Src Induces Podoplanin Expression to Promote Cell Migration*

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Shen, Yongquan; Chen, Chen-Shan; Ichikawa, Hitoshi; Goldberg, Gary S.

2010-01-01

Nontransformed cells can force tumor cells to assume a normal morphology and phenotype by the process of contact normalization. Transformed cells must escape this process to become invasive and malignant. However, mechanisms underlying contact normalization have not been elucidated. Here, we have identified genes that are affected by contact normalization of Src-transformed cells. Tumor cells must migrate to become invasive and malignant. Src must phosphorylate the adaptor protein Cas (Crk-associated substrate) to promote tumor cell motility. We report here that Src utilizes Cas to induce podoplanin (Pdpn) expression to promote tumor cell migration. Pdpn is a membrane-bound extracellular glycoprotein that associates with endogenous ligands to promote tumor cell migration leading to cancer invasion and metastasis. In fact, Pdpn expression accounted for a major part of the increased migration seen in Src-transformed cells. Moreover, nontransformed cells suppressed Pdpn expression in adjacent Src-transformed cells. Of >39,000 genes, Pdpn was one of only 23 genes found to be induced by transforming Src activity and suppressed by contact normalization of Src-transformed cells. In addition, we found 16 genes suppressed by Src and induced by contact normalization. These genes encode growth factor receptors, adaptor proteins, and products that have not yet been annotated and may play important roles in tumor cell growth and migration. PMID:20123990

Lack of Csk-mediated negative regulation in a unicellular SRC kinase.

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Schultheiss, Kira P; Suga, Hiroshi; Ruiz-Trillo, Iñaki; Miller, W Todd

2012-10-16

Phosphotyrosine-based signaling plays a vital role in cellular communication in multicellular organisms. Unexpectedly, unicellular choanoflagellates (the closest phylogenetic group to metazoans) possess numbers of tyrosine kinases that are comparable to those in complex metazoans. Here, we have characterized tyrosine kinases from the filasterean Capsaspora owczarzaki, a unicellular protist representing the sister group to choanoflagellates and metazoans. Two Src-like tyrosine kinases have been identified in C. owczarzaki (CoSrc1 and CoSrc2), both of which have the arrangement of SH3, SH2, and catalytic domains seen in mammalian Src kinases. In Capsaspora cells, CoSrc1 and CoSrc2 localize to punctate structures in filopodia that may represent primordial focal adhesions. We have cloned, expressed, and purified both enzymes. CoSrc1 and CoSrc2 are active tyrosine kinases. Mammalian Src kinases are normally regulated in a reciprocal fashion by autophosphorylation in the activation loop (which increases activity) and by Csk-mediated phosphorylation of the C-terminal tail (which inhibits activity). Similar to mammalian Src kinases, the enzymatic activities of CoSrc1 and CoSrc2 are increased by autophosphorylation in the activation loop. We have identified a Csk-like kinase (CoCsk) in the genome of C. owczarzaki. We cloned, expressed, and purified CoCsk and found that it has no measurable tyrosine kinase activity. Furthermore, CoCsk does not phosphorylate or regulate CoSrc1 or CoSrc2 in cells or in vitro, and CoSrc1 and CoSrc2 are active in Capsaspora cell lysates. Thus, the function of Csk as a negative regulator of Src family kinases appears to have arisen with the emergence of metazoans.

Src controls castration recurrence of CWR22 prostate cancer xenografts

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Su, Bing; Gillard, Bryan; Gao, Lingqiu; Eng, Kevin H; Gelman, Irwin H

2013-01-01

Recurrence of prostate cancer (CaP) after androgen-deprivation therapy continues to have the greatest impact on patient survival. Castration-recurrent (CR)-CaP is likely driven by the activation of androgen receptor (AR) through multiple mechanisms including induction of AR coregulators, AR mutants or splice variants, and AR posttranslational modification such as phosphorylation by Src-family and Ack1 tyrosine kinases. Here, we address whether Src is required for the CR growth of human CWR22 CaP xenografts. The shRNA-mediated Src knockdown or treatment with the Src inhibitors, dasatinib or KXO1, reduced CaP recurrence over controls and increased time-to-recurrence following castration. Moreover, CR-CaP [Src-shRNA] tumors that recurred had similar Src protein and activation levels as those of parental cells, strengthening the notion that Src activity is required for progression to CR-CaP. In contrast, the ability of dasatinib or KXO1 to inhibit Src kinase activity in vitro did not correlate with their ability to inhibit serum-driven in vitro proliferation of CR and androgen-dependent stable cell lines derived from CWR22 tumors (CWR22Rv1 and CWR22PC, respectively), suggesting that the in vitro proliferation of these CaP lines is Src independent. Taken together, these findings strongly suggest that Src is a potent and specific therapeutic target for CR-CaP progression

Src binds cortactin through an SH2 domain cystine-mediated linkage

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Evans, Jason V.; Ammer, Amanda G.; Jett, John E.; Bolcato, Chris A.; Breaux, Jason C.; Martin, Karen H.; Culp, Mark V.; Gannett, Peter M.; Weed, Scott A.

2012-01-01

Summary Tyrosine-kinase-based signal transduction mediated by modular protein domains is critical for cellular function. The Src homology (SH)2 domain is an important conductor of intracellular signaling that binds to phosphorylated tyrosines on acceptor proteins, producing molecular complexes responsible for signal relay. Cortactin is a cytoskeletal protein and tyrosine kinase substrate that regulates actin-based motility through interactions with SH2-domain-containing proteins. The Src kinase SH2 domain mediates cortactin binding and tyrosine phosphorylation, but how Src interacts with cortactin is unknown. Here we demonstrate that Src binds cortactin through cystine bonding between Src C185 in the SH2 domain within the phosphotyrosine binding pocket and cortactin C112/246 in the cortactin repeats domain, independent of tyrosine phosphorylation. Interaction studies show that the presence of reducing agents ablates Src-cortactin binding, eliminates cortactin phosphorylation by Src, and prevents Src SH2 domain binding to cortactin. Tandem MS/MS sequencing demonstrates cystine bond formation between Src C185 and cortactin C112/246. Mutational studies indicate that an intact cystine binding interface is required for Src-mediated cortactin phosphorylation, cell migration, and pre-invadopodia formation. Our results identify a novel phosphotyrosine-independent binding mode between the Src SH2 domain and cortactin. Besides Src, one quarter of all SH2 domains contain cysteines at or near the analogous Src C185 position. This provides a potential alternative mechanism to tyrosine phosphorylation for cysteine-containing SH2 domains to bind cognate ligands that may be widespread in propagating signals regulating diverse cellular functions. PMID:23097045

Src binds cortactin through an SH2 domain cystine-mediated linkage.

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Evans, Jason V; Ammer, Amanda G; Jett, John E; Bolcato, Chris A; Breaux, Jason C; Martin, Karen H; Culp, Mark V; Gannett, Peter M; Weed, Scott A

2012-12-15

Tyrosine-kinase-based signal transduction mediated by modular protein domains is critical for cellular function. The Src homology (SH)2 domain is an important conductor of intracellular signaling that binds to phosphorylated tyrosines on acceptor proteins, producing molecular complexes responsible for signal relay. Cortactin is a cytoskeletal protein and tyrosine kinase substrate that regulates actin-based motility through interactions with SH2-domain-containing proteins. The Src kinase SH2 domain mediates cortactin binding and tyrosine phosphorylation, but how Src interacts with cortactin is unknown. Here we demonstrate that Src binds cortactin through cystine bonding between Src C185 in the SH2 domain within the phosphotyrosine binding pocket and cortactin C112/246 in the cortactin repeats domain, independent of tyrosine phosphorylation. Interaction studies show that the presence of reducing agents ablates Src-cortactin binding, eliminates cortactin phosphorylation by Src, and prevents Src SH2 domain binding to cortactin. Tandem MS/MS sequencing demonstrates cystine bond formation between Src C185 and cortactin C112/246. Mutational studies indicate that an intact cystine binding interface is required for Src-mediated cortactin phosphorylation, cell migration, and pre-invadopodia formation. Our results identify a novel phosphotyrosine-independent binding mode between the Src SH2 domain and cortactin. Besides Src, one quarter of all SH2 domains contain cysteines at or near the analogous Src C185 position. This provides a potential alternative mechanism to tyrosine phosphorylation for cysteine-containing SH2 domains to bind cognate ligands that may be widespread in propagating signals regulating diverse cellular functions.

Hormonal Resistance And Metastasis ER-Coregulartor-Src Signaling Targeted Therapy

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2011-09-01

Con Con ConE2 E2 E2 E2 MCF7 MCF7-PELP1-GFP vector Src-sh1 Src- sh2 R el at iv e lu m in es ce nc e ∗∗ α Fig. 1 Down regulation of Src kinase ...dasatinib significantly inhibited the growth of therapy resistant cells. Since PELP1, HER2, and Src kinase are commonly deregulated in breast cancers...Estrogen receptor, coregulators, nongenomic actions, Src kinase , therapy resistance, metastasis 56 vadlamudi@uthscsa.edu Table of Contents

Gallic acid abolishes the EGFR/Src/Akt/Erk-mediated expression of matrix metalloproteinase-9 in MCF-7 breast cancer cells.

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Chen, Ying-Jung; Lin, Ku-Nan; Jhang, Li-Mei; Huang, Chia-Hui; Lee, Yuan-Chin; Chang, Long-Sen

2016-05-25

Several studies have revealed that natural compounds are valuable resources to develop novel agents against dysregulation of the EGF/EGFR-mediated matrix metalloproteinase-9 (MMP-9) expression in cancer cells. In view of the findings that EGF/EGFR-mediated MMP-9 expression is closely related to invasion and metastasis of breast cancer. To determine the beneficial effects of gallic acid on the suppression of breast cancer metastasis, we explored the effect of gallic acid on MMP-9 expression in EGF-treated MCF-7 breast cancer cells. Treatment with EGF up-regulated MMP-9 mRNA and protein levels in MCF-7 cells. EGF treatment induced phosphorylation of EGFR and elicited Src activation, subsequently promoting Akt/NFκB (p65) and ERK/c-Jun phosphorylation in MCF-7 cells. Activation of Akt/p65 and ERK/c-Jun was responsible for the MMP-9 up-regulation in EGF-treated cells. Gallic acid repressed the EGF-induced activation of EGFR and Src; furthermore, inactivation of Akt/p65 and ERK/c-Jun was a result of the inhibitory effect of gallic acid on the EGF-induced MMP-9 up-regulation. Over-expression of constitutively active Akt and MEK1 or over-expression of constitutively active Src eradicated the inhibitory effect of gallic acid on the EGF-induced MMP-9 up-regulation. A chromosome conformation capture assay showed that EGF induced a chromosomal loop formation in the MMP-9 promoter via NFκB/p65 and AP-1/c-Jun activation. Treatment with gallic acid, EGFR inhibitor, or Src inhibitor reduced DNA looping. Taken together, our data suggest that gallic acid inhibits the activation of EGFR/Src-mediated Akt and ERK, leading to reduced levels of p65/c-Jun-mediated DNA looping and thus inhibiting MMP-9 expression in EGF-treated MCF-7 cells. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Increased radiosensitivity and radiation-induced apoptosis in SRC-3 knockout mice

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Jin Jie; Wang Yu; Xu Yang; Chen Shilei; Wang Junping; Ran Xinze; Su Yongping; Wang Jin

2014-01-01

Steroid receptor coactivator-3 (SRC-3), a multifunctional transcriptional coactivator, plays an important role in regulation of cell apoptosis in chemoresistant cancer cells. However, its role in radiation-induced apoptosis in hematopoietic cells is still unclear. In this study, we used SRC-3 knockout (SRC-3 -/- ) mice to assess the role of SRC-3 in radiation-induced hematopoietic injury in vivo. After a range of doses of irradiation, SRC-3 -/- mice exhibited lower counts of peripheral blood cells and bone marrow (BM) mononuclear cells and excessive BM depression, which resulted in a significantly higher mortality compared with wildtype mice. Moreover, BM mononuclear cells obtained from SRC-3 -/- mice showed a remarkable increase in radiation-induced apoptosis. Collectively, our data demonstrate that SRC-3 plays a role in radiation-induced apoptosis of BM hematopoietic cells. Regulation of SRC-3 might influence the radiosensitivity of hematopoietic cells, which highlights a potential therapeutic target for radiation-induced hematopoietic injury. (author)

Effects of Src on Proliferation and Invasion of Lung Cancer Cells

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Rui ZHENG

2011-04-01

Full Text Available Background and objective It has been proven that Src played pivotal roles in carcinogenesis, cancer progression and metastasis. The aim of this study is to explore the roles of Src phosphorylation on lung cancer cells. Methods Western blot and immunoprecipitation was used to detect the expression and phosphorylation of Src in lung cancer cells. MTT and Boyden chamber assay was used to examine the effects of inhibition of Src phosphorylation on proliferation and invasion of lung cancer cells in vitro, respectively. Results pp60src was expressed in all lung cancer cell lines in this study. All 5 non-small cell lung cancer (NSCLC cell lines had increased autophosphorylated tyrosine-418, while nearly no phosphorylated Src in small cell lung cancer SBC5 cell line was detected. The effect of inhibition of Src tyrosine kinase on cell proliferation varied among the lung cancer cell lines. Submicromolar Src tyrosine kinase inhibitor (≤1 μM remarkably suppressed the proliferation of PC-9 and A549 cells in a dose dependent manner (P < 0.05, while the same concentration of Src tyrosine kinase inhibitor had no significant effect on proliferation of H226, PC14PE6 and RERFLCOK cells. Invasiveness of lung cancer cells was significantly suppressed by Src tyrosine kinase in a dose-dependent manner (P < 0.05. Conclusion Phosphorylation of Src, but not over-expression, plays a pivotal role in proliferation and invasion of NSCLC cell lines in vitro.

Crystallographic analysis of murine constitutive androstane receptor ligand-binding domain complexed with 5α-androst-16-en-3α-ol

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Vincent, Jeremy; Shan, Li; Fan, Ming; Brunzelle, Joseph S.; Forman, Barry M.; Fernandez, Elias J.

2004-01-01

The purification and structure determination of the murine constitutive androstane receptor bound to its inverse agonist/antagonist androstenol is described. The constitutive androstane receptor (CAR) is a member of the nuclear receptor superfamily. In contrast to classical nuclear receptors, which possess small-molecule ligand-inducible activity, CAR exhibits constitutive transcriptional activity in the apparent absence of ligand. CAR is among the most important transcription factors; it coordinately regulates the expression of microsomal cytochrome P450 genes and other drug-metabolizing enzymes. The murine CAR ligand-binding domain (LBD) was coexpressed with the steroid receptor coactivator protein (SRC-1) receptor-interacting domain (RID) in Escherichia coli. The mCAR LBD subunit was purified away from SRC-1 by affinity, anion-exchange and size-exclusion chromatography, crystallized with androstenol and the structure of the complex determined by molecular replacement

The imaging performance of the SRC on Mars Express

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Oberst, J.; Schwarz, G.; Behnke, T.; Hoffmann, H.; Matz, K.-D.; Flohrer, J.; Hirsch, H.; Roatsch, T.; Scholten, F.; Hauber, E.; Brinkmann, B.; Jaumann, R.; Williams, D.; Kirk, R.; Duxbury, T.; Leu, C.; Neukum, G.

2008-01-01

The Mars Express spacecraft carries the pushbroom scanner high-resolution stereo camera (HRSC) and its added imaging subsystem super resolution channel (SRC). The SRC is equipped with its own optical system and a 1024??1024 framing sensor. SRC produces snapshots with 2.3 m ground pixel size from the nominal spacecraft pericenter height of 250 km, which are typically embedded in the central part of the large HRSC scenes. The salient features of the SRC are its light-weight optics, a reliable CCD detector, and high-speed read-out electronics. The quality and effective visibility of details in the SRC images unfortunately falls short of what has been expected. In cases where thermal balance cannot be reached, artifacts, such as blurring and "ghost features" are observed in the images. In addition, images show large numbers of blemish pixels and are plagued by electronic noise. As a consequence, we have developed various image improving algorithms, which are discussed in this paper. While results are encouraging, further studies of image restoration by dedicated processing appear worthwhile. The SRC has obtained more than 6940 images at the time of writing (1 September 2007), which often show fascinating details in surface morphology. SRC images are highly useful for a variety of applications in planetary geology, for studies of the Mars atmosphere, and for astrometric observations of the Martian satellites. This paper will give a full account of the design philosophy, technical concept, calibration, operation, integration with HRSC, and performance, as well as science accomplishments of the SRC. ?? 2007 Elsevier Ltd. All rights reserved.

Interplay of Matrix Stiffness and c-SRC in Hepatic Fibrosis.

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Jan eGörtzen

2015-12-01

Full Text Available Introduction:In liver fibrosis activation of hepatic stellate cells (HSC comprises phenotypical change into profibrotic and myofibroplastic cells with increased contraction and secretion of extracellular matrix (ECM proteins. The small GTPase RhoA orchestrates cytoskeleton formation, migration and mobility via non-receptor tyrosine-protein kinase c-SRC (cellular sarcoma in different cells. Furthermore, RhoA and its downstream effector Rho-kinase also play a crucial role in hepatic stellate cells and hepatic fibrogenesis. Matrix stiffness promotes HSC activation via cytoskeleton modulation. This study investigated the interaction of c-SRC and RhoA under different matrix stiffness conditions.Methods:Liver fibrosis was induced in rats using bile duct ligation (BDL, thioacetamide (TAA or carbon tetrachloride (CCl4 models. mRNA levels of albumin, PDGF-R, RHOA, COL1A1 and αSMA were analyzed via qRT-PCR. Western Blots using phospho-specific antibodies against p-c-SRC418 and p-c-SRC530 analyzed the levels of activating and inactivating c-SRC respectively. LX2 cells and hepatocytes were cultured on acrylamide gels of 1kPa and 12kPa or on plastic to mimic non-fibrotic, fibrotic or cirrhotic environments, then exposed to SRC-inhibitor PP2. Overexpression of RhoA was performed by transfection using RhoA-plasmids. Additionally, samples from cirrhotic patients and controls were collected at liver transplantations and tumor resections were analyzed for RhoA and c-SRC protein expression by Western Blot.Results:Transcription of albumin and RhoA was decreased, whereas transcription and activation of c-SRC was increased in hepatocytes cultured on 12kPa compared to 1kPa gels. LX2 cells cultured on 12kPa gels showed upregulation of RHOA, COL1A1 and αSMA mRNA levels. Inhibition of c-SRC by PP2 in LX2 cells led to an increase in COL1A1 and αSMA most prominently in 12kPa gels. In LX2 cells with RhoA overexpression, c-SRC inhibition by PP2 failed to improve fibrosis

Antiangiogenic and Antitumor Effects of Src Inhibition in Ovarian Carcinoma

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Han, Liz Y.; Landen, Charles N.; Trevino, Jose G.; Halder, Jyotsnabaran; Lin, Yvonne G.; Kamat, Aparna A.; Kim, Tae-Jin; Merritt, William M.; Coleman, Robert L.; Gershenson, David M.; Shakespeare, William C.; Wang, Yihan; Sundaramoorth, Raji; Metcalf, Chester A.; Dalgarno, David C.; Sawyer, Tomi K.; Gallick, Gary E.; Sood, Anil K.

2011-01-01

Src, a nonreceptor tyrosine kinase, is a key mediator for multiple signaling pathways that regulate critical cellular functions and is often aberrantly activated in a number of solid tumors, including ovarian carcinoma. The purpose of this study was to determine the role of activated Src inhibition on tumor growth in an orthotopic murine model of ovarian carcinoma. In vitro studies on HeyA8 and SKOV3ip1 cell lines revealed that Src inhibition by the Src-selective inhibitor, AP23846, occurred within 1 hour and responded in a dose-dependent manner. Furthermore, Src inhibition enhanced the cytotoxicity of docetaxel in both chemosensitive and chemoresistant ovarian cancer cell lines, HeyA8 and HeyA8-MDR, respectively. In vivo, Src inhibition by AP23994, an orally bioavailable analogue of AP23846, significantly decreased tumor burden in HeyA8 (P = 0.02), SKOV3ip1 (P = 0.01), as well as HeyA8-MDR (P < 0.03) relative to the untreated controls. However, the greatest effect on tumor reduction was observed in combination therapy with docetaxel (P < 0.001, P = 0.002, and P = 0.01, for the above models, respectively). Proliferating cell nuclear antigen staining showed that Src inhibition alone (P = 0.02) and in combination with docetaxel (P = 0.007) significantly reduced tumor proliferation. In addition, Src inhibition alone and in combination with docetaxel significantly down-regulated tumoral production of vascular endothelial growth factor and interleukin 8, whereas combination therapy decreased the microvessel density (P = 0.02) and significantly affected vascular permeability (P < 0.05). In summary, Src inhibition with AP23994 has potent antiangiogenic effects and significantly reduces tumor burden in preclinical ovarian cancer models. Thus, Src inhibition may be an attractive therapeutic approach for patients with ovarian carcinoma. PMID:16951177

Novel Role of Src in Priming Pyk2 Phosphorylation.

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Ming Zhao

Full Text Available Proline-rich tyrosine kinase 2 (Pyk2 is a member of the focal adhesion kinase (FAK family of non-receptor tyrosine kinases and plays an important role in diverse cellular events downstream of the integrin-family of receptors, including cell migration, proliferation and survival. Here, we have identified a novel role for Src kinase in priming Pyk2 phosphorylation and subsequent activation upon cell attachment on the integrin-ligand fibronectin. By using complementary methods, we show that Src activity is indispensable for the initial Pyk2 phosphorylation on the Y402 site observed in response to cell attachment. In contrast, the initial fibronectin-induced autophosphorylation of FAK in the homologous Y397 site occurs in a Src-independent manner. We demonstrate that the SH2-domain of Src is required for Src binding to Pyk2 and for Pyk2 phosphorylation at sites Y402 and Y579. Moreover, Y402 phosphorylation is a prerequisite for the subsequent Y579 phosphorylation. While this initial phosphorylation of Pyk2 by Src is independent of Pyk2 kinase activity, subsequent autophosphorylation of Pyk2 in trans is required for full Pyk2 phosphorylation and activation. Collectively, our studies reveal a novel function of Src in priming Pyk2 (but not FAK phosphorylation and subsequent activation downstream of integrins, and shed light on the signaling events that regulate the function of Pyk2.

