK. Deficiencies in inhibitory pathways, such as a loss of the tyrosine kinase Lyn, the phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP1) or membrane receptors CD22 and/or Siglec-G, result in enhanced BCR signaling and decreased Ets1 expression. Restoring Ets1 expression in Lyn- or SHP1-deficient B cells inhibits their enhanced plasma cell differentiation. Our findings indicate that downregulation of Ets1 occurs in response to B cell activation via either BCR or TLR signaling, thereby allowing B cell differentiation and that the maintenance of Ets1 expression is an important function of the inhibitory Lyn → CD22/SiglecG → SHP1 pathway in B cells.

  1. Photometry of the SW Sex-type nova-like BH Lyncis in high state

    CERN Document Server

    Stanishev, V; Genkov, V

    2006-01-01

    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) day. 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 day are detected in two long runs in 2000. A possible connection between SW Sex and negative superhump phenomena through the presenc...

  2. SU Lyncis, a hard X-ray bright M giant: Clues point to a large hidden population of symbiotic stars

    CERN Document Server

    Mukai, K; 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 conclu...

  3. 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 amore 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 favour of shell-burning systems. We conclude that the true population of symbiotic stars has been underestimated, potentially by a large factor.

  4. Application of multiplexed kinase inhibitor beads to study kinome adaptations in drug-resistant leukemia.

    Directory of Open Access Journals (Sweden)

    Matthew J Cooper

    Full Text Available Protein kinases play key roles in oncogenic signaling and are a major focus in the development of targeted cancer therapies. Imatinib, a BCR-Abl tyrosine kinase inhibitor, is a successful front-line treatment for chronic myelogenous leukemia (CML. However, resistance to imatinib may be acquired by BCR-Abl mutations or hyperactivation of Src family kinases such as Lyn. We have used multiplexed kinase inhibitor beads (MIBs and quantitative mass spectrometry (MS to compare kinase expression and activity in an imatinib-resistant (MYL-R and -sensitive (MYL cell model of CML. Using MIB/MS, expression and activity changes of over 150 kinases were quantitatively measured from various protein kinase families. Statistical analysis of experimental replicates assigned significance to 35 of these kinases, referred to as the MYL-R kinome profile. MIB/MS and immunoblotting confirmed the over-expression and activation of Lyn in MYL-R cells and identified additional kinases with increased (MEK, ERK, IKKα, PKCβ, NEK9 or decreased (Abl, Kit, JNK, ATM, Yes abundance or activity. Inhibiting Lyn with dasatinib or by shRNA-mediated knockdown reduced the phosphorylation of MEK and IKKα. Because MYL-R cells showed elevated NF-κB signaling relative to MYL cells, as demonstrated by increased IκBα and IL-6 mRNA expression, we tested the effects of an IKK inhibitor (BAY 65-1942. MIB/MS and immunoblotting revealed that BAY 65-1942 increased MEK/ERK signaling and that this increase was prevented by co-treatment with a MEK inhibitor (AZD6244. Furthermore, the combined inhibition of MEK and IKKα resulted in reduced IL-6 mRNA expression, synergistic loss of cell viability and increased apoptosis. Thus, MIB/MS analysis identified MEK and IKKα as important downstream targets of Lyn, suggesting that co-targeting these kinases may provide a unique strategy to inhibit Lyn-dependent imatinib-resistant CML. These results demonstrate the utility of MIB/MS as a tool to identify

  5. 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.

  6. Detection and Diversity evaluation of tetracycline resistance genes in grassland-based production systems in Colombia, South America

    Directory of Open Access Journals (Sweden)

    Johanna eSantamaría

    2011-12-01

    Full Text Available Grassland-based production systems use approximately 26 percent of land surface on earth. However, there are no evaluations of these systems as a source of antibiotic pollution. This study was conducted to evaluate the presence, diversity, and distribution of tetracycline resistance genes in the grasslands of the Colombian Andes, where administration of antibiotics to animals is limited to treat disease and growth promoters are not included in animals’ diet. Animal (ruminal fluid and feces and environmental (soil and water samples were collected from six different dairy cattle farms and evaluated by PCR for the genes encoding ribosomal protection proteins (RPPs tet(M, tet(O, tetB(P, tet(Q tet(W, tet(S, tet(T, tet(A, and tetracycline efflux pumps tet(A, tet(B, tet(D, tet(H, tet(J, tet(Z, and tet(D. A wide distribution and high frequency for genes tet(W and tet(Q were found in both sample types. Other genes encoding RPPs ( tetB(P, tet(O, tet(M, tet(S and tet(T were detected at lower frequencies and more restricted distributions. Genes encoding efflux pumps were not common in this region, and only two of them, tet(B and tet(Z, were detected. DGGE-PCR followed by comparative sequence analysis of tet(W and tet(Q showed that the sequences detected in animals did not differ from those coming from soil and water, suggesting the transmission of tet genes from animal reservoirs to the environment. Additionally, there seems to be a differential flow of tet genes from one reservoir to the other because gene tet(O and tetB(P, detected in high frequencies in feces, were detected in low frequencies or not detected at all in the environment. Finally, the farms sampled in this study showed more than 50% similarity in relation to the tet genes detected and their frequencies. However, farms closer in space and under the influence of the same hydrographic network were significantly more similar to each other.

  7. Survey of period variations of superhumps in SU UMa-type dwarf novae. V. The fifth year (2012-2013)

    Science.gov (United States)

    Kato, Taichi; Hambsch, Franz-Josef; Maehara, Hiroyuki; Masi, Gianluca; Nocentini, Francesca; Dubovsky, Pavol A.; Kudzej, Igor; Imamura, Kazuyoshi; Ogi, Minako; Tanabe, Kenji; Akazawa, Hidehiko; Krajci, Thomas; Miller, Ian; de Miguel, Enrique; Henden, Arne; Noguchi, Ryo; Ishibashi, Takehiro; Ono, Rikako; Kawabata, Miho; Kobayashi, Hiroshi; Sakai, Daisuke; Nishino, Hirochika; Furukawa, Hisami; Masumoto, Kazunari; Matsumoto, Katsura; Littlefield, Colin; Ohshima, Tomohito; Nakata, Chikako; Honda, Satoshi; Kinugasa, Kenzo; Hashimoto, Osamu; Stein, William; Pickard, Roger D.; Kiyota, Seiichiro; Pavlenko, Elena P.; Antonyuk, Oksana I.; Baklanov, Aleksei V.; Antonyuk, Kirill; Samsonov, Denis; Pit, Nikolaj; Sosnovskij, Aleksei; Oksanen, Arto; Harlingten, Caisey; Tyyskä, Jenni; Monard, Berto; Shugarov, Sergey Yu.; Chochol, Drahomir; Kasai, Kiyoshi; Maeda, Yutaka; Hirosawa, Kenji; Itoh, Hiroshi; Sabo, Richard; Ulowetz, Joseph; Morelle, Etienne; Michel, Raúl; Suárez, Genaro; James, Nick; Dvorak, Shawn; Voloshina, Irina B.; Richmond, Michael; Staels, Bart; Boyd, David; Andreev, Maksim V.; Parakhin, Nikolai; Katysheva, Natalia; Miyashita, Atsushi; Nakajima, Kazuhiro; Bolt, Greg; Padovan, Stefano; Nelson, Peter; Starkey, Donn R.; Buczynski, Denis; Starr, Peter; Goff, William N.; Denisenko, Denis; Kochanek, Christopher S.; Shappee, Benjamin; Stanek, Krzysztof Z.; Prieto, José L.; Itagaki, Koh-ichi; Kaneko, Shizuo; Stubbings, Rod; Muyllaert, Eddy; Shears, Jeremy; Schmeer, Patrick; Poyner, Gary; Rodríguez-Marco, Miguel

    2014-04-01

    Continuing the project described in Kato et al. (2009, PASJ, 61, S395), we collected times of superhump maxima for SU UMa-type dwarf novae mainly observed during the 2012-2013 season. We found three objects (V444 Peg, CSS J203937, and MASTER J212624) having strongly positive period derivatives despite the long orbital period (Porb). By using the period of growing stage (stage A) superhumps, we obtained mass ratios for six objects. We characterized nine new WZ Sge-type dwarf novae. We made a pilot survey of the decline rate in the slowly fading parts of SU UMa-type and WZ Sge-type outbursts. The decline time scale was found to generally follow an expected P_orb^{1/4} dependence, and WZ Sge-type outbursts also generally follow this trend. There are some objects which show slower decline rates, and we consider these objects good candidates for period bouncers. We also studied unusual behavior in some objects, including BK Lyn which made a transition from an ER UMa-type state to a novalike (standstill) state in 2013, and unusually frequent occurrences of superoutbursts in NY Ser and CR Boo. We applied the least absolute shrinkage and selection operator (Lasso) power spectral analysis, which has been proven to be very effective in analyzing the Kepler data, to the ground-based photometry of BK Lyn, and detected a dramatic disappearance of the signal of negative superhumps in 2013. We suggested that the mass-transfer rates did not strongly vary between the ER UMa-type state and novalike state in BK Lyn, and this transition was less likely caused by a systematic variation of the mass-transfer rate.

  8. Dependency on Src-Family Kinases for Recurrence of Androgen-Independent Prostate Cancer

    Science.gov (United States)

    2012-08-01

    Resource at RPCI. Figure 1 demonstrates that shRNAs for both Fyn and Lyn knocked down mRNAs levels in HUVEC by 6.2-fold and 10.6-fold, respectively...tube formation (by HUVEC angiogenesis) of shRNAs specific for inhibition of expression of each of the four major isoforms of SFKs was evaluated...using the same shRNAs as used for the gene expression knock-down studies. HUVEC was employed as a surrogate for primary cultures of prostate

  9. Physical parameters of components in close binary systems: V

    OpenAIRE

    Zola, S.; Kreiner, J. M.; Zakrzewski, B.; Kjurkchieva, D. P.; Marchev, D. V.; Baran, A.; Rucinski, S. M.; Ogloza, W.; Siwak, M.; Koziel, D.; Drozdz, M.; Pokrzywka, B.

    2009-01-01

    The paper presents combined spectroscopic and photometric orbital solutions for ten close binary systems: CN And, V776 Cas, FU Dra, UV Lyn, BB Peg, V592 Per, OU Ser, EQ Tau, HN UMa and HT Vir. The photometric data consist of new multicolor light curves, while the spectroscopy has been recently obtained within the radial velocity program at the David Dunlap Observatory (DDO). Absolute parameters of the components for these binary systems are derived. Our results confirm that CN And is not a co...

  10. Plasmodium falciparum spermidine synthase inhibition results in unique perturbation-specific effects observed on transcript, protein and metabolite levels

    CSIR Research Space (South Africa)

    Becker, JVW

    2010-01-01

    Full Text Available :235 http://www.biomedcentral.com/1471-2164/11/235 Open AccessR E S E A R C H A R T I C L E Research articlePlasmodium falciparum spermidine synthase inhibition results in unique perturbation-specific effects observed on transcript, protein... and metabolite levels John VW Becker†1, Linda Mtwisha†1, Bridget G Crampton1, Stoyan Stoychev1, Anna C van Brummelen1, Shaun Reeksting2, Abraham I Louw2, Lyn-Marie Birkholtz2 and Dalu T Mancama*1 Abstract Background: Plasmodium falciparum, the causative agent...

  11. Anti-degranulating activity in rat basophil leukemia RBL-2H3 cells of flavanone glycosides and their aglycones in citrus fruits.

    Science.gov (United States)

    Murata, Kazuya; Takano, Seiya; Masuda, Megumi; Iinuma, Munekazu; Matsuda, Hideaki

    2013-07-01

    The anti-degranulating activity of flavonoids present in Citrus fruits was comprehensively evaluated. Among these, hesperetin and naringenin, respectively aglycones of hesperidin and narirutin, showed significant activity. The targets of hesperetin and naringenin were found: hesperetin inhibited phosphorylation of Syk and Akt, while naringenin suppressed the expression of Lyn and inhibited the phosphorylation of Akt. These results suggest that hesperetin and naringenin inhibit degranulation by suppression of pathway signals and reduce the symptoms of allergy by inhibiting phosphorylation of Akt, which leads to the suppression of cytokines. In addition, hesperetin showed inhibitory activity against the degranulation induced by calcium ionophores, indicating that hesperetin exerts its inhibitory activity by stabilizing the membrane structure.

  12. 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.

  13. Kodály-metodin hyödyntäminen instrumenttipedagogiikassa : Musiikki kuuluu kaikille

    OpenAIRE

    Kallioniemi, Anni

    2012-01-01

    Tässä opinnäytetyössä tarkastellaan Kodály-metodin keinojen ja välineiden soveltamista soittotuntitilanteissa. Kokemus musiikin teoriaopintojen ja soitonopetuksen irtautumisesta toisistaan antoi intoa opinnäytetyöhön perehtymiseen. Kodály-metodi on unkarilaisen musiikinopetuksen perusta. Tämä pedagoginen suuntaus antaa opettajille hyviä välineitä korkealaatuiseen musiikinopetukseen. Työn keskeistä aineistoa olivat Zoltán Kodályn ja muiden Kodály-pedagogien kirjoitukset sekä oppimateriaal...

  14. Metaphor as Self-Discovery in Anne Carson’s Autobiography of Red: A Novel in Verse

    Directory of Open Access Journals (Sweden)

    Sébastien DUCASSE

    2007-06-01

    Full Text Available In the gap between what one wants to say (or what one perceives there is to say and what one can say (what is sayable, words provide for a collaboration and a desertion. We delight in our sensuous involvement with the materials of language, we long to join words to the world- to close the gap between ourselves and things- and we suffer from doubt and anxiety because of our inability to do so. (Lyn Hejinian The Language of InquiryAnne Carson is a contemporary Canadian poet, essayist and tra...

  15. 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."

  16. Literacy i naturfag og fysikk. Hva kreves av grunnleggende ferdigheter? [VISIONS 2011: Teaching

    Directory of Open Access Journals (Sweden)

    Bente Aamotsbakken

    2012-10-01

    Full Text Available Artikkelen drøfter læreplanens vekt på grunnleggende ferdigheter og argumenterer for at grunnleggende ferdigheter lesing og skriving kan studeres som én ferdighet: literacy. Lærerens rolle blir ansett å være avgjørende for innlæring og styrking av denne ferdigheten, også i fag som naturfag og fysikk. Funnene fra to større forskningsprosjekter finansiert av Forskningsrådet ligger til grunn for valg av to case som vi presenterer og analyserer. I prosjektene har lesing og skriving vært undersøkt, og vi har i begge prosjekt sett på sammenhengen mellom de to ferdighetene. Den er så tett at vi derfor argumenterer for én grunnleggende ferdighet: literacy. Muntlighet inntar en viktig plass i undervisningen, og i artikkelen er det særlig lærerens rolle som modellerer og mediator som knyttes til betydningen av muntlig kommunikasjon.

  17. A funkcionális élelmiszerek potenciális fogyasztói és vásárlói csoportjainak felmérése

    OpenAIRE

    Németh-T., Anett; Vincze-Tóth, Judit; Hegyi, Judit; Troján, Szabolcs

    2013-01-01

    A funkcionális élelmiszerek mint hozzáadottérték-többlettel rendelkező termékek napjainkban a világ élelmiszeriparának innovatív termékei, amit a folyamatosan növekvő piaci részesedésük is alátámaszt. A vizsgálatok összesített eredményei alapján az „átlagos fogyasztók†81%-a nem tartozott a funkcionális élelmiszereket rendszeresen fogyasztók körébe, ezen belül az egyáltalán nem fogyasztók aránya 33%. Az „országos†megkérdezetti kör 65%-ánál a kevés vagy a hiányos információ indokolta a ...

  18. Shrinkage assessment of low shrinkage composites using micro-computed tomography.

    Science.gov (United States)

    Hirata, Ronaldo; Clozza, Emanuele; Giannini, Marcelo; Farrokhmanesh, Ehsan; Janal, Malvin; Tovar, Nick; Bonfante, Estevam A; Coelho, Paulo G

    2015-05-01

    The aim of this study was to quantify the polymerization volumetric shrinkage of one regular and two low shrinkage bulk fill composites in class I cavities with or without an adhesive layer, using three-dimensional (3D) micro-computed tomography (μCT). Class I cavity preparations (2.5 mm depth × 4 mm length × 4 mm wide) were standardized in 36 extracted human third molars, which were randomly divided in six groups (n = 6 each) as follows: Group VIT (regular composite without bonding agent); Group SDR (low shrinkage flowable composite without bonding agent); Group TET (low shrinkage composite without bonding agent); Group VIT/P (regular composite with bonding agent); Group SDR/X (low shrinkage flowable composite with bonding agent); TET/T (low shrinkage composite with bonding agent). Each tooth was scanned via µCT at cavity preparation, immediately after cavity filling, and after light-curing. Acquired μCT data were imported into Amira software for analysis and volume values evaluated between steps from cavity preparation until light-curing. Both low shrinkage composites showed a significantly less volumetric shrinkage than VIT. The use of dental adhesive significantly decreased the average volumetric contraction similarly for the three composites, by about 20%. Both low shrinkage composites showed less volumetric polymerization contraction than the regular composite. The use of dental adhesive decreased the total volumetric shrinkage for all evaluated composites. © 2014 Wiley Periodicals, Inc.

  19. Az árak észlelése és értékelése(Perception and Evaluation of Prices)

    OpenAIRE

    Rekettye, Gábor

    2012-01-01

    A 2008-ban kezdődött gazdasági válság a korábbiaknál is fontosabbá tette az árakat a vásárlók számára. Azt eddig is mindenki tudta, hogy az árak alapvetően befolyásolják a fogyasztók vásárlási döntését. Arra a kérdésre azonban, hogy miképpen, már nem mindig tudunk pontos választ adni. A közgazdaságtan szerint az árak csökkenése növeli a fogyasztók vásárlási hajlandóságát és fordítva, az árak emelkedése kisebbíti azt. A valóság azonban nem mindig írható le közgazdaságtani fogalmakk...

  20. 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.

  1. 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...

  2. Investigating the surface reactivity of SiO2-TiO2-CaO-Na2O/SrO bioceramics as a function of structure and incubation time in simulated body fluid.

    Science.gov (United States)

    Li, Y; Coughlan, A; Wren, Anthony W

    2014-08-01

    This study focuses on evaluating the biocompatibility of a SiO2-TiO2-CaO-Na2O/SrO glass and glass-ceramic series. Glass and ceramic samples were synthesized and characterized using X-ray diffraction. Each material was subject to maturation in simulated body fluid over 1, 7 and 30 days to describe any changes in surface morphology. Calcium phosphate (CaP) deposition was observed predominantly on the Na(+) containing amorphous and crystalline materials, with plate-like morphology. The precipitated surface layer was also observed to crystallize with respect to maturation, which was most evident in the amorphous Na(+) containing glasses, Ly-N and Ly-C. The addition of Sr(2+) greatly reduced the solubility of all samples, with limited CaP precipitation on the amorphous samples and no deposition on the crystalline materials. The morphology of the samples was also different, presenting irregular plate-like structures (Ly-N), needle-like deposits (Ly-C) and globular-like structures (Ly-S). Cell culture analysis presented a significant increase in cell viability with the Na(+) materials, 134%, while the Sr(2+) containing glasses, 60-80% and ceramics, 60-85% presented a general reduction in cell viability, however these reductions were not significant.

  3. Haemophilus ducreyi targets Src family protein tyrosine kinases to inhibit phagocytic signaling.

    Science.gov (United States)

    Mock, Jason R; Vakevainen, Merja; Deng, Kaiping; Latimer, Jo L; Young, Jennifer A; van Oers, Nicolai S C; Greenberg, Steven; Hansen, Eric J

    2005-12-01

    Haemophilus ducreyi, the etiologic agent of the sexually transmitted disease chancroid, has been shown to inhibit phagocytosis of both itself and secondary targets in vitro. Immunodepletion of LspA proteins from H. ducreyi culture supernatant fluid abolished this inhibitory effect, indicating that the LspA proteins are necessary for the inhibition of phagocytosis by H. ducreyi. Fluorescence microscopy revealed that macrophages incubated with wild-type H. ducreyi, but not with a lspA1 lspA2 mutant, were unable to complete development of the phagocytic cup around immunoglobulin G-opsonized targets. Examination of the phosphotyrosine protein profiles of these two sets of macrophages showed that those incubated with wild-type H. ducreyi had greatly reduced phosphorylation levels of proteins in the 50-to-60-kDa range. Subsequent experiments revealed reductions in the catalytic activities of both Lyn and Hck, two members of the Src family of protein tyrosine kinases that are known to be involved in the proximal signaling steps of Fcgamma receptor-mediated phagocytosis. Additional experiments confirmed reductions in the levels of both active Lyn and active Hck in three different immune cell lines, but not in HeLa cells, exposed to wild-type H. ducreyi. This is the first example of a bacterial pathogen that suppresses Src family protein tyrosine kinase activity to subvert phagocytic signaling in hostcells.

  4. The long road to the LHC

    CERN Document Server

    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...

  5. 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

  6. India and CERN: a collaboration in good shape

    CERN Document Server

    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...

  7. Erythropoietin receptor signaling is membrane raft dependent.

    Directory of Open Access Journals (Sweden)

    Kathy L McGraw

    Full Text Available 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.

  8. 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...

  9. Vega环境下的某飞行器视景仿真的实现%Visual simulation based on Vega for a certain flight vehicle

    Institute of Scientific and Technical Information of China (English)

    朱晓辉; 江浩

    2012-01-01

    通过利用视景仿真工具Vega对某飞行器飞行的模拟,讨论了Vega环境下LynX,Vega API的使用,并综合视景仿真中路径创建、视点控制、特殊效果等多项技术,建立了基于MFC多线程Vega应用程序,完成了某飞行器飞行中各个状态的控制,取得了良好的视景仿真的效果.%The visual simulation software, named as Vega, is used to simulate flight scene for a certain flight vehicle. The usage of Vega LynX and Vega API are discussed in this paper. Combined with such technologies as path creation, viewpoint control, and special effects, etc. in the simulation system, a Vega application program based on MFC multithreading technology is developed, which realizes state control in the flight vehicle and gains desired simulation effects.

  10. Molecular hydrogen suppresses FcepsilonRI-mediated signal transduction and prevents degranulation of mast cells.

    Science.gov (United States)

    Itoh, Tomohiro; Fujita, Yasunori; Ito, Mikako; Masuda, Akio; Ohno, Kinji; Ichihara, Masatoshi; Kojima, Toshio; Nozawa, Yoshinori; Ito, Masafumi

    2009-11-27

    Molecular hydrogen ameliorates oxidative stress-associated diseases in animal models. We found that oral intake of hydrogen-rich water abolishes an immediate-type allergic reaction in mice. Using rat RBL-2H3 mast cells, we demonstrated that hydrogen attenuates phosphorylation of the FcepsilonRI-associated Lyn and its downstream signal transduction, which subsequently inhibits the NADPH oxidase activity and reduces the generation of hydrogen peroxide. We also found that inhibition of NADPH oxidase attenuates phosphorylation of Lyn in mast cells, indicating the presence of a feed-forward loop that potentiates the allergic responses. Hydrogen accordingly inhibits all tested signaling molecule(s) in the loop. Hydrogen effects have been solely ascribed to exclusive removal of hydroxyl radical. In the immediate-type allergic reaction, hydrogen exerts its beneficial effect not by its radical scavenging activity but by modulating a specific signaling pathway. Effects of hydrogen in other diseases are possibly mediated by modulation of yet unidentified signaling pathways. Our studies also suggest that hydrogen is a gaseous signaling molecule like nitric oxide.

  11. Role of Ceramide from Glycosphingolipids and Its Metabolites in Immunological and Inflammatory Responses in Humans

    Directory of Open Access Journals (Sweden)

    Kazuhisa Iwabuchi

    2015-01-01

    Full Text Available Glycosphingolipids (GSLs are composed of hydrophobic ceramide and hydrophilic sugar chains. GSLs cluster to form membrane microdomains (lipid rafts on plasma membranes, along with several kinds of transducer molecules, including Src family kinases and small G proteins. However, GSL-mediated biological functions remain unclear. Lactosylceramide (LacCer, CDw17 is highly expressed on the plasma membranes of human phagocytes and mediates several immunological and inflammatory reactions, including phagocytosis, chemotaxis, and superoxide generation. LacCer forms membrane microdomains with the Src family tyrosine kinase Lyn and the Gαi subunit of heterotrimeric G proteins. The very long fatty acids C24:0 and C24:1 are the main ceramide components of LacCer in neutrophil plasma membranes and are directly connected with the fatty acids of Lyn and Gαi. These observations suggest that the very long fatty acid chains of ceramide are critical for GSL-mediated outside-in signaling. Sphingosine is another component of ceramide, with the hydrolysis of ceramide by ceramidase producing sphingosine and fatty acids. Sphingosine is phosphorylated by sphingosine kinase to sphingosine-1-phosphate, which is involved in a wide range of cellular functions, including growth, differentiation, survival, chemotaxis, angiogenesis, and embryogenesis, in various types of cells. This review describes the role of ceramide moiety of GSLs and its metabolites in immunological and inflammatory reactions in human.