Elevated c-Src and c-Yes expression in malignant skin cancers

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Lee Jang

2010-08-01

Full Text Available Abstracts Background Src family kinases (SFKs play an important role in cancer proliferation, survival, motility, invasiveness, metastasis, and angiogenesis. Among the SFKs, c-Src and c-Yes are particularly over-expressed or hyper-activated in many human epithelial cancers. However, only a few studies have attempted to define the expression and role of c-Src and c-Yes in cutaneous carcinomas. Objectives To investigate the expression of c-Src and c-Yes in cutaneous carcinomas to include malignant melanoma (MM, squamous cell carcinoma (SCC and basal cell carcinoma (BCC. Methods We examined 6 normal skin tissues and 18 malignant skin tumor tissues using western blotting for the expression of c-Src and c-Yes. In another set, 16 specimens of MM, 16 SCCs and 16 BCCs were analyzed for the expression of c-Src and c-Yes using immunohistochemical staining. Results Western blotting showed that c-Src was expressed in all malignant skin tumors, but not in normal skin, while c-Yes was expressed in MM and SCC, but not in BCC and normal skin. Immunohistochemical staining results of c-Src and c-Yes in MM, SCC, and BCC mirrored those of the western blot analysis. Conclusions c-Src, rather than c-Yes, plays a key role in the proliferation and progression of malignant skin cancers.

Constitutive MHC class I molecules negatively regulate TLR-triggered inflammatory responses via the Fps-SHP-2 pathway.

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Xu, Sheng; Liu, Xingguang; Bao, Yan; Zhu, Xuhui; Han, Chaofeng; Zhang, Peng; Zhang, Xuemin; Li, Weihua; Cao, Xuetao

2012-04-22

The molecular mechanisms that fine-tune Toll-like receptor (TLR)-triggered innate inflammatory responses remain to be fully elucidated. Major histocompatibility complex (MHC) molecules can mediate reverse signaling and have nonclassical functions. Here we found that constitutively expressed membrane MHC class I molecules attenuated TLR-triggered innate inflammatory responses via reverse signaling, which protected mice from sepsis. The intracellular domain of MHC class I molecules was phosphorylated by the kinase Src after TLR activation, then the tyrosine kinase Fps was recruited via its Src homology 2 domain to phosphorylated MHC class I molecules. This led to enhanced Fps activity and recruitment of the phosphatase SHP-2, which interfered with TLR signaling mediated by the signaling molecule TRAF6. Thus, constitutive MHC class I molecules engage in crosstalk with TLR signaling via the Fps-SHP-2 pathway and control TLR-triggered innate inflammatory responses.

EG-1 interacts with c-Src and activates its signaling pathway.

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Lu, Ming; Zhang, Liping; Sartippour, Maryam R; Norris, Andrew J; Brooks, Mai N

2006-10-01

EG-1 is significantly elevated in breast, colorectal, and prostate cancers. Overexpression of EG-1 stimulates cellular proliferation, and targeted inhibition blocks mouse xenograft tumor growth. To further clarify the function of EG-1, we investigated its role in c-Src activation. We observed that EG-1 overexpression results in activation of c-Src, but found no evidence that EG-1 is a direct Src substrate. EG-1 also binds to other members of the Src family. Furthermore, EG-1 shows interaction with multiple other SH3- and WW-containing molecules involved in various signaling pathways. These observations suggest that EG-1 may be involved in signaling pathways including c-Src activation.

4-Hydroxynonenal activates Src through a non-canonical pathway that involves EGFR/PTP1B

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Zhang, Hongqiao; Forman, Henry Jay

2015-01-01

Src, a non-receptor protein tyrosine kinase involved in many biological processes, can be activated through both redox-dependent and independent mechanisms. 4-Hydroxy-2-nonenal (HNE) is a lipid peroxidation product that is increased in pathophysiological conditions associated with Src activation. This study examined how HNE activates human c-Src. In the canonical pathway Src activation is initiated by dephosphorylation of pTyr530 followed by conformational change that causes Src auto-phosphorylation at Tyr419 and its activation. HNE increased Src activation in both dose- and time-dependent manner, while it also increased Src phosphorylation at Tyr530 (pTyr530 Src), suggesting that HNE activated Src via a non-canonical mechanism. Protein tyrosine phosphatase 1B inhibitor (539741), at concentrations that increased basal pTyr530 Src, also increased basal Src activity and significantly reduced HNE-mediated Src activation. The EGFR inhibitor, AG1478, and EGFR silencing, abrogated HNE-mediated EGFR activation and inhibited basal and HNE-induced Src activity. In addition, AG1478 also eliminated the increase of basal Src activation by a PTP1B inhibitor. Taken together these data suggest that HNE can activate Src partly through a non-canonical pathway involving activation of EGFR and inhibition of PTP1B. PMID:26453921

c-Src activity is differentially required by cancer cell motility modes.

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Logue, Jeremy S; Cartagena-Rivera, Alexander X; Chadwick, Richard S

2018-04-01

Cancer cell migration requires that cells respond and adapt to their surroundings. In the absence of extracellular matrix cues, cancer cells will undergo a mesenchymal to ameboid transition, whereas a highly confining space will trigger a switch to "leader bleb-based" migration. To identify oncogenic signaling pathways mediating these transitions, we undertook a targeted screen using clinically useful inhibitors. Elevated Src activity was found to change actin and focal adhesion dynamics, whereas inhibiting Src triggered focal adhesion disassembly and blebbing. On non-adherent substrates and in collagen matrices, amoeboid-like, blebbing cells having high Src activity formed protrusions of the plasma membrane. To evaluate the role of Src in confined cells, we use a novel approach that places cells under a slab of polydimethylsiloxane (PDMS), which is held at a defined height. Using this method, we find that leader bleb-based migration is resistant to Src inhibition. High Src activity was found to markedly change the architecture of cortical actomyosin, reduce cell mechanical properties, and the percentage of cells that undergo leader bleb-based migration. Thus, Src is a signal transducer that can potently influence transitions between migration modes with implications for the rational development of metastasis inhibitors.

SRC: marker or actor in prostate cancer aggressiveness.

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Vlaeminck-Guillem, Virginie; Gillet, Germain; Rimokh, Ruth

2014-01-01

A key question for urologic practitioners is whether an apparently organ-confined prostate cancer (PCa) is actually aggressive or not. The dilemma is to specifically identify among all prostate tumors the very aggressive high-grade cancers that will become life-threatening by developing extra-prostatic invasion and metastatic potential and the indolent cancers that will never modify a patient's life expectancy. A choice must be made between several therapeutic options to achieve the optimal personalized management of the disease that causes as little harm as possible to patients. Reliable clinical, biological, or pathological markers that would enable distinctions to be made between aggressive and indolent PCas in routine practice at the time of initial diagnosis are still lacking. The molecular mechanisms that explain why a PCa is aggressive or not are also poorly understood. Among the potential markers and/or actors in PCa aggressiveness, Src and other members of the Src kinase family, are valuable candidates. Activation of Src-dependent intracellular pathways is frequently observed in PCa. Indeed, Src is at the cross-roads of several pathways [including androgen receptor (AR), TGFbeta, Bcl-2, Akt/PTEN or MAPK, and ERK …], and is now known to influence some of the cellular and tissular events that accompany tumor progression: cell proliferation, cell motility, invasion, epithelial-to-mesenchymal transition, resistance to apoptosis, angiogenesis, neuroendocrine differentiation, and metastatic spread. Recent work even suggests that Src could also play a part in PCa initiation in coordination with the AR. The aim of this review is to gather data that explore the links between the Src kinase family and PCa progression and aggressiveness.

Src: marker or actor of prostate cancer aggressiveness

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Virginie eVlaeminck-Guillem

2014-08-01

Full Text Available A key question for urologic practitioners is whether an apparently organ-confined prostate cancer is actually aggressive or not. The dilemma is to specifically identify among all prostate tumors the very aggressive high-grade cancers that will become life-threatening by developing extra-prostatic invasion and metastatic potential and the indolent cancers that will never modify a patient’s life expectancy. A choice must be made between several therapeutic options to achieve the optimal personalized management of the disease that causes as little harm as possible to patients. Reliable clinical, biological or pathological markers that would enable distinctions to be made between aggressive and indolen prostate cancers in routine practice at the time of initial diagnosis are still lacking. The molecular mechanisms that explain why a prostate cancer is aggressive or not are also poorly understood. Among the potential markers and/or actors in prostate cancer aggressiveness, Src and other members of the Src kinase family, are valuable candidates. Activation of Src-dependent intracellular pathways is frequently observed in prostate cancer. Indeed, Src is at the cross-roads of several pathways (including androgen receptor, TGFbeta, Bcl-2, Akt/PTEN or MAPK and ERK …, and is now known to influence some of the cellular and tissular events that accompany tumor progression: cell proliferation, cell motility, invasion, epithelial-to-mesenchymal transition, resistance to apoptosis, angiogenesis, neuroendocrine differentiation, and metastatic spread. Recent work even suggests that Src could also play a part in prostate cancer initiation in coordination with the androgen receptor. The aim of this review is to gather data that explores the links between the Src kinase family and prostate cancer progression and aggressiveness.

Roles of Raft-Anchored Adaptor Cbp/PAG1 in Spatial Regulation of c-Src Kinase

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Oneyama, Chitose; Suzuki, Takashi; Okada, Masato

2014-01-01

The tyrosine kinase c-Src is upregulated in numerous human cancers, implying a role for c-Src in cancer progression. Previously, we have shown that sequestration of activated c-Src into lipid rafts via a transmembrane adaptor, Cbp/PAG1, efficiently suppresses c-Src-induced cell transformation in Csk-deficient cells, suggesting that the transforming activity of c-Src is spatially regulated via Cbp in lipid rafts. To dissect the molecular mechanisms of the Cbp-mediated regulation of c-Src, a combined analysis was performed that included mathematical modeling and in vitro experiments in a c-Src- or Cbp-inducible system. c-Src activity was first determined as a function of c-Src or Cbp levels, using focal adhesion kinase (FAK) as a crucial c-Src substrate. Based on these experimental data, two mathematical models were constructed, the sequestration model and the ternary model. The computational analysis showed that both models supported our proposal that raft localization of Cbp is crucial for the suppression of c-Src function, but the ternary model, which includes a ternary complex consisting of Cbp, c-Src, and FAK, also predicted that c-Src function is dependent on the lipid-raft volume. Experimental analysis revealed that c-Src activity is elevated when lipid rafts are disrupted and the ternary complex forms in non-raft membranes, indicating that the ternary model accurately represents the system. Moreover, the ternary model predicted that, if Cbp enhances the interaction between c-Src and FAK, Cbp could promote c-Src function when lipid rafts are disrupted. These findings underscore the crucial role of lipid rafts in the Cbp-mediated negative regulation of c-Src-transforming activity, and explain the positive role of Cbp in c-Src regulation under particular conditions where lipid rafts are perturbed. PMID:24675741

Densification of chipper harvested SRC using on-farm machinery

Energy Technology Data Exchange (ETDEWEB)

Paulson, M.

2003-07-01

This report gives details of a project to density wood chips using on-farm machinery in order to avoid problems encountered in bulk handling and storage of low density short rotation cultivation (SRC) wood chips - especially as some customers can only accept baled material. Trials using different lengths of chips produced by a standard SRC harvester are described, and the failure to produce acceptable bales is reported. The potential cost of modifying equipment is deemed to make the baling of SRC chips using standard farm machinery currently not viable.

Specific Inhibition of SRC Kinase Impairs Malignant Glioma Growth In Vitro and In Vivo

Directory of Open Access Journals (Sweden)

Hanna Stedt

2012-01-01

Full Text Available Malignant glioma is a severe cancer with a poor prognosis. Local occurrence and rare metastases of malignant glioma make it a suitable target for gene therapy. Several studies have demonstrated the importance of Src kinase in different cancers. However, these studies have focused mainly on Src-deficient mice or pharmacological inhibitors of Src. In this study we have used Src small hairpin RNAs (shRNAs in a lentiviral backbone to mimic a long-term stable treatment and determined the role of Src in tumor tissues. Efficacy of Src shRNAs was confirmed in vitro demonstrating up to 90% target gene inhibition. In a mouse malignant glioma model, Src shRNA tumors were almost 50-fold smaller in comparison to control tumors and had significantly reduced vascularity. In a syngenic rat intracranial glioma model, Src shRNA-transduced tumors were smaller and these rats had a survival benefit over the control rats. In vivo treatment was enhanced by chemotherapy and histone deacetylase inhibition. Our results emphasise the importance of Src in tumorigenesis and demonstrate that it can be efficiently inhibited in vitro and in vivo in two independent malignant glioma models. In conclusion, Src is a potential target for RNA interference-mediated treatment of malignant glioma.

A Protein Scaffold Coordinates SRC-Mediated JNK Activation in Response to Metabolic Stress.

Science.gov (United States)

Kant, Shashi; Standen, Claire L; Morel, Caroline; Jung, Dae Young; Kim, Jason K; Swat, Wojciech; Flavell, Richard A; Davis, Roger J

2017-09-19

Obesity is a major risk factor for the development of metabolic syndrome and type 2 diabetes. How obesity contributes to metabolic syndrome is unclear. Free fatty acid (FFA) activation of a non-receptor tyrosine kinase (SRC)-dependent cJun NH 2 -terminal kinase (JNK) signaling pathway is implicated in this process. However, the mechanism that mediates SRC-dependent JNK activation is unclear. Here, we identify a role for the scaffold protein JIP1 in SRC-dependent JNK activation. SRC phosphorylation of JIP1 creates phosphotyrosine interaction motifs that bind the SH2 domains of SRC and the guanine nucleotide exchange factor VAV. These interactions are required for SRC-induced activation of VAV and the subsequent engagement of a JIP1-tethered JNK signaling module. The JIP1 scaffold protein, therefore, plays a dual role in FFA signaling by coordinating upstream SRC functions together with downstream effector signaling by the JNK pathway. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

A Protein Scaffold Coordinates SRC-Mediated JNK Activation in Response to Metabolic Stress

Directory of Open Access Journals (Sweden)

Shashi Kant

2017-09-01

Full Text Available Obesity is a major risk factor for the development of metabolic syndrome and type 2 diabetes. How obesity contributes to metabolic syndrome is unclear. Free fatty acid (FFA activation of a non-receptor tyrosine kinase (SRC-dependent cJun NH2-terminal kinase (JNK signaling pathway is implicated in this process. However, the mechanism that mediates SRC-dependent JNK activation is unclear. Here, we identify a role for the scaffold protein JIP1 in SRC-dependent JNK activation. SRC phosphorylation of JIP1 creates phosphotyrosine interaction motifs that bind the SH2 domains of SRC and the guanine nucleotide exchange factor VAV. These interactions are required for SRC-induced activation of VAV and the subsequent engagement of a JIP1-tethered JNK signaling module. The JIP1 scaffold protein, therefore, plays a dual role in FFA signaling by coordinating upstream SRC functions together with downstream effector signaling by the JNK pathway.

Ecological fate and effects of solvent-refined-coal (SRC) materials: a status report

Energy Technology Data Exchange (ETDEWEB)

Strand, J.A. III; Vaughan, B.E. (eds.)

1981-10-01

Non-occupational health effects associated with SRC operation will be determined by environmental factors governing the form, transport, and persistence of SRC materials and wastes - factors which also mediate exposure to man. Accordingly, the research described is an attempt to determine the fate of disposed solid wastes and spilled SRC materials, and it necessarily focuses on water soluble, persistent materials with greatest potential for mobility and incorporation into water and food supplies. Initially, aqueous equilibrations of SRC-II liquid material and SRC-I nongasified mineral residue were subjected to chemical characterization. Subsequently, laboratory studies were performed on the interaction of aqueous equilibrates of SRC-II liquid and SRC-I non-gasified mineral residue with soil materials isolated suspended sediments, and bottom sediments. These studies were designed to identify effects of specific sorption reactions ion or induced-ion exchange reactions, and toxicity of water soluble, biologically active materials derived from liquid and solid wastes. Results of these experiments have applicability to the environmental fate and effects of biologically active compounds released under different scenarios from product spills and solid waste disposal.

Mechanism of c-Src Synergy with the EGFR in Breast Cancer

National Research Council Canada - National Science Library

Tice, David

1997-01-01

.... To gain further insights into the mechanism of c-Src synergy with the EGFR, stable cell lines containing various c-Src mutants and overexpressed wt EGFR were generated and examined for tumorigenic...

Charge-dependent correlations from event-by-event anomalous hydrodynamics

Energy Technology Data Exchange (ETDEWEB)

Hirono, Yuji [Department of Physics and Astronomy, Stony Brook University, Stony Brook, NY 11794-3800 (United States); Hirano, Tetsufumi [Department of Physics, Sophia University, Tokyo 102-8554 (Japan); Kharzeev, Dmitri E. [Department of Physics and Astronomy, Stony Brook University, Stony Brook, NY 11794-3800 (United States); Department of Physics and RIKEN-BNL Research Center, Brookhaven National Laboratory, Upton, NY 11973-5000 (United States)

2016-12-15

We report on our recent attempt of quantitative modeling of the Chiral Magnetic Effect (CME) in heavy-ion collisions. We perform 3+1 dimensional anomalous hydrodynamic simulations on an event-by-event basis, with constitutive equations that contain the anomaly-induced effects. We also develop a model of the initial condition for the axial charge density that captures the statistical nature of random chirality imbalances created by the color flux tubes. Basing on the event-by-event hydrodynamic simulations for hundreds of thousands of collisions, we calculate the correlation functions that are measured in experiments, and discuss how the anomalous transport affects these observables.

The dual kinase complex FAK-Src as a promising therapeutic target in cancer

Science.gov (United States)

Bolós, Victoria; Gasent, Joan Manuel; López-Tarruella, Sara; Grande, Enrique

2010-01-01

Focal adhesion kinase (FAK) and steroid receptor coactivator (Src) are intracellular (nonreceptor) tyrosine kinases that physically and functionally interact to promote a variety of cellular responses. Plenty of reports have already suggested an additional central role for this complex in cancer through its ability to promote proliferation and anoikis resistance in tumor cells. An important role for the FAK/Src complex in tumor angiogenesis has also been established. Furthermore, FAK and Src have been associated with solid tumor metastasis through their ability to promote the epithelial mesenchymal transition. In fact, a strong correlation between increased FAK/Src expression/phosphorylation and the invasive phenotype in human tumors has been found. Additionally, an association for FAK/Src with resistances to the current anticancer therapies has already been established. Currently, novel anticancer agents that target FAK or Src are under development in a broad variety of solid tumors. In this article we will review the normal cellular functions of the FAK/Src complex as an effector of integrin and/or tyrosine kinase receptor signaling. We will also collect data about their role in cancer and we will summarize the most recent data from the FAK and Src inhibitors under clinical and preclinical development. Furthermore, the association of both these proteins with chemotherapy and hormonal therapy resistances, as a rationale for new combined therapeutic approaches with these novel agents, to abrogate treatment associated resistances, will also be reviewed. PMID:20616959

SRC burn test in 700-hp oil-designed boiler. Annex Volume C. Boiler emission report. Final technical report

Energy Technology Data Exchange (ETDEWEB)

1983-09-01

The Solvent-Refined Coal (SRC) test burn program was conducted at the Pittsburgh Energy Technology Center (PETC) located in Bruceton, Pa. One of the objectives of the study was to determine the feasibility of burning SRC fuels in boilers set up for fuel oil firing and to characterize emissions. Testing was conducted on the 700-hp oil-fired boiler used for research projects. No. 6 fuel oil was used for baseline data comparison, and the following SRC fuels were tested: SRC Fuel (pulverized SRC), SRC Residual Oil, and SRC-Water Slurry. Uncontrolled particulate emission rates averaged 0.9243 lb/10/sup 6/ Btu for SRC Fuel, 0.1970 lb/10/sup 6/ Btu for SRC Residual Oil, and 0.9085 lb/10/sup 6/ Btu for SRC-Water Slurry. On a lb/10/sup 6/ Btu basis, emissions from SRC Residual Oil averaged 79 and 78%, respectively, lower than the SRC Fuel and SRC-Water Slurry. The lower SRC Residual Oil emissions were due, in part, to the lower ash content of the oil and more efficient combustion. The SRC Fuel had the highest emission rate, but only 2% higher than the SRC-Water Slurry. Each fuel type was tested under variable boiler operating parameters to determine its effect on boiler emissions. The program successfully demonstrated that the SRC fuels could be burned in fuel oil boilers modified to handle SRC fuels. This report details the particulate emission program and results from testing conducted at the boiler outlet located before the mobile precipitator take-off duct. The sampling method was EPA Method 17, which uses an in-stack filter.

Integrated crop management of SRC plantations to maximise crop value, wildlife benefits and other added value opportunities

Energy Technology Data Exchange (ETDEWEB)

Sage, R; Tucker, K

1998-07-01

This report summaries the results of a study aiming to develop an integrated approach to pest management (IPM) for the short rotation cultivation (SRC) of willows and poplars. Details are given of crop and site characteristics, non-destructive assessment of SRC biomass, the quantification of crop shadiness, and the effects of wind exposure on crop growth. The section on invertebrates covers invertebrates colonising UK SRC plantations, invertebrates which are or can become pests, natural control agents of SRC pests, the abundance and distribution of chrysomelids between sites, preferences exhibited by chrysomelids for different varieties, overwintering and dispersal of chrysomelids into SRC, and IPM of insects. The section on vertebrate fauna addresses birds in winter, the breeding birds of SRC, gamebird use of SRC, and mammals and other vertebrates of SRC. A section on ground flora deals with changes in ground flora with time, ground flora introductions, the effects of weeds on the growth of SRC, and an overview of integrated crop management in SRC plantations.