  12. 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...

  13. Magnetic fields around evolved stars: further observations of H$_2$O maser polarization

    CERN Document Server

    Leal-Ferreira, M L; Kemball, A; Amiri, N

    2013-01-01

    We aim to detect the magnetic field and infer its properties around four AGB stars using H$_2$O maser observations. The sample we observed consists of the following sources: the semi-regular variable RT Vir and the Mira variables AP Lyn, IK Tau, and IRC+60370. We observed the 6$_{1,6}-5_{2,3}$ H$_2$O maser rotational transition, in full-polarization mode, to determine its linear and circular polarization. Based on the Zeeman effect, one can infer the properties of the magnetic field from the maser polarization analysis. We detected a total of 238 maser features, in three of the four observed sources. No masers were found toward AP Lyn. The observed masers are all located between 2.4 and 53.0 AU from the stars. Linear and circular polarization was found in 18 and 11 maser features, respectively. We more than doubled the number of AGB stars in which magnetic field has been detected from H$_2$O maser polarization, as our results confirm the presence of fields around IK Tau, RT Vir and IRC+60370. The strength of ...

  14. 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.

  15. 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...

  16. New Precision Orbits of Bright Double-Lined Spectroscopic Binaries. I: RR Lyncis, 12 Bootis, and HR 6169

    CERN Document Server

    Tomkin, J; Fekel, Francis C.; Tomkin, Jocelyn

    2006-01-01

    Radial velocities from the 2.1 m telescope at McDonald Observatory supplemented with radial velocities from the coude' feed telescope at KPNO provide new precise orbits for the double-lined spectroscopic binaries RR Lyn (A3/A8/A6), 12 Boo (F8IV), and HR 6169 (A2V). We derive orbital dimensions and minimum masses with accuracies of 0.06 to 0.9 %. The three systems, which have V magnitudes of 5.54, 4.83, and 6.42, respectively, are all sufficiently bright that they are easily within the grasp of modern optical interferometers and so afford the prospect, when our spectroscopic observations are complemented by interferometric observations, of fully-determined orbits, precise masses, and distances. In the case of RR Lyn, which is also a detached eclipsing binary with a well-determined orbital inclination, we are able to determine the semimajor axis of the relative orbit, a = 29.32 +/- 0.04 Rsun, primary and secondary radii of 2.57 +/- 0.02 Rsun and 1.59 +/- 0.03 Rsun, respectively; and primary and secondary masses...

  17. A photometric monitoring of bright high-amplitude delta Scuti stars. II. Period updates for seven stars

    CERN Document Server

    Derekas, A; Székely, P; Alfaro, E J; Csák, B; Mészáros, S; Rodríguez, E; Rolland, A; Sarneczky, K; Szabó, G M; Szatmary, K; Varadi, M; Kiss, C; Meszaros, Sz.; Szabo, Gy.M.; Kiss, Cs.

    2003-01-01

    We present new photometric data for seven high-amplitude delta Scuti stars. The observations were acquired between 1996 and 2002, mostly in the Johnson photometric system. For one star (GW UMa), our observations are the first since the discovery of its pulsational nature from the Hipparcos data.The primary goal of this project was to update our knowledge on the period variations of the target stars. For this, we have collected all available photometric observations from the literature and constructed decades-long O-C diagrams of the stars. This traditional method is useful because of the single-periodic nature of the light variations. Text-book examples of slow period evolution (XX Cyg, DY Her, DY Peg) and cyclic period changes due to light-time effect (LITE) in a binary system (SZ Lyn) are updated with the new observations. For YZ Boo, we find a period decrease instead of increase. The previously suggested LITE-solution of BE Lyn (Kiss & Szatmary 1995) is not supported with the new O-C diagram. Instead o...

  18. 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...

  19. 人M-07e白血病细胞凋亡过程中激活Caspase-3引起的Bcl-2 蛋白酶解与Lynp53/56激酶失活相关%Cleavage of Bcl-2 Protein by Activated Caspase-3 Is Associated with Inactivation of Lynp53/56 Kinase Activity in Human M-07e Leukemic Cells during Apoptosis

    Institute of Scientific and Technical Information of China (English)

    张学敏; 胡美茹; 兰雨; 于鸣; Ben D-M Chen

    2000-01-01

    The growth of M-07e human megakaryocytie leukemia cells is strictly dependent on GM-CSF. In M-07e cells, the GM-CSF receptor (GM-CSF R) is composed of two subunits: a low affinity α subunit and a phosphorylated β subunit, which is constitutively linked to lyn53/56 protein tyrosine kinase. In this study, The role of lyn kinase in regulating TGF-β 1-induced apoptosis in M-07e cells was examined. The removal of rhGM-CSF from the culture medium resulted in down-regulation of lyn kinase activity, followed by growth inhibition and programmed cell death. Apoptosis of M-07e cells was accompanied with a massive cleavage of Bcl-2 and Bax proteins into shortened fragments with molecular mass of 22 kD and 18 kD, respectively. Using specific inhibitors, the cleavage of Bcl-2, but not Bax, was found to be processed through activated caspase-3 (CPP32), which is abundantly expressed in M-07e cells. TGF-β 1 inhibited rhGM-CSF-stimulated cell growth and promoted apoptosis in M-07e cells with a pattern identical to that induced by rhGM-CSF depletion, which included massive cleavage of both Bcl-2 and Bax proteins and inactivation of lyn kinase activity. TGF-β 1 did not affect the levels of lyn protein or the β-subunit, neither did it block the interaction between these two components. Also, TGF-β 1 treatment did not diminish the expression of the α subunit in M-07e cells. Our results showed that TGF-β 1 inhibits cell proliferation and promotes apoptosis in M-07e cells by inactivating the GM-CSF R-associated lyn kinase activity. Further, This study showed that Bcl-2 cleavage by activated CPP32 is a naturally occurring event associated with apoptosis, which is under the regulation of lyn kinase activation.%人巨核白血病细胞系M-07e的生长严格依赖于GM-CSF.在M-07e细胞,GM-CSF受体(GM-CSF R)由两个亚基所组成:低亲合力的配体特异的α亚基和一个磷酸化的β亚基,后者与lynp53/56酪氨酸蛋白激酶固定相连.本研究

  20. 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.

  1. Az elidegeníthető birtoklás és a főnévképző -j- képző esete a -(Vtt főnévképzővel és más főnévképzőkkel

    Directory of Open Access Journals (Sweden)

    Alberti, Gábor

    2015-09-01

    Full Text Available Az elidegeníthető birtoklás -j- képzőjéről (den Dikken 2015 kimutattuk, hogy abban a formában létezik, hogy a magyar főnevek legtöbbjének a fonotaktikai felépítése megengedi egy potenciális reguláris birtokszóváltozat létrehozását, ami az említett -j- komponenst valóban tartalmazza. Mivel azonban a -j- komponenst sok esetben a lexikalizálódott birtokszó-alternatívák is tartalmazzák (vö. ajtója~ajtaja, az elidegeníthető birtoklásra vonatkozóan úgy mondhatunk ki hatékony szabályt, ha az a potenciális reguláris birtokszóváltozat fogalmára épül. A főnévképzéshez mindez a következő módon kötődik. Az Amerika felfedezte(kor és a Péter felfedezettje birtokos szerkezetek között a döntő formai különbség éppen a fent említett, elidegeníthetőségért felelős -j- komponensben rejlik, ami éppen akkor jelenik meg, amikor a birtokos a birtokszó igei tövének Ágense. Általánosítva: az igéből képzett főnevekre maradéktalanul teljesül a szabály, amelyre fentebb utaltunk, ha az „elidegeníthetőséget" a deverbális főnevekkel alkotott birtokos szerkezetek körében az igei tő és a birtokos ágentív vagy „még lazább" kapcsolatában határozzuk meg (ahol a „szoros" kapcsolatot az ige és a hozzá téma szerepben társuló vonzat viszonya jelenti. The derivational suffix -j- of alienable possession (den Dikken 2015 exists in Hungarian in the form that the phonotactic structure of most nouns permits the formation of a potential regular phonetic form of possessee (PRPFP, which inevitably contains the aforementioned component -j-. Since this -j-, however, is often contained by lexicalized possessee alternatives, an efficient rule concerning alienable possession must be based on the concept of PRPFP. What is the relationship between this rule and nominalization? Well, the crucial formal difference between the possessive constructions Amerika felfedeztekor 'at the discovering of

  2. [New methods in the treatment of localized prostate cancer: use of dynamic arc therapy and kV cone-beam CT positioning].

    Science.gov (United States)

    Szappanos, Szabolcs; Farkas, Róbert; Lőcsei, Zoltán; László, Zoltán; Kalincsák, Judit; Bellyei, Szabolcs; Sebestyén, Zsolt; Csapó, László; Sebestyén, Klára; Halász, Judit; Musch, Zoltán; Beöthe, Tamás; Farkas, László; Mangel, László

    2014-08-10

    Bevezetés: A prosztatarák az idősebb életkor és a fejlett világ daganatos megbetegedése. Lokalizált prosztatarák esetében a műtéti ellátás mellett komoly szerepe van a definitív sugárkezelésnek. Célkitűzés: A szerzők intézetében telepített Novalis TX gyorsító segítségével úgynevezett intenzitásmodulált sugárterápia, annak dinamikus ívbesugárzással elvégzett formája, illetve verifikáció során háromdimenziós lágy szöveti képellenőrzést biztosító, integrált kilovoltos cone-beam komputertomográfiával végzett képvezérelt sugárterápia került bevezetésre, amely módszerekkel szerzett első tapasztalataikat ismertetik a szerzők. Módszer: 2011 decembere és 2013 februárja között, dóziseszkalációt követően, 102 dinamikus ívbesugárzással elvégzett kezelést végeztek, majd 10-10 szelektált, alacsony és magas kockázatú betegnél (átlagéletkor 72,5 év) elkészítették a háromdimenziós konformális besugárzási terveket is. Azonos célterület-lefedettség mellett összevetették a rizikószervek dózisterhelését. Eredmények: A dinamikus ívbesugárzással elvégzett kezelések mellett a rizikószervek szignifikánsan alacsonyabb dózisterhelését érték el, amelyet a kedvező korai mellékhatásprofil is alátámaszt. Következtetések: Az intenzitásmodulált sugárterápia dinamikus ívbesugárzással elvégzett formája biztonsággal alkalmazott standard kezelési módozattá vált a szerzők intézetében. Késői mellékhatások és lokális kontroll további vizsgálata szükséges. Orv. Hetil., 2014, 155(32), 1265–1272.

  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. 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

  5. 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.

  6. 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.

  7. Oswald Avery: the professor, DNA, and the Nobel Prize that eluded him.

    Science.gov (United States)

    Ghose, Tarunendu

    2004-01-01

    In 1944, two Canadians, Oswald Avery and Colin MacLeod, and an American, MacLyn McCarty, published a paper in The Journal of Experimental Medicine that demonstrated genes to be the chemical, deoxyribonucleic acid (DNA). Even though this paper is now regarded as the single mos important publication in biology of the 20th century, Avery was not awarded the Nobel Prize. This raises the question as to why his work did not earn him the Prize. These are several possible reasons: the discovery may have been ahead of tis time; all three authors were physician-scientists ans not recognized chemists or geneticists; and Avery, the principal author, had reached an advanced age and characteristically took an extremely cautious and low-key approach to his work. Discussion of these reasons in turn raises other issues surrounding the recognition of the work of celebrated scientist, from Galileo and Copernicus onwards.

  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. Scene Simulation for Airborne SAR Based on Vega%基于Vega的机载SAR场景仿真

    Institute of Scientific and Technical Information of China (English)

    谭淑婷; 沈晓峰

    2008-01-01

    讨论了采用Vega系列软件对机载合成孔径雷达的工作场景进行实时三维视景仿真,着重分析实时场景渲染的一般过程和Vega应用程序的基本框架.采用LynX操作和Vega的API函数共同开发Vega仿真程序的方法对机载SAR工作场境进行实时三维视景仿真,展示仿真结果--机载SAR工作场境的实时三维视景图.

  10. 基于Vega的导弹吊装过程仿真系统设计与实现

    Institute of Scientific and Technical Information of China (English)

    陶阳

    2012-01-01

    以导弹吊装过程为应用基础,采用三维建模技术、程序设计技术,设计出一种基于Vega的仿真系统,实现了导弹吊装过程的模拟仿真.系统运行结果证明,基于MultiGen Creator的三雏建模方法得当,LynX图形界面辅助设计有力,基于MFC的Vega应用程序实现简单,系统仿真效果逼真,吊装过程模拟合理.

  11. Early redox, Src family kinase, and calcium signaling integrate wound responses and tissue regeneration in zebrafish.

    Science.gov (United States)

    Yoo, Sa Kan; Freisinger, Christina M; LeBert, Danny C; Huttenlocher, Anna

    2012-10-15

    Tissue injury can lead to scar formation or tissue regeneration. How regenerative animals sense initial tissue injury and transform wound signals into regenerative growth is an unresolved question. Previously, we found that the Src family kinase (SFK) Lyn functions as a redox sensor in leukocytes that detects H(2)O(2) at wounds in zebrafish larvae. In this paper, using zebrafish larval tail fins as a model, we find that wounding rapidly activated SFK and calcium signaling in epithelia. The immediate SFK and calcium signaling in epithelia was important for late epimorphic regeneration of amputated fins. Wound-induced activation of SFKs in epithelia was dependent on injury-generated H(2)O(2). A SFK member, Fynb, was responsible for fin regeneration. This work provides a new link between early wound responses and late regeneration and suggests that redox, SFK, and calcium signaling are immediate "wound signals" that integrate early wound responses and late epimorphic regeneration.

  12. In vivo Monitoring of Transcriptional Dynamics After Lower Limb Muscle Injury Enables Quantitative Classification of Healing

    Science.gov (United States)

    2015-07-24

    NOS3 ,  DOCK11,  NT5E,  DHCR24,  RBM45,  RAB4B,  CBR4,   ADK,  TOP3A...SLC22A4,  EEF2K,  TUBB5,  TUBB6,  GUCY1A3,   NOS3 ,  SLC22A5,  SIK1,  DOCK11,  DHCR24,  RAP2B,   SRPK2,  RAP2A,  AIFM2,  LYN...ACVRL1,  NUAK2,  ATP10A,   CAMKK1,  CAMKK2,  CKB,  ACTR3,  ADCK1,  SLC22A4,  EEF2K,   NOS3 ,  SLC22A5,  SIK1,  DHCR24,

  13. The Vibrio cholerae cytolysin (VCC) promotes activation of mast cell (T helper 2) cytokine production

    Science.gov (United States)

    Arcidiacono, Diletta; Odom, Sandra; Frossi, Barbara; Rivera, Juan; Paccani, Silvia Rossi; Baldari, Cosima T.; Pucillo, Carlo; Montecucco, Cesare; de Bernard, Marina

    2008-01-01

    Summary Many strains of Vibrio cholerae produce a cytolysin (VCC) that forms oligomeric transmembrane pores responsible for vacuolization of several cell types in culture. Here we report that VCC is a TLR2 agonist able to stimulate mast cells to produce several cytokines (IL-4 included) which could contribute to the Th2 response seen in the natural infection. Moreover, VCC-induced cytokine production was dependent on increased cytosolic Ca2+ and on the presence of the two Src family kinases Lyn and Fyn, known to be required for FcεRI-dependent activation of mast cells. These findings strongly suggest that VCC is endowed with pro-inflammatory activity that promotes a Th2-type immune profile. PMID:18005391

  14. 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

  15. Real-time analysis of imatinib- and dasatinib-induced effects on chronic myelogenous leukemia cell interaction with fibronectin.

    Directory of Open Access Journals (Sweden)

    Adam Obr

    Full Text Available Attachment of stem leukemic cells to the bone marrow extracellular matrix increases their resistance to chemotherapy and contributes to the disease persistence. In chronic myelogenous leukemia (CML, the activity of the fusion BCR-ABL kinase affects adhesion signaling. Using real-time monitoring of microimpedance, we studied in detail the kinetics of interaction of human CML cells (JURL-MK1, MOLM-7 and of control BCR-ABL-negative leukemia cells (HEL, JURKAT with fibronectin-coated surface. The effect of two clinically used kinase inhibitors, imatinib (a relatively specific c-ABL inhibitor and dasatinib (dual ABL/SRC family kinase inhibitor, on cell binding to fibronectin is described. Both imatinib and low-dose (several nM dasatinib reinforced CML cell interaction with fibronectin while no significant change was induced in BCR-ABL-negative cells. On the other hand, clinically relevant doses of dasatinib (100 nM had almost no effect in CML cells. The efficiency of the inhibitors in blocking the activity of BCR-ABL and SRC-family kinases was assessed from the extent of phosphorylation at autophosphorylation sites. In both CML cell lines, SRC kinases were found to be transactivated by BCR-ABL. In the intracellular context, EC50 for BCR-ABL inhibition was in subnanomolar range for dasatinib and in submicromolar one for imatinib. EC50 for direct inhibition of LYN kinase was found to be about 20 nM for dasatinib and more than 10 µM for imatinib. Cells pretreated with 100 nM dasatinib were still able to bind to fibronectin and SRC kinases are thus not necessary for the formation of cell-matrix contacts. However, a minimal activity of SRC kinases might be required to mediate the increase in cell adhesivity induced by BCR-ABL inhibition. Indeed, active (autophosphorylated LYN was found to localize in cell adhesive structures which were visualized using interference reflection microscopy.

  16. A critical role for the regulation of Syk from agglutination to aggregation in human platelets.

    Science.gov (United States)

    Shih, Chun-Ho; Chiang, Tin-Bin; Wang, Wen-Jeng

    2014-01-10

    Agglucetin, a tetrameric glycoprotein (GP) Ibα agonist from Formosan Agkistrodon acutus venom, has been characterized as an agglutination inducer in human washed platelets (WPs). In platelet-rich plasma (PRP), agglucetin dramatically elicits a biphasic response of agglutination and subsequent aggregation. For clarifying the intracellular signaling events from agglutination to aggregation in human platelets, we examined the essential signaling molecules involved through the detection of protein tyrosine phosphorylation (PTP). In WPs, an anti-GPIbα monoclonal antibody (mAb) AP1, but not a Src kinase inhibitor PP1, completely inhibited agglucetin-induced agglutination. However, PP1 but not AP1 had a potent suppression on platelet aggregation by a GPVI activator convulxin. The PTP analyses showed agglucetin alone can cause a weak pattern involving sequential phosphorylation of Lyn/Fyn, Syk, SLP-76 and phospholipase Cγ2 (PLCγ2). Furthermore, a Syk-selective kinase inhibitor, piceatannol, significantly suppressed the aggregating response in agglucetin-activated PRP. Analyzed by flow cytometry, the binding capacity of fluorophore-conjugated PAC-1, a mAb recognizing activated integrin αIIbβ3, was shown to increase in agglucetin-stimulated platelets. Again, piceatannol but not PP1 had a concentration-dependent suppression on agglucetin-induced αIIbβ3 exposure. Moreover, the formation of signalosome, including Syk, SLP-76, VAV, adhesion and degranulation promoting adapter protein (ADAP) and PLCγ2, are required for platelet aggregation in agglucetin/fibrinogen-activated platelets. In addition, GPIbα-ligation via agglucetin can substantially promote the interactions between αIIbβ3 and fibrinogen. Therefore, the signal pathway of Lyn/Fyn/Syk/SLP-76/ADAP/VAV/PLCγ2/PKC is sufficient to trigger platelet aggregation in agglucetin/fibrinogen-pretreated platelets. Importantly, Syk may function as a major regulator for the response from GPIbα-initiated agglutination to

  17. Masitinib combined with standard gemcitabine chemotherapy: in vitro and in vivo studies in human pancreatic tumour cell lines and ectopic mouse model.

    Directory of Open Access Journals (Sweden)

    Martine Humbert

    Full Text Available BACKGROUND: Tyrosine kinases are attractive targets for pancreatic cancer therapy because several are over-expressed, including PDGFRalpha/beta, FAK, Src and Lyn. A critical role of mast cells in the development of pancreatic cancer has also been reported. Masitinib is a tyrosine kinase inhibitor that selectively targets c-Kit, PDGFRalpha/beta, Lyn, and to a lesser extent the FAK pathway, without inhibiting kinases of known toxicities. Masitinib is particularly efficient in controlling the proliferation, differentiation and degranulation of mast cells. This study evaluates the therapeutic potential of masitinib in pancreatic cancer, as a single agent and in combination with gemcitabine. METHODOLOGY/FINDINGS: Proof-of-concept studies were performed in vitro on human pancreatic tumour cell lines and then in vivo using a mouse model of human pancreatic cancer. Molecular mechanisms were investigated via gene expression profiling. Masitinib as a single agent had no significant antiproliferative activity while the masitinib/gemcitabine combination showed synergy in vitro on proliferation of gemcitabine-refractory cell lines Mia Paca2 and Panc1, and to a lesser extent in vivo on Mia Paca2 cell tumour growth. Specifically, masitinib at 10 microM strongly sensitised Mia Paca2 cells to gemcitabine (>400-fold reduction in IC(50; and moderately sensitised Panc1 cells (10-fold reduction. Transcriptional analysis identified the Wnt/beta-catenin signalling pathway as down-regulated in the cell lines resensitised by the masitinib/gemcitabine combination. CONCLUSIONS: These data establish proof-of-concept that masitinib can sensitise gemcitabine-refractory pancreatic cancer cell lines and warrant further in vivo investigation. Indeed, such an effect has been recently observed in a phase 2 clinical study of patients with pancreatic cancer who received a masitinib/gemcitabine combination.

  18. Nef alleles from all major HIV-1 clades activate Src-family kinases and enhance HIV-1 replication in an inhibitor-sensitive manner.

    Directory of Open Access Journals (Sweden)

    Purushottam S Narute

    Full Text Available The HIV-1 accessory factor Nef is essential for high-titer viral replication and AIDS progression. Nef function requires interaction with many host cell proteins, including specific members of the Src kinase family. Here we explored whether Src-family kinase activation is a conserved property of Nef alleles from a wide range of primary HIV-1 isolates and their sensitivity to selective pharmacological inhibitors. Representative Nef proteins from the major HIV-1 subtypes A1, A2, B, C, F1, F2, G, H, J and K strongly activated Hck and Lyn as well as c-Src to a lesser extent, demonstrating for the first time that Src-family kinase activation is a highly conserved property of primary M-group HIV-1 Nef isolates. Recently, we identified 4-amino substituted diphenylfuropyrimidines (DFPs that selectively inhibit Nef-dependent activation of Src-family kinases as well as HIV replication. To determine whether DFP compounds exhibit broad-spectrum Nef-dependent antiretroviral activity against HIV-1, we first constructed chimeric forms of the HIV-1 strain NL4-3 expressing each of the primary Nef alleles. The infectivity and replication of these Nef chimeras was indistinguishable from that of wild-type virus in two distinct cell lines (U87MG astroglial cells and CEM-T4 lymphoblasts. Importantly, the 4-aminopropanol and 4-aminobutanol derivatives of DFP potently inhibited the replication of all chimeric forms of HIV-1 in both U87MG and CEM-T4 cells in a Nef-dependent manner. The antiretroviral effects of these compounds correlated with inhibition of Nef-dependent activation of endogenous Src-family kinases in the HIV-infected cells. Our results demonstrate that the activation of Hck, Lyn and c-Src by Nef is highly conserved among all major clades of HIV-1 and that selective targeting of this pathway uniformly inhibits HIV-1 replication.

  19. Composition of MHC class II-enriched lipid microdomains is modified during maturation of primary dendritic cells.

    Science.gov (United States)

    Setterblad, Niclas; Roucard, Corinne; Bocaccio, Claire; Abastado, Jean-Pierre; Charron, Dominique; Mooney, Nuala

    2003-07-01

    Dendritic cells (DCs) are the most potent antigen presenting cells. Major histocompatibility complex (MHC) class II molecule expression changes with maturation; immature DCs concentrate MHC class II molecules intracellularly, whereas maturation increases surface expression of MHC class II and costimulatory molecules to optimize antigen presentation. Signal transduction via MHC class II molecules localized in lipid microdomains has been described in B lymphocytes and in the THP-1 monocyte cell line. We have characterized MHC class II molecules throughout human DC maturation with particular attention to their localization in lipid-rich microdomains. Only immature DCs expressed empty MHC class II molecules, and maturation increased the level of peptide-bound heterodimers. Ligand binding to surface human leukocyte antigen (HLA)-DR induced rapid internalization in immature DCs. The proportion of cell-surface detergent-insoluble glycosphingolipid-enriched microdomain-clustered HLA-DR was higher in immature DCs despite the higher surface expression of HLA-DR in mature DCs. Constituents of HLA-DR containing microdomains included the src kinase Lyn and the cytoskeletal protein tubulin in immature DCs. Maturation modified the composition of the HLA-DR-containing microdomains to include protein kinase C (PKC)-delta, Lyn, and the cytoskeletal protein actin, accompanied by the loss of tubulin. Signaling via HLA-DR redistributed HLA-DR and -DM and PKC-delta as well as enriching the actin content of mature DC microdomains. The increased expression of HLA-DR as a result of DC maturation was therefore accompanied by modification of the spatial organization of HLA-DR. Such regulation could contribute to the distinct responses induced by ligand binding to MHC class II molecules in immature versus mature DCs.