The dual kinase complex FAK-Src as a promising therapeutic target in cancer

Directory of Open Access Journals (Sweden)

Victoria Bolós

2010-06-01

Full Text Available Victoria Bolós1,*, Joan Manuel Gasent2,*, Sara López-Tarruella3, Enrique Grande1,#1Pfizer Oncology, Madrid, Spain; 2Hospital Gral. Universitario Marina Alta, Oncology Department, Denia Alicante, 3,#Hospital Clínico San Carlos, Oncology Department, ∗These authors contributed equally to this work, #Center affiliated to the Red Temática de Investigación Cooperativa (RD06/0020/0021. Instituto de Salud Carlos III (ISCIII, Spanish Ministry of Science and InnovationAbstract: Focal adhesion kinase (FAK and steroid receptor coactivator (Src are intracellular (nonreceptor tyrosine kinases that physically and functionally interact to promote a variety of cellular responses. Plenty of reports have already suggested an additional central role for this complex in cancer through its ability to promote proliferation and anoikis resistance in tumor cells. An important role for the FAK/Src complex in tumor angiogenesis has also been established. Furthermore, FAK and Src have been associated with solid tumor metastasis through their ability to promote the epithelial mesenchymal transition. In fact, a strong correlation between increased FAK/Src expression/phosphorylation and the invasive phenotype in human tumors has been found. Additionally, an association for FAK/Src with resistances to the current anticancer therapies has already been established. Currently, novel anticancer agents that target FAK or Src are under development in a broad variety of solid tumors. In this article we will review the normal cellular functions of the FAK/Src complex as an effector of integrin and/or tyrosine kinase receptor signaling. We will also collect data about their role in cancer and we will summarize the most recent data from the FAK and Src inhibitors under clinical and preclinical development. Furthermore, the association of both these proteins with chemotherapy and hormonal therapy resistances, as a rationale for new combined therapeutic approaches with these novel

Anomalous transport from holography. Part I

Energy Technology Data Exchange (ETDEWEB)

Bu, Yanyan [Department of Physics, Ben-Gurion University of the Negev,Beer-Sheva 84105 (Israel); Lublinsky, Michael [Department of Physics, Ben-Gurion University of the Negev,Beer-Sheva 84105 (Israel); Physics Department, University of Connecticut,2152 Hillside Road, Storrs, CT 06269-3046 (United States); Sharon, Amir [Department of Physics, Ben-Gurion University of the Negev,Beer-Sheva 84105 (Israel)

2016-11-17

We revisit the transport properties induced by the chiral anomaly in a charged plasma holographically dual to anomalous U(1){sub V}×U(1){sub A} Maxwell theory in Schwarzschild-AdS{sub 5}. Off-shell constitutive relations for vector and axial currents are derived using various approximations generalising most of known in the literature anomaly-induced phenomena and revealing some new ones. In a weak external field approximation, the constitutive relations have all-order derivatives resummed into six momenta-dependent transport coefficient functions: the diffusion, the electric/magnetic conductivity, and three anomaly induced functions. The latter generalise the chiral magnetic and chiral separation effects. Nonlinear transport is studied assuming presence of constant background external fields. The chiral magnetic effect, including all order nonlinearity in magnetic field, is proven to be exact when the magnetic field is the only external field that is turned on. Non-linear corrections to the constitutive relations due to electric and axial external fields are computed.

Anomalous transport from holography. Part I

International Nuclear Information System (INIS)

Bu, Yanyan; Lublinsky, Michael; Sharon, Amir

2016-01-01

We revisit the transport properties induced by the chiral anomaly in a charged plasma holographically dual to anomalous U(1)_V×U(1)_A Maxwell theory in Schwarzschild-AdS_5. Off-shell constitutive relations for vector and axial currents are derived using various approximations generalising most of known in the literature anomaly-induced phenomena and revealing some new ones. In a weak external field approximation, the constitutive relations have all-order derivatives resummed into six momenta-dependent transport coefficient functions: the diffusion, the electric/magnetic conductivity, and three anomaly induced functions. The latter generalise the chiral magnetic and chiral separation effects. Nonlinear transport is studied assuming presence of constant background external fields. The chiral magnetic effect, including all order nonlinearity in magnetic field, is proven to be exact when the magnetic field is the only external field that is turned on. Non-linear corrections to the constitutive relations due to electric and axial external fields are computed.

76 FR 57763 - Alaska Region's Subsistence Resource Commission (SRC) Program

Science.gov (United States)

2011-09-16

... Hunting Plan Recommendation 10-01 12. New Business 13. Public and other Agency Comments 14. SRC Work... the meeting dates and location are changed, a notice will be published in local newspapers and announced on local radio stations prior to the meeting date. SRC meeting locations and dates may need to be...

Inhibition of SRC-3 enhances sensitivity of human cancer cells to histone deacetylase inhibitors

Energy Technology Data Exchange (ETDEWEB)

Zou, Zhengzhi, E-mail: zouzhengzhi@m.scnu.edu.cn [MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510000 (China); Luo, Xiaoyong [Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang 471000 (China); Nie, Peipei [KingMed Diagnostics and KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 510000 (China); Wu, Baoyan; Zhang, Tao; Wei, Yanchun [MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510000 (China); Wang, Wenyi [Xiamen Cancer Center, Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen 361000 (China); Geng, Guojun; Jiang, Jie [Xiamen Cancer Center, Department of Thoracic Surgery, The First Affiliated Hospital of Xiamen University, Xiamen 361000 (China); Mi, Yanjun, E-mail: myjgj_77@163.com [Xiamen Cancer Center, Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen 361000 (China)

2016-09-09

SRC-3 is widely expressed in multiple tumor types and involved in cancer cell proliferation and apoptosis. Histone deacetylase (HDAC) inhibitors are promising antitumor drugs. However, the poor efficacy of HDAC inhibitors in solid tumors has restricted its further clinical application. Here, we reported the novel finding that depletion of SRC-3 enhanced sensitivity of breast and lung cancer cells to HDAC inhibitors (SAHA and romidepsin). In contrast, overexpression of SRC-3 decreased SAHA-induced cancer cell apoptosis. Furthermore, we found that SRC-3 inhibitor bufalin increased cancer cell apoptosis induced by HDAC inhibitors. The combination of bufalin and SAHA was particular efficient in attenuating AKT activation and reducing Bcl-2 levels. Taken together, these accumulating data might guide development of new breast and lung cancer therapies. - Highlights: • Depletion of SRC-3 enhanced sensitivity of breast and lung cancer cells to HDAC inhibitors. • Overexpression of SRC-3 enhanced cancer cell resistance to HDAC inhibitors. • SRC-3 inhibitor bufalin increased cancer cell apoptosis induced by HDAC inhibitors. • Bufalin synergized with HDAC inhibitor attenuated AKT activation and reduced Bcl-2 levels in human cancer cell.

Identification of a functional interaction between Kv4.3 channels and c-Src tyrosine kinase.

Science.gov (United States)

Gomes, Pedro; Saito, Tomoaki; Del Corsso, Cris; Alioua, Abderrahmane; Eghbali, Mansoureh; Toro, Ligia; Stefani, Enrico

2008-10-01

Voltage-gated K(+) (Kv) channels are key determinants of cardiac and neuronal excitability. A substantial body of evidence has accumulated in support of a role for Src family tyrosine kinases in the regulation of Kv channels. In this study, we examined the possibility that c-Src tyrosine kinase participates in the modulation of the transient voltage-dependent K(+) channel Kv4.3. Supporting a mechanistic link between Kv4.3 and c-Src, confocal microscopy analysis of HEK293 cells stably transfected with Kv4.3 showed high degree of co-localization of the two proteins at the plasma membrane. Our results further demonstrate an association between Kv4.3 and c-Src by co-immunoprecipitation and GST pull-down assays, this interaction being mediated by the SH2 and SH3 domains of c-Src. Furthermore, we show that Kv4.3 is tyrosine phosphorylated under basal conditions. The functional relevance of the observed interaction between Kv4.3 and c-Src was established in patch-clamp experiments, where application of the Src inhibitor PP2 caused a decrease in Kv4.3 peak current amplitude, but not the inactive structural analogue PP3. Conversely, intracellular application of recombinant c-Src kinase or the protein tyrosine phosphatase inhibitor bpV(phen) increased Kv4.3 peak current amplitude. In conclusion, our findings provide evidence that c-Src-induced Kv4.3 channel activation involves their association in a macromolecular complex and suggest a role for c-Src-Kv4.3 pathway in regulating cardiac and neuronal excitability.

Fertilization of SRC willow. II

DEFF Research Database (Denmark)

Sevel, L; Ingerslev, Morten; Nord-Larsen, Thomas

2014-01-01

impacts of different doses of mineral fertilizer, manure and sewage sludge in a commercially grown SRC willow stand. We examined macro nutrient and heavy metal leaching rates and calculated element balances to evaluate the environmental impact. Growth responses were reported in a former paper (Sevel et al...

Functional diversity of Csk, Chk, and Src SH2 domains due to a single residue variation.

Science.gov (United States)

Ayrapetov, Marina K; Nam, Nguyen Hai; Ye, Guofeng; Kumar, Anil; Parang, Keykavous; Sun, Gongqin

2005-07-08

The C-terminal Src kinase (Csk) family of protein tyrosine kinases contains two members: Csk and Csk homologous kinase (Chk). Both phosphorylate and inactivate Src family kinases. Recent reports suggest that the Src homology (SH) 2 domains of Csk and Chk may bind to different phosphoproteins, which provides a basis for different cellular functions for Csk and Chk. To verify and characterize such a functional divergence, we compared the binding properties of the Csk, Chk, and Src SH2 domains and investigated the structural basis for the functional divergence. First, the study demonstrated striking functional differences between the Csk and Chk SH2 domains and revealed functional similarities between the Chk and Src SH2 domains. Second, structural analysis and mutagenic studies revealed that the functional differences among the three SH2 domains were largely controlled by one residue, Glu127 in Csk, Ile167 in Chk, and Lys200 in Src. Mutating these residues in the Csk or Chk SH2 domain to the Src counterpart resulted in dramatic gain of function similar to Src SH2 domain, whereas mutating Lys200 in Src SH2 domain to Glu (the Csk counterpart) resulted in loss of Src SH2 function. Third, a single point mutation of E127K rendered Csk responsive to activation by a Src SH2 domain ligand. Finally, the optimal phosphopeptide sequence for the Chk SH2 domain was determined. These results provide a compelling explanation for the functional differences between two homologous protein tyrosine kinases and reveal a new structure-function relationship for the SH2 domains.

Preliminary study of semi-refined carrageenan (SRC) as secondary gelling agent in natural rubber (NR) latex foam

Science.gov (United States)

Norhazariah, S.; Azura, A. R.; Azahari, B.; Sivakumar, R.

2017-12-01

Semi-refined carrageenan (SRC) product is considerably cheaper and easier to produce as a natural polysaccharide, which was utilized in food and other product application. However, the application in latex is limited. The aim of this work is to evaluate the SRC produced from low industrial grade seaweed (LIGS) in the latex foam application. The FTIR spectra showed the SRC produced as kappa type carrageenan with lower sulfur content compared to native LIGS. NR latex foam is produced by using the Dunlop method with some modifications. The effect of SRC loading as a secondary gelling agent in NR latex foam is investigated. The density and morphology of the NR latex foam with the addition of the SRC are analyzed. NR latex foam density increased with SRC loading and peaked at 1.8 phr SRC. The addition of SRC has induced the bigger cell size compared to the cell size of the control NR latex foam, as shown in the optical micrograph. It can be concluded that SRC LIGS could be acted as secondary gelling agent in NR latex foam.

SH2 Ligand-Like Effects of Second Cytosolic Domain of Na/K-ATPase α1 Subunit on Src Kinase.

Science.gov (United States)

Banerjee, Moumita; Duan, Qiming; Xie, Zijian

2015-01-01

Our previous studies have suggested that the α1 Na/K-ATPase interacts with Src to form a receptor complex. In vitro binding assays indicate an interaction between second cytosolic domain (CD2) of Na/K-ATPase α1 subunit and Src SH2 domain. Since SH2 domain targets Src to specific signaling complexes, we expressed CD2 as a cytosolic protein and studied whether it could act as a Src SH2 ligand in LLC-PK1 cells. Co-immunoprecipitation analyses indicated a direct binding of CD2 to Src, consistent with the in vitro binding data. Functionally, CD2 expression increased basal Src activity, suggesting a Src SH2 ligand-like property of CD2. Consistently, we found that CD2 expression attenuated several signaling pathways where Src plays an important role. For instance, although it increased surface expression of Na/K-ATPase, it decreased ouabain-induced activation of Src and ERK by blocking the formation of Na/K-ATPase/Src complex. Moreover, it also attenuated cell attachment-induced activation of Src/FAK. Consequently, CD2 delayed cell spreading, and inhibited cell proliferation. Furthermore, these effects appear to be Src-specific because CD2 expression had no effect on EGF-induced activation of EGF receptor and ERK. Hence, the new findings indicate the importance of Na/K-ATPase/Src interaction in ouabain-induced signal transduction, and support the proposition that the CD2 peptide may be utilized as a Src SH2 ligand capable of blocking Src-dependent signaling pathways via a different mechanism from a general Src kinase inhibitor.

Constitutively active signaling by the G protein βγ-subunit mediates intrinsically increased phosphodiesterase-4 activity in human asthmatic airway smooth muscle cells.

Directory of Open Access Journals (Sweden)

Aihua Hu

Full Text Available Signaling by the Gβγ subunit of Gi protein, leading to downstream c-Src-induced activation of the Ras/c-Raf1/MEK-ERK1/2 signaling pathway and its upregulation of phosphodiesterase-4 (PDE4 activity, was recently shown to mediate the heightened contractility in proasthmatic sensitized isolated airway smooth muscle (ASM, as well as allergen-induced airway hyperresponsiveness and inflammation in an in vivo animal model of allergic asthma. This study investigated whether cultured human ASM (HASM cells derived from asthmatic donor lungs exhibit constitutively increased PDE activity that is attributed to intrinsically upregulated Gβγ signaling coupled to c-Src activation of the Ras/MEK/ERK1/2 cascade. We show that, relative to normal cells, asthmatic HASM cells constitutively exhibit markedly increased intrinsic PDE4 activity coupled to heightened Gβγ-regulated phosphorylation of c-Src and ERK1/2, and direct co-localization of the latter with the PDE4D isoform. These signaling events and their induction of heightened PDE activity are acutely suppressed by treating asthmatic HASM cells with a Gβγ inhibitor. Importantly, along with increased Gβγ activation, asthmatic HASM cells also exhibit constitutively increased direct binding of the small Rap1 GTPase-activating protein, Rap1GAP, to the α-subunit of Gi protein, which serves to cooperatively facilitate Ras activation and, thereby, enable enhanced Gβγ-regulated ERK1/2-stimulated PDE activity. Collectively, these data are the first to identify that intrinsically increased signaling via the Gβγ subunit, facilitated by Rap1GAP recruitment to the α-subunit, mediates the constitutively increased PDE4 activity detected in asthmatic HASM cells. These new findings support the notion that interventions targeted at suppressing Gβγ signaling may lead to novel approaches to treat asthma.

Predicting Sensitivity of Breast Tumors to Src-Targeted Therapies through Assessment of Cas/Src/BCAR3 Activity

Science.gov (United States)

2016-10-01

GFP-BCAR3 or R171V/L744E/R748E GFP-BCAR3 and lysed in a non- denaturing buffer 24 h post transfection. Total cell protein and Cas immune complexes...assess the role of a signaling pathway comprised of the protein tyrosine kinase c-Src (Src) and two adaptor molecules, Cas and BCAR3, in promoting...1. Introduction …………………………………………………..……….4 2. Keywords………………………………………………………..…….4 3. Accomplishments………..…………………………………….……...4 4

Significance of ERa and c-Src Interaction in the Progression of Hormone Independent Breast Cancer

Science.gov (United States)

2005-12-01

defects in estrogen signaling [1]. Because of global defects in estrogen signaling observed in these c-Src deficient mice, we have recently generated...1998). Interestingly, the region of the kinase domain of ErbB-2 that correlates with c-Src association, referred to as TK2 (Segatto et al., 1991...ductive organs that are dependent on ERa in c-Src- deficient mice. We show that the loss of the c-Src tyrosine kinase correlates with defects in ductal

v-Src causes delocalization of Mklp1, Aurora B, and INCENP from the spindle midzone during cytokinesis failure

Energy Technology Data Exchange (ETDEWEB)

Soeda, Shuhei [Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8675 (Japan); Nakayama, Yuji, E-mail: nakayama@mb.kyoto-phu.ac.jp [Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8675 (Japan); Department of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414 (Japan); Honda, Takuya; Aoki, Azumi; Tamura, Naoki; Abe, Kohei; Fukumoto, Yasunori [Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8675 (Japan); Yamaguchi, Naoto, E-mail: nyama@faculty.chiba-u.jp [Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8675 (Japan)

2013-06-10

Src-family tyrosine kinases are aberrantly activated in cancers, and this activation is associated with malignant tumor progression. v-Src, encoded by the v-src transforming gene of the Rous sarcoma virus, is a mutant variant of the cellular proto-oncogene c-Src. Although investigations with temperature sensitive mutants of v-Src have shown that v-Src induces many oncogenic processes, the effects on cell division are unknown. Here, we show that v-Src inhibits cellular proliferation of HCT116, HeLa S3 and NIH3T3 cells. Flow cytometry analysis indicated that inducible expression of v-Src results in an accumulation of 4N cells. Time-lapse analysis revealed that binucleation is induced through the inhibition of cytokinesis, a final step of cell division. The localization of Mklp1, which is essential for cytokinesis, to the spindle midzone is inhibited in v-Src-expressing cells. Intriguingly, Aurora B, which regulates Mklp1 localization at the midzone, is delocalized from the spindle midzone and the midbody but not from the metaphase chromosomes upon v-Src expression. Mklp2, which is responsible for the relocation of Aurora B from the metaphase chromosomes to the spindle midzone, is also lost from the spindle midzone. These results suggest that v-Src inhibits cytokinesis through the delocalization of Mklp1 and Aurora B from the spindle midzone, resulting in binucleation. -- Highlights: • v-Src inhibits cell proliferation of HCT116, HeLa S3 and NIH3T3 cells. • v-Src induces binucleation together with cytokinesis failure. • v-Src causes delocalization of Mklp1, Aurora B and INCENP from the spindle midzone.

SH2 Ligand-Like Effects of Second Cytosolic Domain of Na/K-ATPase α1 Subunit on Src Kinase.

Directory of Open Access Journals (Sweden)

Moumita Banerjee

Full Text Available Our previous studies have suggested that the α1 Na/K-ATPase interacts with Src to form a receptor complex. In vitro binding assays indicate an interaction between second cytosolic domain (CD2 of Na/K-ATPase α1 subunit and Src SH2 domain. Since SH2 domain targets Src to specific signaling complexes, we expressed CD2 as a cytosolic protein and studied whether it could act as a Src SH2 ligand in LLC-PK1 cells. Co-immunoprecipitation analyses indicated a direct binding of CD2 to Src, consistent with the in vitro binding data. Functionally, CD2 expression increased basal Src activity, suggesting a Src SH2 ligand-like property of CD2. Consistently, we found that CD2 expression attenuated several signaling pathways where Src plays an important role. For instance, although it increased surface expression of Na/K-ATPase, it decreased ouabain-induced activation of Src and ERK by blocking the formation of Na/K-ATPase/Src complex. Moreover, it also attenuated cell attachment-induced activation of Src/FAK. Consequently, CD2 delayed cell spreading, and inhibited cell proliferation. Furthermore, these effects appear to be Src-specific because CD2 expression had no effect on EGF-induced activation of EGF receptor and ERK. Hence, the new findings indicate the importance of Na/K-ATPase/Src interaction in ouabain-induced signal transduction, and support the proposition that the CD2 peptide may be utilized as a Src SH2 ligand capable of blocking Src-dependent signaling pathways via a different mechanism from a general Src kinase inhibitor.

Structural requirements for cub domain containing protein 1 (CDCP1 and Src dependent cell transformation.

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Gwendlyn Kollmorgen

Full Text Available Cub domain containing protein 1 (CDCP1 is strongly expressed in tumors derived from lung, colon, ovary, or kidney. It is a membrane protein that is phosphorylated and then bound by Src family kinases. Although expression and phosphorylation of CDCP1 have been investigated in many tumor cell lines, the CDCP1 features responsible for transformation have not been fully evaluated. This is in part due to the lack of an experimental system in which cellular transformation depends on expression of exogenous CDCP1 and Src. Here we use retrovirus mediated co-overexpression of c-Src and CDCP1 to induce focus formation of NIH3T3 cells. Employing different mutants of CDCP1 we show that for a full transformation capacity, the intact amino- and carboxy-termini of CDCP1 are essential. Mutation of any of the core intracellular tyrosine residues (Y734, Y743, or Y762 abolished transformation, and mutation of a palmitoylation motif (C689,690G strongly reduced it. Src kinase binding to CDCP1 was not required since Src with a defective SH2 domain generated even more CDCP1 dependent foci whereas Src myristoylation was necessary. Taken together, the focus formation assay allowed us to define structural requirements of CDCP1/Src dependent transformation and to characterize the interaction of CDCP1 and Src.

Antitumor Effect of KX-01 through Inhibiting Src Family Kinases and Mitosis.

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Kim, Seongyeong; Min, Ahrum; Lee, Kyung-Hun; Yang, Yaewon; Kim, Tae-Yong; Lim, Jee Min; Park, So Jung; Nam, Hyun-Jin; Kim, Jung Eun; Song, Sang-Hyun; Han, Sae-Won; Oh, Do-Youn; Kim, Jee Hyun; Kim, Tae-You; Hangauer, David; Lau, Johnson Yiu-Nam; Im, Kyongok; Lee, Dong Soon; Bang, Yung-Jue; Im, Seock-Ah

2017-07-01

KX-01 is a novel dual inhibitor of Src and tubulin. Unlike previous Src inhibitors that failed to show clinical benefit during treatment of breast cancer, KX-01 can potentially overcome the therapeutic limitations of current Src inhibitors through inhibition of both Src and tubulin. The present study further evaluates the activity and mechanism of KX-01 in vitro and in vivo . The antitumor effect of KX-01 in triple negative breast cancer (TNBC) cell lines was determined by MTT assay. Wound healing and immunofluorescence assays were performed to evaluate the action mechanisms of KX-01. Changes in the cell cycle and molecular changes induced by KX-01 were also evaluated. A MDA-MB-231 mouse xenograft model was used to demonstrate the in vivo effects. KX-01 effectively inhibited the growth of breast cancer cell lines. The expression of phospho-Src and proliferative-signaling molecules were down-regulated in KX-01-sensitive TNBC cell lines. In addition, migration inhibition was observed by wound healing assay. KX-01-induced G2/M cell cycle arrest and increased the aneuploid cell population in KX-01-sensitive cell lines. Multi-nucleated cells were significantly increased after KX-01 treatment. Furthermore, KX-01 effectively delayed tumor growth in a MDA-MB-231 mouse xenograft model. KX-01 effectively inhibited cell growth and migration of TNBC cells. Moreover, this study demonstrated that KX-01 showed antitumor effects through the inhibition of Src signaling and the induction of mitotic catastrophe. The antitumor effects of KX-01 were also demonstrated in vivo using a mouse xenograft model.

Dihydrotestosterone Potentiates EGF-Induced ERK Activation by Inducing SRC in Fetal Lung Fibroblasts

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Smith, Susan M.; Murray, Sandy; Pham, Lucia D.; Minoo, Parviz; Nielsen, Heber C.

2014-01-01

Lung maturation is regulated by interactions between mesenchymal and epithelial cells, and is delayed by androgens. Fibroblast–Type II cell communications are dependent on extracellular signal-regulated kinases (ERK) 1/2 activation by the ErbB receptor ligands epidermal growth factor (EGF), transforming growth factor (TGF)-α, and neuregulin (Nrg). In other tissues, dihydrotestosterone (DHT) has been shown to activate SRC by a novel nontranscriptional mechanism, which phosphorylates EGF receptors to potentiate EGF-induced ERK1/2 activation. This study sought to determine if DHT potentiates EGFR signaling by a nontranscriptional mechanism. Embryonic day (E)17 fetal lung cells were isolated from dams treated with or without DHT since E12. Cells were exposed to 30 ng/ml DHT for periods of 30 minutes to 3 days before being stimulated with 100 ng/ml EGF, TGF-α, or Nrg for up to 30 minutes. Lysates were immunoblotted for ErbB and SRC pathway signaling intermediates. DHT increased ERK1/2 activation by EGF, TGF-α, and Nrg in fibroblasts and Type II cells. Characterization in fibroblasts showed that potentiation of the EGF pathway was significant after 60 minutes of DHT exposure and persisted in the presence of the translational inhibitor cycloheximide. SRC and EGF receptor phosphorylation was increased by DHT, as was EGF-induced SHC1 phosphorylation and subsequent association with GRB2. Finally, SRC silencing, SRC inhibition with PP2, and overexpression of a dominant-negative SRC each prevented DHT from increasing EGF-induced ERK1/2 phosphorylation. These results suggest that DHT activates SRC to potentiate the signaling pathway leading from the EGF receptor to ERK activation in primary fetal lung fibroblasts. PMID:24484548

DMPD: Regulation of phagocyte migration and recruitment by Src-family kinases. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 18385944 Regulation of phagocyte migration and recruitment by Src-family kinases. B...how Regulation of phagocyte migration and recruitment by Src-family kinases. PubmedID 18385944 Title Regulat...ion of phagocyte migration and recruitment by Src-family kinases. Authors Baruzzi

Acetylation within the N- and C-Terminal Domains of Src Regulates Distinct Roles of STAT3-Mediated Tumorigenesis.

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Huang, Chao; Zhang, Zhe; Chen, Lihan; Lee, Hank W; Ayrapetov, Marina K; Zhao, Ting C; Hao, Yimei; Gao, Jinsong; Yang, Chunzhang; Mehta, Gautam U; Zhuang, Zhengping; Zhang, Xiaoren; Hu, Guohong; Chin, Y Eugene

2018-06-01

Posttranslational modifications of mammalian c-Src N-terminal and C-terminal domains regulate distinct functions. Myristoylation of G 2 controls its cell membrane association and phosphorylation of Y419/Y527 controls its activation or inactivation, respectively. We provide evidence that Src-cell membrane association-dissociation and catalytic activation-inactivation are both regulated by acetylation. In EGF-treated cells, CREB binding protein (CBP) acetylates an N-terminal lysine cluster (K5, K7, and K9) of c-Src to promote dissociation from the cell membrane. CBP also acetylates the C-terminal K401, K423, and K427 of c-Src to activate intrinsic kinase activity for STAT3 recruitment and activation. N-terminal domain phosphorylation (Y14, Y45, and Y68) of STAT3 by c-Src activates transcriptionally active dimers of STAT3. Moreover, acetyl-Src translocates into nuclei, where it forms the Src-STAT3 enhanceosome for gene regulation and cancer cell proliferation. Thus, c-Src acetylation in the N-terminal and C-terminal domains play distinct roles in Src activity and regulation. Significance: CBP-mediated acetylation of lysine clusters in both the N-terminal and C-terminal regions of c-Src provides additional levels of control over STAT3 transcriptional activity. Cancer Res; 78(11); 2825-38. ©2018 AACR . ©2018 American Association for Cancer Research.

Erratum to: Fertilization of SRC Willow

DEFF Research Database (Denmark)

Sevel, L; Ingerslev, Morten; Nord-Larsen, Thomas

2014-01-01

impacts of different doses of mineral fertilizer, manure and sewage sludge in a commercially grown SRC willow stand. We examined macro nutrient and heavy metal leaching rates and calculated element balances to evaluate the environmental impact. Growth responses were reported in a former paper (Sevel et al...

76 FR 3653 - Alaska Region's Subsistence Resource Commission (SRC) Program; Public Meeting

Science.gov (United States)

2011-01-20

... subsistence management issues. The NPS SRC program is authorized under Title VIII, Section 808 of the Alaska...: 1. Call to order. 2. SRC Roll Call and Confirmation of Quorum. 3. Welcome and Introductions. 4... Board of Game Update. 12. Old Business. a. Subsistence Uses of Horns, Antlers, Bones and Plants EA...

The IpaC carboxyterminal effector domain mediates Src-dependent actin polymerization during Shigella invasion of epithelial cells.

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Joëlle Mounier

2009-01-01

Full Text Available Shigella, the causative agent of bacillary dysentery, invades epithelial cells by locally reorganizing the actin cytoskeleton. Shigella invasion requires actin polymerization dependent on the Src tyrosine kinase and a functional bacterial type III secretion (T3S apparatus. Using dynamic as well as immunofluorescence microscopy, we show that the T3S translocon component IpaC allows the recruitment of the Src kinase required for actin polymerization at bacterial entry sites during the initial stages of Shigella entry. Src recruitment occurred at bacterial-cell contact sites independent of actin polymerization at the onset of the invasive process and was still observed in Shigella strains mutated for translocated T3S effectors of invasion. A Shigella strain with a polar mutation that expressed low levels of the translocator components IpaB and IpaC was fully proficient for Src recruitment and bacterial invasion. In contrast, a Shigella strain mutated in the IpaC carboxyterminal effector domain that was proficient for T3S effector translocation did not induce Src recruitment. Consistent with a direct role for IpaC in Src activation, cell incubation with the IpaC last 72 carboxyterminal residues fused to the Iota toxin Ia (IaC component that translocates into the cell cytosol upon binding to the Ib component led to Src-dependent ruffle formation. Strikingly, IaC also induced actin structures resembling bacterial entry foci that were enriched in activated Src and were inhibited by the Src inhibitor PP2. These results indicate that the IpaC effector domain determines Src-dependent actin polymerization and ruffle formation during bacterial invasion.

Regulation of mTORC1 Signaling by Src Kinase Activity Is Akt1-Independent in RSV-Transformed Cells

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Martina Vojtěchová

2008-02-01

Full Text Available Increased activity of the Src tyrosine protein kinase that has been observed in a large number of human malignancies appears to be a promising target for drug therapy. In the present study, a critical role of the Src activity in the deregulation of mTOR signaling pathway in Rous sarcoma virus (RSV-transformed hamster fibroblasts, H19 cells, was shown using these cells treated with the Src-specific inhibitor, SU6656, and clones of fibroblasts expressing either the active Src or the dominant-negative Src kinase-dead mutant. Disruption of the Src kinase activity results in substantial reduction of the phosphorylation and activity of the Akt/protein kinase B (PKB, phosphorylation of tuberin (TSC2, mammalian target of rapamycin (mTOR, S6K1, ribosomal protein S6, and eukaryotic initiation factor 4E-binding protein 4E-BP1. The ectopic, active Akt1 that was expressed in Src-deficient cells significantly enhanced phosphorylation of TSC2 in these cells, but it failed to activate the inhibited components of the mTOR pathway that are downstream of TSC2. The data indicate that the Src kinase activity is essential for the activity of mTOR-dependent signaling pathway and suggest that mTOR targets may be controlled by Src independently of Akt1/TSC2 cascade in cells expressing hyperactive Src protein. These observations might have an implication in drug resistance to mTOR inhibitor-based cancer therapy in certain cell types.

SLAP displays tumour suppressor functions in colorectal cancer via destabilization of the SRC substrate EPHA2

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Naudin, Cécile; Sirvent, Audrey; Leroy, Cédric; Larive, Romain; Simon, Valérie; Pannequin, Julie; Bourgaux, Jean-François; Pierre, Josiane; Robert, Bruno; Hollande, Frédéric; Roche, Serge

2014-01-01

The adaptor SLAP is a negative regulator of receptor signalling in immune cells but its role in human cancer is ill defined. Here we report that SLAP is abundantly expressed in healthy epithelial intestine but strongly downregulated in 50% of colorectal cancer. SLAP overexpression suppresses cell tumorigenicity and invasiveness while SLAP silencing enhances these transforming properties. Mechanistically, SLAP controls SRC/EPHA2/AKT signalling via destabilization of the SRC substrate and receptor tyrosine kinase EPHA2. This activity is independent from CBL but requires SLAP SH3 interaction with the ubiquitination factor UBE4A and SLAP SH2 interaction with pTyr594-EPHA2. SRC phosphorylates EPHA2 on Tyr594, thus creating a feedback loop that promotes EPHA2 destruction and thereby self-regulates its transforming potential. SLAP silencing enhances SRC oncogenicity and sensitizes colorectal tumour cells to SRC inhibitors. Collectively, these data establish a tumour-suppressive role for SLAP in colorectal cancer and a mechanism of SRC oncogenic induction through stabilization of its cognate substrates.

Structure-based design of an osteoclast-selective, nonpeptide Src homology 2 inhibitor with in vivo antiresorptive activity

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Shakespeare, William; Yang, Michael; Bohacek, Regine; Cerasoli, Franklin; Stebbins, Karin; Sundaramoorthi, Raji; Azimioara, Mihai; Vu, Chi; Pradeepan, Selvi; Metcalf, Chester; Haraldson, Chad; Merry, Taylor; Dalgarno, David; Narula, Surinder; Hatada, Marcos; Lu, Xiaode; van Schravendijk, Marie Rose; Adams, Susan; Violette, Shelia; Smith, Jeremy; Guan, Wei; Bartlett, Catherine; Herson, Jay; Iuliucci, John; Weigele, Manfred; Sawyer, Tomi

2000-01-01

Targeted disruption of the pp60src (Src) gene has implicated this tyrosine kinase in osteoclast-mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone-related diseases. Herein we describe the discovery of a nonpeptide inhibitor (AP22408) of Src that demonstrates in vivo antiresorptive activity. Based on a cocrystal structure of the noncatalytic Src homology 2 (SH2) domain of Src complexed with citrate [in the phosphotyrosine (pTyr) binding pocket], we designed 3′,4′-diphosphonophenylalanine (Dpp) as a pTyr mimic. In addition to its design to bind Src SH2, the Dpp moiety exhibits bone-targeting properties that confer osteoclast selectivity, hence minimizing possible undesired effects on other cells that have Src-dependent activities. The chemical structure AP22408 also illustrates a bicyclic template to replace the post-pTyr sequence of cognate Src SH2 phosphopeptides such as Ac-pTyr-Glu-Glu-Ile (1). An x-ray structure of AP22408 complexed with Lck (S164C) SH2 confirmed molecular interactions of both the Dpp and bicyclic template of AP22408 as predicted from molecular modeling. Relative to the cognate phosphopeptide, AP22408 exhibits significantly increased Src SH2 binding affinity (IC50 = 0.30 μM for AP22408 and 5.5 μM for 1). Furthermore, AP22408 inhibits rabbit osteoclast-mediated resorption of dentine in a cellular assay, exhibits bone-targeting properties based on a hydroxyapatite adsorption assay, and demonstrates in vivo antiresorptive activity in a parathyroid hormone-induced rat model. PMID:10944210

Distinct protease pathways control cell shape and apoptosis in v-src-transformed quail neuroretina cells

International Nuclear Information System (INIS)

Neel, Benjamin D.; Aouacheria, Abdel; Nouvion, Anne-Laure; Ronot, Xavier; Gillet, Germain

2005-01-01

Intracellular proteases play key roles in cell differentiation, proliferation and apoptosis. In nerve cells, little is known about their relative contribution to the pathways which control cell physiology, including cell death. Neoplastic transformation of avian neuroretina cells by p60 v-src tyrosine kinase results in dramatic morphological changes and deregulation of apoptosis. To identify the proteases involved in the cellular response to p60 v-src , we evaluated the effect of specific inhibitors of caspases, calpains and the proteasome on cell shape changes and apoptosis induced by p60 v-src inactivation in quail neuroretina cells transformed by tsNY68, a thermosensitive strain of Rous sarcoma virus. We found that the ubiquitin-proteasome pathway is recruited early after p60 v-src inactivation and is critical for morphological changes, whereas caspases are essential for cell death. This study provides evidence that distinct intracellular proteases are involved in the control of the morphology and fate of v-src-transformed cells

Trihydrophobin 1 Phosphorylation by c-Src Regulates MAPK/ERK Signaling and Cell Migration

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Wu, Weibin; Sun, Zhichao; Wu, Jingwen; Peng, Xiaomin; Gan, Huacheng; Zhang, Chunyi; Ji, Lingling; Xie, Jianhui; Zhu, Haiyan; Ren, Shifang

2012-01-01

c-Src activates Ras-MAPK/ERK signaling pathway and regulates cell migration, while trihydrophobin 1 (TH1) inhibits MAPK/ERK activation and cell migration through interaction with A-Raf and PAK1 and inhibiting their kinase activities. Here we show that c-Src interacts with TH1 by GST-pull down assay, coimmunoprecipitation and confocal microscopy assay. The interaction leads to phosphorylation of TH1 at Tyr-6 in vivo and in vitro. Phosphorylation of TH1 decreases its association with A-Raf and PAK1. Further study reveals that Tyr-6 phosphorylation of TH1 reduces its inhibition on MAPK/ERK signaling, enhances c-Src mediated cell migration. Moreover, induced tyrosine phosphorylation of TH1 has been found by EGF and estrogen treatments. Taken together, our findings demonstrate a novel mechanism for the comprehensive regulation of Ras/Raf/MEK/ERK signaling and cell migration involving tyrosine phosphorylation of TH1 by c-Src. PMID:22238675

SP600125 Induces Src and Type I IGF Receptor Phosphorylation Independent of JNK

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Qingbin Kong

2014-09-01

Full Text Available c-Jun N-terminal kinases (JNK are members of the mitogen-activated protein kinase (MAPK family that have important roles in signal transduction. The small molecule SP600125 is widely used in biochemical studies as a JNK inhibitor. However, recent studies indicate that SP600125 may also act independent of JNK. Here, we report that SP600125 can induce Src, type I insulin-like growth factor receptor (IGF-IR, Akt and Erk1/2 phosphorylation. Notably, these effects are independent of its inhibition of JNK. Inhibition of Src abrogates the stimulation of IGF-IR, Akt and Erk1/2 phosphorylation. IGF-IR knockdown blunts the induction of both Akt and Erk1/2 phosphorylation by SP600125. Moreover, combination of SP600125 and the Src inhibitor saracatinib synergistically inhibits cell proliferation. We conclude that SP600125 can activate Src-IGF-IR-Akt/Erk1/2 signaling pathways independent of JNK.

Adaptor protein GRB2 promotes Src tyrosine kinase activation and podosomal organization by protein-tyrosine phosphatase ϵ in osteoclasts.

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Levy-Apter, Einat; Finkelshtein, Eynat; Vemulapalli, Vidyasiri; Li, Shawn S-C; Bedford, Mark T; Elson, Ari

2014-12-26

The non-receptor isoform of protein-tyrosine phosphatase ϵ (cyt-PTPe) supports adhesion of bone-resorbing osteoclasts by activating Src downstream of integrins. Loss of cyt-PTPe reduces Src activity in osteoclasts, reduces resorption of mineralized matrix both in vivo and in cell culture, and induces mild osteopetrosis in young female PTPe KO mice. Activation of Src by cyt-PTPe is dependent upon this phosphatase undergoing phosphorylation at its C-terminal Tyr-638 by partially active Src. To understand how cyt-PTPe activates Src, we screened 73 Src homology 2 (SH2) domains for binding to Tyr(P)-638 of cyt-PTPe. The SH2 domain of GRB2 bound Tyr(P)-638 of cyt-PTPe most prominently, whereas the Src SH2 domain did not bind at all, suggesting that GRB2 may link PTPe with downstream molecules. Further studies indicated that GRB2 is required for activation of Src by cyt-PTPe in osteoclast-like cells (OCLs) in culture. Overexpression of GRB2 in OCLs increased activating phosphorylation of Src at Tyr-416 and of cyt-PTPe at Tyr-638; opposite results were obtained when GRB2 expression was reduced by shRNA or by gene inactivation. Phosphorylation of cyt-PTPe at Tyr-683 and its association with GRB2 are integrin-driven processes in OCLs, and cyt-PTPe undergoes autodephosphorylation at Tyr-683, thus limiting Src activation by integrins. Reduced GRB2 expression also reduced the ability of bone marrow precursors to differentiate into OCLs and reduced the fraction of OCLs in which podosomal adhesion structures assume organization typical of active, resorbing cells. We conclude that GRB2 physically links cyt-PTPe with Src and enables cyt-PTPe to activate Src downstream of activated integrins in OCLs. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Src kinases in chondrosarcoma chemoresistance and migration: dasatinib sensitises to doxorubicin in TP53 mutant cells

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van Oosterwijk, J G; van Ruler, M A J H; Briaire-de Bruijn, I H; Herpers, B; Gelderblom, H; van de Water, B; Bovée, J V M G

2013-01-01

Background: Chondrosarcomas are malignant cartilage-forming tumours of bone. Because of their resistance to conventional chemotherapy and radiotherapy, currently no treatment strategies exist for unresectable and metastatic chondrosarcoma. Previously, PI3K/AKT/GSK3β and Src kinase pathways were shown to be activated in chondrosarcoma cell lines. Our aim was to investigate the role of these kinases in chemoresistance and migration in chondrosarcoma in relation to TP53 mutation status. Methods: We used five conventional and three dedifferentiated chondrosarcoma cell lines and investigated the effect of PI3K/AKT/GSK3β pathway inhibition (enzastaurin) and Src pathway inhibition (dasatinib) in chemoresistance using WST assay and live cell imaging with AnnexinV staining. Immunohistochemistry on tissue microarrays (TMAs) containing 157 cartilaginous tumours was performed for Src family members. Migration assays were performed with the RTCA xCelligence System. Results: Src inhibition was found to overcome chemoresistance, to induce apoptosis and to inhibit migration. Cell lines with TP53 mutations responded better to combination therapy than wild-type cell lines (P=0.002). Tissue microarray immunohistochemistry confirmed active Src (pSrc) signalling, with Fyn being most abundantly expressed (76.1%). Conclusion: These results strongly indicate Src family kinases, in particular Fyn, as a potential target for the treatment of inoperable and metastatic chondrosarcomas, and to sensitise for doxorubicin especially in the presence of TP53 mutations. PMID:23922104

FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway

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Juan Tornin

2018-01-01

Full Text Available Deregulated SRC/FAK signaling leads to enhanced migration and invasion in many types of tumors. In myxoid and round cell liposarcoma (MRCLS, an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one of the most activated kinases. Here we used a cell-of-origin model of MRCLS and an MRCLS cell line to thoroughly characterize the mechanisms of cell invasion induced by FUS-CHOP using in vitro (3D spheroid invasion assays and in vivo (chicken chorioallantoic membrane model approaches. FUS-CHOP expression activated SRC-FAK signaling and increased the invasive ability of MRCLS cells. In addition, FAK expression was found to significantly correlate with tumor aggressiveness in sarcoma patient samples. The involvement of SRC/FAK activation in FUS-CHOP–mediated invasion was further confirmed using the SRC inhibitor dasatinib, the specific FAK inhibitor PF-573228, and FAK siRNA. Notably, dasatinib and PF573228 could also efficiently block the invasion of cancer stem cell subpopulations. Downstream of SRC/FAK signaling, we found that FUS-CHOP expression increases the levels of the RHO/ROCK downstream effector phospho-MLC2 (T18/S19 and that this activation was prevented by dasatinib or PF573228. Moreover, the ROCK inhibitor RKI-1447 was able to completely abolish invasion in FUS-CHOP–expressing cells. These data uncover the involvement of SRC/FAK/RHO/ROCK signaling axis in FUS-CHOP–mediated invasion, thus providing a rationale for testing inhibitors of this pathway as potential novel antimetastatic agents for MRCLS treatment.

SRC-willow (Salix viminalis) as a resource for flower-visiting insects

Energy Technology Data Exchange (ETDEWEB)

Reddersen, J. [National Environmental Research Institute, Ronde (Denmark). Dept. of Landscape Ecology

2001-07-01

The potential habitat value of commercial short rotation coppice (SRC)-willow plantations for flower-visiting insects was investigated. During 1998-2000, at a single typical intensive Danish farmland site, 11 Salix viminalis plantations were sampled by late April to quantify willow catkin abundance and flower sex. Mean plantation size was 1.1 ha and included one or more of clones: orm, rapp, ulv, jorr, christina and jorrun. Plot-year means of catkin abundance and of proportion of willows flowering were related to the coppicing cycle, i.e. the number of growth years since last harvest of plot ('year' 0-4). In 1998, the ground layer vegetation was sampled. Monitoring flower-visiting insects by means of line-transect counts failed due to the local scarcity of bees. At the plantation scale, flowering was discontinuous across the harvest cycle as it was totally absent in the year immediately following harvest. In successive years (1-4), individual willows flowered frequently and, occasionally, at high abundances, and catkin abundance increased with time. Within 3-4 year of harvest cycle, all plots flowered in most years with most plots exhibiting at least some flowering in any 1 year. Thus, willow catkin abundance was generally high in the total area due to: high frequency of flowering in plots, occasional high flowering abundance, plots not being harvested simultaneously and large total number of willows within plots and landscape. Similarly, flower sex ratio, and thus flower value, varied greatly between plots while variation was damped across plots. Alternative simultaneous flower resources in ground layer vegetation were few except for Dandelion. SRC willow may constitute an important resource for bees, even under the stress of the harvest cycle, and recommendations are given for improving this biodiversity aspect. (author)

Solvent Refined Coal (SRC) process: trace elements. Research and development report No. 53, interim report No. 30. Volume III. Pilot plant development work. Part 6. The fate of trace elements in the SRC process

International Nuclear Information System (INIS)

Khalil, S.R.