  20. Membrane-localized β-subunits alter the PIP2 regulation of high-voltage activated Ca2+ channels.

    Science.gov (United States)

    Suh, Byung-Chang; Kim, Dong-Il; Falkenburger, Björn H; Hille, Bertil

    2012-02-21

    The β-subunits of voltage-gated Ca(2+) (Ca(V)) channels regulate the functional expression and several biophysical properties of high-voltage-activated Ca(V) channels. We find that Ca(V) β-subunits also determine channel regulation by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP(2)). When Ca(V)1.3, -2.1, or -2.2 channels are cotransfected with the β3-subunit, a cytosolic protein, they can be inhibited by activating a voltage-sensitive lipid phosphatase to deplete PIP(2). When these channels are coexpressed with a β2a-subunit, a palmitoylated peripheral membrane protein, the inhibition is much smaller. PIP(2) sensitivity could be increased by disabling the two palmitoylation sites in the β2a-subunit. To further test effects of membrane targeting of Ca(V) β-subunits on PIP(2) regulation, the N terminus of Lyn was ligated onto the cytosolic β3-subunit to confer lipidation. This chimera, like the Ca(V) β2a-subunit, displayed plasma membrane localization, slowed the inactivation of Ca(V)2.2 channels, and increased the current density. In addition, the Lyn-β3 subunit significantly decreased Ca(V) channel inhibition by PIP(2) depletion. Evidently lipidation and membrane anchoring of Ca(V) β-subunits compete with the PIP(2) regulation of high-voltage-activated Ca(V) channels. Compared with expression with Ca(V) β3-subunits alone, inhibition of Ca(V)2.2 channels by PIP(2) depletion could be significantly attenuated when β2a was coexpressed with β3. Our data suggest that the Ca(V) currents in neurons would be regulated by membrane PIP(2) to a degree that depends on their endogenous β-subunit combinations.

  1. Anti-inflammatory and anti-allergic effects and underlying mechanisms of Huang-Lian-Jie-Du extract: Implication for atopic dermatitis treatment.

    Science.gov (United States)

    Chen, Yunlong; Xian, Yanfang; Lai, Zhengquan; Loo, Steven; Chan, Wood Yee; Lin, Zhi-Xiu

    2016-06-05

    Huang-Lian-Jie-Du Decoction (HLJDD), a well-known Chinese herbal formula recorded in the Tang dynasty, is composed of Coptidis rhizoma (Huang-Lian), Scutellariae radix (Huang-Qin), Phellodendri Chinensis cortex (Huang-Bai) and Gardenia fructus (Zhi-Zi). It has clinical efficacy of purging fire for removing toxin and is commonly used for the treatment of disease including Alzheimer's disease, stroke and gastrointestinal disorders. HLJDD is also frequently applied for the treatment of various skin diseases, such as atopic dermatitis (AD) and various types of eczema. The aim of this study is to investigate the anti-inflammatory and anti-allergic actions of Huang-Lian-Jie-Du ethanolic extract (HLJDE) and to elucidate underlying molecular mechanisms of action using relevant in vitro experimental models. The anti-inflammatory effects of HLJDE were investigated through evaluating the change of nitric oxide (NO) and the production of several cytokines and chemokines in lipopolysaccharide (LPS)-stimulated RAW264.7 cell line. Expression of mitogen-activated protein kinases (MAPKs), NF-κB p65 phosphorylation, inhibitor-κBα (IκBα) degradation were further investigated to elucidate its anti-inflammatory molecular mechanisms. Meanwhile, the anti-allergic activities of HLJDE was also evaluated using antigen-induced RBL-2H3 cell line. β-hexosaminidase and histamine release and selected cytokines and chemokines were measured to evaluate the anti-allergic activities of HLJDE. In addition, intracellular Ca(2+)level, MAPKs and Lyn phosphorylation were further investigated to reveal its anti-allergic molecular mechanisms. HLJDE could significantly suppress the secretion of NO, IL-1β, IL-4, MCP-1 and GM-CSF in RAW264.7 cells in a dose-dependent manner. In addition, HLJDE also markedly reduced the phosphorylation of MAPKs, and inhibited the transcriptional activity of NF-κB and IκBα degradation. Furthermore, HLJDE exerted marked anti-allergic activity through inhibiting the

  2. [New method for measuring the cortical auditory evoked potentials: the HEARLab].

    Science.gov (United States)

    Bach, Adám; Tóth, Ferenc; Matievics, Vera; Kiss, József Géza; Jóri, József; Szakál, Beáta; Balogh, Norbert; Soós, Alexandra; Rovó, László

    2014-09-21

    Bevezetés: Az akusztikusan kiváltott corticalis válaszok mérése objektív módon teszi lehetővé, hogy a hallórendszer legmagasabb szintjének működéséről kapjunk információkat. Célkitűzés: A szerzők célja egy új, a klinikai gyakorlatban is rutinszerűen alkalmazható, az akusztikusan kiváltott corticalis válaszok mérésére alkalmas eszköz, a HEARLab bemutatása és ép hallású egyénekben a vizsgált paraméterek standardjainak felállítása volt. Módszer: 25 ép hallású felnőtt beszédhangok által kiváltott válaszait vizsgálták, emellett frekvenciaspecifikus tesztelést is végeztek. Eredmények: A corticalis válaszok latenciájának és amplitúdójának elemzése során kapott eredmények alátámasztják a nemzetközileg is újnak számító eljárással kapcsolatban leírtakat. Következtetések: A HEARLab a hagyományos audiológiai vizsgálómódszerek nehezítettsége esetén kiváló segítség lehet. A vizsgálat kooperációra képtelen egyéneknél is elvégezhető, akár hallókészülék használata mellett is, továbbá a vizsgálat frekvenciaspecifikus és nem igényel altatást. Orv. Hetil., 2014, 155(38), 1524–1529.

  3. Evaluation of Enterococcus spp. from rainbow trout (Oncorhynchus mykiss, Walbaum), feed, and rearing environment against fish pathogens.

    Science.gov (United States)

    Araújo, Carlos; Muñoz-Atienza, Estefanía; Hernández, Pablo E; Herranz, Carmen; Cintas, Luis M; Igrejas, Gilberto; Poeta, Patrícia

    2015-04-01

    The use of lactic acid bacteria of aquatic origin as probiotics constitutes an alternative strategy to the antibiotic treatment for disease control in aquaculture. Enterococci are currently used as probiotics in human and animal health. In this study, we evaluated the safety of 64 enterococci isolated from rainbow trout (Oncorhynchus mykiss, Walbaum), feed and rearing environment, and their antimicrobial activity against 9 fish pathogens. The 64 enterococcal isolates were identified to the species level by polymerase chain reaction (PCR), using specific primers for the different enterococcal species, and confirmed by superoxide dismutase gene sequencing. Enterococcus faecium and E. hirae were the most common species (42.2 and 35.9%, respectively). A total of 48 isolates (75%) showed phenotypic resistance to at least 1 antibiotic determined by a disk-diffusion method, and 25 isolates (39.1%) harbored at least 1 antibiotic resistance gene [erm(B), tet(M), tet(S), tet(K), tet(L), tet(T), vanC2, and aad(E)], detected by PCR. One (1.6%) isolate produced gelatinase and none produced hemolysin, using a plate assay. The virulence genes gelE (46.9%), efaAfs (17.2%), agg (1.6%), and hyl (1.6%) were detected by PCR. A total of 48 isolates (75%) exerted antimicrobial activity against 1 or more of the tested fish pathogens, using a stab-on-agar test. From these isolates, 21 (43.8%) harbored at least 1 bacteriocin-encoding gene (entP, entL50A and entL50B, hirJM79, entSE-K4, entQ and entA), detected by PCR. None of the enterococci showed bile deconjugation and mucin degradation abilities. A total of 17 enterococcal isolates (26.6%) that did not harbor any antibiotic resistance or virulence factor were considered safe for application as probiotics, including 6 isolates (35.3%) that showed antimicrobial activity against at least 1 fish pathogen and harbored at least 1 bacteriocin-encoding gene. Rainbow trout, feed, and rearing environment constitute an appropriate source for the

  4. [MicroRNA expression profiles in squamous cell carcinomas of the meso- and hypopharynx].

    Science.gov (United States)

    Orosz, Eva; Gombos, Katalin; Révész, Péter; Kiss, István; Pytel, József; Gerlinger, Imre; Szanyi, István

    2014-07-01

    Bevezetés: A mikro-RNS-ek a gének szabályozásán keresztül szerepet játszanak a daganatok kialakulásában. Célkitűzés: A szerzők a „cancer field” elmélet tükrében nemcsak magát a tumoros folyamatot, hanem annak környezetét is vizsgálva igyekeztek feltérképezni a meso- és hypopharynxlaphám-carcinomák mikro-RNS-mintázatát. Módszer: A szerzők által kidolgozott térképbiopsziás (1.: tumor, 2.: tumortól 1 cm-re, 3.: 2 cm-re és 4.: 3 cm-re) mintavételt követően 13 friss fagyasztott szövetből real-time quantitative polimeráz láncreakciós módszerrel határozták meg a mikro-RNS-expressziót. Eredmények: A miR-221 csak mesopharynxszövetekben, míg a miR-21, miR-143 és miR-155 hypopharynxdaganatokban mutatott szignifikánsan magasabb expressziót. A tumoros és a hozzá közeli mikroszkóposan ép szövet mikro-RNS-mintázata hasonló volt, míg a távoli ép szöveteké eltért a tumortól. Következtetések: A szerzők a mikro-RNS-expressziós mintázat alapján sikeresen különítették el a hypopharynx- és mesopharynxdaganatokat, valamint a tumor környéki szöveteket. A módszer jövőbeni jelentőségét az adja, hogy betekintést enged a szövetek epigenetikus szabályozásába, így a tumoros folyamat olyan korán fellelhető, amikor a sejt még fenotípusosan ép. Orv. Hetil., 2014, 155(27), 1063–1070.

  5. 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

  6. [Treatment of acute myeloid leukemia -- a single center experience (2007-2013)].

    Science.gov (United States)

    Selmeczi, Anna; Udvardy, Miklós; Illés, Arpád; Telek, Béla; Kiss, Attila; Batár, Péter; Reményi, Gyula; Szász, Róbert; Ujj, Zsófia; Márton, Adrienn; Ujfalusi, Anikó; Hevessy, Zsuzsanna; Pinczés, László; Bedekovics, Judit; Rejtő, László

    2014-04-27

    Bevezetés: Heveny myeloid leukaemiában a fiatal felnőttek (myeloid leukaemiás betegeik kezelésével szerzett tapasztalataik elemzését tűzték ki célul. Módszer: 2007–2013 között 173 heveny myeloid leukaemiás beteget kezeltek. A betegeket a European LeukemiaNet javaslata alapján osztályozták. Vizsgálták az életkor, a „de novo” vagy „szekunder” betegség, a daunoblastin dózisa, a bortezomib, a minimális residualis betegség és a betegség lefolyása közötti összefüggést. Eredmények: A fiatal betegek ötéves túlélése 25%, az időseké 2% volt. A túlélést a prognosztikai tényezők jelentősen befolyásolták: a fiatal, jó prognózisú betegek túlélése 50% volt. Fiataloknál a 90 mg/m2 daunoblastin előnyös volt, míg a 45 mg/m2 és 60 mg/m2 hatékonysága között nem volt jelentős különbség. A bortezomibbal kiegészített standard indukciós kezelés ígéretesnek tűnt, de ennek megítéléséhez nagyobb számú beteg vizsgálata szükséges. Következtetések: A remisszió kialakulásának gyorsasága és mélysége, valamint a kiindulási fehérvérsejtszám jelentősen befolyásolhatják a betegség lefolyását a European LeukemiaNet osztályozás szerinti azonos csoportokon belül is. Orv. Hetil., 2014, 155(17), 653–658.

  7. Inhibitory effects of mulberry fruit extract in combination with naringinase on the allergic response in IgE-activated RBL-2H3 cells.

    Science.gov (United States)

    Yoo, Jae-Myung; Kim, Na Yeon; Seo, Jeong Min; Kim, Sun-Ju; Lee, Sang Yoon; Kim, Sang Kyum; Kim, Hyung Don; Lee, Sang Won; Kim, Mee Ree

    2014-02-01

    In this study, we investigated the anti-allergic action of mulberry fruit extract (MFE) or MFE in combination with naringinase (MFEN) in IgE-activated RBL-2H3 cells, and investigated the mechanisms responsible for the anti-allergic effects of MFEN. β-hexosaminidase release assay was used to measure the amount of β-hexosaminidase released from the cells, and ELISA was used to measure the levels of tumor necrosis factor-α (TNF-α). We found that MFE significantly reduced the release of β-hexosaminidase (IC(50), 10.59 mg/ml) and TNF-α (IC(50), 4.87 mg/ml). Moreover, MFEN enhanced the inhibitory effects on the release of β-hexosaminidase (IC(50), 123.10 µg/ml) and TNF-α (IC(50), 65.01 µg/ml). Furthermore, MFEN had no cytotoxicity at the concentration range used to exert the anti-allergic effects. In addition, we evaluated the effects of MFEN on the formation of pro-inflammatory lipid mediators, such as prostaglandin D(2) (PGD(2)), leukotriene C(4) (LTC(4)) and leukotriene B(4) (LTB(4)) using enzyme immunoassay (EIA) kits. MFEN markedly reduced the formation of PGD(2) (IC(50), 6.47 µg/ml) and LTC(4) (IC(50), 0.31 µg/ml), but not LTB(4) (IC(50), 25.75 µg/ml). In mechanistic analyses, we measured the phosphorylation of Syk, Lyn and Fyn by immunoblot analysis. MFEN significantly inhibited the phosphorylation of Syk, but not that of Lyn or Fyn. MFEN also suppressed the phosphorylation of phospholipase C (PLC)γ1/2, protein kinase C (PKC)δ, linker for activation of T cells (LAT), extracellular signal-regulated protein kinase (ERK)1/2, JNK, GRB2-associated binding protein 2 (Gab2), phosphoinositide-3-kinase (PI3K), Akt, cytosolic phospholipase A2 and 5-lipoxygenase, as well as the expression of cyclooxygenase-2. In conclusion, these results suggest that MFEN exerts potent inhibitory effects on allergic response through the suppression of the activation of the FcεRI signaling cascade. Our data demonstrating the anti-allergic effects of MFEN may provide further

  8. Functional confirmation of PLAG1 as the candidate causative gene underlying major pleiotropic effects on body weight and milk characteristics

    Science.gov (United States)

    Fink, Tania; Tiplady, Kathryn; Lopdell, Thomas; Johnson, Thomas; Snell, Russell G.; Spelman, Richard J.; Davis, Stephen R.; Littlejohn, Mathew D.

    2017-01-01

    A major pleiotropic quantitative trait locus (QTL) located at ~25 Mbp on bovine chromosome 14 affects a myriad of growth and developmental traits in Bos taurus and indicus breeds. These QTL have been attributed to two functional variants in the bidirectional promoter of PLAG1 and CHCHD7. Although PLAG1 is a good candidate for mediating these effects, its role remains uncertain given that these variants are also associated with expression of five additional genes at the broader locus. In the current study, we conducted expression QTL (eQTL) mapping of this region using a large, high depth mammary RNAseq dataset representing 375 lactating cows. Here we show that of the seven previously implicated genes, only PLAG1 and LYN are differentially expressed by QTL genotype, and only PLAG1 bears the same association signature of the growth and body weight QTLs. For the first time, we also report significant association of PLAG1 genotype with milk production traits, including milk fat, volume, and protein yield. Collectively, these data strongly suggest PLAG1 as the causative gene underlying this diverse range of traits, and demonstrate new effects for the locus on lactation phenotypes. PMID:28322319

  9. 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...

  10. BK Lyncis: The Oldest Old Nova?... And a Bellwether for Cataclysmic-Variable Evolution

    CERN Document Server

    Patterson, Joseph; Kemp, Jonathan; de Miguel, Enrique; Krajci, Thomas; Foote, Jerry; Hambsch, Franz-Josef; Campbell, Tut; Roberts, George; Cejudo, David; Dvorak, Shawn; Vanmunster, Tonny; Koff, Robert; Skillman, David; Harvey, David; Martin, Brian; Rock, John; Boyd, David; Oksanen, Arto; Morelle, Etienne; Ulowetz, Joseph; Kroes, Anthony; Sabo, Richard; Jensen, Lasse

    2012-01-01

    We summarize the results of a 20-year campaign to study the light curves of BK Lyncis, a nova-like star strangely located below the 2-3 hour orbital period gap in the family of cataclysmic variables. Two apparent "superhumps" dominate the nightly light curves - with periods 4.6% longer, and 3.0% shorter, than P_orb. The first appears to be associated with the star's brighter states (V~14), while the second appears to be present throughout and becomes very dominant in the low state (V~15.7). Starting in the year 2005, the star's light curve became indistinguishable from that of a dwarf nova - in particular, that of the ER UMa subclass. Reviewing all the star's oddities, we speculate: (a) BK Lyn is the remnant of the probable nova on 30 December 101, and (b) it has been fading ever since, but has taken ~2000 years for the accretion rate to drop sufficiently to permit dwarf-nova eruptions. If such behavior is common, it can explain other puzzles of CV evolution. One: why the ER UMa class even exists (because all...

  11. The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.

    Directory of Open Access Journals (Sweden)

    Mariam Ibáñez

    Full Text Available Preliminary Acute Promyelocytic Leukemia (APL whole exome sequencing (WES studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11 with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations.

  12. 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.

  13. Membrane lipid rafts, master regulators of hematopoietic stem cell retention in bone marrow and their trafficking.

    Science.gov (United States)

    Ratajczak, M Z; Adamiak, M

    2015-07-01

    Cell outer membranes contain glycosphingolipids and protein receptors, which are integrated into glycoprotein microdomains, known as lipid rafts, which float freely in the membrane bilayer. These structures have an important role in assembling signaling molecules (e.g., Rac-1, RhoH and Lyn) together with surface receptors, such as the CXCR4 receptor for α-chemokine stromal-derived factor-1, the α4β1-integrin receptor (VLA-4) for vascular cell adhesion molecule-1 and the c-kit receptor for stem cell factor, which together regulate several aspects of hematopoietic stem/progenitor cell (HSPC) biology. Here, we discuss the role of lipid raft integrity in the retention and quiescence of normal HSPCs in bone marrow niches as well as in regulating HSPC mobilization and homing. We will also discuss the pathological consequences of the defect in lipid raft integrity seen in paroxysmal nocturnal hemoglobinuria and the emerging evidence for the involvement of lipid rafts in hematological malignancies.

  14. The synaptic recruitment of lipid rafts is dependent on CD19-PI3K module and cytoskeleton remodeling molecules.

    Science.gov (United States)

    Xu, Liling; Auzins, Arturs; Sun, Xiaolin; Xu, Yinsheng; Harnischfeger, Fiona; Lu, Yun; Li, Zhanguo; Chen, Ying-Hua; Zheng, Wenjie; Liu, Wanli

    2015-08-01

    Sphingolipid- and cholesterol-rich lipid raft microdomains are important in the initiation of BCR signaling. Although it is known that lipid rafts promote the coclustering of BCR and Lyn kinase microclusters within the B cell IS, the molecular mechanism of the recruitment of lipid rafts into the B cell IS is not understood completely. Here, we report that the synaptic recruitment of lipid rafts is dependent on the cytoskeleton-remodeling proteins, RhoA and Vav. Such an event is also efficiently regulated by motor proteins, myosin IIA and dynein. Further evidence suggests the synaptic recruitment of lipid rafts is, by principle, an event triggered by BCR signaling molecules and second messenger molecules. BCR-activating coreceptor CD19 potently enhances such an event depending on its cytoplasmic Tyr421 and Tyr482 residues. The enhancing function of the CD19-PI3K module in synaptic recruitment of lipid rafts is also confirmed in human peripheral blood B cells. Thus, these results improve our understanding of the molecular mechanism of the recruitment of lipid raft microdomains in B cell IS.

  15. 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.

  16. 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...

  17. 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.

  18. Identification of ovarian cancer associated genes using an integrated approach in a Boolean framework

    Science.gov (United States)

    2013-01-01

    Background Cancer is a complex disease where molecular mechanism remains elusive. A systems approach is needed to integrate diverse biological information for the prognosis and therapy risk assessment using mechanistic approach to understand gene interactions in pathways and networks and functional attributes to unravel the biological behaviour of tumors. Results We weighted the functional attributes based on various functional properties observed between cancerous and non-cancerous genes reported from literature. This weighing schema was then encoded in a Boolean logic framework to rank differentially expressed genes. We have identified 17 genes to be differentially expressed from a total of 11,173 genes, where ten genes are reported to be down-regulated via epigenetic inactivation and seven genes are up-regulated. Here, we report that the overexpressed genes IRAK1, CHEK1 and BUB1 may play an important role in ovarian cancer. We also show that these 17 genes can be used to form an ovarian cancer signature, to distinguish normal from ovarian cancer subjects and that the set of three genes, CHEK1, AR, and LYN, can be used to classify good and poor prognostic tumors. Conclusion We provided a workflow using a Boolean logic schema for the identification of differentially expressed genes by integrating diverse biological information. This integrated approach resulted in the identification of genes as potential biomarkers in ovarian cancer. PMID:23383610

  19. Fingolimod alters the transcriptome profile of circulating CD4+ cells in multiple sclerosis

    Science.gov (United States)

    Friess, Jörg; Hecker, Michael; Roch, Luisa; Koczan, Dirk; Fitzner, Brit; Angerer, Ines Charlotte; Schröder, Ina; Flechtner, Kristin; Thiesen, Hans-Jürgen; Winkelmann, Alexander; Zettl, Uwe Klaus

    2017-01-01

    Multiple sclerosis is a demyelinating disease affecting the central nervous system. T cells are known to contribute to this immune-mediated condition. Fingolimod modulates sphingosine-1-phosphate receptors, thereby preventing the egress of lymphocytes, especially CCR7-expressing CD8+ and CD4+ T cells, from lymphoid tissues. Using Affymetrix Human Transcriptome Arrays (HTA 2.0), we performed a transcriptome profiling analysis of CD4+ cells obtained from the peripheral blood of patients with highly active relapsing-remitting multiple sclerosis. The samples were drawn before the first administration of fingolimod as well as 24 hours and 3 months after the start of therapy. Three months after treatment initiation, 890 genes were found to be differentially expressed with fold-change >2.0 and t-test p-value CCR7 as expected, while 618 genes showed an increase in expression, e.g., CCR2, CX3CR1, CD39, CD58 as well as LYN, PAK1 and TLR2. To conclude, we studied the gene expression of CD4+ cells to evaluate the effects of fingolimod treatment, and we identified 890 genes to be altered in expression after continuous drug administration. T helper cells circulating in the blood during fingolimod therapy present a distinct gene expression signature. PMID:28155899

  20. 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...

  1. Combination of bortezomib and mitotic inhibitors down-modulate Bcr-Abl and efficiently eliminates tyrosine-kinase inhibitor sensitive and resistant Bcr-Abl-positive leukemic cells.

    Science.gov (United States)

    Bucur, Octavian; Stancu, Andreea Lucia; Goganau, Ioana; Petrescu, Stefana Maria; Pennarun, Bodvael; Bertomeu, Thierry; Dewar, Rajan; Khosravi-Far, Roya

    2013-01-01

    Emergence of resistance to Tyrosine-Kinase Inhibitors (TKIs), such as imatinib, dasatinib and nilotinib, in Chronic Myelogenous Leukemia (CML) demands new therapeutic strategies. We and others have previously established bortezomib, a selective proteasome inhibitor, as an important potential treatment in CML. Here we show that the combined regimens of bortezomib with mitotic inhibitors, such as the microtubule-stabilizing agent Paclitaxel and the PLK1 inhibitor BI2536, efficiently kill TKIs-resistant and -sensitive Bcr-Abl-positive leukemic cells. Combined treatment activates caspases 8, 9 and 3, which correlate with caspase-induced PARP cleavage. These effects are associated with a marked increase in activation of the stress-related MAP kinases p38MAPK and JNK. Interestingly, combined treatment induces a marked decrease in the total and phosphorylated Bcr-Abl protein levels, and inhibits signaling pathways downstream of Bcr-Abl: downregulation of STAT3 and STAT5 phosphorylation and/or total levels and a decrease in phosphorylation of the Bcr-Abl-associated proteins CrkL and Lyn. Moreover, we found that other mitotic inhibitors (Vincristine and Docetaxel), in combination with bortezomib, also suppress the Bcr-Abl-induced pro-survival signals and result in caspase 3 activation. These results open novel possibilities for the treatment of Bcr-Abl-positive leukemias, especially in the imatinib, dasatinib and nilotinib-resistant CML cases.