1980-02-01

Instrumental neutron activation analysis was used to study the distribution and fate of up to 36 elements in the Solvent Refined Coal Process Pilot Plant located at Fort Lewis, Washington. The elements Ti, V, Mg, Ca, Al, Cl, Mn, As, Br, Na, K, Sm, La, Ga, Cu, Sb, Se, Hg, Ni, Co, Cr, Fe, Rb, Cs, Sc, Tb, Eu, Ce, Sr, Ba, Th, U, Hf, Ta, Zr and Zn were measured in feed coal, insoluble residues, process solvent, process and effluent waters, by-product sulfur, SRC-I solid product, liquid-liquid separator oils and SRC-II liquid products. The material balance was calculated for each element from the concentration data and yields of each process fraction for both the SRC-I and SRC-II processes. Except for Ti, Cl and Br in the SRC-I mode and Hg in the SRC-II mode, each element was substantially lower in the SRC products than in the original feed coal. Residues from the process contained more than 80% of the trace element content found in the coal, except for Hg. More than 98.5% of the total contents of K and Fe in coal were retained in the insoluble residues. Elements such as Hg, Se, As and Sb can form volatile compounds (such as Hg 0 , H 2 Se, AsH 3 and SbH 3 ) stable under the process conditions. The high enhancement factors of Se (957), As (202) and Sb (27.4) in the aqueous phase of the separator water compared to that of the oil are evidence for the formation of volatile species which are more soluble in water than in the oil phase

The Role of C-SRC Activation in Prostate Tumor Progression

Science.gov (United States)

2006-07-01

cancer cell line PANC -1 and prostrate cancer cell line PC-3 (B2-fold increase relative to control in both cell lines), while the Src inhibitory PP2 blocks...at normoxia in PANC -1 and PC-3 cells, its levels significantly increase in response to hypoxia (B4.5–8-fold induction). Inhibition of endo- genous c...Src activation in PANC -1 and PC-3 cells by PP2 drastically reduced HIF-1a levels to below those levels observed at normoxia (Figure 1a). STAT3 has

Digitalis-induced cell signaling by the sodium pump: on the relation of Src to Na(+)/K(+)-ATPase.

Science.gov (United States)

Gable, Marjorie E; Abdallah, Simon L; Najjar, Sonia M; Liu, Lijun; Askari, Amir

2014-04-18

In addition to performing its essential transport function, the sodium pump also activates multiple cell signaling pathways in response to digitalis drugs such as ouabain. Based mainly on cell-free studies with mixtures of purified Src kinase and Na(+)/K(+)-ATPase, a well-advocated hypothesis on how ouabain initiates the activation of signaling pathways is that there is a preexisting physiological complex of inactive Src bound to the α-subunit of Na(+)/K(+)-ATPase, and that ouabain binding to this subunit disrupts the bound Src and activates it. Because of the published disagreements of the results of such cell-free experiments of two other laboratories, our aim was to attempt the resolution of these discrepancies. We reexamined the effects of ouabain, vanadate, and oligomycin on mixtures of Src, Na(+)/K(+)-ATPase, Mg(2+), and ATP as specified in prior studies; and assayed for Src-418 autophosphorylation as the measure of Src activation. In contrast to the findings of the proponents of the above hypothesis, our results showed similar effects of the three inhibitors of Na(+)/K(+)-ATPase; indicating that Src activation in such experiments is primarily due to the ATP-sparing effect of the ATPase inhibitor on the mixture of two enzymes competing for ATP. We conclude that there is no solid evidence for direct molecular interaction of Src with Na(+)/K(+)-ATPase under physiological conditions. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Src kinase conformational activation: thermodynamics, pathways, and mechanisms.

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Sichun Yang

2008-03-01

Full Text Available Tyrosine kinases of the Src-family are large allosteric enzymes that play a key role in cellular signaling. Conversion of the kinase from an inactive to an active state is accompanied by substantial structural changes. Here, we construct a coarse-grained model of the catalytic domain incorporating experimental structures for the two stable states, and simulate the dynamics of conformational transitions in kinase activation. We explore the transition energy landscapes by constructing a structural network among clusters of conformations from the simulations. From the structural network, two major ensembles of pathways for the activation are identified. In the first transition pathway, we find a coordinated switching mechanism of interactions among the alphaC helix, the activation-loop, and the beta strands in the N-lobe of the catalytic domain. In a second pathway, the conformational change is coupled to a partial unfolding of the N-lobe region of the catalytic domain. We also characterize the switching mechanism for the alphaC helix and the activation-loop in detail. Finally, we test the performance of a Markov model and its ability to account for the structural kinetics in the context of Src conformational changes. Taken together, these results provide a broad framework for understanding the main features of the conformational transition taking place upon Src activation.

Specific oncogenic activity of the Src-family tyrosine kinase c-Yes in colon carcinoma cells.

Directory of Open Access Journals (Sweden)

Florence Sancier

Full Text Available c-Yes, a member of the Src tyrosine kinase family, is found highly activated in colon carcinoma but its importance relative to c-Src has remained unclear. Here we show that, in HT29 colon carcinoma cells, silencing of c-Yes, but not of c-Src, selectively leads to an increase of cell clustering associated with a localisation of β-catenin at cell membranes and a reduction of expression of β-catenin target genes. c-Yes silencing induced an increase in apoptosis, inhibition of growth in soft-agar and in mouse xenografts, inhibition of cell migration and loss of the capacity to generate liver metastases in mice. Re-introduction of c-Yes, but not c -Src, restores transforming properties of c-Yes depleted cells. Moreover, we found that c-Yes kinase activity is required for its role in β-catenin localisation and growth in soft agar, whereas kinase activity is dispensable for its role in cell migration. We conclude that c-Yes regulates specific oncogenic signalling pathways important for colon cancer progression that is not shared with c-Src.

Heterozygous Null Bone Morphogenetic Protein Receptor Type 2 Mutations Promote SRC Kinase-dependent Caveolar Trafficking Defects and Endothelial Dysfunction in Pulmonary Arterial Hypertension*

Science.gov (United States)

Prewitt, Allison R.; Ghose, Sampa; Frump, Andrea L.; Datta, Arumima; Austin, Eric D.; Kenworthy, Anne K.; de Caestecker, Mark P.

2015-01-01

Hereditary pulmonary arterial hypertension (HPAH) is a rare, fatal disease of the pulmonary vasculature. The majority of HPAH patients inherit mutations in the bone morphogenetic protein type 2 receptor gene (BMPR2), but how these promote pulmonary vascular disease is unclear. HPAH patients have features of pulmonary endothelial cell (PEC) dysfunction including increased vascular permeability and perivascular inflammation associated with decreased PEC barrier function. Recently, frameshift mutations in the caveolar structural protein gene Caveolin-1 (CAV-1) were identified in two patients with non-BMPR2-associated HPAH. Because caveolae regulate endothelial function and vascular permeability, we hypothesized that defects in caveolar function might be a common mechanism by which BMPR2 mutations promote pulmonary vascular disease. To explore this, we isolated PECs from mice carrying heterozygous null Bmpr2 mutations (Bmpr2+/−) similar to those found in the majority of HPAH patients. We show that Bmpr2+/− PECs have increased numbers and intracellular localization of caveolae and caveolar structural proteins CAV-1 and Cavin-1 and that these defects are reversed after blocking endocytosis with dynasore. SRC kinase is also constitutively activated in Bmpr2+/− PECs, and localization of CAV-1 to the plasma membrane is restored after treating Bmpr2+/− PECs with the SRC kinase inhibitor 3-(4-chlorophenyl)-1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP2). Late outgrowth endothelial progenitor cells isolated from HPAH patients show similar increased activation of SRC kinase. Moreover, Bmpr2+/− PECs have impaired endothelial barrier function, and barrier function is restored after treatment with PP2. These data suggest that heterozygous null BMPR2 mutations promote SRC-dependent caveolar trafficking defects in PECs and that this may contribute to pulmonary endothelial barrier dysfunction in HPAH patients. PMID:25411245

Src Kinase becomes preferentially associated with the VEGFR, KDR/Flk-1, following VEGF stimulation of vascular endothelial cells

Directory of Open Access Journals (Sweden)

Wang Jing

2002-12-01

Full Text Available Abstract Background The cytoplasmic tyrosine kinase, Src, has been found to play a crucial role in VEGF (vascular endothelial growth factor – dependent vascular permeability involved in angiogenesis. The two main VEGFRs present on vascular endothelial cells are KDR/Flk-1 (kinase insert domain-containing receptor/fetal liver kinase-1 and Flt-1 (Fms-like tyrosine kinase-1. However, to date, it has not been determined which VEGF receptor (VEGFR is involved in binding to and activating Src kinase following VEGF stimulation of the receptors. Results In this report, we demonstrate that Src preferentially associates with KDR/Flk-1 rather than Flt-1 in human umbilical vein endothelial cells (HUVECs, and that VEGF stimulation resulted in an increase of Src activity associated with activated KDR/Flk-1. These findings were determined through immunoprecipitation-kinase experiments and coimmunoprecipitation studies, and were further confirmed by GST-pull-down assays and Far Western studies. However, Fyn and Yes, unlike Src, were found to associate preferentially with Flt-1. Conclusions Thus, Src preferentially associates with KDR/Flk-1, rather than with Flt-1, upon VEGF stimulation in endothelial cells. Our findings further highlight the potential significance of upregulated KDR/Flk-1-associated Src activity in the process of angiogenesis, and help to elucidate more clearly the specific roles and mechanisms involving Src family tyrosine kinase in VEGF-stimulated signal transduction events.

Focal adhesion kinase-dependent focal adhesion recruitment of SH2 domains directs SRC into focal adhesions to regulate cell adhesion and migration.

Science.gov (United States)

Wu, Jui-Chung; Chen, Yu-Chen; Kuo, Chih-Ting; Wenshin Yu, Helen; Chen, Yin-Quan; Chiou, Arthur; Kuo, Jean-Cheng

2015-12-18

Directed cell migration requires dynamical control of the protein complex within focal adhesions (FAs) and this control is regulated by signaling events involving tyrosine phosphorylation. We screened the SH2 domains present in tyrosine-specific kinases and phosphatases found within FAs, including SRC, SHP1 and SHP2, and examined whether these enzymes transiently target FAs via their SH2 domains. We found that the SRC_SH2 domain and the SHP2_N-SH2 domain are associated with FAs, but only the SRC_SH2 domain is able to be regulated by focal adhesion kinase (FAK). The FAK-dependent association of the SRC_SH2 domain is necessary and sufficient for SRC FA targeting. When the targeting of SRC into FAs is inhibited, there is significant suppression of SRC-mediated phosphorylation of paxillin and FAK; this results in an inhibition of FA formation and maturation and a reduction in cell migration. This study reveals an association between FAs and the SRC_SH2 domain as well as between FAs and the SHP2_N-SH2 domains. This supports the hypothesis that the FAK-regulated SRC_SH2 domain plays an important role in directing SRC into FAs and that this SRC-mediated FA signaling drives cell migration.

Optically Anomalous Crystals

CERN Document Server

Shtukenberg, Alexander; Kahr, Bart

2007-01-01

Optical anomalies in crystals are puzzles that collectively constituted the greatest unsolved problems in crystallography in the 19th Century. The most common anomaly is a discrepancy between a crystal’s symmetry as determined by its shape or by X-ray analysis, and that determined by monitoring the polarization state of traversing light. These discrepancies were perceived as a great impediment to the development of the sciences of crystals on the basis of Curie’s Symmetry Principle, the grand organizing idea in the physical sciences to emerge in the latter half of the 19th Century. Optically Anomalous Crystals begins with an historical introduction covering the contributions of Brewster, Biot, Mallard, Brauns, Tamman, and many other distinguished crystallographers. From this follows a tutorial in crystal optics. Further chapters discuss the two main mechanisms of optical dissymmetry: 1. the piezo-optic effect, and 2. the kinetic ordering of atoms. The text then tackles complex, inhomogeneous crystals, and...

Characterization of a novel weak interaction between MUC1 and Src-SH3 using nuclear magnetic resonance spectroscopy

Energy Technology Data Exchange (ETDEWEB)

Gunasekara, Nirosha [Department of Laboratory Medicine and Pathology, University of Alberta, 5B4.21 WCM Health Science Centre, 8440-112th Street, Edmonton, Alberta, Canada T6G 2R7 (Canada); Sykes, Brian, E-mail: brian.sykes@ualberta.ca [Department of Biochemistry, 4-19B Medical Sciences Bldg., University of Alberta Edmonton, Alberta, Canada T6G 2H7 (Canada); Hugh, Judith, E-mail: judithh@ualberta.ca [Department of Laboratory Medicine and Pathology, University of Alberta, 5B4.21 WCM Health Science Centre, 8440-112th Street, Edmonton, Alberta, Canada T6G 2R7 (Canada)

2012-05-18

Highlights: Black-Right-Pointing-Pointer MUC1 binds the Src-SH3 domain potentially triggering Src dependent cell migration. Black-Right-Pointing-Pointer NMR Spectroscopy was used to monitor MUC1-CD and Src SH3 domain titrations. Black-Right-Pointing-Pointer MUC1-CD peptides bind with a low affinity (K{sub d} of 2-3 mM) to a non-canonical site. Black-Right-Pointing-Pointer Weak interactions may mediate dynamic processes like migration. Black-Right-Pointing-Pointer The MUC1-CD and Src-SH3 interaction may be a prime target to inhibit cell migration. -- Abstract: Breast cancer causes death through cancer cell migration and subsequent metastasis to distant organs. In vitro, the MUC1 mucin can mediate breast cancer cell migration by binding to intercellular adhesion molecule-1 (ICAM-1). This migration is dependent on MUC1 cytoplasmic domain (MUC1-CD) activation of the non-receptor tyrosine kinase, Src, possibly through competitive displacement of an inhibitory Src intramolecular SH3 binding. Therefore, we characterized the binding site and affinity of the MUC1-CD for Src-SH3 using multidimensional nuclear magnetic resonance (NMR) spectroscopy to monitor the titration of the {sup 15}N labeled Src-SH3 domain with synthetic native and mutant peptides of MUC1-CD. The results revealed that the dissociation constant (K{sub d}) for the interaction of the native MUC1-CD peptides and Src-SH3 domain was weak with a K{sub d} of 2-3 mM. Notably, the SH3 residues most perturbed upon peptide binding were located outside the usual hydrophobic binding cleft in a previously described alternate binding site on the Src-SH3, suggesting that MUC1-CD binds to a non-canonical site. The binding characteristics outlined here suggest that the interaction between Src-SH3 and MUC1-CD represents a novel weak electrostatic interaction of the type which is increasingly recognized as important in transient and dynamic protein complexes required for cell migration and signal transduction. As such, this

c-Src activation through a TrkA and c-Src interaction is essential for cell proliferation and hematological malignancies

International Nuclear Information System (INIS)

Kim, Min Soo; Kim, Gyoung Mi; Choi, Yun-Jeong; Kim, Hye Joung; Kim, Yoo-Jin; Jin, Wook

2013-01-01

Highlights: •TrkA was mainly present in other types of leukemia including AML. •TrkA enhances the survival of leukemia by activation of PI3K/Akt pathway. •TrkA induced significant hematological malignancies by inducing PLK-1 and Twist-1. •TrkA acted as a key regulator of leukemogenesis and survival through c-Src activation. -- Abstract: Although the kinase receptor TrkA may play an important role in acute myeloid leukemia (AML), its involvement in other types of leukemia has not been reported. Furthermore, how it contributes to leukemogenesis is unknown. Here, we describe a molecular network that is important for TrkA function in leukemogenesis. We found that TrkA is frequently overexpressed in other types of leukemia such as acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) including AML. In addition, TrkA was overexpressed in patients with MDS or secondary AML evolving from MDS. TrkA induced significant hematological malignancies by inducing PLK-1 and Twist-1, and enhanced survival and proliferation of leukemia, which was correlated with activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway. Moreover, endogenous TrkA associated with c-Src complexes was detected in leukemia. Suppression of c-Src activation by TrkA resulted in markedly decreased expression of PLK-1 and Twist-1 via suppressed activation of Akt/mTOR cascades. These data suggest that TrkA plays a key role in leukemogenesis and reveal an unexpected physiological role for TrkA in the pathogenesis of leukemia. These data have important implications for understanding various hematological malignancies

c-Src activation through a TrkA and c-Src interaction is essential for cell proliferation and hematological malignancies

Energy Technology Data Exchange (ETDEWEB)

Kim, Min Soo; Kim, Gyoung Mi; Choi, Yun-Jeong [Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840 (Korea, Republic of); Kim, Hye Joung [Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-701 (Korea, Republic of); Kim, Yoo-Jin, E-mail: yoojink@catholic.ac.kr [Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-701 (Korea, Republic of); Jin, Wook, E-mail: jinwo@gachon.ac.kr [Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840 (Korea, Republic of); Gachon Medical Research Institute, Gil Medical Center, Incheon 405-760 (Korea, Republic of)

2013-11-15

Highlights: •TrkA was mainly present in other types of leukemia including AML. •TrkA enhances the survival of leukemia by activation of PI3K/Akt pathway. •TrkA induced significant hematological malignancies by inducing PLK-1 and Twist-1. •TrkA acted as a key regulator of leukemogenesis and survival through c-Src activation. -- Abstract: Although the kinase receptor TrkA may play an important role in acute myeloid leukemia (AML), its involvement in other types of leukemia has not been reported. Furthermore, how it contributes to leukemogenesis is unknown. Here, we describe a molecular network that is important for TrkA function in leukemogenesis. We found that TrkA is frequently overexpressed in other types of leukemia such as acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) including AML. In addition, TrkA was overexpressed in patients with MDS or secondary AML evolving from MDS. TrkA induced significant hematological malignancies by inducing PLK-1 and Twist-1, and enhanced survival and proliferation of leukemia, which was correlated with activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway. Moreover, endogenous TrkA associated with c-Src complexes was detected in leukemia. Suppression of c-Src activation by TrkA resulted in markedly decreased expression of PLK-1 and Twist-1 via suppressed activation of Akt/mTOR cascades. These data suggest that TrkA plays a key role in leukemogenesis and reveal an unexpected physiological role for TrkA in the pathogenesis of leukemia. These data have important implications for understanding various hematological malignancies.

Differential Requirements for Src-Family Kinases in SYK or ZAP70-Mediated SLP-76 Phosphorylation in Lymphocytes

Directory of Open Access Journals (Sweden)

Frank Fasbender

2017-07-01

Full Text Available In a synthetic biology approach using Schneider (S2 cells, we show that SLP-76 is directly phosphorylated at tyrosines Y113 and Y128 by SYK in the presence of ITAM-containing adapters such as CD3ζ, DAP12, or FcεRγ. This phosphorylation was dependent on at least one functional ITAM and a functional SH2 domain within SYK. Inhibition of Src-kinases by inhibitors PP1 and PP2 did not reduce SLP-76 phosphorylation in S2 cells, suggesting an ITAM and SYK dependent, but Src-kinase independent signaling pathway. This direct ITAM/SYK/SLP-76 signaling pathway therefore differs from previously described ITAM signaling. However, the SYK-family kinase ZAP70 required the additional co-expression of the Src-family kinases Fyn or Lck to efficiently phosphorylate SLP-76 in S2 cells. This difference in Src-family kinase dependency of SYK versus ZAP70-mediated ITAM-based signaling was further demonstrated in human lymphocytes. ITAM signaling in ZAP70-expressing T cells was dependent on the activity of Src-family kinases. In contrast, Src-family kinases were partially dispensable for ITAM signaling in SYK-expressing B cells or in natural killer cells, which express SYK and ZAP70. This demonstrates that SYK can signal using a Src-kinase independent ITAM-based signaling pathway, which may be involved in calibrating the threshold for lymphocyte activation.

Coupled motions in the SH2 and kinase domains of Csk control Src phosphorylation.

Science.gov (United States)

Wong, Lilly; Lieser, Scot A; Miyashita, Osamu; Miller, Meghan; Tasken, Kjetil; Onuchic, Josè N; Adams, Joseph A; Woods, Virgil L; Jennings, Patricia A

2005-08-05

The C-terminal Src kinase (Csk) phosphorylates and down-regulates Src family tyrosine kinases. The Csk-binding protein (Cbp) localizes Csk close to its substrates at the plasma membrane, and increases the specific activity of the kinase. To investigate this long-range catalytic effect, the phosphorylation of Src and the conformation of Csk were investigated in the presence of a high-affinity phosphopeptide derived from Cbp. This peptide binds tightly to the SH2 domain and enhances Src recognition (lowers K(m)) by increasing the apparent phosphoryl transfer rate in the Csk active site, a phenomenon detected in rapid quench flow experiments. Previous studies demonstrated that the regulation of Csk activity is linked to conformational changes in the enzyme that can be probed with hydrogen-deuterium exchange methods. We show that the Cbp peptide impacts deuterium incorporation into its binding partner (the SH2 domain), and into the SH2-kinase linker and several sequences in the kinase domain, including the glycine-rich loop in the active site. These findings, along with computational data from normal mode analyses, suggest that the SH2 domain moves in a cantilever fashion with respect to the small lobe of the kinase domain, ordering the active site for catalysis. The binding of a small Cbp-derived peptide to the SH2 domain of Csk modifies these motions, enhancing Src recognition.

Atypical protein kinase C activity is required for extracellular matrix degradation and invasion by Src-transformed cells.

Science.gov (United States)

Rodriguez, Elena M; Dunham, Elizabeth E; Martin, G Steven

2009-10-01

Atypical protein kinase C (aPKC) isoforms have been shown to mediate Src-dependent signaling in response to growth factor stimulation. To determine if aPKC activity contributes to the transformed phenotype of cells expressing oncogenic Src, we have examined the activity and function of aPKCs in 3T3 cells expressing viral Src (v-Src). aPKC activity and tyrosine phosphorylation were found to be elevated in some but not all clones of mouse fibroblasts expressing v-Src. aPKC activity was inhibited either by addition of a membrane-permeable pseudosubstrate, by expression of a dominant-negative aPKC, or by RNAi-mediated knockdown of specific aPKC isoforms. aPKC activity contributes to morphological transformation and stress fiber disruption, and is required for migration of Src-transformed cells and for their ability to polarize at the edge of a monolayer. The lambda isoform of aPKC is specifically required for invasion through extracellular matrix in Boyden chamber assays and for degradation of the extracellular matrix in in situ zymography assays. Tyrosine phosphorylation of aPKClambda is required for its ability to promote cell invasion. The defect in invasion upon aPKC inhibition appears to result from a defect in the assembly and/or function of podosomes, invasive adhesions on the ventral surface of the cell that are sites of protease secretion. aPKC was also found to localize to podosomes of v-Src transformed cells, suggesting a direct role for aPKC in podosome assembly and/or function. We conclude that basal or elevated aPKC activity is required for the ability of Src-transformed cells to degrade and invade the extracellular matrix. Copyright 2009 Wiley-Liss, Inc.

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.

Receptor protein tyrosine phosphatase alpha activates Src-family kinases and controls integrin-mediated responses in fibroblasts

DEFF Research Database (Denmark)

Su, J; Muranjan, M; Sap, J

1999-01-01

of tyrosine kinases, the activity of which is tightly controlled by inhibitory phosphorylation of a carboxyterminal tyrosine residue (Tyr527 in chicken c-Src); this phosphorylation induces the kinases to form an inactive conformation. Whereas the identity of such inhibitory Tyr527 kinases has been well...... established, no corresponding phosphatases have been identified that, under physiological conditions, function as positive regulators of c-Src and Fyn in fibroblasts. RESULTS: Receptor protein tyrosine phosphatase alpha (RPTPalpha) was inactivated by homologous recombination. Fibroblasts derived from...... these RPTPalpha-/- mice had impaired tyrosine kinase activity of both c-Src and Fyn, and this was accompanied by a concomitant increase in c-Src Tyr527 phosphorylation. RPTPalpha-/- fibroblasts also showed a reduction in the rate of spreading on fibronectin substrates, a trait that is a phenocopy of the effect...

Estrogen Receptor Folding Modulates cSrc Kinase SH2 Interaction via a Helical Binding Mode

NARCIS (Netherlands)

Nieto, Lidia; Tharun, Inga M; Balk, Mark; Wienk, Hans; Boelens, Rolf; Ottmann, Christian; Milroy, Lech-Gustav; Brunsveld, Luc

2015-01-01

The estrogen receptors (ERs) feature, next to their transcriptional role, important nongenomic signaling actions, with emerging clinical relevance. The Src Homology 2 (SH2) domain mediated interaction between cSrc kinase and ER plays a key role in this; however the molecular determinants of this

Estrogen receptor folding modulates cSrc kinase SH2 interaction via a helical binding mode

NARCIS (Netherlands)

Nieto, L.; Tharun, I.M.; Balk, M.; Wienk, H.; Boelens, R.; Ottmann, C.; Milroy, L.-G.; Brunsveld, L.

2015-01-01

The estrogen receptors (ERs) feature, next to their transcriptional role, important nongenomic signaling actions, with emerging clinical relevance. The Src Homology 2 (SH2) domain mediated interaction between cSrc kinase and ER plays a key role in this; however the molecular determinants of this

The Role of Src in Mammary Epithelial Tumorigenesis

National Research Council Canada - National Science Library

Kusdra, Leonard

2007-01-01

...') similar to the physiological lobular-aveoli structures found in the mammary tissue. Additionally, more invasive carcinoma cells (MDA-MB-231 cells) whereby Src signaling was pharmacologically or genetically inhibited were unable to form actin-rich invasive structures in 3D-rBM culture.

Report of the SRC working party on databases and database management systems

International Nuclear Information System (INIS)

Crennell, K.M.

1980-10-01

An SRC working party, set up to consider the subject of support for databases within the SRC, were asked to identify interested individuals and user communities, establish which features of database management systems they felt were desirable, arrange demonstrations of possible systems and then make recommendations for systems, funding and likely manpower requirements. This report describes the activities and lists the recommendations of the working party and contains a list of databses maintained or proposed by those who replied to a questionnaire. (author)

Complexes of γ-tubulin with nonreceptor protein tyrosine kinases Src and Fyn in differentiating P19 embryonal carcinoma cells

International Nuclear Information System (INIS)

Kukharskyy, Vitaliy; Sulimenko, Vadym; Macurek, Libor; Sulimenko, Tetyana; Draberova, Eduarda; Draber, Pavel

2004-01-01

Nonreceptor protein tyrosine kinases of the Src family have been shown to play an important role in signal transduction as well as in regulation of microtubule protein interactions. Here we show that γ-tubulin (γ-Tb) in P19 embryonal carcinoma cells undergoing neuronal differentiation is phosphorylated and forms complexes with protein tyrosine kinases of the Src family, Src and Fyn. Elevated expression of both kinases during differentiation corresponded with increased level of proteins phosphorylated on tyrosine. Immunoprecipitation experiments with antibodies against Src, Fyn, γ-tubulin, and with anti-phosphotyrosine antibody revealed that γ-tubulin appeared in complexes with these kinases. In vitro kinase assays showed tyrosine phosphorylation of proteins in γ-tubulin complexes isolated from differentiated cells. Pretreatment of cells with Src family selective tyrosine kinase inhibitor PP2 reduced the amount of phosphorylated γ-tubulin in the complexes. Binding experiments with recombinant SH2 and SH3 domains of Src and Fyn kinases revealed that protein complexes containing γ-tubulin bound to SH2 domains and that these interactions were of SH2-phosphotyrosine type. The combined data suggest that Src family kinases might have an important role in the regulation of γ-tubulin interaction with tubulin dimers or other proteins during neurogenesis

Ror2-Src signaling in metastasis of mouse melanoma cells is inhibited by NRAGE.

Science.gov (United States)

Lai, Shan-Shan; Xue, Bin; Yang, Yang; Zhao, Li; Chu, Chao-Shun; Hao, Jia-Yin; Wen, Chuan-Jun

2012-11-01

The receptor tyrosine kinase (RTK) Ror2 plays important roles in developmental morphogenesis and mediates the filopodia formation in Wnt5a-induced cell migration. However, the function of Ror2 in noncanonical Wnt signaling resulting in cancer metastasis is largely unknown. Here, we show that Ror2 expression is higher in the highly metastatic murine B16-BL6 melanoma cells than in the low metastatic variant B16 cells. Overexpression of Ror2 increases the metastasis ability of B16 cells, and knockdown of Ror2 reduces the migration ability of B16-BL6 cells. Furthermore, the inhibition of Src kinase activity is critical for the Ror2-mediated cell migration upon Wnt5a treatment. The C-terminus of Ror2, which is deleted in brachydactyly type B (BDB), is essential for the mutual interaction with the SH1 domain of Src. Intriguingly, the Neurotrophin receptor-interacting MAGE homologue (NRAGE), which, as we previously reported, can remodel the cellular skeleton and inhibit cell-cell adhesion and metastasis of melanoma and pancreatic cancer, sharply blocks the interaction between Src and Ror2 and inhibits Ror2-mediated B16 cell migration by decreasing the activity of Src and focal adhesion kinase (FAK). Our data show that Ror2 is a potential factor in the tumorigenesis and metastasis in a Src-dependent manner that is negatively regulated by NRAGE. Copyright © 2012. Published by Elsevier Inc.

v-Src oncogene product increases sphingosine kinase 1 expression through mRNA stabilization: alteration of AU-rich element-binding proteins.

Science.gov (United States)

Sobue, S; Murakami, M; Banno, Y; Ito, H; Kimura, A; Gao, S; Furuhata, A; Takagi, A; Kojima, T; Suzuki, M; Nozawa, Y; Murate, T

2008-10-09

Sphingosine kinase 1 (SPHK1) is overexpressed in solid tumors and leukemia. However, the mechanism of SPHK1 overexpression by oncogenes has not been defined. We found that v-Src-transformed NIH3T3 cells showed a high SPHK1 mRNA, SPHK1 protein and SPHK enzyme activity. siRNA of SPHK1 inhibited the growth of v-Src-NIH3T3, suggesting the involvement of SPHK1 in v-Src-induced oncogenesis. v-Src-NIH3T3 showed activations of protein kinase C-alpha, signal transducers and activators of transcription 3 and c-Jun NH(2)-terminal kinase. Their inhibition suppressed SPHK1 expression in v-Src-NIH3T3, whereas their overexpression increased SPHK1 mRNA in NIH3T3. Unexpectedly, the nuclear run-on assay and the promoter analysis using 5'-promoter region of mouse SPHK1 did not show any significant difference between mock- and v-Src-NIH3T3. Furthermore, the half-life of SPHK1 mRNA in mock-NIH3T3 was nearly 15 min, whereas that of v-Src-NIH3T3 was much longer. Examination of two AU-rich region-binding proteins, AUF1 and HuR, that regulate mRNA decay reciprocally, showed decreased total AUF1 protein associated with increased tyrosine-phosphorylated form and increased serine-phosphorylated HuR protein in v-Src-NIH3T3. Modulation of AUF1 and HuR by their overexpression or siRNA revealed that SPHK1 mRNA in v-Src- and mock-NIH3T3 was regulated reciprocally by these factors. Our results showed, for the first time, a novel mechanism of v-Src-induced SPHK1 overexpression.

Anomalous gauge theories revisited

International Nuclear Information System (INIS)

Matsui, Kosuke; Suzuki, Hiroshi

2005-01-01

A possible formulation of chiral gauge theories with an anomalous fermion content is re-examined in light of the lattice framework based on the Ginsparg-Wilson relation. It is shown that the fermion sector of a wide class of anomalous non-abelian theories cannot consistently be formulated within this lattice framework. In particular, in 4 dimension, all anomalous non-abelian theories are included in this class. Anomalous abelian chiral gauge theories cannot be formulated with compact U(1) link variables, while a non-compact formulation is possible at least for the vacuum sector in the space of lattice gauge fields. Our conclusion is not applied to effective low-energy theories with an anomalous fermion content which are obtained from an underlying anomaly-free theory by sending the mass of some of fermions to infinity. For theories with an anomalous fermion content in which the anomaly is cancelled by the Green-Schwarz mechanism, a possibility of a consistent lattice formulation is not clear. (author)

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

Science.gov (United States)

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

2017-05-05

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

Src is activated by the nuclear receptor peroxisome proliferator-activated receptor β/δ in ultraviolet radiation-induced skin cancer.

Science.gov (United States)

Montagner, Alexandra; Delgado, Maria B; Tallichet-Blanc, Corinne; Chan, Jeremy S K; Sng, Ming K; Mottaz, Hélén; Degueurce, Gwendoline; Lippi, Yannick; Moret, Catherine; Baruchet, Michael; Antsiferova, Maria; Werner, Sabine; Hohl, Daniel; Saati, Talal Al; Farmer, Pierre J; Tan, Nguan S; Michalik, Liliane; Wahli, Walter

2014-01-01

Although non-melanoma skin cancer (NMSC) is the most common human cancer and its incidence continues to rise worldwide, the mechanisms underlying its development remain incompletely understood. Here, we unveil a cascade of events involving peroxisome proliferator-activated receptor (PPAR) β/δ and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPARβ/δ activity, which directly stimulated Src expression, increased Src kinase activity and enhanced the EGFR/Erk1/2 signalling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression. Consistent with these observations, PPARβ/δ-null mice developed fewer and smaller skin tumours, and a PPARβ/δ antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPARβ/δ positively correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma (SCC), and critically, linear models applied to several human epithelial cancers revealed an interaction between PPARβ/δ and SRC and TGFβ1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARβ/δ modulators to attenuate the development of several epithelial cancers.

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

Science.gov (United States)

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

1996-10-10

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

Sewage sludge and wastewater fertilisation of Short Rotation Coppice (SRC) for increased bioenergy production - Biological and economic potential

International Nuclear Information System (INIS)

Dimitriou, I.; Rosenqvist, H.

2011-01-01

Application of municipal residues, e.g. wastewater or sewage sludge, to Short Rotation Coppice (SRC) is among the most attractive methods for attaining environmental and energy goals set for Europe. At current woodchip prices in Sweden, the gross margin for SRC cultivation is positive only if biomass production is >9 t DM/ha yr. The gross profit margin increases (by 39 and 199 EUR/GJ, respectively) if sewage sludge and wastewater are applied to SRC. Application of residues to SRC has proved to be an acceptable alternative treatment method, and the farmer's profit can be markedly increased if compensation is paid for waste treatment. If all available sludge and wastewater were applied to SRC plantations, they could be grown on large agricultural areas in Europe, and c. 6000 PJ of renewable energy could be produced annually. However, a more economical landuse strategy, e.g. the use of more P-rich residues, appears more rational, and is biologically justifiable. (author)

Sewage sludge and wastewater fertilisation of Short Rotation Coppice (SRC) for increased bioenergy production - Biological and economic potential

Energy Technology Data Exchange (ETDEWEB)

Dimitriou, I. [Department of Crop Production Ecology, Swedish University of Agricultural Sciences, P.O. Box 7043, SE 750 07 Uppsala (Sweden); Rosenqvist, H. [Department of Agriculture-Farming Systems, Technology and Product Quality, Swedish University of Agricultural Sciences, P.O. Box 17, SE-261 21 Billeberga (Sweden)

2011-02-15

Application of municipal residues, e.g. wastewater or sewage sludge, to Short Rotation Coppice (SRC) is among the most attractive methods for attaining environmental and energy goals set for Europe. At current woodchip prices in Sweden, the gross margin for SRC cultivation is positive only if biomass production is >9 t DM/ha yr. The gross profit margin increases (by 39 and 199 EUR/GJ, respectively) if sewage sludge and wastewater are applied to SRC. Application of residues to SRC has proved to be an acceptable alternative treatment method, and the farmer's profit can be markedly increased if compensation is paid for waste treatment. If all available sludge and wastewater were applied to SRC plantations, they could be grown on large agricultural areas in Europe, and c. 6000 PJ of renewable energy could be produced annually. However, a more economical landuse strategy, e.g. the use of more P-rich residues, appears more rational, and is biologically justifiable. (author)

Tyrosine phosphorylation of LRP6 by Src and Fer inhibits Wnt/β-catenin signalling

Science.gov (United States)

Chen, Qing; Su, Yi; Wesslowski, Janine; Hagemann, Anja I; Ramialison, Mirana; Wittbrodt, Joachim; Scholpp, Steffen; Davidson, Gary

2014-01-01

Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) function as transmembrane receptors to transduce Wnt signals. A key mechanism for signalling is Wnt-induced serine/threonine phosphorylation at conserved PPPSPxS motifs in the LRP6 cytoplasmic domain, which promotes pathway activation. Conserved tyrosine residues are positioned close to all PPPSPxS motifs, which suggests they have a functional significance. Using a cell culture-based cDNA expression screen, we identified the non-receptor tyrosine kinases Src and Fer as novel LRP6 modifiers. Both Src and Fer associate with LRP6 and phosphorylate LRP6 directly. In contrast to the known PPPSPxS Ser/Thr kinases, tyrosine phosphorylation by Src and Fer negatively regulates LRP6-Wnt signalling. Epistatically, they function upstream of β-catenin to inhibit signalling and in agreement with a negative role in regulating LRP6, MEF cells lacking these kinases show enhanced Wnt signalling. Wnt3a treatment of cells enhances tyrosine phosphorylation of endogenous LRP6 and, mechanistically, Src reduces cell surface LRP6 levels and disrupts LRP6 signalosome formation. Interestingly, CK1γ inhibits Fer-induced LRP6 phosphorylation, suggesting a mechanism whereby CK1γ acts to de-represses inhibitory LRP6 tyrosine phosphorylation. We propose that LRP6 tyrosine phosphorylation by Src and Fer serves a negative regulatory function to prevent over-activation of Wnt signalling at the level of the Wnt receptor, LRP6. Subject Categories Membrane & Intracellular Transport; Post-translational Modifications, Proteolysis & Proteomics PMID:25391905

v-src induction of the TIS10/PGS2 prostaglandin synthase gene is mediated by an ATF/CRE transcription response element.

Science.gov (United States)

Xie, W; Fletcher, B S; Andersen, R D; Herschman, H R

1994-10-01

We recently reported the cloning of a mitogen-inducible prostaglandin synthase gene, TIS10/PGS2. In addition to growth factors and tumor promoters, the v-src oncogene induces TIS10/PGS2 expression in 3T3 cells. Deletion analysis, using luciferase reporters, identifies a region between -80 and -40 nucleotides 5' of the TIS10/PGS2 transcription start site that mediates pp60v-src induction in 3T3 cells. This region contains the sequence CGTCACGTG, which includes overlapping ATF/CRE (CGTCA) and E-box (CACGTG) sequences. Gel shift-oligonucleotide competition experiments with nuclear extracts from cells stably transfected with a temperature-sensitive v-src gene demonstrate that the CGTCACGTG sequence can bind proteins at both the ATF/CRE and E-box sequences. Dominant-negative CREB and Myc proteins that bind DNA, but do not transactivate, block v-src induction of a luciferase reporter driven by the first 80 nucleotides of the TIS10/PGS2 promoter. Mutational analysis distinguishes which TIS10/PGS2 cis-acting element mediates pp60v-src induction. E-box mutation has no effect on the fold induction in response to pp60v-src. In contrast, ATF/CRE mutation attenuates the pp60v-src response. Antibody supershift and methylation interference experiments demonstrate that CREB and at least one other ATF transcription factor in these extracts bind to the TIS10/PGS2 ATF/CRE element. Expression of a dominant-negative ras gene also blocks TIS10/PGS2 induction by v-src. Our data suggest that Ras mediates pp60v-src activation of an ATF transcription factor, leading to induced TIS10/PGS2 expression via the ATF/CRE element of the TIS10/PGS2 promoter. This is the first description of v-src activation of gene expression via an ATF/CRE element.

Isthmin is a novel vascular permeability inducer that functions through cell-surface GRP78-mediated Src activation.

Science.gov (United States)

Venugopal, Shruthi; Chen, Mo; Liao, Wupeng; Er, Shi Yin; Wong, Wai-Shiu Fred; Ge, Ruowen

2015-07-01

Isthmin (ISM) is a recently identified 60 kDa secreted angiogenesis inhibitor. Two cell-surface receptors for ISM have been defined, the high-affinity glucose-regulated protein 78 kDa (GRP78) and the low-affinity αvβ5 integrin. As αvβ5 integrin plays an important role in pulmonary vascular permeability (VP) and ISM is highly expressed in mouse lung, we sought to clarify the role of ISM in VP. Recombinant ISM (rISM) dose-dependently enhances endothelial monolayer permeability in vitro and local dermal VP when administered intradermally in mice. Systemic rISM administration through intravenous injection leads to profound lung vascular hyperpermeability but not in other organs. Mechanistic investigations using molecular, biochemical approaches and specific chemical inhibitors revealed that ISM-GRP78 interaction triggers a direct interaction between GRP78 and Src, leading to Src activation and subsequent phosphorylation of adherens junction proteins and loss of junctional proteins from inter-endothelial junctions, resulting in enhanced VP. Dynamic studies of Src activation, VP and apoptosis revealed that ISM induces VP directly via Src activation while apoptosis contributes indirectly only after prolonged treatment. Furthermore, ISM is significantly up-regulated in lipopolysaccharide (LPS)-treated mouse lung. Blocking cell-surface GRP78 by systemic infusion of anti-GRP78 antibody significantly attenuates pulmonary vascular hyperpermeability in LPS-induced acute lung injury (ALI) in mice. ISM is a novel VP inducer that functions through cell-surface GRP78-mediated Src activation as well as induction of apoptosis. It induces a direct GRP78-Src interaction, leading to cytoplasmic Src activation. ISM contributes to pulmonary vascular hyperpermeability of LPS-induced ALI in mice. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Diffraction anomalous fine structure using X-ray anomalous dispersion

International Nuclear Information System (INIS)

Soejima, Yuji; Kuwajima, Shuichiro

1998-01-01

A use of X-ray anomalous dispersion effects for structure investigation has recently been developed by using synchrotron radiation. One of the interesting method is the observation of anomalous fine structure which arise on diffraction intensity in energy region of incident X-ray at and higher than absorption edge. The phenomenon is so called Diffraction Anomalous Fine Structure (DAFS). DAFS originates in the same physical process an that of EXAFS: namely photoelectric effect at the corresponding atom and the interaction of photoelectron waves between the atom and neighboring atoms. In contrast with EXAFS, the method is available for only the crystalline materials, but shows effective advantages of the structure investigations by a use of diffraction: one is the site selectivity and the other is space selectivity. In the present study, demonstrations of a use of X-ray anomalous dispersion effect for the superstructure determination will be given for the case of PbZrO 3 , then recent trial investigations of DAFS in particular on the superlattice reflections will be introduced. In addition, we discuss about Forbidden Reflection near Edge Diffraction (FRED) which is more recently investigated as a new method of the structure analysis. (author)

Src kinases regulate de novo actin polymerization during exocytosis in neuroendocrine chromaffin cells.

Directory of Open Access Journals (Sweden)

María José Olivares

Full Text Available The cortical actin network is dynamically rearranged during secretory processes. Nevertheless, it is unclear how de novo actin polymerization and the disruption of the preexisting actin network control transmitter release. Here we show that in bovine adrenal chromaffin cells, both formation of new actin filaments and disruption of the preexisting cortical actin network are induced by Ca2+ concentrations that trigger exocytosis. These two processes appear to regulate different stages of exocytosis; whereas the inhibition of actin polymerization with the N-WASP inhibitor wiskostatin restricts fusion pore expansion, thus limiting the release of transmitters, the disruption of the cortical actin network with cytochalasin D increases the amount of transmitter released per event. Further, the Src kinase inhibitor PP2, and cSrc SH2 and SH3 domains also suppress Ca2+-dependent actin polymerization, and slow down fusion pore expansion without disturbing the cortical F-actin organization. Finally, the isolated SH3 domain of c-Src prevents both the disruption of the actin network and the increase in the quantal release induced by cytochalasin D. These findings support a model where a rise in the cytosolic Ca2+ triggers actin polymerization through a mechanism that involves Src kinases. The newly formed actin filaments would speed up the expansion of the initial fusion pore, whereas the preexisting actin network might control a different step of the exocytosis process.

Melatonin regulates CRE-dependent gene transcription underlying osteoblast proliferation by activating Src and PKA in parallel.

Science.gov (United States)

Tao, Lin; Zhu, Yue

2018-01-01

Several studies have indicated a relationship between melatonin and idiopathic scoliosis, including our previous work which demonstrated that melatonin can inhibit osteoblast proliferation; however, the mechanism remains unclear. Here, we utilized a MTT assay to show that melatonin significantly reduces osteoblast proliferation in a concentration-and time-dependent manner. Through a combination of techniques, including real-time PCR, MTT assays, immunofluorescence, and luciferase assays, we confirmed that melatonin-induced changes in phosphorylated cAMP response element-binding protein (CREB) reduced transcriptional activity in a melatonin receptor-dependent manner. Surprisingly, treatment of osteoblasts with the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor PD98059 up-regulated other cascades upstream of CREB. We next treated cells with PKA and Src inhibitors and observed that melatonin can also activate the protein kinase A (PKA) and Src pathways. To examine whether Src is upstream from the cAMP-PKA pathway, we measured cAMP levels in response to melatonin with and without a Src inhibitor (PP2) and found that PP2 had no additional effect. Therefore, the transcription-dependent mechanisms involved in CREB phosphorylation, along with melatonin, activated Src via a parallel signaling pathway that was separate from that of PKA. Finally, we transfected osteoblasts with lentiviral CREB short hairpin (sh) RNAs and found a decrease in the expression of proliferating cell nuclear antigen (PCNA) and osteoblast proliferation. These results suggest that CREB and PCNA are downstream targets of melatonin signaling, and that the down-regulation of CREB, which is regulated via PKA and Src pathways, contributes to the melatonin-induced inhibition of osteoblast proliferation.

A Discovery Strategy for Selective Inhibitors of c-Src in Complex with the Focal Adhesion Kinase SH3/SH2-binding Region.