  2. 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...

  3. 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...

  4. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells.

    Science.gov (United States)

    Seda, Vaclav; Mraz, Marek

    2015-03-01

    The physiology of B cells is intimately connected with the function of their B-cell receptor (BCR). B-cell lymphomas frequently (dys)regulate BCR signalling and thus take advantage of this pre-existing pathway for B-cell proliferation and survival. This has recently been underscored by clinical trials demonstrating that small molecules (fosfamatinib, ibrutinib, idelalisib) inhibiting BCR-associated kinases (SYK, BTK, PI3K) have an encouraging clinical effect. Here we describe the current knowledge of the specific aspects of BCR signalling in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukaemia (CLL) and normal B cells. Multiple factors can contribute to BCR pathway (dys)regulation in these malignancies and the activation of 'chronic' or 'tonic' BCR signalling. In lymphoma B cells, the balance of initiation, amplitude and duration of BCR activation can be influenced by a specific immunoglobulin structure, the expression and mutations of adaptor molecules (like GAB1, BLNK, GRB2, CARD11), the activity of kinases (like LYN, SYK, PI3K) or phosphatases (like SHIP-1, SHP-1 and PTEN) and levels of microRNAs. We also discuss the crosstalk of BCR with other signalling pathways (NF-κB, adhesion through integrins, migration and chemokine signalling) to emphasise that the 'BCR inhibitors' target multiple pathways interconnected with BCR, which might explain some of their clinical activity.

  5. 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...

  6. 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...

  7. Final LHC synchronization test a success

    CERN Multimedia

    Geneva, 25 August 2008.CERN has today announced the success of the second and final test of the Large Hadron Collider’s beam synchronization systems which will allow the LHC operations team to inject the first beam into the LHC.Friday evening 22 August, a single bunch of a few particles travelled down the transfer line from the Super Proton Synchrotron (SPS) accelerator to the LHC. After a period of optimization, one bunch was kicked up from the transfer line into the LHC beam pipe and steered counter-clockwise about 3 kilometres around the LHC.“Thanks to a fantastic team, both the clock-wise and counter-clockwise tests went without a hitch. We look forward to a resounding success when we make our first attempt to send a beam all the way around the LHC,” said Lyn Evans, LHC Project Leader.For more information, and for details about upcoming events marking the LHC start-up, go to: http://lhc-first-beam.web.cern.ch/lhc%2Dfirst%2Dbeam/News/FinalLHCsyncTest.html

  8. 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.

  9. 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...

  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. Single-cell measurements of IgE-mediated FcεRI signaling using an integrated microfluidic platform.

    Directory of Open Access Journals (Sweden)

    Yanli Liu

    Full Text Available Heterogeneity in responses of cells to a stimulus, such as a pathogen or allergen, can potentially play an important role in deciding the fate of the responding cell population and the overall systemic response. Measuring heterogeneous responses requires tools capable of interrogating individual cells. Cell signaling studies commonly do not have single-cell resolution because of the limitations of techniques used such as Westerns, ELISAs, mass spectrometry, and DNA microarrays. Microfluidics devices are increasingly being used to overcome these limitations. Here, we report on a microfluidic platform for cell signaling analysis that combines two orthogonal single-cell measurement technologies: on-chip flow cytometry and optical imaging. The device seamlessly integrates cell culture, stimulation, and preparation with downstream measurements permitting hands-free, automated analysis to minimize experimental variability. The platform was used to interrogate IgE receptor (FcεRI signaling, which is responsible for triggering allergic reactions, in RBL-2H3 cells. Following on-chip crosslinking of IgE-FcεRI complexes by multivalent antigen, we monitored signaling events including protein phosphorylation, calcium mobilization and the release of inflammatory mediators. The results demonstrate the ability of our platform to produce quantitative measurements on a cell-by-cell basis from just a few hundred cells. Model-based analysis of the Syk phosphorylation data suggests that heterogeneity in Syk phosphorylation can be attributed to protein copy number variations, with the level of Syk phosphorylation being particularly sensitive to the copy number of Lyn.

  12. Measuring A Customer Intimacy Culture In A Value Discipline Context

    Directory of Open Access Journals (Sweden)

    A. Potgieter

    2004-11-01

    Full Text Available The purpose of the study was to evaluate a questionnaire for the assessment of a customer intimacy culture in the value discipline context. The main survey was completed by using a convenience sample of permanent employees (N = 200 at line, middle and top management levels of an organisation in the entertainment industry. This sample was taken from staff on structured developmental paths, while attending scheduled training events. The 169 completed questionnaires that were returned were used for the final data analyses. Owing to the small sample size, an adapted procedure for first- and second-level factor analyses was used, followed by an iterative item analysis. The preliminary findings suggest that the questionnaire can be applied for assessing customer intimacy cultures. OpsommingDie doel van hierdie studie was om ’n vraelys te evalueer vir die beoordeling van ’n kliëntintimiteitskultuur in die waardedissipline konteks. Die hoofopname is voltooi deur ’n gerieflikheidsteekproef (N = 200 van permanente personeel in lyn, middel- en topbestuursvlakke van ’n organisasie in die vermaaklikheidsbedryf te gebruik. Dié steekproef is geneem vanuit personeel in gestruktureerde ontwikkelingspaaie wat geskeduleerde opleidingsgeleenthede bygewoon het. Die 169 voltooide vraelyste wat terugontvang is, is vir die finale dataontleding gebruik. Weens die klein steekproefgrootte, is ’n aangepaste prosedure vir eerste- en tweedevlakfaktorontleding gebruik, gevolg deur ’n iteratiewe itemontleding. Die voorlopige bevindinge dui daarop dat die vraelys toegepas kan word vir die beoordeling van ’n kliëntintimiteitskultuur.

  13. 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...

  14. Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas.

    Science.gov (United States)

    Colomba, A; Courilleau, D; Ramel, D; Billadeau, D D; Espinos, E; Delsol, G; Payrastre, B; Gaits-Iacovoni, F

    2008-04-24

    The majority of anaplastic large cell lymphomas (ALCLs) express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein, which is oncogenic due to its constitutive tyrosine kinase activity. Transformation by NPM-ALK not only increases proliferation, but also modifies cell shape and motility in both lymphoid and fibroblastic cells. We report that the Rac1 GTPase, a known cytoskeletal regulator, is activated by NPM-ALK in ALCL cell lines (Karpas 299 and Cost) and transfected cells (lymphoid Ba/F3 cells, NIH-3T3 fibroblasts). We have identified Vav3 as one of the exchange factors involved in Rac1 activation. Stimulation of Vav3 and Rac1 by NPM-ALK is under the control of Src kinases. It involves formation of a signaling complex between NPM-ALK, pp60(c-src), Lyn and Vav3, in which Vav3 associates with tyrosine 343 of NPM-ALK via its SH2 domain. Moreover, Vav3 is phosphorylated in NPM-ALK positive biopsies from patients suffering from ALCL, demonstrating the pathological relevance of this observation. The use of Vav3-specific shRNA and a dominant negative Rac1 mutant demonstrates the central role of GTPases in NPM-ALK elicited motility and invasion.

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

    CERN Document Server

    Hinse, Tobias C; Wittenmyer, Robert A

    2014-01-01

    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 sub-stellar 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 behaviour. 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...

  16. HIGHLIGHTS LHC First Beam - Accelerating Science : 10 September 2008

    CERN Multimedia

    CERN Audiovisual Service

    2008-01-01

    First beam in the LHC - accelerating science A historic moment in the CERN Control Centre: the beam was successfully steered around the accelerator. Channel 1 : International Channel 2 : English guide A historic moment in the CERN Control Centre: the beam was successfully steered around the accelerator. Geneva, 10 September 2008. The first beam in the Large Hadron Collider at CERN1 was successfully steered around the full 27 kilometres of the world’s most powerful particle accelerator at 10h28 this morning. This historic event 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 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 synchronized to under a billionth of a...

  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. Fully transparent LHC

    CERN Document Server

    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 ...

  19. The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.

    Science.gov (United States)

    Ibáñez, Mariam; Carbonell-Caballero, José; García-Alonso, Luz; Such, Esperanza; Jiménez-Almazán, Jorge; Vidal, Enrique; Barragán, Eva; López-Pavía, María; LLop, Marta; Martín, Iván; Gómez-Seguí, Inés; Montesinos, Pau; Sanz, Miguel A; Dopazo, Joaquín; Cervera, José

    2016-01-01

    Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations.

  20. Identifying Candidate Genes for Type 2 Diabetes Mellitus and Obesity through Gene Expression Profiling in Multiple Tissues or Cells

    Science.gov (United States)

    Meng, Yuhuan; Zhou, Jinghui; Zhuo, Min; Ling, Fei; Zhang, Yu; Du, Hongli; Wang, Xiaoning

    2013-01-01

    Type 2 Diabetes Mellitus (T2DM) and obesity have become increasingly prevalent in recent years. Recent studies have focused on identifying causal variations or candidate genes for obesity and T2DM via analysis of expression quantitative trait loci (eQTL) within a single tissue. T2DM and obesity are affected by comprehensive sets of genes in multiple tissues. In the current study, gene expression levels in multiple human tissues from GEO datasets were analyzed, and 21 candidate genes displaying high percentages of differential expression were filtered out. Specifically, DENND1B, LYN, MRPL30, POC1B, PRKCB, RP4-655J12.3, HIBADH, and TMBIM4 were identified from the T2DM-control study, and BCAT1, BMP2K, CSRNP2, MYNN, NCKAP5L, SAP30BP, SLC35B4, SP1, BAP1, GRB14, HSP90AB1, ITGA5, and TOMM5 were identified from the obesity-control study. The majority of these genes are known to be involved in T2DM and obesity. Therefore, analysis of gene expression in various tissues using GEO datasets may be an effective and feasible method to determine novel or causal genes associated with T2DM and obesity. PMID:24455749

  1. Identifying Candidate Genes for Type 2 Diabetes Mellitus and Obesity through Gene Expression Profiling in Multiple Tissues or Cells

    Directory of Open Access Journals (Sweden)

    Junhui Chen

    2013-01-01

    Full Text Available Type 2 Diabetes Mellitus (T2DM and obesity have become increasingly prevalent in recent years. Recent studies have focused on identifying causal variations or candidate genes for obesity and T2DM via analysis of expression quantitative trait loci (eQTL within a single tissue. T2DM and obesity are affected by comprehensive sets of genes in multiple tissues. In the current study, gene expression levels in multiple human tissues from GEO datasets were analyzed, and 21 candidate genes displaying high percentages of differential expression were filtered out. Specifically, DENND1B, LYN, MRPL30, POC1B, PRKCB, RP4-655J12.3, HIBADH, and TMBIM4 were identified from the T2DM-control study, and BCAT1, BMP2K, CSRNP2, MYNN, NCKAP5L, SAP30BP, SLC35B4, SP1, BAP1, GRB14, HSP90AB1, ITGA5, and TOMM5 were identified from the obesity-control study. The majority of these genes are known to be involved in T2DM and obesity. Therefore, analysis of gene expression in various tissues using GEO datasets may be an effective and feasible method to determine novel or causal genes associated with T2DM and obesity.

  2. Identifying candidate genes for Type 2 Diabetes Mellitus and obesity through gene expression profiling in multiple tissues or cells.

    Science.gov (United States)

    Chen, Junhui; Meng, Yuhuan; Zhou, Jinghui; Zhuo, Min; Ling, Fei; Zhang, Yu; Du, Hongli; Wang, Xiaoning

    2013-01-01

    Type 2 Diabetes Mellitus (T2DM) and obesity have become increasingly prevalent in recent years. Recent studies have focused on identifying causal variations or candidate genes for obesity and T2DM via analysis of expression quantitative trait loci (eQTL) within a single tissue. T2DM and obesity are affected by comprehensive sets of genes in multiple tissues. In the current study, gene expression levels in multiple human tissues from GEO datasets were analyzed, and 21 candidate genes displaying high percentages of differential expression were filtered out. Specifically, DENND1B, LYN, MRPL30, POC1B, PRKCB, RP4-655J12.3, HIBADH, and TMBIM4 were identified from the T2DM-control study, and BCAT1, BMP2K, CSRNP2, MYNN, NCKAP5L, SAP30BP, SLC35B4, SP1, BAP1, GRB14, HSP90AB1, ITGA5, and TOMM5 were identified from the obesity-control study. The majority of these genes are known to be involved in T2DM and obesity. Therefore, analysis of gene expression in various tissues using GEO datasets may be an effective and feasible method to determine novel or causal genes associated with T2DM and obesity.

  3. 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...

  4. Survey of Period Variations of Superhumps in SU UMa-Type Dwarf Novae. V: The Fifth Year (2012-2013)

    CERN Document Server

    Kato, Taichi; Maehara, Hiroyuki; Nocentini, Gianluca Masi Francesca; Dubovsky, Pavol A; Kudzej, Igor; Ogi, Kazuyoshi Imamura Minako; Tanabe, Kenji; Akazawa, Hidehiko; Krajci, Thomas; de Miguel, Ian Miller Enrique; Henden, Arne; Littlefield, Colin; Ishibashi, Ryo Noguchi Takehiro; Ono, Rikako; Kawabata, Miho; Sakai, Hiroshi Kobayashi Daisuke; Nishino, Hirochika; Furukawa, Hisami; Matsumoto, Kazunari Masumoto Katsura; Ohshima, Tomohito; Nakata, Chikako; Kinugasa, Satoshi Honda Kenzo; Hashimoto, Osamu; Stein, William; Kiyota, Roger D Pickard Seiichiro; Pavlenko, Elena P; Antonyuk, Oksana I; Antonyuk, Aleksei V Baklanov Kirill; Samsonov, Denis; Pit, Nikolaj; Oksanen, Aleksei Sosnovskij Arto; Harlingten, Caisey; Tyyska, Jenni; Shugarov, Berto Monard Sergey Yu; Chochol, Drahomir; Kasai, Kiyoshi; Hirosawa, Yutaka Maeda Kenji; Itoh, Hiroshi; Sabo, Richard; Morelle, Joseph Ulowetz Etienne; Michel, Raul; Suarez, Genaro; James, Nick; Voloshina, Shawn Dvorak Irina B; Richmond, Michael; Staels, Bart; Andreev, David Boyd Maksim V; Parakhin, Nikolai; Miyashita, Natalia Katysheva Atsushi; Nakajima, Kazuhiro; Bolt, Greg; Nelson, Stefano Padovan Peter; Starkey, Donn R; Buczynski, Denis; Starr, Peter; Denisenko, William N Goff Denis; Kochanek, Christopher S; Stanek, Benjamin Shappee Krzysztof Z; Prieto, Jose L; Itagaki, Koh-ichi; Stubbings, Shizuo Kaneko Rod; Muyllaert, Eddy; Schmeer, Jeremy Shears Patrick; Poyner, Gary; Marco, Miguel Rodriguez

    2013-01-01

    Continuing the project described by Kato et al. (2009a, arXiv:0905.1757), we collected times of superhump maxima for SU UMa-type dwarf novae mainly observed during the 2012-2013 season. We found three objects (V444 Peg, CSS J203937 and MASTER J212624) having strongly positive period derivatives despite the long orbital period (Porb). By using the period of growing stage (stage A) superhumps, we obtained mass ratios for six objects. We characterized nine new WZ Sge-type dwarf novae. We made a pilot survey of the decline rate of slowly fading part of SU UMa-type and WZ Sge-type outbursts. The decline time scale was found to generally follow the expected Porb^(1/4) dependence and WZ Sge-type outbursts also generally follow this trend. There are some objects which show slower decline rates, and we consider these objects good candidates for period bouncers. We also studied unusual behavior in some objects, including BK Lyn which made a transition from an ER UMa-type state to the novalike (standstill) state in 2013...

  5. Final LHC Synchronization Test a Success

    CERN Multimedia

    CERN Audiovisual Service

    2008-01-01

    Geneva, 25 August 2008. CERN has today announced the success of the second and final test of the Large Hadron Collider’s beam synchronization systems which will allow the LHC operations team to inject the first beam into the LHC. Friday evening 22 August, a single bunch of a few particles travelled down the transfer line from the Super Proton Synchrotron (SPS) accelerator to the LHC. After a period of optimization, one bunch was kicked up from the transfer line into the LHC beam pipe and steered counter-clockwise about 3 kilometres around the LHC. “Thanks to a fantastic team, both the clock-wise and counter-clockwise tests went without a hitch. We look forward to a resounding success when we make our first attempt to send a beam all the way around the LHC,” said Lyn Evans, LHC Project Leader. Both the counter-clockwise and clockwise tests are part of the preparations to ready the LHC, the world’s most powerful particle accelerator, for the eventual acceleration and collision of two beams at an energy ...

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

    Science.gov (United States)

    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

    2006-02-03

    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.

  7. Identification and Characterization of FaFT1: A Homolog of FLOWERING LOCUS T from Strawberry

    Directory of Open Access Journals (Sweden)

    Hengjiu Lei

    2015-05-01

    Full Text Available FLOWERING LOCUS T(FT -like genes play crucial roles in flowering transition in several plant species. In this study, a homolog of FT, designated as FaFT1, was isolated and characterized from strawberry. The open reading frame of FaFT1 was 531 bp, encoding a protein of 176 amino acids. Phylogenetic and sequence analysis showed that the FaFT1 protein contained the conservation of Tyr84 and Gln139, as well as the highly conserved amino acid sequences LGRQTVYAPGWRQN and LYN and that it was a member of the FT-like genes of dicots. Subcellular localization analysis revealed that the FaFT1 protein mainly localized in the nuclei of the Arabidopsis protoplasts. FaFT1 was highly expressed in strawberry mature leaves and its expression level decreased under floral induction conditions. Additionally, FaFT1 expression exhibited diurnal circadian rhythm both under SD and LD conditions. Over expression of FaFT1 in wild-type Arabidopsis caused early flowering. Taken together, these results indicate that FaFT1 is a putative FT homolog in strawberry, acting as a floral promoter in Arabidopsis.

  8. Altered B cell receptor signaling in human systemic lupus erythematosus

    Science.gov (United States)

    Jenks, Scott A.; Sanz, Iñaki

    2009-01-01

    Regulation of B cell receptor signaling is essential for the development of specific immunity while retaining tolerance to self. Systemic lupus erythematosus (SLE) is characterized by a loss of B cell tolerance and the production of anti-self antibodies. Accompanying this break down in tolerance are alterations in B cell receptor signal transduction including elevated induced calcium responses and increased protein phosphorylation. Specific pathways that negatively regulate B cell signaling have been shown to be impaired in some SLE patients. These patients have reduced levels of the kinase Lyn in lipid raft microdomains and this reduction is inversely correlated with increased CD45 in lipid rafts. Function and expression of the inhibitory immunoglobulin receptor FcγRIIB is also reduced in Lupus IgM- CD27+ memory cells. Because the relative contribution of different memory and transitional B cell subsets can be abnormal in SLE patients, we believe studies targeted to well defined B cell subsets will be necessary to further our understanding of signaling abnormalities in SLE. Intracellular flow cytometric analysis of signaling is a useful approach to accomplish this goal. PMID:18723129

  9. A mathematical model of CR3/TLR2 crosstalk in the context of Francisella tularensis infection.

    Directory of Open Access Journals (Sweden)

    Rachel Leander

    Full Text Available Complement Receptor 3 (CR3 and Toll-like Receptor 2 (TLR2 are pattern recognition receptors expressed on the surface of human macrophages. Although these receptors are essential components for recognition by the innate immune system, pathogen coordinated crosstalk between them can suppress the production of protective cytokines and promote infection. Recognition of the virulent Schu S4 strain of the intracellular pathogen Francisella tularensis by host macrophages involves CR3/TLR2 crosstalk. Although experimental data provide evidence that Lyn kinase and PI3K are essential components of the CR3 pathway that influences TLR2 activity, additional responsible upstream signaling components remain unknown. In this paper we construct a mathematical model of CR3 and TLR2 signaling in response to F. tularensis. After demonstrating that the model is consistent with experimental results we perform numerical simulations to evaluate the contributions that Akt and Ras-GAP make to ERK inhibition. The model confirms that phagocytosis-associated changes in the composition of the cell membrane can inhibit ERK activity and predicts that Akt and Ras-GAP synergize to inhibit ERK.

  10. On-sky observations with an achromatic hybrid phase knife coronagraph in the visible

    CERN Document Server

    Abe, Lyu; Vakili, Farrokh; Gay, Jean; Rivet, Jean-Pierre; Dervaux, Sebastien; De Souza, Armando Domiciano

    2007-01-01

    CONTEXT: The four-quadrant phase mask stellar coronagraph, introduced by D. Rouan et al., is capable of achieving very high dynamical range imaging and was studied in the context of the direct detection of extra-solar planets. Achromatic four-quadrant phase mask is currently being developed for broadband IR applications. AIMS: We report on laboratory and on-sky tests of a prototype coronagraph in the visible. This prototype, the achromatic hybrid phase knife coronagraph, was derived from the four-quadrant phase mask principle. METHODS: The instrumental setup implementing the coronagraph itself was designed to record the pre- and post-coronagraphic images simultaneously so that an efficient real-time image selection procedure can be performed. We describe the coronagraph and the associated tools that enable robust and repeatable observations. We present an algorithm of image selection that has been tested against the real on-sky data of the binary star HD80081 (* 38 Lyn). RESULTS Although the observing conditi...

  11. Leishmania donovani activates SREBP2 to modulate macrophage membrane cholesterol and mitochondrial oxidants for establishment of infection.

    Science.gov (United States)

    Mukherjee, Madhuchhanda; Basu Ball, Writoban; Das, Pijush K

    2014-10-01

    Establishment of infection by an intracellular pathogen depends on successful internalization with a concomitant neutralization of host defense machinery. Leishmania donovani, an intramacrophage pathogen, targets host SREBP2, a critical transcription factor, to regulate macrophage plasma membrane cholesterol and mitochondrial reactive oxygen species generation, favoring parasite invasion and persistence. Leishmania infection triggered membrane-raft reorientation-dependent Lyn-PI3K/Akt pathway activation which in turn deactivated GSK3β to stabilize nuclear SREBP2. Moreover, cells perceiving less available intracellular cholesterol due to its sequestration at the plasma membrane resulted in the deregulation of the ER-residing SCAP-SREBP2-Insig circuit thereby assisting increased nuclear translocation of SREBP2. Both increased nuclear transport and stabilization of SREBP2 caused HMGCR-catalyzed cholesterol biosynthesis-mediated plasma membrane cholesterol enrichment leading to decreased membrane-fluidity and plausibly assisting delay in phagosomal acidification. Parasite survival ensuing entry was further ensured by SREBP2-dependent transcriptional up-regulation of UCP2, which suppressed mitochondrial ROS generation, one of the primary microbicidal molecules in macrophages recognized for its efficacy against Leishmania. Functional knock-down of SREBP2 both in vitro and in vivo was associated with reduction in macrophage plasma membrane cholesterol, increased ROS production and lower parasite survival. To our knowledge, this study, for the first time, reveals that Leishmania exploits macrophage cholesterol-dependent SREBP2 circuit to facilitate its entry and survival within the host.

  12. Gene expression profiling identifies FYN as an important molecule in tamoxifen resistance and a predictor of early recurrence in patients treated with endocrine therapy

    DEFF Research Database (Denmark)

    Elias, D; (Hansen) Vever, Henriette; Lænkholm, A-V;

    2015-01-01

    To elucidate the molecular mechanisms of tamoxifen resistance in breast cancer, we performed gene array analyses and identified 366 genes with altered expression in four unique tamoxifen-resistant (TamR) cell lines vs the parental tamoxifen-sensitive MCF-7/S0.5 cell line. Most of these genes were...... an important role in tamoxifen resistance, and its subcellular localization in breast tumor cells may be an important novel biomarker of response to endocrine therapy in breast cancer.Oncogene advance online publication, 2 June 2014; doi:10.1038/onc.2014.138.......To elucidate the molecular mechanisms of tamoxifen resistance in breast cancer, we performed gene array analyses and identified 366 genes with altered expression in four unique tamoxifen-resistant (TamR) cell lines vs the parental tamoxifen-sensitive MCF-7/S0.5 cell line. Most of these genes were...... functionally linked to cell proliferation, death and control of gene expression, and include FYN, PRKCA, ITPR1, DPYD, DACH1, LYN, GBP1 and PRLR. Treatment with FYN-specific small interfering RNA or a SRC family kinase inhibitor reduced cell growth of TamR cell lines while exerting no significant effect on MCF...