Science.gov (United States)

Moroco, Jamie A; Baumgartner, Matthew P; Rust, Heather L; Choi, Hwan Geun; Hur, Wooyoung; Gray, Nathanael S; Camacho, Carlos J; Smithgall, Thomas E

2015-08-01

The c-Src tyrosine kinase co-operates with the focal adhesion kinase to regulate cell adhesion and motility. Focal adhesion kinase engages the regulatory SH3 and SH2 domains of c-Src, resulting in localized kinase activation that contributes to tumor cell metastasis. Using assay conditions where c-Src kinase activity required binding to a tyrosine phosphopeptide based on the focal adhesion kinase SH3-SH2 docking sequence, we screened a kinase-biased library for selective inhibitors of the Src/focal adhesion kinase peptide complex versus c-Src alone. This approach identified an aminopyrimidinyl carbamate compound, WH-4-124-2, with nanomolar inhibitory potency and fivefold selectivity for c-Src when bound to the phospho-focal adhesion kinase peptide. Molecular docking studies indicate that WH-4-124-2 may preferentially inhibit the 'DFG-out' conformation of the kinase active site. These findings suggest that interaction of c-Src with focal adhesion kinase induces a unique kinase domain conformation amenable to selective inhibition. © 2014 John Wiley & Sons A/S.

Numerical simulation of the anomalous transport at the plasma-edge

International Nuclear Information System (INIS)

Pohn, E.

2001-03-01

In addition to the classical transport which is caused by Coloumb-collisions two further transport mechanisms take place in an inhomogeneous magnetically confined thermonuclear fusion-plasma, the neoclassical and the anomalous transport. The anomalous transport is caused by collective motion of the plasma-particles respectively turbulence and essentially affects the energy-confinement-time of the plasma. The energy-confinement-time in turn constitutes an important criterion with respect to the feasibility of using nuclear fusion for energy production. The anomalous transport is theoretically not yet well understood. By means of numerical simulations of the anomalous transport in the plasma edge, it is the intention of this work to contribute to the understanding of this transport mechanism. The Vlasov-Poisson-system constitutes the starting point for all performed simulations. This system consists of kinetic equations, which model for each particle-species the motion of the particles composing the plasma in six-dimensional phase-space. A coupling of these kinetic equations occurs due to the Poisson-equation, resulting in a nonlinear system of differential equations. The time evolution of this system was calculated numerically. On the one hand, simulations were performed where the whole velocity-space was retained. This fully-kinetic model was applied for the spatially one- as well as two-dimensional case. In the one-dimensional case only the radial direction of the plasma-edge was modeled, i.e. the direction along which the plasma joins to the vacuum. When performing the spatially two-dimensional simulations, in addition the poloidal direction has been regarded. A second set of simulations was performed using a gyro-kinetic model. In this model only the velocity-component parallel to the magnetic field vector is retained. The components perpendicular to the magnetic field vector, which are responsible for the gyration of particles, are omitted from phase-space but

Report on evaluation for SRC-2 coal liquefaction project; SRC-II sekitan ekika project hyoka sagyo hokokusho

Energy Technology Data Exchange (ETDEWEB)

NONE

1979-10-01

Among the EDS, H-Coal and SRC-2 lined up in the coal liquefaction project of the U.S., the SRC is aimed at producing 6,000 t/day as a module for a 30,000 t/day commercial plant. They expect Ash contents (iron, sulfur, etc.) in coal without basically using catalysts. The products are applicable to fuels for electricity and gas for the moment. In the element technology, there are some problems in manufacturing hydrogen by gasification of residuals as well as in slurry systems, reaction towers, etc.. In the 30,000 ton commercial plant, the coal-liquefied oil costs $19.89/bbl (price as of 1978) assuming coal costs $29.47; therefore, the feasibility is strong as a substitute for petroleum. Japan's share for the required funds will be 86.8 billion yen (if 250 yen per dollar). Since the kinds of coal are conceivably increased in number through the improvement of the process, the Pacific rim countries and these which lie on the Indian Ocean are assumed to be the major coal producing countries for Japan. The stability in storage of coal-liquefied oil is experimentally excellent, as is the compatibility with petroleum products for example. Great results can be expected in the technical know-how and the spread of element technology for Japan. (NEDO)

Report on evaluation for SRC-2 coal liquefaction project; SRC-II sekitan ekika project hyoka sagyo hokokusho

Energy Technology Data Exchange (ETDEWEB)

NONE

1979-10-01

Among the EDS, H-Coal and SRC-2 lined up in the coal liquefaction project of the U.S., the SRC is aimed at producing 6,000 t/day as a module for a 30,000 t/day commercial plant. They expect Ash contents (iron, sulfur, etc.) in coal without basically using catalysts. The products are applicable to fuels for electricity and gas for the moment. In the element technology, there are some problems in manufacturing hydrogen by gasification of residuals as well as in slurry systems, reaction towers, etc.. In the 30,000 ton commercial plant, the coal-liquefied oil costs $19.89/bbl (price as of 1978) assuming coal costs $29.47; therefore, the feasibility is strong as a substitute for petroleum. Japan's share for the required funds will be 86.8 billion yen (if 250 yen per dollar). Since the kinds of coal are conceivably increased in number through the improvement of the process, the Pacific rim countries and these which lie on the Indian Ocean are assumed to be the major coal producing countries for Japan. The stability in storage of coal-liquefied oil is experimentally excellent, as is the compatibility with petroleum products for example. Great results can be expected in the technical know-how and the spread of element technology for Japan. (NEDO)

Harvester development for new high yielding SRC crops and markets

Energy Technology Data Exchange (ETDEWEB)

Paulson, Mark

2005-07-01

This report describes the development of harvesting equipment for short rotation cultivation (SRC) crops produced in the UK that can produce fuel to a required specification in a single pass at a cost that is profitable for the grower while minimising the cost of the product. Details are given of the manufacture and installation of new components for large crop harvesting, and production of fuel suitable for co-firing in a coal combustion system using pulverised fuel and fuel suitable for gasification. The development of the drive chain to cope with the higher yielding crops, field tests on SRC crops, and determination of the most economic harvesting system are discussed along with the remanufacture of the chipping drum, and production of market chip samples. Harvesting guidance and an economic analysis of harvesting systems are presented.

Interplay of Matrix Stiffness and c-SRC in Hepatic Fibrosis

DEFF Research Database (Denmark)

Görtzen, Jan; Schierwagen, Robert; Bierwolf, Jeanette

2015-01-01

. This study investigated the interaction of c-SRC and RhoA under different matrix stiffness conditions. METHODS: Liver fibrosis was induced in rats using bile duct ligation (BDL), thioacetamide (TAA) or carbon tetrachloride (CCl4) models. mRNA levels of albumin, PDGF-R, RHOA, COL1A1, and αSMA were analyzed......INTRODUCTION: In liver fibrosis activation of hepatic stellate cells (HSC) comprises phenotypical change into profibrotic and myofibroplastic cells with increased contraction and secretion of extracellular matrix (ECM) proteins. The small GTPase RhoA orchestrates cytoskeleton formation, migration......, and mobility via non-receptor tyrosine-protein kinase c-SRC (cellular sarcoma) in different cells. Furthermore, RhoA and its downstream effector Rho-kinase also play a crucial role in hepatic stellate cells and hepatic fibrogenesis. Matrix stiffness promotes HSC activation via cytoskeleton modulation...

Harvester development for new high yielding SRC crops and markets

International Nuclear Information System (INIS)

Paulson, Mark

2005-01-01

This report describes the development of harvesting equipment for short rotation cultivation (SRC) crops produced in the UK that can produce fuel to a required specification in a single pass at a cost that is profitable for the grower while minimising the cost of the product. Details are given of the manufacture and installation of new components for large crop harvesting, and production of fuel suitable for co-firing in a coal combustion system using pulverised fuel and fuel suitable for gasification. The development of the drive chain to cope with the higher yielding crops, field tests on SRC crops, and determination of the most economic harvesting system are discussed along with the remanufacture of the chipping drum, and production of market chip samples. Harvesting guidance and an economic analysis of harvesting systems are presented

1-o-acetylbritannilactone (ABL) inhibits angiogenesis and lung cancer cell growth through regulating VEGF-Src-FAK signaling

Energy Technology Data Exchange (ETDEWEB)

Zhengfu, He; Hu, Zhang; Huiwen, Miao; Zhijun, Li [Department of Thoracic Surgery, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou (China); Jiaojie, Zhou [Zhejiang University School of Medicine, Hangzhou (China); Xiaoyi, Yan, E-mail: xiaoyiyan163@163.com [Zhejiang University School of Medicine, Hangzhou (China); Xiujun, Cai, E-mail: xiujuncaomaj@163.com [Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou (China)

2015-08-21

The search for safe, effective and affordable therapeutics against non-small cell lung cancer (NSCLC) and other lung cancers is important. Here we explored the potential effect of 1-o-acetylbritannilactone (ABL), a novel extract from Inula britannica-F, on angiogenesis and lung cancer cell growth. We demonstrated that ABL dose-dependently inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, and capillary structure formation of cultured human umbilical vascular endothelial cells (HUVECs). In vivo, ABL administration suppressed VEGF-induced new vasculature formation in Matrigel plugs. For the mechanism investigations, we found that ABL largely inhibited VEGF-mediated activation of Src kinase and focal adhesion kinase (FAK) in HUVECs. Furthermore, treatment of A549 NSCLC cells with ABL resulted in cell growth inhibition and Src-FAK in-activation. Significantly, administration of a single dose of ABL (12 mg/kg/day) remarkably suppressed growth of A549 xenografts in nude mice. In vivo microvessels formation and Src activation were also significantly inhibited in ABL-treated xenograft tumors. Taken together, our findings suggest that ABL suppresses angiogenesis and lung cancer cell growth possibly via regulating the VEGFR-Src-FAK signaling. - Highlights: • 1-o-acetylbritannilactone (ABL) inhibits VEGF-induced angiogenesis in vivo. • ABL inhibits VEGF-induced HUVEC migration, proliferation, capillary tube formation. • ABL inhibits VEGF-mediated activation of Src and FAK in HUVECs. • ABL inhibits growth and Src-FAK activation in A549 cells. • ABL administration inhibits A549 tumor angiogenesis and growth in nude mice.

v-src Induction of the TIS10/PGS2 prostaglandin synthase gene is mediated by an ATF/CRE transcription response element

Energy Technology Data Exchange (ETDEWEB)

Xie, W.; Fletcher, B.S.; Andersen, R.D.; Herschman, H.R. [Univ. of California, Los Angeles, CA (United States)

1994-10-01

The authors recently reported the cloning of a mitogen-inducible prostaglandin synthase gene, TIS10/PGS2. In addition to growth factor and tumor promoters, the v-src oncogene induces TIS10/PGS2 expression in 3T3 cells. Deletion analysis, using luciferase reporters, identifies a region between -80 and -40 nucleotides 5{prime} of the TIS10/PGS2 transcription start site that mediates pp60{sup v-src} induction in 3T3 cells. This region contains the sequence CGTCACGTG, which includes overlapping ATF/CRE (CGTCA) and E-box (CACGTG) sequences. Gel shift-oligonucleotide competition experiments with nuclear extracts from cells stably transfected with a temperature-sensitive v-src gene demonstrate that the CGTCACGTG sequence can bind proteins at both the AFT/CRE and E-box sequences. Dominant-negative CREB and Myc proteins that bind DNA, but do not transactivate, block v-src induction of a luciferase reporter driven by the first 80 nucleotides of the TIS10/PGS2 promoter. Mutational analysis distinguishes which TIS10/PGS2 cis-acting element mediates pp60{sup v-src} induction. E-box mutation has no effect on the fold induction in response to pp60{sup v-src}. In contrast, ATF/CRE mutation attenuates the pp{sup v-src} response. Antibody supershift and methylation interference experiments demonstrate that CREB and at least one other ATF transcription factor in these extracts bind to the TIS10/PGS2 ATF/CRE element. Expression of a dominant-negative ras gene also blocks TIS10/PGS2 induction by v-src. The data suggest that Ras mediates pp60{sup v-src} activation of an ATF transcription factor, leading to induced TIS10/PGS2 expression via the ATF/CRE element of the TIS10/PGS2 promoter. This is the first description of v-src activation of gene expression via an ATF/CRE element. 64 refs., 8 figs.

Band 3 tyrosine kinase in avian erythrocyte plasma membrane is immunologically related to pp60c-src

International Nuclear Information System (INIS)

Hillsgrove, D.; Shores, C.G.; Parker, J.C.; Maness, P.F.

1987-01-01

The authors have identified in the plasma membrane of the chicken erythrocyte a 60-kDa tyrosine-specific protein kinase immunologically related to the transforming protein pp60 v-src of Rous sarcoma virus. The erythrocyte protein kinase phosphorylated heavy chains of tumor-bearing rabbit (TBR) antibodies reactive with pp60 c-src at tyrosine in immune complex protein kinase assays. The kinase was identified as a 60-kDa protein by [ 35 S]methionine labeling of erythrocytes and by autophosphorylation in immune complexes. The kinase migrated on two-dimensional gel electrophoresis with an apparent pI and molecular mass similar to pp60 c-src . A plasma membrane-enriched fraction isolated from chicken red cells contained the majority of the kinase activity. Incubation of the plasma membrane fraction with [ 32 P]ATP resulted in tyrosine phosphorylation of the anion transport protein band 3. Band 3 phosphorylation was blocked by TBR antibodies, indicting that the kinase recognized by pp60 c-src antibodies was responsible for band 3 phosphorylation. These results demonstrate that the avian erythrocyte plasma membrane contains a tightly bound tyrosine-specific protein kinase identical or closely related to pp60 c-src and that this kinase is responsible for band 3 phosphorylation in vitro

The v-Src and c-Src tyrosine kinases immunoprecipitated from Rous sarcoma virus-transformed cells display different peptide substrate specificities

Czech Academy of Sciences Publication Activity Database

Vojtěchová, Martina; Tuháčková, Zdena; Hlaváček, Jan; Velek, Jiří; Sovová, Vlasta

2004-01-01

Roč. 421, č. 2 (2004), s. 277-282 ISSN 0003-9861 R&D Projects: GA ČR GV312/96/K205; GA ČR GA301/00/0269 Institutional research plan: CEZ:AV0Z4055905; CEZ:AV0Z1003909 Keywords : Src kinase, in vitro phosphorylation, peptide substrate specificity Subject RIV: CE - Biochemistry Impact factor: 2.657, year: 2004

Micro-Environmental Stress Induces Src-Dependent Activation of Invadopodia and Cell Migration in Ewing Sarcoma

Directory of Open Access Journals (Sweden)

Kelly M. Bailey

2016-08-01

Full Text Available Metastatic Ewing sarcoma has a very poor prognosis and therefore new investigations into the biologic drivers of metastatic progression are key to finding new therapeutic approaches. The tumor microenvironment is highly dynamic, leading to exposure of different regions of a growing solid tumor to changes in oxygen and nutrient availability. Tumor cells must adapt to such stress in order to survive and propagate. In the current study, we investigate how Ewing sarcoma cells respond to the stress of growth factor deprivation and hypoxia. Our findings reveal that serum deprivation leads to a reversible change in Ewing cell cytoskeletal phenotypes. Using an array of migration and invasion techniques, including gelatin matrix degradation invadopodia assays, we show that exposure of Ewing sarcoma cells to serum deprivation and hypoxia triggers enhanced migration, invadopodia formation, matrix degradation and invasion. Further, these functional changes are accompanied by and dependent on activation of Src kinase. Activation of Src, and the associated invasive cell phenotype, were blocked by exposing hypoxia and serum-deprived cells to the Src inhibitor dasatinib. These results indicate that Ewing sarcoma cells demonstrate significant plasticity in response to rapidly changing micro-environmental stresses that can result from rapid tumor growth and from necrosis-causing therapies. In response to these stresses, Ewing cells transition to a more migratory and invasive state and our data show that Src is an important mediator of this stress response. Our data support exploration of clinically available Src inhibitors as adjuvant agents for metastasis prevention in Ewing sarcoma.

76 FR 1458 - Public Meeting for the National Park Service Alaska Region's Subsistence Resource Commission (SRC...

Science.gov (United States)

2011-01-10

... Plan Update. c. Subsistence Uses of Horns, Antlers, Bones and Plants EA Update. 13. New Business. 14... guarantee that we will be able to do so. Wrangell-St. Elias National Park SRC Meeting Date and Location: The... if all business is completed. For Further Information on the Gates of the Arctic National Park SRC...

Alterations in c-Src/HER1 and estrogen receptor α signaling pathways in mammary gland and tumors of hexachlorobenzene-treated rats

International Nuclear Information System (INIS)

Peña, Delfina; Pontillo, Carolina; García, María Alejandra; Cocca, Claudia; Alvarez, Laura; Chiappini, Florencia; Bourguignon, Nadia; Frahm, Isabel; Bergoc, Rosa; Kleiman de Pisarev, Diana; Randi, Andrea

2012-01-01

Hexachlorobenzene (HCB) is an organochlorine pesticide that acts as an endocrine disruptor in humans and rodents. The development of breast cancer strongly depends on endocrine conditions modulated by environmental factors. We have demonstrated that HCB is a tumor co-carcinogen in rats and an inducer of proliferation in MCF-7 cells, in an estrogen receptor α (ERα)-dependent manner, and of migration in MDA-MB-231 breast cancer cell line. In the present study, we examined HCB effect on c-Src/human epidermal growth factor receptor (HER1) and ERα signaling pathways in mammary glands and in N-nitroso-N-methylurea (NMU)-induced mammary tumors in rats. Furthermore, we evaluated histopathological changes and serum hormone levels. Rats were separated into four groups: control, HCB (100 mg/kg b.w.), NMU (50 mg/kg b.w.) and NMU-HCB. Our data show that HCB increases c-Src and HER1 activation, c-Src/HER1 association, and Y699-STAT5b and ERK1/2 phosphorylation in mammary glands. HCB also enhances Y537-ERα phosphorylation and ERα/c-Src physical interaction. In tumors, HCB also induces c-Src and HER1 activation, c-Src/HER1 association, as well as T308-Akt and Y699-STAT5b phosphorylation. In addition, the pesticide increases ERα protein content and decreases p-Y537-ERα levels and ERα/c-Src association in tumors. HCB increases serum 17-beta estradiol and prolactin contents and decreases progesterone, FSH and LH levels in rats without tumors, while the opposite effect was observed in rats with tumors. Taken together, our results indicate that HCB induces an estrogenic effect in mammary gland, increasing c-Src/HER1 and ERα signaling pathways. HCB stimulates c-Src/HER1 pathway, but decreases ERα activity in tumors, appearing to shift them towards a higher malignancy phenotype.

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

Directory of Open Access Journals (Sweden)

Jamie A Moroco

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

HSP27 phosphorylation modulates TRAIL-induced activation of Src-Akt/ERK signaling through interaction with β-arrestin2.

Science.gov (United States)

Qi, Shimei; Xin, Yinqiang; Qi, Zhilin; Xu, Yimiao; Diao, Ying; Lan, Lei; Luo, Lan; Yin, Zhimin

2014-03-01

Heat shock protein 27 (HSP27) regulates critical cellular functions such as development, differentiation, cell growth and apoptosis. A variety of stimuli induce the phosphorylation of HSP27, which affects its cellular functions. However, most previous studies focused on the role of HSP27 protein itself in apoptosis, the particular role of its phosphorylation state in signaling transduction remains largely unclear. In the present study, we reported that HSP27 phosphorylation modulated TRAIL-triggered pro-survival signaling transduction. In HeLa cells, suppression of HSP27 phosphorylation by specific inhibitor KRIBB3 or MAPKAPK2 (MK2) knockdown and by overexpression of non-phosphorylatable HSP27(3A) mutant demonstrated that hindered HSP27 phosphorylation enhanced the TRAIL-induced apoptosis. In addition, reduced HSP27 phosphorylation by KRIBB3 treatment or MK2 knockdown attenuated the TRAIL-induced activation of Akt and ERK survival signaling through suppressing the phosphorylation of Src. By overexpression of HSP27(15A) or HSP27(78/82A) phosphorylation mutant, we further showed that phosphorylation of HSP27 at serine 78/82 residues was essential to TRAIL-triggered Src-Akt/ERK signaling transduction. Co-immunoprecipitation and confocal microscopy showed that HSP27 interacted with Src and scaffolding protein β-arrestin2 in response of TRAIL stimulation and suppression of HSP27 phosphorylation apparently disrupted the TRAIL-induced interaction of HSP27 and Src or interaction of HSP27 and β-arrestin2. We further demonstrated that β-arrestin2 mediated HSP27 action on TRAIL-induced Src activation, which was achieved by recruiting signaling complex of HSP27/β-arrestin2/Src in response to TRAIL. Taken together, our study revealed that HSP27 phosphorylation modulates TRAIL-triggered activation of Src-Akt/ERK pro-survival signaling via interacting with β-arrestin2 in HeLa cells. Copyright © 2013 Elsevier Inc. All rights reserved.

Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

Science.gov (United States)

Wei, Hongen; Malik, Mazhar; Sheikh, Ashfaq M.; Merz, George; Ted Brown, W.; Li, Xiaohong

2011-01-01

Recent studies suggest that one of the major pathways to the pathogenesis of autism is reduced cell migration. Focal adhesion kinase (FAK) has an important role in neural migration, dendritic morphological characteristics, axonal branching, and synapse formation. The FAK-Src complex, activated by upstream reelin and integrin β1, can initiate a cascade of phosphorylation events to trigger multiple intracellular pathways, including mitogen-activated protein kinase–extracellular signal–regulated kinase and phosphatidylinositol 3-kinase–Akt signaling. In this study, by using B lymphoblasts as a model, we tested whether integrin β1 and FAK-Src signaling are abnormally regulated in autism and whether abnormal FAK-Src signaling leads to defects in B-lymphoblast adhesion, migration, proliferation, and IgG production. To our knowledge, for the first time, we show that protein expression levels of both integrin β1 and FAK are significantly decreased in autistic lymphoblasts and that Src protein expression and the phosphorylation of an active site (Y416) are also significantly decreased. We also found that lymphoblasts from autistic subjects exhibit significantly decreased migration, increased adhesion properties, and an impaired capacity for IgG production. The overexpression of FAK in autistic lymphoblasts countered the adhesion and migration defects. In addition, we demonstrate that FAK mediates its effect through the activation of Src, phosphatidylinositol 3-kinase–Akt, and mitogen-activated protein kinase signaling cascades and that paxillin is also likely involved in the regulation of adhesion and migration in autistic lymphoblasts. PMID:21703394

Andrographolide downregulates the v-Src and Bcr-Abl oncoproteins and induces Hsp90 cleavage in the ROS-dependent suppression of cancer malignancy.