  13. FcɛRI-mediated mast cell degranulation requires calcium-independent microtubule-dependent translocation of granules to the plasma membrane

    Science.gov (United States)

    Nishida, Keigo; Yamasaki, Satoru; Ito, Yukitaka; Kabu, Koki; Hattori, Kotaro; Tezuka, Tohru; Nishizumi, Hirofumi; Kitamura, Daisuke; Goitsuka, Ryo; Geha, Raif S.; Yamamoto, Tadashi; Yagi, Takeshi; Hirano, Toshio

    2005-01-01

    The aggregation of high affinity IgE receptors (Fcɛ receptor I [FcɛRI]) on mast cells is potent stimulus for the release of inflammatory and allergic mediators from cytoplasmic granules. However, the molecular mechanism of degranulation has not yet been established. It is still unclear how FcɛRI-mediated signal transduction ultimately regulates the reorganization of the cytoskeleton and how these events lead to degranulation. Here, we show that FcɛRI stimulation triggers the formation of microtubules in a manner independent of calcium. Drugs affecting microtubule dynamics effectively suppressed the FcɛRI-mediated translocation of granules to the plasma membrane and degranulation. Furthermore, the translocation of granules to the plasma membrane occurred in a calcium-independent manner, but the release of mediators and granule–plasma membrane fusion were completely dependent on calcium. Thus, the degranulation process can be dissected into two events: the calcium-independent microtubule-dependent translocation of granules to the plasma membrane and calcium-dependent membrane fusion and exocytosis. Finally, we show that the Fyn/Gab2/RhoA (but not Lyn/SLP-76) signaling pathway plays a critical role in the calcium-independent microtubule-dependent pathway. PMID:15998803

  14. Development of 'Redox Arrays' for identifying novel glutathionylated proteins in the secretome.

    Science.gov (United States)

    Mullen, Lisa; Seavill, Miles; Hammouz, Raneem; Bottazzi, Barbara; Chan, Philippe; Vaudry, David; Ghezzi, Pietro

    2015-09-29

    Proteomics techniques for analysing the redox status of individual proteins in complex mixtures tend to identify the same proteins due to their high abundance. We describe here an array-based technique to identify proteins undergoing glutathionylation and apply it to the secretome and the proteome of human monocytic cells. The method is based on incorporation of biotinylated glutathione (GSH) into proteins, which can then be identified following binding to a 1000-protein antibody array. We thus identify 38 secreted and 55 intracellular glutathionylated proteins, most of which are novel candidates for glutathionylation. Two of the proteins identified in these experiments, IL-1 sRII and Lyn, were then confirmed to be susceptible to glutathionylation. Comparison of the redox array with conventional proteomic methods confirmed that the redox array is much more sensitive, and can be performed using more than 100-fold less protein than is required for methods based on mass spectrometry. The identification of novel targets of glutathionylation, particularly in the secretome where the protein concentration is much lower, shows that redox arrays can overcome some of the limitations of established redox proteomics techniques.

  15. Exposing and deposing hyper-economized school science

    Science.gov (United States)

    Bencze, John Lawrence

    2010-06-01

    Despite indications of the problematic nature of laissez faire capitalism, such as the convictions of corporate leaders and the global financial crisis that appeared to largely stem from a de-regulated financial services industry, it seems clear that societies and environments continue to be strongly influenced by hyper-economized worldviews and practices. Given the importance of societal acceptance of a potentially dominant ideological perspective, it is logical to assume that it would be critical for students to be prepared to function in niches prioritizing unrestricted for-profit commodity exchanges. Indeed, in their article in this issue, Lyn Carter and Ranjith Dediwalage appear to support this claim in their analyses of the large-scale and expensive Australian curriculum and instruction project, Sustainability by the Bay. More specifically, they effectively demonstrate that this project manifests several characteristics that would suggest neoliberal and neoconservative influences—ideological perspectives that they argue are largely fundamental to the functioning of the global economic system. In this forum article, possible adverse effects of neoliberalism and neoconservatism on school science are discussed—with further justification for Carter and Dediwalage's concerns. Additionally, however, this article raises the possibility of subverting neoliberalism and neoconservatism in science education through application of communitarian ideals.

  16. The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis.

    Science.gov (United States)

    Hunter, Zachary R; Xu, Lian; Yang, Guang; Zhou, Yangsheng; Liu, Xia; Cao, Yang; Manning, Robert J; Tripsas, Christina; Patterson, Christopher J; Sheehy, Patricia; Treon, Steven P

    2014-03-13

    The genetic basis for Waldenström macroglobulinemia (WM) remains to be clarified. Although 6q losses are commonly present, recurring gene losses in this region remain to be defined. We therefore performed whole genome sequencing (WGS) in 30 WM patients, which included germline/tumor sequencing for 10 patients. Validated somatic mutations occurring in >10% of patients included MYD88, CXCR4, and ARID1A that were present in 90%, 27%, and 17% of patients, respectively, and included the activating mutation L265P in MYD88 and warts, hypogammaglobulinemia, infection, and myelokathexis-syndrome-like mutations in CXCR4 that previously have only been described in the germline. WGS also delineated copy number alterations (CNAs) and structural variants in the 10 paired patients. The CXCR4 and CNA findings were validated in independent expansion cohorts of 147 and 30 WM patients, respectively. Validated gene losses due to CNAs involved PRDM2 (93%), BTG1 (87%), HIVEP2 (77%), MKLN1 (77%), PLEKHG1 (70%), LYN (60%), ARID1B (50%), and FOXP1 (37%). Losses in PLEKHG1, HIVEP2, ARID1B, and BCLAF1 constituted the most common deletions within chromosome 6. Although no recurrent translocations were observed, in 2 patients deletions in 6q corresponded with translocation events. These studies evidence highly recurring somatic events, and provide a genomic basis for understanding the pathogenesis of WM.

  17. Slit-2/Robo-1 modulates the CXCL12/CXCR4-induced chemotaxis of T cells.

    Science.gov (United States)

    Prasad, Anil; Qamri, Zahida; Wu, Jane; Ganju, Ramesh K

    2007-09-01

    Slit, which mediates its function by binding to the Roundabout (Robo) receptor, has been shown to regulate neuronal, dendritic, and leukocyte migration. However, the molecular mechanism by which the Slit/Robo complex inhibits the migration of cells is not well defined. Here, we showed that Slit-2 can inhibit the CXCL12-induced chemotaxis and transendothelial migration of T cells and monocytes. We observed that CXCR4 associates with Robo-1 and that Slit-2 treatment enhances this association with the Robo-1 receptor. Robo-1 is a single-pass transmembrane receptor whose intracellular region contains four conserved motifs designated as CC0, CC1, CC2, and CC3. Structural and functional analyses of Robo receptors revealed that interaction of the CC3 motif with the CXCR4 receptor may regulate the CXCL12-induced chemotaxis of T cells. We further characterized Slit-2-mediated inhibition of the CXCL12/CXCR4 chemotactic pathway and found that Slit-2 can block the CXCL12-induced activation of the Src and Lck kinases but not Lyn kinase. Although Slit-2 did not inhibit the CXCL12-induced activation of MAPKs, it did inhibit the Akt phosphorylation and Rac activation induced by this chemokine. Altogether, our studies indicate a novel mechanism by which the Slit/Robo complex may inhibit the CXCR4/CXCL12-mediated chemotaxis of T cells.

  18. Planetary Companions to Evolved Intermediate-Mass Stars: 14 Andromedae, 81 Ceti, 6 Lyncis, and HD 167042

    CERN Document Server

    Sato, Bun'ei; Omiya, Masashi; Izumiura, Hideyuki; Kambe, Eiji; Masuda, Seiji; Takeda, Yoichi; Itoh, Yoichi; Ando, Hiroyasu; Yoshida, Michitoshi; Kokubo, Eiichiro; Ida, Shigeru

    2008-01-01

    We report on the detection of four extrasolar planets orbiting evolved intermediate-mass stars from a precise Doppler survey of G and K giants at Okayama Astrophysical Observatory. All of the host stars are considered to be formerly early F-type or A-type dwarfs when they were on the main sequence. 14 And (K0 III) is a clump giant with a mass of 2.2 M_solar and has a planet of minimum mass m_2sin i=4.8 M_Jup in a nearly circular orbit with a 186 day period. This is one of the innermost planets around evolved intermediate-mass stars and such planets have only been discovered in clump giants. 81 Cet (G5 III) is a clump giant with 2.4 M_solar hosting a planet of m_2sin i=5.3 M_Jup in a 953 day orbit with an eccentricity of e=0.21. 6 Lyn (K0 IV) is a less evolved subgiant with 1.7 M_solar and has a planet of m_2sin i=2.4 M_Jup in a 899 day orbit with e=0.13. HD 167042 (K1 IV) is also a less evolved star with 1.5 M_solar hosting a planet of m_2sin i=1.6 M_Jup in a 418 day orbit with e=0.10. This planet was indepen...

  19. Regulation of Nucleocytoplasmic Shuttling of Bruton's Tyrosine Kinase (Btk) through a Novel SH3-Dependent Interaction with Ankyrin Repeat Domain 54 (ANKRD54)

    Science.gov (United States)

    Hussain, Alamdar; Mohammad, Dara K.; Mohamed, Abdalla J.; Nguyen, Vivian; Metalnikov, Pavel; Colwill, Karen; Pawson, Tony; Nore, Beston F.

    2012-01-01

    Bruton's tyrosine kinase (Btk), belonging to the Tec family of tyrosine kinases (TFKs), is essential for B-lymphocyte development. Abrogation of Btk signaling causes human X-linked agammaglobulinemia (XLA) and murine X-linked immunodeficiency (Xid). We employed affinity purification of Flag-tagged Btk, combined with tandem mass spectrometry, to capture and identify novel interacting proteins. We here characterize the interaction with ankryin repeat domain 54 protein (ANKRD54), also known as Lyn-interacting ankyrin repeat protein (Liar). While Btk is a nucleocytoplasmic protein, the Liar pool was found to shuttle at a higher rate than Btk. Importantly, our results suggest that Liar mediates nuclear export of both Btk and another TFK, Txk/Rlk. Liar-mediated Btk shuttling was enriched for activation loop, nonphosphorylated Btk and entirely dependent on Btk's SH3 domain. Liar also showed reduced binding to an aspartic acid phosphomimetic SH3 mutant. Three other investigated nucleus-located proteins, Abl, estrogen receptor β (ERβ), and transcription factor T-bet, were all unaffected by Liar. We mapped the interaction site to the C terminus of the Btk SH3 domain. A biotinylated, synthetic Btk peptide, ARDKNGQEGYIPSNYVTEAEDS, was sufficient for this interaction. Liar is the first protein identified that specifically influences the nucleocytoplasmic shuttling of Btk and Txk and belongs to a rare group of known proteins carrying out this activity in a Crm1-dependent manner. PMID:22527282

  20. 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.

  1. Effect of oxidant exposure on the release of intracellular microcystin, MIB, and geosmin from three cyanobacteria species.

    Science.gov (United States)

    Wert, Eric C; Korak, Julie A; Trenholm, Rebecca A; Rosario-Ortiz, Fernando L

    2014-04-01

    The release of intracellular microcystin-LR (MC-LR), 2-methylisoborneol (MIB), and geosmin was investigated after the oxidation of three cyanobacteria (Microcystis aeruginosa (MA), Oscillatoria sp. (OSC), and Lyngbya sp. (LYN)). During the oxidation of 200,000 cells/mL of MA, release of intracellular MC-LR exceeded the World Health Organization (WHO) guideline of 1 μg/L during the lowest oxidant exposures (CT) tested: ozone (0 mg-min/L, below the ozone demand), chlorine (geosmin exceeded reported threshold odor values after exposure to chlorine, chlorine dioxide, and chloramine, which have low reactivity with these taste and odor compounds. Ozone oxidation of OSC yielded an increase in MIB concentration at lower exposures (≤2.9 mg-min/L), likely due to insufficient oxidation by hydroxyl radicals. The release of intracellular organic matter (IOM) was also measured to determine the potential of bulk measurements to act as a surrogate for cyanotoxins and metabolite release. In all cases, the dissolved organic carbon (DOC) release was less than 0.25 mgC/L, which lacked the sensitivity to indicate the release of MC-LR, MIB, or geosmin. The fluorescence index proved to be a more sensitive indicator of intracellular organic matter release than DOC for MA. These results illustrate that toxic or odorous compounds may be released from cyanobacteria cells during oxidation processes with minimal changes in the DOC concentration.

  2. Die verbondeling in verband

    Directory of Open Access Journals (Sweden)

    J. A.L. Taljaard

    1964-03-01

    Full Text Available Daar is dikwels en deur groot outoriteite al geskryf oor die mens in die samelewing. Hier wil ons egter die saak probeer aanraak uit ’n nuwe hoek, veral om die Skrifbeligting van die siening te benader. Vanselfsprekend verg hierdie benaming ’n skrifmatige mensbeskouing, maar ook ’n skrifmatige verbandsbeskouing. Die mens staan egter nie slegs in verhouding tot sy medemens nie maar ook in verhou­ ding tot stof, plant en dier. Boweal staan die mens in verhouding tot God, en hierdie verhouding is deurslaggewend vir al die ander verhoudinge waarin die mens hom bevind. Tog staan die mens ook in verhouding tot homself; wie kan die diepere roersele van die menslike siel peil, wie weet van die wroeginge, vreugde, leed en genot van die mens beter as hyself? Ook hierdie aspek verdien ons aandag. Op volledigheid kan nie aanspraak gemaak word nie, dit is ook nie my bedoeling nie. Die bedoeling is maar om die omvang van die tema aan te dui, die gedagtes te prikkel en veral om aan te spoor tot nuwe denkoriëntering waarin ook terminologies gebreek behoort te word met die neo-skolastiek binne reformatoriese lyn.

  3. Identification of molecular pathway changes after spinal cord injury by microarray analysis.

    Science.gov (United States)

    Zhang, Haocong; Wang, Yan

    2016-09-15

    Spinal cord injury (SCI) is highly related to the devastating sensory and motor dysfunction. The GSE45006 gene expression profile dataset was downloaded from Gene Expression Omnibus, which was collected from 24 rats including 20 animals with injured T7 spinal cords using an aneurysm clip impact-compression injury model and killed after 1 day, 3 days, 1 week, 2 weeks, and 8 weeks and four sham-operated rats. Differentially expressed genes (DEGs) between the injured rats at each time point and the sham-operated rats were screened. DEGs commonly detected throughout different time points were further identified, followed by comparing the expression level of these DEGs at each time point between the injured spinal cord samples and controls. Pathway enrichment analysis of the common DEGs was performed. The difference in the expression level of 416 common DEGs was significant between the injured spinal cord samples and the controls at each time point (P neuronal death, inflammation, and neuronal regeneration after SCI. AKT3, RAC2, VAV1, RAP18, LYN, and HCK may have critical roles in the pathological responses to SCI.

  4. 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.

  5. Aprendizaje sabor-sabor en la adquisición de preferencias gustativas

    Directory of Open Access Journals (Sweden)

    F. Baeyens

    2004-01-01

    Full Text Available En este trabajo, en el que se emplean ratas como sujetos experimentales, ponemos a prueba la hipótesis según la cual el aprendizaje de preferencias adquiridas con respecto a sabores sin consecuencia nutritivas post-ingesta se rige por mecanismos de condicionamiento clásico (por ej., Fedorchak, 1997. Con este objetivo llevamos a cabo dos experimentos. En el Experimento 1 utilizamos un diseño entre-sujetos para analizar el desarrollo de preferencias gustativas condicionadas hacia un sabor inicialmente no preferido (ácido cítrico. Para ello, se emparejó el ácido cítrico con otro sabor de demostrado valor hedónico positivo (sacarina que carece de poder calórico (Capaldi, Hunter y Lyn, 1997. En el segundo experimento comprobamos la posible naturaleza asociativa de este aprendizaje devaluando el valor reforzante de la sacarina mediante su emparejamiento con una inyección de Cloruro de Litio. En general, los resultados mostraron un efecto de preferencia condicionada hacia el ácido cítrico tras su emparejamiento con la sacarina. Esta preferencia condicionada fue eliminada tras devaluar el valor reforzante de la sacarina mostrando que el mecanismo responsable de la asociación sabor-sabor es de naturaleza asociativa.

  6. Phosphorylation of cystic fibrosis transmembrane conductance regulator (CFTR) serine-511 by the combined action of tyrosine kinases and CK2: the implication of tyrosine-512 and phenylalanine-508.

    Science.gov (United States)

    Cesaro, Luca; Marin, Oriano; Venerando, Andrea; Donella-Deana, Arianna; Pinna, Lorenzo A

    2013-12-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) harbors, close to Phe-508, whose deletion is the commonest cause of cystic fibrosis, a conserved potential CK2 phospho-acceptor site (Ser511), which however is not susceptible to phosphorylation by CK2. To shed light on this apparent paradox, a series of systematically substituted peptides encompassing Ser511 were assayed for their ability to be phosphorylated. The main outcomes of our study are the following: (a) Tyr512 plays a prominent role as a negative determinant as its replacement by Ala restores Ser511 phosphorylation by CK2; (b) an even more pronounced phosphorylation of Ser511 is promoted if Tyr512 is replaced by phospho-tyrosine instead of alanine; (c) Tyr512 and, to a lesser extent, Tyr515 are readily phosphorylated by Lyn, a protein tyrosine kinase of the Src family, in a manner which is enhanced by the concomitant Phe508 deletion. Collectively taken, our data, in conjunction with the notion that Tyr515 is phosphorylated in vivo, disclose the possibility that CFTR Ser511 can be phosphorylated by the combined action of tyrosine kinases and CK2 and disclose a new mechanism of hierarchical phosphorylation where the role of the priming kinase is that of removing negative determinant(s).

  7. 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.

  8. Defective signaling through the B cell antigen receptor in Epstein-Barr virus-transformed ataxia-telangiectasia cells.

    Science.gov (United States)

    Khanna, K K; Yan, J; Watters, D; Hobson, K; Beamish, H; Spring, K; Shiloh, Y; Gatti, R A; Lavin, M F

    1997-04-04

    A characteristic series of immunological abnormalities are observed in the human genetic disorder ataxia-telangiectasia (A-T). The recent cloning of a gene mutated in this syndrome provides additional evidence for a defect in intracellular signaling in A-T. We have investigated the possibility that signaling through the B cell antigen receptor is one manifestation of the A-T defect. In response to cross-linking of the B cell receptor, several A-T cell lines were defective in their mitogenic response; in addition Ca2+ mobilization from internal stores was either absent or considerably reduced in these cell lines in response to cross-linking. The defect in signaling was not due to difference in expression of surface immunoglobulin. The defective response in A-T cells was also evident in several arms of the intracellular cascade activated by B cell cross-linking. Tyrosine phosphorylation of phospholipase Cgamma1, a key step in activation of the enzyme, was reduced or negligible in some A-T cell lines. This defect in signaling was also seen at the level of Lyn tyrosine kinase activation and its association with and activation of phosphatidylinositol 3-kinase. Our results provide evidence for a role for the ATM gene product in intracellular signaling which may account at least in part for the abnormalities in B cell function in A-T.

  9. 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

  10. Large Eddy Simulation of Dilute Sediment Suspension in an Open Channel Flow

    Science.gov (United States)

    Agegnehu, Getnet; Smith, Heather D.

    2012-11-01

    Flow and suspended sediment transport in fully developed turbulent open channel flow has been investigated using Large Eddy Simulation. We used a three-dimensional, non-hydrostatic model, OpenFOAM for this study. Pre-evaluation of three existing turbulence closure schemes is performed by comparing the mean flow and turbulent quantities with the direct numerical simulation results of Moser et al. (1999). It is found that the Dynamic Mixed Smagorinsky model underestimates the wall shear stress compared to the Dynamic Smagorinsky and one equation Eddy Viscosity schemes. Moreover, the Dynamic Smagorinsky scheme gives relatively better results in both the mean and turbulent quantities. The advection-diffusion equation is solved for suspended sediment transport and the effect of sediment roughness is included in the momentum equation based on the rough wall formulation proposed by Cebeci and Bradshaw (1977). A pick up function based on van Rijn (1984) is used to determine the sediment erosion. The settling process is taken into account with a settling velocity appearing in the concentration equation. Sediment and flow quantities are validated by comparing with the experimental data of Lyn (1988). The coupled hydrodynamics results are in good agreement with the experimental data.

  11. 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...

  12. 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...

  13. The inhibitory effect of piperine from Fructus piperis extract on the degranulation of RBL-2H3 cells.

    Science.gov (United States)

    Huang, Jing; Zhang, Tao; Han, Shengli; Cao, Jingjing; Chen, Qinhua; Wang, Sicen

    2014-12-01

    Allergy is an abnormal immune response to an allergen. Type I hypersensitivity is an immunoglobulin (Ig) E-mediated allergic disorder. Fructus piperis is derived from the ripe fruit of the pepper, which is widely used as a spice in human diets and is also administered as a medicine in many countries. Piperine has been shown to have anti-oxidant, anti-depressant, anti-tumor, and anti-inflammatory activities. However, the effect of piperine on IgE-mediated allergic responses has not been reported. Here, the rat basophilic leukemia cells by membrane chromatography (RBL-2H3/CMC) coupled to high performance liquid chromatography/mass spectrometry (HPLC/MS) to discover and identify piperine can bind to RBL-2H3 cell membranes. Piperine inhibited the expression of cytokines, and the release of both β-hexosaminidase and histamine, which could be stimulated by antigen in RBL-2H3 mast cells. We found that the levels of intracellular Ca(2+) also decreased. Furthermore, RT-PCR showed that the mRNA expression levels of IL-4, IL-13, and TNF-α were significantly suppressed by piperine. The inhibitory effect of piperine on IgE-mediated degranulation and cytokine production by RBL-2H3 cells may be caused by the inhibition of IgE-mediated signaling pathways, including the phosphorylation of Lyn, p38, Erk, and Ras. In summary, piperine can inhibit antigen-induced allergic reactions that control degranulation.

  14. 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...

  15. 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...

  16. 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...

  17. 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 ...

  18. 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...

  19. 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.

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

    Science.gov (United States)

    Je, In-Gyu; Kim, Duk-Sil; Kim, Sung-Wan; Lee, Soyoung; Lee, Hyun-Shik; Park, Eui Kyun; Khang, Dongwoo; Kim, Sang-Hyun

    2015-01-01

    Allergic diseases such as atopic dermatitis, rhinitis, asthma, and anaphylaxis are attractive research areas. Tyrosol (2-(4-hydroxyphenyl)ethanol) 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.

  1. 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.

  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. [Analysis of health insurance data on home nursing care in Hungary].

    Science.gov (United States)

    Cs Horváth, Zoltán; Sebestyén, Andor; Molics, Bálint; Ágoston, István; Endrei, Dóra; Oláh, András; Betlehem, József; Imre, László; Bagosi, Gabriella; Boncz, Imre

    2014-04-13

    Bevezetés: Az otthoni szakápolás 1996 végén indult meg Magyarországon. Célkitűzés: A szerzők célja a magyar otthoni szakápolási rendszer egészségbiztosítási és igénybevételi mutatóinak bemutatása. Módszer: Az elemzésben szereplő adatok az Országos Egészségbiztosítási Pénztár finanszírozási adatbázisából (2001–2012) származnak. Elemezték a betegszámokat, a vizitszámokat, a szakápolási és szakirányú terápiás tevékenységek (gyógytorna, fizioterápia, logopédia) arányát. Eredmények: Az ellátott betegek száma a 2001. évi 36 560-ról 2012-re 51 647-re nőtt, 41,3%-kal emelkedett. A teljesített vizitek száma ugyanezen időszak alatt 841 715-ről 1 194 670-re, 41,9%-kal nőtt. A szakápolási és szakirányú terápiás tevékenységek, valamint az ápolási fokozatok vonatkozásában jelentős megyék közötti eltéréseket figyeltek meg. A szakápolásra kifizetett összegek aránya a legmagasabb volt Nógrád (80,4%), Szabolcs-Szatmár-Bereg (79,7%) és Komárom-Esztergom (74,6%) megyékben, míg a legalacsonyabb Zala (53,0%) és Csongrád (52,7%) megyékben, illetve Budapesten (47,9%). Következtetések: Az otthoni szakápolásban jelentős területi egyenlőtlenségek mutatkoznak, amelyek mérsékléséhez olyan szakmai irányelvek fejlesztésére van szükség, amelyek az otthoni szakápolás speciális vonatkozásait szabályozzák. Orv. Hetil., 2014, 155(15), 597–603.

  4. [Evaluation of ambulatory antibiotic use in Hungary using drug-specific quality indicators].

    Science.gov (United States)

    Matuz, Mária; Benkő, Ria; Hajdú, Edit; Viola, Réka; Soós, Gyöngyvér

    2013-06-16

    Bevezetés: A bakteriális rezisztencia visszaszorítására az antibiotikumok átgondolt alkalmazása lehetséges beavatkozási pont. Célkitűzés: A hazai ambuláns antibiotikum-alkalmazás gyakorlatának nemzetközi minőségi indikátorokon keresztül történő bemutatása. Módszer: Az 1996–2010 közötti időszakra vonatkozó nyers, nagykereskedői eladásokon alapuló, ambuláns szisztémás antibiotikum-felhasználási adatokat az Egészségügyi Világszervezet 2010. évi napi terápiás dózisai (defined daily dose – DDD) figyelembevételével DDD/1000 fő/nap egységben adták meg. Az antibiotikum-felhasználás értékelésére a nemzetközileg kidolgozott és validált minőségi indikátorokat alkalmazták. Eredmények: A hazai ambuláns antibiotikum-alkalmazás a vizsgálat során mennyiségileg kiegyenlített (18,0±1,8 DDD/1000 fő/nap) volt, szerkezetében azonban jelentős változások történtek. A széles versus szűk spektrumú béta-laktámok és makrolidek felhasználási aránya többszörösére nőtt (1996: 2,2 vs. 2010: 15,8), a fluorokinolonok felhasználása megháromszorozódott. A vizsgált tíz minőségi indikátor közül Magyarország három indikátor esetében az európai elithez, négy, valamint három esetében a gyengébb, illetve leggyengébb országok közé tartozott. Következtetés: A hazai ambuláns antibiotikum-felhasználás mennyiségileg a skandináv, az összetétel tekintetében a déli országokhoz hasonlít. Orv. Hetil., 2013, 154, 947–956.

  5. Caratteristiche sismiche e geodinamiche della Val Padana flua li risultano dali' attività sismica ivi verificatasi dall' inizio dell' Era Volgare a tutto il 1969

    Directory of Open Access Journals (Sweden)

    M. C. SPADEA

    1970-06-01

    Full Text Available Ai fllli ,li trarre (lualche elelllollto, attu a eontribuin'
    alla ,'Ulloscellza ,Iella sisillicit.i~ ,Iella Val j'a,lana - - illLesa ill sellso lato
    ~i è ritelluto utile esalilinare i terr"mo1.i, verifica1.isi nell'l'ra volgare, Ira
    le Pn'alpi (inl'luHe e l'avamJlaese degli AJlJlllllnini.
    ~atumlmente, l'esame si è CUllereLato ilei Lm,lul'I'e sui gru(li ,li ulla
    scala si~mi{'a (ilei easo speeil1('o, la seala .'IIen:alli a Il gradi, le Ilotizie ma(·.ro·
    ~ismÌl'.he, quali risultano da veuchie (·.rolla(·he, in Jlarticolare ,bil volume
    del Baratt.a sui Terremoti d'[talia . ~i SOIlO eo~ì ottenute le i~oHism", relativ"
    ad oltre treeento t.elTemoti, chc ~OIlO servite per la det.erminazione appros.
    simativa delle pro[ondit.à ipocentmli e delle energie ~ vihtppate all'ipoeentro.
    l"el [ICriu,lu che va (Ial 1100 al 1.'i00 ca, si SOIlU veriticati nella Yall'adall:!
    (specialmellte nella sua parte urielltale ,l('i torre moti violelltis~imi fra i
    più violenti uhe si UOIiOScallO , (·.he llanno provo{'ato vi1:1.ime e (Ianni in·
    genti>;i;imi ili ZUlle mulLu c~te~o. Tale at.tiviti~ è all(lat.a gradualmclIte ~cf'_·
    malldo Ilei seculi SU(·.l'c~sivi, {'.onservalllio ulla l'erta illten~itil e fn;qlwllza ai
    margini noni orÌell1.ali (l'rCallli helhmesi e sud orientali ("[.'orlivese eRa·
    vennate ,ldla Valle.
    La sismicitii. viene ,Iisclssa nei suoi aspetti geologici e tett.uniei.
    Viene tentata la detel'lilillazione ,lell'aeeeleraziulle orizzullLale, ill zona
    epieentmlc, 1('1' dno tCl'1'omot.i, origillallti in Val l'adalla, a profolldità ,li·
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    la sUJlel'l1uie di '!o!Jorovick (Delta, ~ulla llf~se ,Ielle registrazioni miero·
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    cosi ehe le massime acee!emziolli - « ('etori~ paril

  6. [Hemorrhagic complications of chronic anticoagulant treatment in a single intensive care unit].

    Science.gov (United States)

    Tinyei, Ilona; Kocsi, Zsuzsanna; Pénzes, István; Nyulasi, Tibor

    2013-11-17

    Bevezetés: A krónikus antikoaguláns kezelést jól körülhatárolt indikációs körrel, széles körben alkalmazzák. Kevesebb szó esik azonban az általa okozott vérzéses szövődményekről, amelyek súlyosak vagy akár halálos kimenetelűek is lehetnek. Célkitűzés: A Szent János Kórház és Észak-budai Egyesített Kórházak Központi Aneszteziológiai és Intenzív Terápiás Osztályán 2006. január 1. és 2011. december 31. között krónikus antikoaguláns kezelés kapcsán kialakult vérzéses szövődményes esetek elemzése. Módszer: A szerzők multidiszciplináris intenzív osztályán a vizsgált hat év alatt összesen 73 betegnél fordult elő intenzív ellátást igénylő vérzéses szövődmény krónikus antikoagulálás kapcsán. Eredmények: Hatvanhárom esetben intracranialis vérzést észleltek, ezen belül leggyakrabban traumás eredetűt. Kisebb számban előfordult még spinalis haematoma, gastrointestinalis vérzés, haemorrhagiás cystitis, haemothorax és hasüregi vérzés. A betegek felvételi INR-értéke 43 esetben a terápiás tartományon kívül esett. A betegek mortalitása igen magas volt, a komplex intenzív kezelés ellenére 49 beteg halt meg a vérzéssel összefüggésben (75,5%). Következtetések: A gyakori traumás eredetre, a terápiás tartományon kívül eső INR-értékek nagy számára és a magas mortalitásra tekintettel a szerzők véleménye szerint rendszeres betegkövetéssel, részletes felvilágosítással, a társbetegségek alakulásával párhuzamosan revideált indikáció/kontraindikáció alapján folytatott krónikus antikoaguláns kezeléssel a vérzéses szövődmények száma csökkenthető lenne. Orv. Hetil., 2013, 154(46), 1829–1835.

  7. [The relationship of work-related psychosocial risk factors with depressive symptoms among Hungarian workers: preliminary results of the Hungarian Work Stress Survey].

    Science.gov (United States)

    Nistor, Katalin; Nistor, Anikó; Ádám, Szilvia; Szabó, Anita; Konkolÿ Thege, Barna; Stauder, Adrienne

    2015-03-01

    Bevezetés: Nemzetközi és hazai kutatások egyaránt igazolják, hogy a pszichoszociális stressz mentális megbetegedések kockázati tényezője. Célkitűzés: Jelen tanulmány célja az Országos Munkahelyi Stresszfelmérés előzetes eredményeinek feldolgozása a depressziós tünetegyüttes és a stresszterhelés kapcsolatának vonatkozásában. Módszer: Keresztmetszeti kérdőíves vizsgálat magyar munkavállalók körében (n = 1058, 27,5% férfi, 72,5% nő, átlagéletkor 37,2 év, SD = 11). A pszichoszociális tényezőket a COPSOQ II (Koppenhágai Kérdőív a Munkahelyi Pszichoszociális Tényezőkről II), míg a depressziós tünetegyüttest a rövidített Beck Depresszió Kérdőívvel mértük fel. A pszichoszociális tényezők és a depresszió kapcsolatát korrelációval, illetve bináris logisztikus regresszió analízissel vizsgáltuk. Eredmények: A minta negyede közepesen súlyos vagy súlyos depressziós tünetekről számolt be. Az eredmények igazolják a depressziós tünetegyüttes (BDI≥19) összefüggését a munka–család konfliktussal (OR = 2,21, CI: 1,82–2,68), a fejlődési lehetőségekkel (OR = 0,76, CI: 0,59–0,97), a munka értelmességével (OR = 0,69, CI: 0,59–0,89) és a munkahely iránti elkötelezettséggel (OR = 0,60, CI: 0,47–0,78). Következtetések: A munkavállalók mentális egészségének védelme szempontjából az eredmények felvetik olyan szervezeti szintű intézkedések szükségességét, amelyek lehetővé teszik a pszichoszociális stressz csökkentését. Orv. Hetil., 2015, 156(11), 439–448.

  8. [Impact of attachment to God and religious coping on life satisfaction].

    Science.gov (United States)

    Láng, András

    2013-11-17

    Bevezetés: A vallásosság hatása a mentális és fizikai egészségre, illetve az élettel való elégedettségre sokat vizsgált területe a pszichológiának. Ugyanakkor ezek a vizsgálatok kevesebb figyelmet fordítanak arra, hogy a vallásosság megélése, az Isten-kapcsolat milyen szerepet játszik hívő emberek élettel való elégedettségében. Célkitűzés: A szerző célkitűzése az volt, hogy megvizsgálja az Istenhez való kötődés és a vallásos megküzdés hatását az élettel való elégedettségre. Módszer: A kérdőívcsomagot 94 (49 nő, 45 férfi), önmagát római katolikusnak valló személy töltötte ki. Átlagéletkoruk 30,8±6,2 év volt. Túlnyomó többségük (96,8%) legalább érettségivel rendelkezett. A kérdőívcsomag a Kötődés Istenhez Leltárt, a Vallásos Megküzdés Skála rövidített változatát, valamint a Diener-féle Élettel Való Elégedettség Skálát tartalmazta. Eredmények: A negatív vallásos megküzdés és az Istenhez való szorongó kötődés a demográfiai változókon felül, negatív irányban befolyásolták az élettel való elégedettség mértékét. Következtetések: Az eredmények rámutatnak arra, hogy a negatív Isten-kép jelentősen befolyásolhatja a hívők élettel való elégedettségét, ami mentális és fizikai egészségükre is kihatással lehet. Orv. Hetil., 2013, 154(46), 1843–1847.

  9. [Cryptosporidium and Giardia as water contaminant pathogens in Hungary].

    Science.gov (United States)

    Plutzer, Judit

    2013-11-17

    Bevezetés: A Cryptosporidium több faja és a Giardia duodenalis két csoportja emberben leggyakrabban akut hasmenést okoznak. Ezek a paraziták rendkívül ellenálló, vastag falú (oo)cysták formájában kerülnek a környezetbe, ahol hosszú ideig megőrzik fertőzőképességüket. Célkitűzés: A fenti protozoonok hazai előfordulásának vizsgálata különböző vízforrásokban, kiegészítve a vízgyűjtő területeken található szennyezőforrások tanulmányozásával és egy epidemiológiai felméréssel. Módszer: A vizsgálatokhoz modern molekuláris és epidemiológiai módszerek széles körét használtuk. Eredmények: Magasabb (oo)cystaszámokat szennyvízbefolyások után, illetve erdei környezetben mutattunk ki. A vizsgálatok megerősítették, hogy a szarvasmarhatelepek jelentős vízszennyező források lehetnek, a vízimadarak pedig szerepet játszhatnak az (oo)cysták terjesztésében. Az epidemiológiai felmérés elgondolkodtató adatokat sorakoztatott fel az aszimptomatikus giardiosis és a vízfogyasztás összefüggéseiről. Új, olcsó, gyors és hatékony detektálási módszert fejlesztettünk ki a monitoringvizsgálatokhoz és az állapotfelmérésekhez. Következtetések: A bemutatott eredmények nagymértékben hozzájárulnak a fenti paraziták epidemiológiai jelentőségének megismeréséhez és a járványok, fertőzések elkerüléséhez Magyarországon. Orv. Hetil., 2013, 154(46), 1836–1842.

  10. [Role of implantable loop recorder in the clinical diagnosis of syncope: results of the introduction of an effective diagnostic tool].

    Science.gov (United States)

    Somlói, Miklós; Toldy-Schedel, Emil; Nényei, Zoltán; Böszörményi, Róbert; Tomcsányi, János

    2015-04-01

    Bevezetés: A spontán események monitorozásának kiterjesztése loop recorder beültetésével megnövelheti a definitív diagnózisok arányát a syncope kivizsgálása során. Célkitűzés: A szerzők retrospektív obszervációs vizsgálatban kívánták meghatározni az implantálható loop recorder diagnosztikus teljesítményét a syncope kivizsgálásában a mindennapi klinikai gyakorlat körülményei között. Módszer: A szerzők kardiológiai osztályán 2005 és 2014 közötti időszakban ismeretlen eredetű ismételt syncope miatt loop recorder beültetésen átesett összes beteg elektronikus adatbázisban tárolt adatait elemezték. Eredmények: A vizsgált időszakban 52 loop recorder beültetés történt. A monitorozás átlagosan 167 (±136) napja alatt 36 (69,2%) diagnosztikus esemény történt. Az események kétharmadában, azaz az összes vizsgálat 46,2%-ában a monitorozás arrhythmiás mechanizmust igazolt, amely ezen esetekben definitív terápiát tett lehetővé. Ebben a válogatott betegcsoportban az életkor, az ismert kockázatprediktorok és a syncopét kísérő trauma nem mutattak összefüggést az eszméletvesztés mechanizmusával. Következtetések: A loop recorder használatával a mindennapi gyakorlatban elért magas diagnózisarány összhangban van a klinikai vizsgálatok eredményeivel, ami alátámasztja a módszer korai alkalmazását a syncope kivizsgálási menetében. Orv. Hetil., 2015, 156(15), 609–613.

  11. Bírói kérdésfeltevések a magyar tanú- és szakértői bizonyításokban

    Directory of Open Access Journals (Sweden)

    Varga, Marianna

    2015-12-01

    Full Text Available Judges' questions in the Hungarian witness testimony and expert evidence *** In my paper, I investigate the types of questions asked by judges in the Hungarian courtroom discourses regarding their role how they could or could not influence witnesses and experts in the course of complex testimony and evidence. The corpus is made up of 16 trials, half of which are civil, the other half criminal. 13 of these trials were recorded - 22 hours and 14 minutes of recording in total - and three other trials were observed with written notes about them. I use a complex method to analyze these discourses based on conversation analysis combined with functional pragmatics. However, psychological and judicial knowledge was also necessary in addition to linguistics approach. In the present paper, I especially concentrate on the importance of agent omission, presuppositions in questions, and the preference organization with respect to answers over nonanswer responses, type-conformity over nonconformity, and affirmation over disaffirmation. Thus, examining the questions asked during trials in an integrated linguistics and judicial framework, I propose a more reliable and detailed typology of questions. *** Tanulmányomban a bírák által feltett kérdések típusait vizsgálom a tanúk és szakértők befolyásolásának és befolyásolhatóságának szempontjából, a magyar tanú- és szakértői bizonyításokban betöltött komplex szerepükből kiindulva. A vizsgálat korpuszát 16 tárgyalás alkotja, fele-fele arányban büntető és polgári peres eljárás. Ezek közül 13 tárgyalást diktafonnal rögzítettem, így összesen 22 óra 14 perc hangfelvételt és a további 3 tárgyalás során készített írásbeli jegyzetet elemeztem egy komplex szempontrendszer alapján: a konverzációelemzés módszereit ötvöztem funkcionális pragmatikai nézetekkel, valamint jogi és pszichológiai ismeretekre is szükség volt. Vizsgáltam az ágens kihagy

  12. 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.

  13. Mechanisms of interferon-γ production by neutrophils and its function during Streptococcus pneumoniae pneumonia.

    Science.gov (United States)

    Gomez, John C; Yamada, Mitsuhiro; Martin, Jessica R; Dang, Hong; Brickey, W June; Bergmeier, Wolfgang; Dinauer, Mary C; Doerschuk, Claire M

    2015-03-01

    Bacterial pneumonia is a common public health problem associated with significant mortality, morbidity, and cost. Neutrophils are usually the earliest leukocytes to respond to bacteria in the lungs. Neutrophils rapidly sequester in the pulmonary microvasculature and migrate into the lung parenchyma and alveolar spaces, where they perform numerous effector functions for host defense. Previous studies showed that migrated neutrophils produce IFN-γ early during pneumonia induced by Streptococcus pneumoniae and that early production of IFN-γ regulates bacterial clearance. IFN-γ production by neutrophils requires Rac2, Hck/Lyn/Fgr Src family tyrosine kinases, and NADPH oxidase. Our current studies examined the mechanisms that regulate IFN-γ production by lung neutrophils during acute S. pneumoniae pneumonia in mice and its function. We demonstrate that IFN-γ production by neutrophils is a tightly regulated process that does not require IL-12. The adaptor molecule MyD88 is critical for IFN-γ production by neutrophils. The guanine nucleotide exchange factor CalDAG-GEFI modulates IFN-γ production. The CD11/CD18 complex, CD44, Toll-like receptors 2 and 4, TRIF, and Nrf2 are not required for IFN-γ production by neutrophils. The recently described neutrophil-dendritic cell hybrid cell, identified by its expression of Ly6G and CD11c, is present at low numbers in pneumonic lungs and is not a source of IFN-γ. IFN-γ produced by neutrophils early during acute S. pneumoniae pneumonia induces transcription of target genes in the lungs, which are critical for host defense. These studies underline the complexity of the neutrophil responses during pneumonia in the acute inflammatory response and in subsequent resolution or initiation of immune responses.

  14. 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.

  15. Masitinib (AB1010, a potent and selective tyrosine kinase inhibitor targeting KIT.

    Directory of Open Access Journals (Sweden)

    Patrice Dubreuil

    Full Text Available BACKGROUND: The stem cell factor receptor, KIT, is a target for the treatment of cancer, mastocytosis, and inflammatory diseases. Here, we characterise the in vitro and in vivo profiles of masitinib (AB1010, a novel phenylaminothiazole-type tyrosine kinase inhibitor that targets KIT. METHODOLOGY/PRINCIPAL FINDINGS: In vitro, masitinib had greater activity and selectivity against KIT than imatinib, inhibiting recombinant human wild-type KIT with an half inhibitory concentration (IC(50 of 200+/-40 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC(50 of 150+/-80 nM in Ba/F3 cells expressing human or mouse wild-type KIT. Masitinib also potently inhibited recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, masitinib demonstrated weak inhibition of ABL and c-Fms and was inactive against a variety of other tyrosine and serine/threonine kinases. This highly selective nature of masitinib suggests that it will exhibit a better safety profile than other tyrosine kinase inhibitors; indeed, masitinib-induced cardiotoxicity or genotoxicity has not been observed in animal studies. Molecular modelling and kinetic analysis suggest a different mode of binding than imatinib, and masitinib more strongly inhibited degranulation, cytokine production, and bone marrow mast cell migration than imatinib. Furthermore, masitinib potently inhibited human and murine KIT with activating mutations in the juxtamembrane domain. In vivo, masitinib blocked tumour growth in mice with subcutaneous grafts of Ba/F3 cells expressing a juxtamembrane KIT mutant. CONCLUSIONS: Masitinib is a potent and selective tyrosine kinase inhibitor targeting KIT that is active, orally bioavailable in vivo, and has low toxicity.

  16. There is a tide in the affairs of men ... Die uitdaging om werkbare en billike(-r keuringsmeganismes te ontwerp

    Directory of Open Access Journals (Sweden)

    J. G. Maree

    2003-09-01

    Full Text Available Navorsing rakende die toelating van studente tot studierigtings aan tersiêre instansies is aanvanklik primêr gefokus op ’n soeke na meganismes om die aantal risikostudente betekenisvol te verminder – ’n uiters komplekse aangeleentheid. Onlangse veranderings in die Suid-Afrikaanse samelewing noodsaak tersiêre inrigtings om innoverend oor hul eie aard en doelstellings te dink. Die fokus is tans veral op moontlike wyses om die tradisioneel agtergeblewe deel van die Suid-Afrikaanse samelewing ’n billiker kans te gee op toelating tot en die behaal van sukses aan tersiêre instansies. Die druk op tersiêre instansies om te sorg dat die demografie van die studentekorps aan tersiêre instansies meer verteenwoordigend van die algemene bevolking raak, neem hand-oor-hand toe. Keuring van studente in studierigtings soos medies, tandheelkunde, ingenieurswese en sielkunde sal waarskynlik in die afsienbare toekoms in die brandpunt bly, aangesien die verhouding swart : wit studente wat tot hierdie studierigtings toegelaat word, steeds heeltemal ontoereikend (ten koste van swart studente is en nie naastenby in lyn met die doelwitte wat deur regeringslui gestel word nie. Die navorsers ondersoek in die onderhawige artikel die prestasie van senaatsdiskresionêre studente aan die Fakulteit Opvoedkunde van die Universiteit van Pretoria en kom tot die gevolgtrekking dat nóg ’n minimum M-telling van 11, nóg ’n toelatingstoetspunt tersiêre prestasie akkuraat voorspel. Uitkomsgebaseerde Onderrig en veranderende wyses van assessering en ‘bepunting’ in Graad 12 maak die situasie ingewikkelder. ’n Nasionale tweejaarstrategie word bepleit om die eskalerende uitdaging van billike keuring en toelating tot tersiêre opleidingsinstansies te fasiliteer.

  17. Neutrophil-delivered myeloperoxidase dampens the hydrogen peroxide burst after tissue wounding in zebrafish.

    Science.gov (United States)

    Pase, Luke; Layton, Judith E; Wittmann, Christine; Ellett, Felix; Nowell, Cameron J; Reyes-Aldasoro, Constantino Carlos; Varma, Sony; Rogers, Kelly L; Hall, Chris J; Keightley, M Cristina; Crosier, Philip S; Grabher, Clemens; Heath, Joan K; Renshaw, Stephen A; Lieschke, Graham J

    2012-10-09

    Prompt neutrophil arrival is critical for host defense immediately after injury [1-3]. Following wounding, a hydrogen peroxide (H(2)O(2)) burst generated in injured tissues is the earliest known leukocyte chemoattractant [4]. Generating this tissue-scale H(2)O(2) gradient uses dual oxidase [4] and neutrophils sense H(2)O(2) by a mechanism involving the LYN Src-family kinase [5], but the molecular mechanisms responsible for H(2)O(2) clearance are unknown [6]. Neutrophils carry abundant amounts of myeloperoxidase, an enzyme catalyzing an H(2)O(2)-consuming reaction [7, 8]. We hypothesized that this neutrophil-delivered myeloperoxidase downregulates the high tissue H(2)O(2) concentrations that follow wounding. This was tested in zebrafish using simultaneous fluorophore-based imaging of H(2)O(2) concentrations and leukocytes [4, 9-11] and a new neutrophil-replete but myeloperoxidase-deficient mutant (durif). Leukocyte-depleted zebrafish had an abnormally sustained wound H(2)O(2) burst, indicating that leukocytes themselves were required for H(2)O(2) downregulation. Myeloperoxidase-deficient zebrafish also had abnormally sustained high wound H(2)O(2) concentrations despite similar numbers of arriving neutrophils. A local H(2)O(2)/myeloperoxidase interaction within wound-recruited neutrophils was demonstrated. These data demonstrate that leukocyte-delivered myeloperoxidase cell-autonomously downregulates tissue-generated wound H(2)O(2) gradients in vivo, defining a new requirement for myeloperoxidase during inflammation. Durif provides a new animal model of myeloperoxidase deficiency closely phenocopying the prevalent human disorder [7, 12, 13], offering unique possibilities for investigating its clinical consequences.

  18. Novel Molecular Insights into Classical and Alternative Activation States of Microglia as Revealed by Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC)-based Proteomics.

    Science.gov (United States)

    Bell-Temin, Harris; Culver-Cochran, Ashley E; Chaput, Dale; Carlson, Christina M; Kuehl, Melanie; Burkhardt, Brant R; Bickford, Paula C; Liu, Bin; Stevens, Stanley M

    2015-12-01

    Microglia, the resident immune cells of the brain, have been shown to display a complex spectrum of roles that span from neurotrophic to neurotoxic depending on their activation status. Microglia can be classified into four stages of activation, M1, which most closely matches the classical (pro-inflammatory) activation stage, and the alternative activation stages M2a, M2b, and M2c. The alternative activation stages have not yet been comprehensively analyzed through unbiased, global-scale protein expression profiling. In this study, BV2 mouse immortalized microglial cells were stimulated with agonists specific for each of the four stages and total protein expression for 4644 protein groups was quantified using SILAC-based proteomic analysis. After validating induction of the various stages through a targeted cytokine assay and Western blotting of activation states, the data revealed novel insights into the similarities and differences between the various states. The data identify several protein groups whose expression in the anti-inflammatory, pro-healing activation states are altered presumably to curtail inflammatory activation through differential protein expression, in the M2a state including CD74, LYN, SQST1, TLR2, and CD14. The differential expression of these proteins promotes healing, limits phagocytosis, and limits activation of reactive nitrogen species through toll-like receptor cascades. The M2c state appears to center around the down-regulation of a key member in the formation of actin-rich phagosomes, SLP-76. In addition, the proteomic data identified a novel activation marker, DAB2, which is involved in clathrin-mediated endocytosis and is significantly different between M2a and either M1 or M2b states. Western blot analysis of mouse primary microglia stimulated with the various agonists of the classical and alternative activation states revealed a similar trend of DAB2 expression compared with BV2 cells.

  19. The Inhibitory Effects of Low-Dose Ionizing Radiation in IgE-Mediated Allergic Responses.

    Directory of Open Access Journals (Sweden)

    Hae Mi Joo

    Full Text Available Ionizing radiation has different biological effects according to dose and dose rate. In particular, the biological effect of low-dose radiation is unclear. Low-dose whole-body gamma irradiation activates immune responses in several ways. However, the effects and mechanism of low-dose radiation on allergic responses remain poorly understood. Previously, we reported that low-dose ionizing radiation inhibits mediator release in IgE-mediated RBL-2H3 mast cell activation. In this study, to have any physiological relevance, we investigated whether low-dose radiation inhibits allergic responses in activated human mast cells (HMC-1(5C6 and LAD2 cells, mouse models of passive cutaneous anaphylaxis and the late-phase cutaneous response. High-dose radiation induced cell death, but low-dose ionizing radiation of <0.5 Gy did not induce mast cell death. Low-dose ionizing radiation that did not induce cell death significantly suppressed mediator release from human mast cells (HMC-1(5C6 and LAD2 cells that were activated by antigen-antibody reaction. To determine the inhibitory mechanism of mediator released by low-dose ionizing radiation, we examined the phosphorylation of intracellular signaling molecules such as Lyn, Syk, phospholipase Cγ, and protein kinase C, as well as the intracellular free Ca2+ concentration ([Ca2+]i. The phosphorylation of signaling molecules and [Ca2+]i following stimulation of FcεRI receptors was inhibited by low dose ionizing radiation. In agreement with its in vitro effect, ionizing radiation also significantly inhibited inflammatory cells infiltration, cytokine mRNA expression (TNF-α, IL-4, IL-13, and symptoms of passive cutaneous anaphylaxis reaction and the late-phase cutaneous response in anti-dinitrophenyl IgE-sensitized mice. These results indicate that ionizing radiation inhibits both mast cell-mediated immediate- and delayed-type allergic reactions in vivo and in vitro.

  20. 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.

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

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    Kathy L McGraw

    Full Text Available 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.

  2. Role of calcium, protein kinase C and MAP kinase in the activation of mast cells

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    Michael A. Beaven

    1996-01-01

    Full Text Available The mechanisms of activation of mast cells have been studied in most detail in rat RBL-2H3 cells. These cells respond to antigen via the IgE receptor (FceRI through sequential activation of the tyrosine kinases, Lyn and Syk, and to adenosine analogs via the adenosine A3 receptor (A3R and a pertussis toxin-sensitive G protein, most likely Gi-3. Other receptors, introduced through gene transfection, include the muscarinic ml receptor (mlR which acts via Gq/11. Stimulation of cells via FceRI, A3R or ml R leads to the activation of phospholipase (PL C, PLD and mitogen-activated protein (MAP kinase resulting in the generation of inositol phosphates and diglycerides, an increase of cytosolic Ca2+, the activation of protein kinase C (PKC and the phosphorylation of various proteins by PKC and MAP kinase. The extent and time course of these events varies for each receptor. These variations, as well as the effects of pharmacologic probes, gene transfection and reconstitution of responses in washed permeabilized cells, indicate how these events relate to functional responses. A modest but sustained elevation of cytosolic Ca2+ through an influx of extracellular Ca2+ and activation of PKCβ and PKCδ are sufficient for optimal release of preformed secretory granules. Phosphorylation of a cytosolic PLAj by AMP kinase (p42mapk and a modest increase in cytosolic Ca2+ are necessary for the activation of Pl^ and the binding of PLA2 to membranes, respectively. Finally, both de novo generation and secretion via Golgi-derived vesicles of certain cytokines are dependent on Ca2+ and PKC as well as additional signals most probably phosphorylation of proteins by Syk and p42mapk.

  3. The Nogo-C2/Nogo receptor complex regulates the morphogenesis of zebrafish lateral line primordium through modulating the expression of dkk1b, a Wnt signal inhibitor.

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    Hao-Wei Han

    Full Text Available The fish lateral line (LL is a mechanosensory system closely related to the hearing system of higher vertebrates, and it is composed of several neuromasts located on the surface of the fish. These neuromasts can detect changes in external water flow, to assist fish in maintaining a stationary position in a stream. In the present study, we identified a novel function of Nogo/Nogo receptor signaling in the formation of zebrafish neuromasts. Nogo signaling in zebrafish, like that in mammals, involves three ligands and four receptors, as well as three co-receptors (TROY, p75, and LINGO-1. We first demonstrated that Nogo-C2, NgRH1a, p75, and TROY are able to form a Nogo-C2 complex, and that disintegration of this complex causes defective neuromast formation in zebrafish. Time-lapse recording of the CldnB::lynEGFP transgenic line revealed that functional obstruction of the Nogo-C2 complex causes disordered morphogenesis, and reduces rosette formation in the posterior LL (PLL primordium during migration. Consistent with these findings, hair-cell progenitors were lost from the PLL primordium in p75, TROY, and Nogo-C2/NgRH1a morphants. Notably, the expression levels of pea3, a downstream marker of Fgf signaling, and dkk1b, a Wnt signaling inhibitor, were both decreased in p75, TROY, and Nogo-C2/NgRH1a morphants; moreover, dkk1b mRNA injection could rescue the defects in neuromast formation resulting from knockdown of p75 or TROY. We thus suggest that a novel Nogo-C2 complex, consisting of Nogo-C2, NgRH1a, p75, and TROY, regulates Fgf signaling and dkk1b expression, thereby ensuring stable organization of the PLL primordium.

  4. Co-expression network analysis and genetic algorithms for gene prioritization in preeclampsia.

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    Tejera, Eduardo; Bernardes, João; Rebelo, Irene

    2013-11-12

    In this study, we explored the gene prioritization in preeclampsia, combining co-expression network analysis and genetic algorithms optimization approaches. We analysed five public projects obtaining 1,146 significant genes after cross-platform and processing of 81 and 149 microarrays in preeclamptic and normal conditions, respectively. After co-expression network construction, modular and node analysis were performed using several approaches. Moreover, genetic algorithms were also applied in combination with the nearest neighbour and discriminant analysis classification methods. Significant differences were found in the genes connectivity distribution, both in normal and preeclampsia conditions pointing to the need and importance of examining connectivity alongside expression for prioritization. We discuss the global as well as intra-modular connectivity for hubs detection and also the utility of genetic algorithms in combination with the network information. FLT1, LEP, INHA and ENG genes were identified according to the literature, however, we also found other genes as FLNB, INHBA, NDRG1 and LYN highly significant but underexplored during normal pregnancy or preeclampsia. Weighted genes co-expression network analysis reveals a similar distribution along the modules detected both in normal and preeclampsia conditions. However, major differences were obtained by analysing the nodes connectivity. All models obtained by genetic algorithm procedures were consistent with a correct classification, higher than 90%, restricting to 30 variables in both classification methods applied.Combining the two methods we identified well known genes related to preeclampsia, but also lead us to propose new candidates poorly explored or completely unknown in the pathogenesis of preeclampsia, which may have to be validated experimentally.

  5. PKCθ activation in pancreatic acinar cells by gastrointestinal hormones/neurotransmitters and growth factors is needed for stimulation of numerous important cellular signaling cascades

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    Sancho, Veronica; Berna, Marc J.; Thill, Michelle; Jensen, R. T.

    2011-01-01

    The novel PKCθ isoform is highly expressed in T-cells, brain and skeletal muscle and originally thought to have a restricted distribution. It has been extensively studied in T-cells and shown to be important for apoptosis, T-cell activation and proliferation. Recent studies showed its presence in other tissues and importance in insulin signaling, lung surfactant secretion, intestinal barrier permeability, platelet and mast-cell functions. However, little information is available for PKCθ activation by gastrointestinal(GI) hormones/neurotransmitters and growth factors. In the present study we used rat pancreatic acinar cells to explore their ability to activate PKCθ and the possible interactions with important cellular mediators of their actions. Particular attention was paid to cholecystokinin(CCK), a physiological regulator of pancreatic function and important in pathological processes affecting acinar function, like pancreatitis. PKCθ-protein/mRNA were present in the pancreatic acini, and T538-PKCθ phosphorylation/activation was stimulated only by hormones/neurotransmitters activating phospholipase C. PKCθ was activated in time- and dose-related manner by CCK, mediated 30% by high-affinity CCKA-receptor activation. CCK stimulated PKCθ translocation from cytosol to membrane. PKCθ inhibition (by pseudostrate-inhibitor or dominant negative) inhibited CCK- and TPA-stimulation of PKD, Src, RafC, PYK2, p125FAK and IKKα/β, but not basal/stimulated enzyme secretion. Also CCK- and TPA-induced PKCθ activation produced an increment in PKCθ’s direct association with AKT, RafA, RafC and Lyn. These results show for the first time PKCθ presence in pancreatic acinar cells, its activation by some GI hormones/neurotransmitters and involvement in important cell signaling pathways mediating physiological responses (enzyme secretion, proliferation, apoptosis, cytokine expression, and pathological responses like pancreatitis and cancer growth). PMID:21810446

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

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    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.

  7. Editorial

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    Editorial Office

    2009-07-01

    Full Text Available Die redaksie is dankbaar om nog ’n uitgawe van In die Skriflig aan ons lesers te bied. Hierdie uitgawe bied ’n artikel van Fritz de Wet wat handel oor ’n pneumaties-bepaalde teoretiese raamwerk vir ’n navorsingsmetodologie in Praktiese Teologie. Hy wys op die unieke aard van prakties-teologiese wetenskapsbeoefening en toon aan hoe ’n pneumaties-bepaalde teoretiese raamwerk binne hierdie pro- ses diensbaar kan wees. Hierdie artikel is ’n belangrike bydrae vir navorsingsmetodologie in ’n tyd waarin sodanige metodologie weer in Teologie aan die orde gestel word. Hannes van der Walt vra die vraag of “Spiritualiteit” die nuwe godsdiens van ons tyd geword het? Hierdie vraag het belangrik geword in die postmoderne geestes- klimaat waar, in verset teen die dominansie van die rede, weer ge- soek word na “ervaring” en “gevoelsbelewing” binne ’n religieuse verband. Sy konklusie is dat hoewel “Spiritualiteit” nie werklik as ’n nuwe religie gesien kan word nie, dit tog waar is dat mense en- toesiasties soek na nuwe geestelike ervarings. Daarom draai baie mense hulle rug op die hoofstroomkerke waarin hulle meen hulle nie sulke ervarings kan beleef nie. Benno Zuiddam ondersoek die teo- logiese verskuiwing in die denke van David Faure, die negentiende- eeuse Kaapse predikant. Aanvanklik het Faure sy teologie in die lyn van die rasionalisme bedink, maar het daarna sy toevlug tot spiri- tisme geneem. Op grond van hierdie historiese gebeurtenis vra Benno die vraag of dit nie ook die lot gaan wees van die Nuwe Her- vormingbeweging in Suid-Afrika nie.

  8. Involvement of BLT1 endocytosis and Yes kinase activation in leukotriene B4-induced neutrophil degranulation.

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    Gaudreault, Eric; Thompson, Charles; Stankova, Jana; Rola-Pleszczynski, Marek

    2005-03-15

    One of the important biological activities of human neutrophils is degranulation, which can be induced by leukotriene B4 (LTB4). Here we investigated the intracellular signaling events involved in neutrophil degranulation mediated by the high affinity LTB4 receptor, BLT1. Peripheral blood neutrophils as well as the promyeloid PLB-985 cell line, stably transfected with BLT1 cDNA and differentiated into a neutrophil-like cell phenotype, were used throughout this study. LTB4-induced enzyme release was inhibited by 50-80% when cells were pretreated with the pharmacological inhibitors of endocytosis sucrose, Con A and NH4Cl. In addition, transient transfection with a dominant negative form of dynamin (K44A) resulted in approximately 70% inhibition of ligand-induced degranulation. Pretreating neutrophils or BLT1-expressing PLB-985 cells with the Src family kinase inhibitor PP1 resulted in a 30-60% inhibition in BLT1-mediated degranulation. Yes kinase, but not c-Src, Fgr, Hck, or Lyn, was found to exhibit up-regulated kinase activity after LTB4 stimulation. Moreover, BLT1 endocytosis was found to be necessary for Yes kinase activation in neutrophils. LTB4-induced degranulation was also sensitive to inhibition of PI3K. In contrast, it was not affected by inhibition of the mitogen-activated protein kinase MEK kinase, the Janus kinases, or the receptor tyrosine kinase epidermal growth factor receptor or platelet-derived growth factor receptor. Taken together, our results suggest an essential role for BLT1 endocytosis and Yes kinase activation in LTB4-mediated degranulation of human neutrophils.

  9. Rehmannia Glutinosa Pharmacopuncture Solution Regulates Functional Activation, FcεRI Expression, and Signaling Events in Mast Cells

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    Kang Kyung-Hwa

    2012-12-01

    Full Text Available Objectives: Rehmannia glutinosa pharmacopuncture solution (RGPS was investigated to determine both its anti-allergic inflammatory effects on mast cells and its detailed mechanism of actions. Methods: We investigated whether RGPS suppress cytokines, enzymes, FcεRI expression and FcεRI mediated signaling in RBL-2H3 cells stimulated with anti-DNP IgE/DNP-HSA. The suppressive effects of RGPS on the levels of cytokines such as IL-1β, IL-6 and GM-CSF were measured using emzyme-linked immunospecific assay (ELISA. The mRNA expression levels of cytokines, enzymes (HDC2, COX-1, COX-2 and 5LO and FcεRI αβγ subunits were measured using reverse transcription polymerase chain reaction (RTPCR method. The activation of FcεRI-mediated signaling was examined using Western blot analyses. Results: RGPS suppressed production of proinflammatory cytokines (IL-1β, IL-6, and GM-CSF in stimulated RBL-2H3 cells significantly (P < 0.05. RGPS also suppressed mRNA expression of inflammatory enzymes (HDC2, COX-1, COX-2, 5LO. In addition, mRNA expression levels of FcεRIα, FcεRIβ and FcεRIγ were lowered by treatment with RGPS. Finally, RGPS prevented phosphrylation of Lyn, Syk, LAT, Gab2, PLC γ1/2, PI3K, Akt, cPLA2 and IκBα. Conclusions: RGPS effectively suppresses mast cell activations such as degranulation and inflammatory response via down-regulation of the FcεRI-mediated signaling pathways in IgE/Ag-stimulated mast cells.

  10. Inhibitory Effect of Methyleugenol on IgE-Mediated Allergic Inflammation in RBL-2H3 Cells

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    Feng Tang

    2015-01-01

    Full Text Available Allergic diseases, such as asthma and allergic rhinitis, are common. Therefore, the discovery of therapeutic drugs for these conditions is essential. Methyleugenol (ME is a natural compound with antiallergic, antianaphylactic, antinociceptive, and anti-inflammatory effects. This study examined the antiallergic effect of ME on IgE-mediated inflammatory responses and its antiallergy mechanism in the mast cell line, RBL-2H3. We found that ME significantly inhibited the release of β-hexosaminidase, tumor necrosis factor- (TNF- α, and interleukin- (IL- 4, and was not cytotoxic at the tested concentrations (0–100 μM. Additionally, ME markedly reduced the production of the proinflammatory lipid mediators prostaglandin E2 (PGE2, prostaglandin D2 (PGD2, leukotriene B4 (LTB4, and leukotriene C4 (LTC4. We further evaluated the effect of ME on the early stages of the FcεRI cascade. ME significantly inhibited Syk phosphorylation and expression but had no effect on Lyn. Furthermore, it suppressed ERK1/2, p38, and JNK phosphorylation, which is implicated in proinflammatory cytokine expression. ME also decreased cytosolic phospholipase A2 (cPLA2 and 5-lipoxygenase (5-LO phosphorylation and cyclooxygenase-2 (COX-2 expression. These results suggest that ME inhibits allergic response by suppressing the activation of Syk, ERK1/2, p38, JNK, cPLA2, and 5-LO. Furthermore, the strong inhibition of COX-2 expression may also contribute to the antiallergic action of ME. Our study provides further information about the biological functions of ME.

  11. 2-Hydroxy-3-methoxybenzoic acid attenuates mast cell-mediated allergic reaction in mice via modulation of the FcεRI signaling pathway.

    Science.gov (United States)

    Kim, Yeon-Yong; Je, In-Gyu; Kim, Min Jong; Kang, Byeong-Cheol; Choi, Young-Ae; Baek, Moon-Chang; Lee, Byungheon; Choi, Jin Kyeong; Park, Hae Ran; Shin, Tae-Yong; Lee, Soyoung; Yoon, Seung-Bin; Lee, Sang-Rae; Khang, Dongwoo; Kim, Sang-Hyun

    2017-01-01

    Mast cells are important effector cells in immunoglobulin (Ig) E-mediated allergic reactions such as asthma, atopic dermatitis and rhinitis. Vanillic acid, a natural product, has shown anti-oxidant and anti-inflammatory activities. In the present study, we investigated the anti-allergic inflammatory effects of ortho-vanillic acid (2-hydroxy-3-methoxybenzoic acid, o-VA) that was a derivative of vanillic acid isolated from Amomum xanthioides. In mouse anaphylaxis models, oral administration of o-VA (2, 10, 50 mg/kg) dose-dependently attenuated ovalbumin-induced active systemic anaphylaxis and IgE-mediated cutaneous allergic reactions such as hypothermia, histamine release, IgE production and vasodilation; administration of o-VA also suppressed the mast cell degranulator compound 48/80-induced anaphylaxis. In cultured mast cell line RBL-2H3 and isolated rat peritoneal mast cells in vitro, pretreatment with o-VA (1-100 μmol/L) dose-dependently inhibited DNP-HSA-induced degranulation of mast cells by decreasing the intracellular free calcium level, and suppressed the expression of pro-inflammatory cytokines TNF-α and IL-4. Pretreatment of RBL-2H3 cells with o-VA suppressed DNP-HSA-induced phosphorylation of Lyn, Syk, Akt, and the nuclear translocation of nuclear factor-κB. In conclusion, o-VA suppresses the mast cell-mediated allergic inflammatory response by blocking the signaling pathways downstream of high affinity IgE receptor (FcεRI) on the surface of mast cells.

  12. The Inhibitory Effects of Low-Dose Ionizing Radiation in IgE-Mediated Allergic Responses.

    Science.gov (United States)

    Joo, Hae Mi; Kang, Su Jin; Nam, Seon Young; Yang, Kwang Hee; Kim, Cha Soon; Lee, In Kyung; Kim, Ji Young

    2015-01-01

    Ionizing radiation has different biological effects according to dose and dose rate. In particular, the biological effect of low-dose radiation is unclear. Low-dose whole-body gamma irradiation activates immune responses in several ways. However, the effects and mechanism of low-dose radiation on allergic responses remain poorly understood. Previously, we reported that low-dose ionizing radiation inhibits mediator release in IgE-mediated RBL-2H3 mast cell activation. In this study, to have any physiological relevance, we investigated whether low-dose radiation inhibits allergic responses in activated human mast cells (HMC-1(5C6) and LAD2 cells), mouse models of passive cutaneous anaphylaxis and the late-phase cutaneous response. High-dose radiation induced cell death, but low-dose ionizing radiation of Low-dose ionizing radiation that did not induce cell death significantly suppressed mediator release from human mast cells (HMC-1(5C6) and LAD2 cells) that were activated by antigen-antibody reaction. To determine the inhibitory mechanism of mediator released by low-dose ionizing radiation, we examined the phosphorylation of intracellular signaling molecules such as Lyn, Syk, phospholipase Cγ, and protein kinase C, as well as the intracellular free Ca2+ concentration ([Ca2+]i). The phosphorylation of signaling molecules and [Ca2+]i following stimulation of FcεRI receptors was inhibited by low dose ionizing radiation. In agreement with its in vitro effect, ionizing radiation also significantly inhibited inflammatory cells infiltration, cytokine mRNA expression (TNF-α, IL-4, IL-13), and symptoms of passive cutaneous anaphylaxis reaction and the late-phase cutaneous response in anti-dinitrophenyl IgE-sensitized mice. These results indicate that ionizing radiation inhibits both mast cell-mediated immediate- and delayed-type allergic reactions in vivo and in vitro.

  13. Phosphoproteomics of collagen receptor networks reveals SHP-2 phosphorylation downstream of wild-type DDR2 and its lung cancer mutants.

    Science.gov (United States)

    Iwai, Leo K; Payne, Leo S; Luczynski, Maciej T; Chang, Francis; Xu, Huifang; Clinton, Ryan W; Paul, Angela; Esposito, Edward A; Gridley, Scott; Leitinger, Birgit; Naegle, Kristen M; Huang, Paul H

    2013-09-15

    Collagen is an important extracellular matrix component that directs many fundamental cellular processes including differentiation, proliferation and motility. The signalling networks driving these processes are propagated by collagen receptors such as the β1 integrins and the DDRs (discoidin domain receptors). To gain an insight into the molecular mechanisms of collagen receptor signalling, we have performed a quantitative analysis of the phosphorylation networks downstream of collagen activation of integrins and DDR2. Temporal analysis over seven time points identified 424 phosphorylated proteins. Distinct DDR2 tyrosine phosphorylation sites displayed unique temporal activation profiles in agreement with in vitro kinase data. Multiple clustering analysis of the phosphoproteomic data revealed several DDR2 candidate downstream signalling nodes, including SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase 2), NCK1 (non-catalytic region of tyrosine kinase adaptor protein 1), LYN, SHIP-2 [SH2 (Src homology 2)-domain-containing inositol phosphatase 2], PIK3C2A (phosphatidylinositol-4-phosphate 3-kinase, catalytic subunit type 2α) and PLCL2 (phospholipase C-like 2). Biochemical validation showed that SHP-2 tyrosine phosphorylation is dependent on DDR2 kinase activity. Targeted proteomic profiling of a panel of lung SCC (squamous cell carcinoma) DDR2 mutants demonstrated that SHP-2 is tyrosine-phosphorylated by the L63V and G505S mutants. In contrast, the I638F kinase domain mutant exhibited diminished DDR2 and SHP-2 tyrosine phosphorylation levels which have an inverse relationship with clonogenic potential. Taken together, the results of the present study indicate that SHP-2 is a key signalling node downstream of the DDR2 receptor which may have therapeutic implications in a subset of DDR2 mutations recently uncovered in genome-wide lung SCC sequencing screens.

  14. Pliocene-Pleistocene changes in Arctic sea-ice cover: New biomarker records from Fram Strait/Yermak Plateau (ODP Sites 911 and 912)

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    Stein, Ruediger; Fahl, Kirsten

    2013-04-01

    . Organic Geochemistry 38, 16-27. 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. Fahl, K. and Stein, R., 2012. Modern seasonal variability and deglacial/Holocene change of central Arctic Ocean sea-ice cover: New insights from biomarker proxy records. Earth Planetary Science Letters 351-352C, 123-133, doi:10.1016/j.epsl.2012.07.009. Massé, G., Rowland, S.J., Sicre, M.-A., Jacob, J., Jansen, E., Belt, S.T., 2008. Abrupt climate changes for Iceland during the last millennium: Evidence from high resolution sea ice reconstructions. Earth Planetary Science Letters 269, 565-569. 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. Müller, J., Wagner, A., Fahl, K., Stein, R., Prange, M., Lohmann, G., 2011. Towards quantitative sea ice reconstructions in the northern North Atlantic: A combined biomarker and numerical modelling approach. Earth Planetary Science Letters 306, 137-148. Stein, R. and Fahl, K., 2012. Biomarker proxy IP25 shows potential for studying entire Quaternary Arctic sea-ice history. Organic Geochemistry; doi: 10.1016/j.orggeochem.2012.11.005. Stein, R., Fahl, K., and Müller, J., 2012. Proxy reconstruction of Arctic Ocean sea ice history: "From IRD to IP25". Polarforschung 82, 37-71. Vare, L.L., Massé, G., Gregory, T.R., Smart, C.W., Belt, S.T., 2009. Sea ice variations in the central Canadian Arctic Archipelago during the Holocene. Quaternary Science Reviews 28, 1354-1366.

  15. Retinoic acid therapy resistance progresses from unilineage to bilineage in HL-60 leukemic blasts.

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    Holly A Jensen

    Full Text Available Emergent resistance can be progressive and driven by global signaling aberrations. All-trans retinoic acid (RA is the standard therapeutic agent for acute promyelocytic leukemia, but 10-20% of patients are not responsive, and initially responsive patients relapse and develop retinoic acid resistance. The patient-derived, lineage-bipotent acute myeloblastic leukemia (FAB M2 HL-60 cell line is a potent tool for characterizing differentiation-induction therapy responsiveness and resistance in t(15;17-negative cells. Wild-type (WT HL-60 cells undergo RA-induced granulocytic differentiation, or monocytic differentiation in response to 1,25-dihydroxyvitamin D3 (D3. Two sequentially emergent RA-resistant HL-60 cell lines, R38+ and R38-, distinguishable by RA-inducible CD38 expression, do not arrest in G1/G0 and fail to upregulate CD11b and the myeloid-associated signaling factors Vav1, c-Cbl, Lyn, Fgr, and c-Raf after RA treatment. Here, we show that the R38+ and R38- HL-60 cell lines display a progressive reduced response to D3-induced differentiation therapy. Exploiting the biphasic dynamic of induced HL-60 differentiation, we examined if resistance-related defects occurred during the first 24 h (the early or "precommitment" phase or subsequently (the late or "lineage-commitment" phase. HL-60 were treated with RA or D3 for 24 h, washed and retreated with either the same, different, or no differentiation agent. Using flow cytometry, D3 was able to induce CD38, CD11b and CD14 expression, and G1/G0 arrest when present during the lineage-commitment stage in R38+ cells, and to a lesser degree in R38- cells. Clustering analysis of cytometry and quantified Western blot data indicated that WT, R38+ and R38- HL-60 cells exhibited decreasing correlation between phenotypic markers and signaling factor expression. Thus differentiation induction therapy resistance can develop in stages, with initial partial RA resistance and moderate vitamin D3 responsiveness

  16. A critical role of Src family kinase in SDF-1/CXCR4-mediated bone-marrow progenitor cell recruitment to the ischemic heart.

    Science.gov (United States)

    Cheng, Min; Huang, Kai; Zhou, Junlan; Yan, Dewen; Tang, Yao-Liang; Zhao, Ting C; Miller, Richard J; Kishore, Raj; Losordo, Douglas W; Qin, Gangjian

    2015-04-01

    The G protein-coupled receptor CXCR4 and its ligand stromal-cell derived factor 1 (SDF-1) play a crucial role in directing progenitor cell (PC) homing to ischemic tissue. The Src family protein kinases (SFK) can be activated by, and serve as effectors of, G proteins. In this study we sought to determine whether SFK play a role in SDF-1/CXCR4-mediated PC homing. First, we investigated whether SDF-1/CXCR4 signaling activates SFK. Bone-marrow mononuclear cells (BM MNCs) were isolated from WT and BM-specific CXCR4-KO mice and treated with SDF-1 and/or CXCR4 antagonist AMD3100. SDF-1 treatment rapidly induced phosphorylation (activation) of hematopoietic Src (i.e., Lyn, Fgr, and Hck) in WT cells but not in AMD3100-treated cells or CXCR4-KO cells. Then, we investigated whether SFK are involved in SDF-1/CXCR4-mediated PC chemotaxis. In a combined chemotaxis and endothelial-progenitor-cell (EPC) colony assay, Src inhibitor SU6656 dose-dependently inhibited the SDF-1-induced migration of colony-forming EPCs. Next, we investigated whether SFK play a role in SDF-1/CXCR4-mediated BM PC homing to the ischemic heart. BM MNCs from CXCR4BAC:eGFP reporter mice were i.v. injected into WT and SDF-1BAC:SDF1-RFP transgenic mice following surgically-induced myocardial infarction (MI). eGFP(+) MNCs and eGFP(+)c-kit(+) PCs that were recruited in the infarct border zone in SDF-1BAC:SDF1-RFP recipients were significantly more than that in WT recipients. Treatments of mice with SU6656 significantly reduced eGFP(+) and eGFP(+)c-kit(+) cell recruitment in both WT and SDF-1BAC:RFP recipients and abrogated the difference between the two groups. Remarkably, PCs isolated from BM-specific C-terminal Src kinase (CSK)-KO (Src activated) mice were recruited more efficiently than PCs from WT PCs in the WT recipients. In conclusion, SFK are activated by SDF-1/CXCR4 signaling and play an essential role in SDF-1/CXCR4-mediated BM PC chemotactic response and ischemic cardiac recruitment.

  17. Detection of selection signatures in dairy and beef cattle using high-density genomic information.

    Science.gov (United States)

    Zhao, Fuping; McParland, Sinead; Kearney, Francis; Du, Lixin; Berry, Donagh P

    2015-06-19

    Artificial selection for economically important traits in cattle is expected to have left distinctive selection signatures on the genome. Access to high-density genotypes facilitates the accurate identification of genomic regions that have undergone positive selection. These findings help to better elucidate the mechanisms of selection and to identify candidate genes of interest to breeding programs. Information on 705 243 autosomal single nucleotide polymorphisms (SNPs) in 3122 dairy and beef male animals from seven cattle breeds (Angus, Belgian Blue, Charolais, Hereford, Holstein-Friesian, Limousin and Simmental) were used to detect selection signatures by applying two complementary methods, integrated haplotype score (iHS) and global fixation index (FST). To control for false positive results, we used false discovery rate (FDR) adjustment to calculate adjusted iHS within each breed and the genome-wide significance level was about 0.003. Using the iHS method, 83, 92, 91, 101, 85, 101 and 86 significant genomic regions were detected for Angus, Belgian Blue, Charolais, Hereford, Holstein-Friesian, Limousin and Simmental cattle, respectively. None of these regions was common to all seven breeds. Using the FST approach, 704 individual SNPs were detected across breeds. Annotation of the regions of the genome that showed selection signatures revealed several interesting candidate genes i.e. DGAT1, ABCG2, MSTN, CAPN3, FABP3, CHCHD7, PLAG1, JAZF1, PRKG2, ACTC1, TBC1D1, GHR, BMP2, TSG1, LYN, KIT and MC1R that play a role in milk production, reproduction, body size, muscle formation or coat color. Fifty-seven common candidate genes were found by both the iHS and global FST methods across the seven breeds. Moreover, many novel genomic regions and genes were detected within the regions that showed selection signatures; for some candidate genes, signatures of positive selection exist in the human genome. Multilevel bioinformatic analyses of the detected candidate genes

  18. Phenotyping and auto-antibody production by liver-infiltrating B cells in primary sclerosing cholangitis and primary biliary cholangitis.

    Science.gov (United States)

    Chung, Brian K; Guevel, Bardia T; Reynolds, Gary M; Gupta Udatha, D B R K; Henriksen, Eva Kristine Klemsdal; Stamataki, Zania; Hirschfield, Gideon M; Karlsen, Tom Hemming; Liaskou, Evaggelia

    2017-02-01

    Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are immune-mediated biliary diseases that demonstrate prominent and restricted genetic association with human leukocyte antigen (HLA) alleles. In PBC, anti-mitochondrial antibodies (AMA) are specific and used as diagnostic biomarkers. PSC-relevant auto-antibodies remain controversial despite a distinct HLA association that mirrors archetypical auto-antigen driven disorders. Herein, we compared antibody-secreting B cells (ASCs) in PSC and PBC liver explants to determine if liver-infiltrating ASCs represent an opportune and novel source of disease-relevant auto-antibodies. Using enzymatic digestion and mechanical disruption, liver mononuclear cells (LIMCs) were isolated from fresh PSC and PBC explants and plasmablast (CD19+CD27+CD38(hi)CD138-) and plasma cell (CD19+CD27+CD38(hi)CD138+) ASCs were enumerated by flow cytometry. We observed 45-fold fewer plasma cells in PSC explants (n = 9) compared to PBC samples (n = 5, p < 0.01) and 10-fold fewer IgA-, IgG- and IgM-positive ASCs (p < 0.05). Liver-infiltrating ASCs from PSC and PBC explants were functional and produced similar concentrations of IgA, IgG and IgM following 2 weeks of culture. Antibody production by PBC ASCs (n = 3) was disease-specific as AMA to pyruvate dehydrogenase complex E2 subunit (PDC-E2) was detected by immunostaining, immunoblotting and ELISA. Antibody profiling of PSC supernatants (n = 9) using full-length recombinant human protein arrays (Cambridge Protein Arrays) revealed reactivities to nucleolar protein 3 (5/9) and hematopoietic cell-specific Lyn substrate 1 (3/9). Array analysis of PBC supernatants (n = 3) detected reactivities to PDC-E2 and hexokinase 1 (3/3). In conclusion, we detected unique frequencies of liver-infiltrating ASCs in PSC and PBC and in so doing, highlight a feasible approach for understanding disease-relevant antibodies in PSC. Copyright © 2016. Published by Elsevier Ltd.

  19. Effect of endocannabinoids on IgE-mediated allergic response in RBL-2H3 cells.

    Science.gov (United States)

    Yoo, Jae-Myung; Sok, Dai-Eun; Kim, Mee Ree

    2013-09-01

    Recently, some endocannabinoids were reported to show anti-inflammatory and anti-allergic activities. In this respect, various arachidonoyl endocannabinoids were screened for the inhibition of allergic response in IgE-activated RBL-2H3 cells. Among arachidonoyl endocannabinoids with a low cytotoxicity, only NA-5HT remarkably inhibited the release of β-hexosaminidase (IC(50), 13.58 μM), a marker of degranulation, and tumor necrosis factor-α (IC(50), 12.52 μM), a pro-inflammatory cytokine, in IgE-activated RBL-2H3 cells. Additionally, NA-5HT markedly suppressed the formation of prostaglandin D(2) (PGD(2)) with IC(50) value of 1.27 μM and leukotriene B(4) (LTB(4)) with IC(50) value of 1.20 μM, and slightly LTC4. When effect of NA-5HT on early stage of FcεRI cascade was investigated, it significantly inhibited phosphorylation of Syk, but not Lyn. Furthermore, NA-5HT suppressed phosphorylation of PLCγ1/2 and PKCδ, related to degranulation process, as well as phosphorylation of LAT, ERK1/2, p38, JNK, Gab2, PI3K and Akt, implicated in the expression of pro-inflammatory cytokines. Relative to its effect on the late stage, NA-5HT slightly reduced phosphorylation of 5-lipoxygenase (5-LO) and cyclooxygenase-2 (COX-2). Additionally, NA-5HT significantly reduced the level of p40(phox), and partially inhibited the expression of p47(phox) and p67(phox). From these results, it is suggested that NA-5HT expresses anti-allergic action by suppressing the activation of Syk, LAT, p38, JNK, PI3K and Akt, as well as the expression of ERK1/2 and NADPH oxidase subunits. Further, a strong inhibition of PGD(2) or LTB(4) biosynthesis by NA-5HT may be an additional mechanism for its anti-allergic action. Such anti-allergic actions of NA-5HT may contribute to further information about its biological functions.

  20. Fine tuning inflammation at the front door: macrophage complement receptor 3-mediates phagocytosis and immune suppression for Francisella tularensis.

    Directory of Open Access Journals (Sweden)

    Shipan Dai

    2013-01-01

    Full Text Available Complement receptor 3 (CR3, CD11b/CD18 is a major macrophage phagocytic receptor. The biochemical pathways through which CR3 regulates immunologic responses have not been fully characterized. Francisella tularensis is a remarkably infectious, facultative intracellular pathogen of macrophages that causes tularemia. Early evasion of the host immune response contributes to the virulence of F. tularensis and CR3 is an important receptor for its phagocytosis. Here we confirm that efficient attachment and uptake of the highly virulent Type A F. tularensis spp. tularensis strain Schu S4 by human monocyte-derived macrophages (hMDMs requires complement C3 opsonization and CR3. However, despite a>40-fold increase in uptake following C3 opsonization, Schu S4 induces limited pro-inflammatory cytokine production compared with non-opsonized Schu S4 and the low virulent F. novicida. This suggests that engagement of CR3 by opsonized Schu S4 contributes specifically to the immune suppression during and shortly following phagocytosis which we demonstrate by CD11b siRNA knockdown in hMDMs. This immune suppression is concomitant with early inhibition of ERK1/2, p38 MAPK and NF-κB activation. Furthermore, TLR2 siRNA knockdown shows that pro-inflammatory cytokine production and MAPK activation in response to non-opsonized Schu S4 depends on TLR2 signaling providing evidence that CR3-TLR2 crosstalk mediates immune suppression for opsonized Schu S4. Deletion of the CD11b cytoplasmic tail reverses the CR3-mediated decrease in ERK and p38 activation during opsonized Schu-S4 infection. The CR3-mediated signaling pathway involved in this immune suppression includes Lyn kinase and Akt activation, and increased MKP-1, which limits TLR2-mediated pro-inflammatory responses. These data indicate that while the highly virulent F. tularensis uses CR3 for efficient uptake, optimal engagement of this receptor down-regulates TLR2-dependent pro-inflammatory responses by inhibiting

  1. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  3. Human clinical studies of tea polyphenols in allergy or life style-related diseases.

    Science.gov (United States)

    Maeda-Yamamoto, Mari

    2013-01-01

    Many previous epidemiological studies have revealed that green tea or green tea catechins contributed to the preveintion of lifestyle-related diseases. Several cohort studies on the relationship between green tea consumption and cardiovascular disease (CVD) risk/type 2 diabetes mellitus risk have been conducted. The results showed that green tea consumption (5 or more cups/day) was inversely associated with mortality from CVD and all causes. Within CVD mortality, the strongest inverse association was observed for stroke mortality. Furthermore, consumption of green tea, coffee, and total caffeine was associated with a reduced risk for type 2 diabetes. On the other hand, the analysis of randomized clinical trial (RCT) studies showed that the administration of green tea beverages or extracts resulted in significant reductions in serum total cholesterol and LDL-cholesterol concentrations, but had no apparent effect on HDL-cholesterol. Green tea reduced fasting blood glucose levels in a small intervention trial, although no improvements in HbA1c levels were seen. Continuous intake of green tea containing catechins and caffeine (5 or more cups per day) may be beneficial for body weight management, vascular disease risk reduction via LDL-cholesterol improvement, and type 2 diabetes risk reduction through the lowering of fasting blood glucose levels. Epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3"Me) isolated from cv. "Benifuuki" green tea has been shown to strongly inhibit mast cell activation and histamine release after FcepsilonRI cross-linking through the suppression of tyrosine phosphorylation (Lyn) of cellular protein kinase, and the suppression of myosin light chain phosphorylation and high-affinity IgE receptor expression via the binding to 67 kDa laminin receptors. A double-blind clinical study on subjects with Japanese cedar pollinosis was carried out. At the eleventh week after starting intake, which was coincident with the most severe period of cedar pollen

  4. Retinoic acid therapy resistance progresses from unilineage to bilineage in HL-60 leukemic blasts.

    Science.gov (United States)

    Jensen, Holly A; Bunaciu, Rodica P; Ibabao, Christopher N; Myers, Rebecca; Varner, Jeffrey D; Yen, Andrew

    2014-01-01

    Emergent resistance can be progressive and driven by global signaling aberrations. All-trans retinoic acid (RA) is the standard therapeutic agent for acute promyelocytic leukemia, but 10-20% of patients are not responsive, and initially responsive patients relapse and develop retinoic acid resistance. The patient-derived, lineage-bipotent acute myeloblastic leukemia (FAB M2) HL-60 cell line is a potent tool for characterizing differentiation-induction therapy responsiveness and resistance in t(15;17)-negative cells. Wild-type (WT) HL-60 cells undergo RA-induced granulocytic differentiation, or monocytic differentiation in response to 1,25-dihydroxyvitamin D3 (D3). Two sequentially emergent RA-resistant HL-60 cell lines, R38+ and R38-, distinguishable by RA-inducible CD38 expression, do not arrest in G1/G0 and fail to upregulate CD11b and the myeloid-associated signaling factors Vav1, c-Cbl, Lyn, Fgr, and c-Raf after RA treatment. Here, we show that the R38+ and R38- HL-60 cell lines display a progressive reduced response to D3-induced differentiation therapy. Exploiting the biphasic dynamic of induced HL-60 differentiation, we examined if resistance-related defects occurred during the first 24 h (the early or "precommitment" phase) or subsequently (the late or "lineage-commitment" phase). HL-60 were treated with RA or D3 for 24 h, washed and retreated with either the same, different, or no differentiation agent. Using flow cytometry, D3 was able to induce CD38, CD11b and CD14 expression, and G1/G0 arrest when present during the lineage-commitment stage in R38+ cells, and to a lesser degree in R38- cells. Clustering analysis of cytometry and quantified Western blot data indicated that WT, R38+ and R38- HL-60 cells exhibited decreasing correlation between phenotypic markers and signaling factor expression. Thus differentiation induction therapy resistance can develop in stages, with initial partial RA resistance and moderate vitamin D3 responsiveness (unilineage

  5. [Is daily chest X-ray necessary after lung resection? Evidence-based decision making].

    Science.gov (United States)

    Furák, József; Géczi, Tibor; Pécsy, Balázs; Morvay, Zita

    2014-08-01

    Bevezetés: A hazai mellkassebészetek jó részében érvényben lévő aranyszabály szerint napi rutinmellkasröntgen- (RTG-) vizsgálat elvégzése javasolt tüdőlobectomia után mindaddig, amíg a betegeknek mellkasi csövük van. Más itthoni centrumokban viszont nem ragaszkodnak ehhez a gyakorlathoz. A szerzők e két szemlélet eredményeit hasonlítják össze osztályuk anyagában. Anyag és módszer: 148 olyan beteget értékeltek, akiknél problémamentes lobectomia és egy mellkasi cső behelyezése történt. A rutinmellkas-RTG-csoportba (R-RTG) 50 beteg tartozik, akiknél közvetlenül a műtét után, valamint a szívás idején naponta rutinszerűen és a cső eltávolítását követő napon szintén mellkas-RTG-felvétel készült. 98 betegnél csak tünetek és/vagy panasz esetén (láz, hypoxia, subcutan emphysema, tartós levegőkilépés) és/vagy a mellkasi drain eltávolítását követő napon készült RTG (T-RTG). A következő műtét utáni adatokat értékelték: láz, kóros RTG kép/lelet (pneumothorax [PTX], folyadék, atelectasia, subcutan emphysema, haematoma), RTG-felvételek száma, drainage-tartam és esetleges új cső behelyezése. Eredmények: Az átlagos drainage-idő 3,7 és 3,8 nap volt az R-RTG- és a T-RTG-csoportokban. A mellkasi cső eltávolítását követően kóros RTG-leletet az R-RTG-csoport betegeinek 50%-ában (25/50) és a T-RTG-csoport 46,9%-ában (46/98) (p = 0,724) kaptak, de új cső behelyezésére az R-RTG-csoportban csak 12%-ban (3/25), illetve a T-RTG-csoportban csak 15,2%-ban (7/46) volt szükség. Az elkészített RTG-felvételek száma az R-RTG-csoportban 5,0, míg a T-RTG-csoportban 2,3 volt (p = 0,0001). Következtetés: Nem volt több műtét utáni szövődmény és csőeltávolítás utáni kóros RTG-lelet, ha az RTG-felvétel csak a betegek tünetei/panaszai alapján készült a rutinszerű napi RTG-vizsgálatok helyett. A kóros RTG-leleteken jelzett szövődményeknek csak 12–15%-a ig

  6. [Efficacy of tumor necrosis factor-alpha inhibitors in fistulising perianal Crohn's disease].

    Science.gov (United States)

    Bor, Renáta; Farkas, Klaudia; Bálint, Anita; Szűcs, Mónika; Abrahám, Szabolcs; Baradnay, Gellért; Wittmann, Tibor; Szepes, Zoltán; Nagy, Ferenc; Molnár, Tamás

    2013-12-08

    Bevezetés: A tumornekrózis-faktor-alfa-gátlókat egyre gyakrabban alkalmazzák a súlyos Crohn-betegség kezelésében. Célkitűzés: A szerzők retrospektív módon értékelték a perianalis fisztulázó Crohn-betegség miatt indított anti-TNF-alfa terápia rövid és hosszú távú hatékonyságát. Módszer: Tumornekrózis-faktor-alfa-gátló kezelésben részesült 68 betegnél meghatározták a luminaris és perianalis aktivitás változását, a komplett fisztulazáródás arányát és a műtéti beavatkozások szükségességét. Eredmények: A kezelés megkezdése után 12 héttel a betegek több mint 80%-ánál a perianalis aktivitás csökkent, 60%-ukban komplett remissziót láttak. Egyéves kezelés alatt a betegek harmadánál a fisztulák záródtak, de a biológiai szer elhagyását követően minden második személynél a sipolyok recidiváltak. Legtöbb esetben a tumornekrózis-faktor-alfa-gátló mellett szükség volt immunszuppresszív kezelésre. A befejezett egyéves terápia alatt a betegek 45%-ánál legalább egy alkalommal végeztek sebészi beavatkozást, többségében ismételt seton-drenázst vagy tályogfeltárást. Következtetések: A tumornekrózis-faktor-alfa-gátló kezelés hatékony a perianalis Crohn-betegség kezelésében. Az immunszuppresszív szerek sok esetben nem hagyhatók el, és nagy arányban van szükség rectummegtartó sebészi beavatkozásokra. A terápia elhagyása utáni magas sipolyrecidíva-arány miatt mérlegelendő a folyamatos tumornekrózis-faktor-alfa-gátló kezelés. Orv. Hetil., 2013, 154(49), 1943–1948.

  7. The Toronto General Hospital Transitional Pain Service: development and implementation of a multidisciplinary program to prevent chronic postsurgical pain

    Directory of Open Access Journals (Sweden)

    Katz J

    2015-10-01

    Full Text Available Joel Katz,1–3 Aliza Weinrib,1,2 Samantha R Fashler,2 Rita Katznelzon,1,3 Bansi R Shah,1 Salima SJ Ladak,1 Jiao Jiang,1 Qing Li,1 Kayla McMillan,1 Daniel Santa Mina,5,6 Kirsten Wentlandt,7 Karen McRae,1,3 Diana Tamir,1,3 Sheldon Lyn,1,3 Marc de Perrot,8 Vivek Rao,9 David Grant,10 Graham Roche-Nagle,11 Sean P Cleary,12 Stefan OP Hofer,13 Ralph Gilbert,14 Duminda Wijeysundera,1,3 Paul Ritvo,15 Tahir Janmohamed,16 Gerald O’Leary,1,3 Hance Clarke1,3 1Department of Anesthesia and Pain Management, Toronto General Hospital, University Health Network, University of Toronto, 2Department of Psychology, York University, 3Department of Anesthesia, University of Toronto, 4Palliative Care, University Health Network, University of Toronto, 5Princess Margaret Cancer Centre, University Health Network, University of Toronto, 6Faculty of Kinesiology and Physical Education, University of Toronto, 7Department of Family and Community Medicine, University of Toronto, 8Division of Thoracic Surgery, Toronto General Hospital, 9Division of Cardiovascular Surgery, Toronto General Hospital, 10Multiorgan Transplant Program, Toronto General Hospital, 11Division of Vascular Surgery, Toronto General Hospital, 12Division of General Surgery, Toronto General Hospital, 13Division of Plastic Surgery, Toronto General Hospital, 14Division of Otolaryngology – Head and Neck Surgery, Toronto General Hospital, 15Department of Kinesiology and Health Science, York University, 16ManagingLife, Toronto, ON, CanadaAbstract: Chronic postsurgical pain (CPSP, an often unanticipated result of necessary and even life-saving procedures, develops in 5–10% of patients one-year after major surgery. Substantial advances have been made in identifying patients at elevated risk of developing CPSP based on perioperative pain, opioid use, and negative affect, including depression, anxiety, pain catastrophizing, and posttraumatic stress disorder-like symptoms. The Transitional Pain Service (TPS at

  8. 先锋派群体与个人才华:以语言派诗歌为例%Avant-Garde Community and the Individual Talent: The Case of Language Poetry

    Institute of Scientific and Technical Information of China (English)

    玛乔瑞·帕洛夫

    2006-01-01

    This essay examines the trajectory of Western avant-garde movements in the 20th century, especially the relationship of group formation, typical of these avant-gardes, to the individual talent. I classify movements like the Russian avant-garde and Italian futurism according to various criteria and trace their rise and fall. How, for example, does Marcel Duchamp relate to the Dada movement and how did Dada dissolve? After surveying avant-garde movements broadly in the first part of the essay, I turn to the case of a contemporary avant-garde movement, Language Poetry. The essay details the theoretical principles of the Language movement, founded in the late 1970s, and then studies the way this radical movement has evolved over the past twenty years. Language poetics, closely related to French Post-Structuralist aesthetic and Marxist ideology, was gradually assimilated into the mainstream and its stylistic features absorbed into more conventional modes. The movement is now essentially over, but it has produced a number of important poets, for example, Susan Howe and Charles Bernstein, Lyn Hejinian and Steve McCaffery. These poets typically transcend the movement of which they have been a part, and eventually find their own mode and style.%本文主要探讨西方20世纪先锋派运动的轨迹,特别考察了一些典型的先锋派群体的形成与个人才华之间的关系.文章根据不同的标准对先锋派运动进行了分类,如俄国先锋派和意大利未来派等,并探讨他们的兴衰.例如,马塞尔·迪尚与达达派运动是否有关,达达派如何解散?本文上半部分对先锋派作了广泛审视,下半部分则转向作为美国当代先锋派运动一部分的语言诗派进行个案研究:首先详细讨论了语言诗派的建立于20世纪70年代末期的理论准则,然后分析了这一激进诗歌运动近20年来的发展轨迹.语言派诗学与法国后结构主义美学和马克思主义意识形态有着密

  9. 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.

  10. 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

  11. 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

  12. 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

  13. 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