Science.gov (United States)

Liu, Sheng-Hung; Lin, Chao-Hsiung; Liang, Fong-Ping; Chen, Pei-Fen; Kuo, Cheng-Deng; Alam, Mohd Mujahid; Maiti, Barnali; Hung, Shih-Kai; Chi, Chin-Wen; Sun, Chung-Ming; Fu, Shu-Ling

2014-01-15

Andrographolide is a diterpenoid compound isolated from Andrographis paniculata that exhibits anticancer activity. We previously reported that andrographolide suppressed v-Src-mediated cellular transformation by promoting the degradation of Src. In the present study, we demonstrated the involvement of Hsp90 in the andrographolide-mediated inhibition of Src oncogenic activity. Using a proteomics approach, a cleavage fragment of Hsp90α was identified in andrographolide-treated cells. The concentration- and time-dependent induction of Hsp90 cleavage that accompanied the reduction in Src was validated in RK3E cells transformed with either v-Src or a human truncated c-Src variant and treated with andrographolide. In cancer cells, the induction of Hsp90 cleavage by andrographolide and its structural derivatives correlated well with decreased Src levels, the suppression of transformation, and the induction of apoptosis. Moreover, the andrographolide-induced Hsp90 cleavage, Src degradation, inhibition of transformation, and induction of apoptosis were abolished by a ROS inhibitor, N-acetyl-cysteine. Notably, Hsp90 cleavage, decreased levels of Bcr-Abl (another known Hsp90 client protein), and the induction of apoptosis were also observed in human K562 leukemia cells treated with andrographolide or its active derivatives. Together, we demonstrated a novel mechanism by which andrographolide suppressed cancer malignancy that involved inhibiting Hsp90 function and reducing the levels of Hsp90 client proteins. Our results broaden the molecular basis of andrographolide-mediated anticancer activity. Copyright © 2013 Elsevier Inc. All rights reserved.

Renewal-anomalous-heterogeneous files

International Nuclear Information System (INIS)

Flomenbom, Ophir

2010-01-01

Renewal-anomalous-heterogeneous files are solved. A simple file is made of Brownian hard spheres that diffuse stochastically in an effective 1D channel. Generally, Brownian files are heterogeneous: the spheres' diffusion coefficients are distributed and the initial spheres' density is non-uniform. In renewal-anomalous files, the distribution of waiting times for individual jumps is not exponential as in Brownian files, yet obeys: ψ α (t)∼t -1-α , 0 2 >, obeys, 2 >∼ 2 > nrml α , where 2 > nrml is the MSD in the corresponding Brownian file. This scaling is an outcome of an exact relation (derived here) connecting probability density functions of Brownian files and renewal-anomalous files. It is also shown that non-renewal-anomalous files are slower than the corresponding renewal ones.

The N-terminus of survivin is a mitochondrial-targeting sequence and Src regulator

Science.gov (United States)

Dunajová, Lucia; Cash, Emily; Markus, Robert; Rochette, Sophie; Townley, Amelia R.

2016-01-01

ABSTRACT Survivin (also known as BIRC5) is a cancer-associated protein that exists in several locations in the cell. Its cytoplasmic residence in interphase cells is governed by CRM1 (also known as XPO1)-mediated nuclear exportation, and its localisation during mitosis to the centromeres and midzone microtubules is that of a canonical chromosomal passenger protein. In addition to these well-established locations, survivin is also a mitochondrial protein, but how it gets there and its function therein is presently unclear. Here, we show that the first ten amino acids at the N-terminus of survivin are sufficient to target GFP to the mitochondria in vivo, and ectopic expression of this decapeptide decreases cell adhesion and accelerates proliferation. The data support a signalling mechanism in which this decapeptide regulates the tyrosine kinase Src, leading to reduced focal adhesion plaques and disruption of F-actin organisation. This strongly suggests that the N-terminus of survivin is a mitochondrial-targeting sequence that regulates Src, and that survivin acts in concert with Src to promote tumorigenesis. PMID:27246243

Fractional Diffusion Equations and Anomalous Diffusion

Science.gov (United States)

Evangelista, Luiz Roberto; Kaminski Lenzi, Ervin

2018-01-01

Preface; 1. Mathematical preliminaries; 2. A survey of the fractional calculus; 3. From normal to anomalous diffusion; 4. Fractional diffusion equations: elementary applications; 5. Fractional diffusion equations: surface effects; 6. Fractional nonlinear diffusion equation; 7. Anomalous diffusion: anisotropic case; 8. Fractional Schrödinger equations; 9. Anomalous diffusion and impedance spectroscopy; 10. The Poisson–Nernst–Planck anomalous (PNPA) models; References; Index.

Anomalous high-frequency wave activity flux preceding anomalous changes in the Northern polar jet

Science.gov (United States)

Nakamura, Mototaka; Kadota, Minoru; Yamane, Shozo

2010-05-01

Anomalous forcing by quasi-geostrophic (QG) waves has been reported as an important forcing factor in the Northern Annular Mode (NAM) in recent literatures. In order to shed a light on the dynamics of the NAM from a different angle, we have examined anomalous behavior of the winter jets in the upper troposphere and stratosphere by focusing our diagnosis on not the anomalous geopotential height (Z) itself, but on the anomalous change in the Z (dZ) between two successive months and preceding transient QG wave activity flux during the cold season. We calculated EOFs of dZ between two successive months at 150hPa for a 46-year period, from 1958 to 2003, using the monthly mean NCEP reanalysis data. We then formed anomaly composites of changes in Z and the zonal velocity (U), as well as the preceding and following wave activity flux, Z, U, and temperature at various heights, for both positive and negative phases of the first EOF. For the wave forcing fields, we adopted the diagnostic system for the three-dimensional QG transient wave activity flux in the zonally-varying three-dimensional mean flow developed by Plumb (1986) with a slight modification in its application to the data. Our choice of the Plumb86 is based on the fact that the winter mean flow in the Northern Hemisphere is characterized by noticeable zonal asymmetry, and has a symbiotic relationship with waves in the extra-tropics. The Plumb86 flux was calculated for high-frequency (period of 2 to 7 days) and low-frequency (period of 10 to 20 days) waves with the ultra-low-frequency (period of 30 days or longer) flow as the reference state for each time frame of the 6 hourly NCEP reanalysis data from 1958 to 2003. By replacing the mean flow with the ultra-low-frequency flow in the application of the Plumb86 formula, the flux fields were calculated as time series at 6 hour intervals. The time series of the wave activity flux was then averaged for each month. The patterns of composited anomalous dZ and dU clearly

1170-MW(t) HTGR-PS/C plant application study report: SRC-II process application

International Nuclear Information System (INIS)

Rao, R.; McMain, A.T. Jr.

1981-05-01

The solvent refined coal (SRC-II) process is an advanced process being developed by Gulf Mineral Resources Ltd. (a Gulf Oil Corporation subsidiary) to produce a clean, non-polluting liquid fuel from high-sulfur bituminous coals. The SRC-II commercial plant will process about 24,300 tonnes (26,800 tons) of feed coal per stream day, producing primarily fuel oil plus secondary fuel gases. This summary report describes the integration of a high-temperature gas-cooled reactor operating in a process steam/cogeneration mode (HTGR-PS/C) to provide the energy requirements for the SRC-II process. The HTGR-PS/C plant was developed by General Atomic Company (GA) specifically for industries which require energy in the form of both steam and electricity. General Atomic has developed an 1170-MW(t) HTGR-PS/C design which is particularly well suited to industrial applications and is expected to have excellent cost benefits over other sources of energy

Comprehensive analysis of interactions between the Src-associated protein in mitosis of 68 kDa and the human Src-homology 3 proteome.

Directory of Open Access Journals (Sweden)

Benedikt Asbach

Full Text Available The protein Sam68 is involved in many cellular processes such as cell-cycle regulation, RNA metabolism, or signal transduction. Sam68 comprises a central RNA-binding domain flanked by unstructured tails containing docking sites for signalling proteins including seven proline-rich sequences (denoted P0 to P6 as potential SH3-domain binding motifs. To comprehensively assess Sam68-SH3-interactions, we applied a phage-display screening of a library containing all approx. 300 human SH3 domains. Thereby we identified five new (from intersectin 2, the osteoclast stimulating factor OSF, nephrocystin, sorting nexin 9, and CIN85 and seven already known high-confidence Sam68-ligands (mainly from the Src-kinase family, as well as several lower-affinity binders. Interaction of the high-affinity Sam68-binders was confirmed in independent assays in vitro (phage-ELISA, GST-pull-down and in vivo (FACS-based FRET-analysis with CFP- and YFP-tagged proteins. Fine-mapping analyses with peptides established P0, P3, P4, and P5 as exclusive docking-sites for SH3 domains, which showed varying preferences for these motifs. Mutational analyses identified individual residues within the proline-rich motifs being crucial for the interactions. Based on these data, we generated a Sam68-mutant incapable of interacting with SH3 domains any more, as subsequently demonstrated by FRET-analyses. In conclusion, we present a thorough characterization of Sam68's interplay with the SH3 proteome. The observed interaction between Sam68 and OSF complements the known Sam68-Src and OSF-Src interactions. Thus, we propose, that Sam68 functions as a classical scaffold protein in this context, assembling components of an osteoclast-specific signalling pathway.

The role of Na,K-ATPase/Src-kinase signaling pathway in the vascular wall contaction

DEFF Research Database (Denmark)

Bouzinova, Elena

Aim: Na,K-ATPase is essential for maintaining the transmembrane ion gradient and might initiate various intracellular signaling. These signals possibly act through a modification of the local ion concentrations or via Src-kinase activation. It is known that inhibition of the α-2 isoform of Na......,K-ATPase by ouabain elevates blood pressure. Consequently, ouabain was shown to potentiate arterial contraction in vitro. In contrast, we have demonstrated that siRNA-induced down-regulation of the α-2 isoform Na,K-ATPase expression reduced arterial sensitivity to agonist stimulation and prevented the effect......) phosphorylation assay. Down-regulation of the α-2 isoform Na,K-ATPase prevented the inhibitory effect of Src inhibitors on arterial contraction. Conclusions: The pro-contractile action of ouabain-sensitive Na,K-ATPase inhibition is associated with Src-kinase inhibition suggesting the role of this signaling...

Mechanism of c-Src Synergy with the EGFR In Breast Cancer

National Research Council Canada - National Science Library

Tice, David

1999-01-01

... on tumorigenicity and growth of breast tumor cells. Furthermore, we have discovered a mechanism of c-Src synergy with the EGFR and located specific points at which the pathway can be interdicted...

The Interaction of Src Kinase with beta 3 Integrin Tails : A Potential Therapeutic Target in Thrombosis and Cancer

NARCIS (Netherlands)

Huveneers, Stephan; Danen, Erik H. J.

2010-01-01

Activation of Src family kinases is an important event downstream of integrin adhesion signaling in many cell types. A particularly intriguing connection between an integrin and a Src family kinase was first discovered in platelets, where the selective direct interaction of alpha IIb beta 3

On the quantum mechanics of consciousness, with application to anomalous phenomena

International Nuclear Information System (INIS)

Jahn, R.G.; Dunne, B.J.

1986-01-01

Theoretical explication of a growing body of empirical data on consciousness-related anomalous phenomena is unlikely to be achieved in terms of known physical processes. Rather, it will first be necessary to formulate the basic role of consciousness in the definition of reality before such anomalous experience can adequately be represented. This paper takes the position that reality is constituted only in the interaction of consciousness with its environment, and therefore that any scheme of conceptual organization developed to represent that reality must reflect the processes of consciousness as well as those of its environment. In this spirit, the concepts and formalisms of elementary quantum mechanics, as originally proposed to explain anomalous atomic-scale physical phenomena, are appropriated via metaphor to represent the general characteristics of consciousness interacting with any environment. More specifically, if consciousness is represented by a quantum mechanical wave function, and its environment by an appropriate potential profile, Schrodinger wave mechanics defines eigenfunctions and eigenvalues that can be associated with the cognitive and emotional experiences of that consciousness in that environment. To articulate this metaphor it is necessary to associate certain aspects of the formalism, such as the coordinate system, the quantum numbers, and even the metric itself, with various impressionistic descriptors of consciousness, such as its intensity, perspective, approach/avoidance attitude, balance between cognitive and emotional activity, and receptive/assertive disposition

Shear stress induces cell apoptosis via a c-Src-phospholipase D-mTOR signaling pathway in cultured podocytes

Energy Technology Data Exchange (ETDEWEB)

Huang, Chunfa, E-mail: chunfa.huang@case.edu [Louis Stokes Cleveland Veteran Affairs Medical Center, Case Western Reserve University (United States); Department of Medicine, Case Western Reserve University (United States); Rammelkamp Center for Research and Education, MetroHealth System Campus, Cleveland, OH 44106 (United States); Bruggeman, Leslie A. [Department of Medicine, Case Western Reserve University (United States); Rammelkamp Center for Research and Education, MetroHealth System Campus, Cleveland, OH 44106 (United States); Hydo, Lindsey M. [Louis Stokes Cleveland Veteran Affairs Medical Center, Case Western Reserve University (United States); Miller, R. Tyler [Louis Stokes Cleveland Veteran Affairs Medical Center, Case Western Reserve University (United States); Department of Medicine, Case Western Reserve University (United States); Rammelkamp Center for Research and Education, MetroHealth System Campus, Cleveland, OH 44106 (United States)

2012-06-10

The glomerular capillary wall, composed of endothelial cells, the glomerular basement membrane and the podocytes, is continually subjected to hemodynamic force arising from tractional stress due to blood pressure and shear stress due to blood flow. Exposure of glomeruli to abnormal hemodynamic force such as hyperfiltration is associated with glomerular injury and progressive renal disease, and the conversion of mechanical stimuli to chemical signals in the regulation of the process is poorly understood in podocytes. By examining DNA fragmentation, apoptotic nuclear changes and cytochrome c release, we found that shear stress induced cell apoptosis in cultured podocytes. Meanwhile, podocytes exposed to shear stress also stimulated c-Src phosphorylation, phospholipase D (PLD) activation and mammalian target of rapamycin (mTOR) signaling. Using the antibodies against c-Src, PLD{sub 1}, and PLD{sub 2} to perform reciprocal co-immunoprecipitations and in vitro PLD activity assay, our data indicated that c-Src interacted with and activated PLD{sub 1} but not PLD{sub 2}. The inhibition of shear stress-induced c-Src phosphorylation by PP{sub 2} (a specific inhibitor of c-Src kinase) resulted in reduced PLD activity. Phosphatidic acid, produced by shear stress-induced PLD activation, stimulated mTOR signaling, and caused podocyte hypertrophy and apoptosis.

ER-bound protein tyrosine phosphatase PTP1B interacts with Src at the plasma membrane/substrate interface.

Directory of Open Access Journals (Sweden)

Melisa C Monteleone

Full Text Available PTP1B is an endoplasmic reticulum (ER anchored enzyme whose access to substrates is partly dependent on the ER distribution and dynamics. One of these substrates, the protein tyrosine kinase Src, has been found in the cytosol, endosomes, and plasma membrane. Here we analyzed where PTP1B and Src physically interact in intact cells, by bimolecular fluorescence complementation (BiFC in combination with temporal and high resolution microscopy. We also determined the structural basis of this interaction. We found that BiFC signal is displayed as puncta scattered throughout the ER network, a feature that was enhanced when the substrate trapping mutant PTP1B-D181A was used. Time-lapse and co-localization analyses revealed that BiFC puncta did not correspond to vesicular carriers; instead they localized at the tip of dynamic ER tubules. BiFC puncta were retained in ventral membrane preparations after cell unroofing and were also detected within the evanescent field of total internal reflection fluorescent microscopy (TIRFM associated to the ventral membranes of whole cells. Furthermore, BiFC puncta often colocalized with dark spots seen by surface reflection interference contrast (SRIC. Removal of Src myristoylation and polybasic motifs abolished BiFC. In addition, PTP1B active site and negative regulatory tyrosine 529 on Src were primary determinants of BiFC occurrence, although the SH3 binding motif on PTP1B also played a role. Our results suggest that ER-bound PTP1B dynamically interacts with the negative regulatory site at the C-terminus of Src at random puncta in the plasma membrane/substrate interface, likely leading to Src activation and recruitment to adhesion complexes. We postulate that this functional ER/plasma membrane crosstalk could apply to a wide array of protein partners, opening an exciting field of research.

Letrozole regulates actin cytoskeleton polymerization dynamics in a SRC-1 dependent manner in the hippocampus of mice.

Science.gov (United States)

Zhao, Yangang; Yu, Yanlan; Zhang, Yuanyuan; He, Li; Qiu, Linli; Zhao, Jikai; Liu, Mengying; Zhang, Jiqiang

2017-03-01

In the hippocampus, local estrogens (E 2 ) derived from testosterone that is catalyzed by aromatase play important roles in the regulation of hippocampal neural plasticity, but the underlying mechanisms remain unclear. The actin cytoskeleton contributes greatly to hippocampal synaptic plasticity; however, whether it is regulated by local E 2 and the related mechanisms remain to be elucidated. In this study, we first examined the postnatal developmental profiles of hippocampal aromatase and specific proteins responsible for actin cytoskeleton dynamics. Then we used aromatase inhibitor letrozole (LET) to block local E 2 synthesis and examined the changes of these proteins and steroid receptor coactivator-1 (SRC-1), the predominant coactivator for steroid nuclear receptors. Finally, SRC-1 specific RNA interference was used to examine the effects of SRC-1 on the expression of these actin remodeling proteins. The results showed a V-type profile for aromatase and increased profiles for actin cytoskeleton proteins in both male and female hippocampus without obvious sex differences. LET treatment dramatically decreased the F-actin/G-actin ratio, the expression of Rictor, phospho-AKT (ser473), Profilin-1, phospho-Cofilin (Ser3), and SRC-1 in a dose-dependent manner. In vitro studies demonstrated that LET induced downregulation of these proteins could be reversed by E 2 , and E 2 induced increase of these proteins were significantly suppressed by SRC-1 shRNA interference. These results for the first time clearly demonstrated that local E 2 inhibition could induce aberrant actin polymerization; they also showed an important role of SRC-1 in the mediation of local E 2 action on hippocampal synaptic plasticity by regulation of actin cytoskeleton dynamics. Copyright © 2016 Elsevier Ltd. All rights reserved.

77 FR 4581 - Alaska Region's Subsistence Resource Commission (SRC) Program

Science.gov (United States)

2012-01-30

... DEPARTMENT OF THE INTERIOR National Park Service [NPS-AKR-LACL; 9924-PYS] Alaska Region's... public meeting for the National Park Service (NPS) Alaska Region's Subsistence Resource Commission (SRC... Meeting Debora R. Cooper, Associate Regional Director, Resources and Subsistence, Alaska Region. [FR Doc...

Technical support to the Solvent Refined Coal (SRC) demonstration projects: assessment of current research and development

Energy Technology Data Exchange (ETDEWEB)

Edwards, M.S.; Rodgers, B.R.; Brown, C.H.; Carlson, P.K.; Gambill, W.R.; Gilliam, T.M.; Holmes, J.M.; Krishnan, R.P.; Parsly, L.F.

1980-12-01

A program to demonstrate Solvent Refined Coal (SRC) technology has been initiated by the US Department of Energy (DOE) in partnership with two industrial groups. Project management responsibility has been assigned to the Oak Ridge Operations Office (ORO) of DOE. ORO requested that the Oak Ridge National Laboratory assess current research and development (R and D) activities and develop recommendations for those activities that might contribute to successful completion of the SRC demonstration plant projects. The objectives of this final report are to discuss in detail the problem areas in SRC; to discuss the current and planned R and D investigations relevant to the problems identified; and to suggest appropriate R and D activities in support of designs for the SRC demonstration plants. Four types of R and D activities are suggested: continuation of present and planned activities; coordination of activities and results, present and proposed; extension/redirection of activities not involving major equipment purchase or modifications; and new activities. Important examples of the first type of activity include continuation of fired heater, slurry rheology, and slurry mixing studies at Ft. Lewis. Among the second type of activity, coordination of data acquisition and interpretation is recommended in the areas of heat transfer, vapor/liquid equilibria, and physical properties. Principal examples of recommendations for extension/redirection include screening studies at laboratory scale on the use of carbonaceous precoat (e.g., anthracite) infiltration, and 15- to 30-day continuous tests of the Texaco gasifier at the Texaco Montebello facility (using SRC residues).

Simian Immunodeficiency Virus and Human Immunodeficiency Virus Type 1 Nef Proteins Show Distinct Patterns and Mechanisms of Src Kinase Activation

Science.gov (United States)

Greenway, Alison L.; Dutartre, Hélène; Allen, Kelly; McPhee, Dale A.; Olive, Daniel; Collette, Yves

1999-01-01

The nef gene from human and simian immunodeficiency viruses (HIV and SIV) regulates cell function and viral replication, possibly through binding of the nef product to cellular proteins, including Src family tyrosine kinases. We show here that the Nef protein encoded by SIVmac239 interacts with and also activates the human Src kinases Lck and Hck. This is in direct contrast to the inhibitory effect of HIV type 1 (HIV-1) Nef on Lck catalytic activity. Unexpectedly, however, the interaction of SIV Nef with human Lck or Hck is not mediated via its consensus proline motif, which is known to mediate HIV-1 Nef binding to Src homology 3 (SH3) domains, and various experimental analyses failed to show significant interaction of SIV Nef with the SH3 domain of either kinase. Instead, SIV Nef can bind Lck and Hck SH2 domains, and its N-terminal 50 amino acid residues are sufficient for Src kinase binding and activation. Our results provide evidence for multiple mechanisms by which Nef binds to and regulates Src kinases. PMID:10364375

77 FR 4579 - Alaska Region's Subsistence Resource Commission (SRC) Program

Science.gov (United States)

2012-01-30

... DEPARTMENT OF THE INTERIOR National Park Service [NPS-AKR-DENA; 9924-PYS] Alaska Region's... public meeting for the National Park Service (NPS) Alaska Region's Subsistence Resource Commission (SRC..., Associate Regional Director, Resources and Subsistence, Alaska Region. [FR Doc. 2012-1877 Filed 1-27-12; 8...

Cell Signaling Associated with Na+/K+-ATPase: Activation of Phosphatidylinositide 3-Kinase IA/Akt by Ouabain Is Independent of Src

Science.gov (United States)

2013-01-01

Exposure of intact cells to selective inhibitors of Na+/K+-ATPase such as ouabain activates several growth-related cell signaling pathways. It has been suggested that the initial event of these pathways is the binding of ouabain to a preexisting complex of Src with Na+/K+-ATPase of the plasma membrane. The aim of this work was to evaluate the role of Src in the ouabain-induced activation of phosphatidylinositide 3-kinase 1A (PI3K1A) and its downstream consequences. When fibroblasts devoid of Src (SYF cells) and controls (Src++ cells) were exposed to ouabain, PI3K1A, Akt, and proliferative growth were similarly stimulated in both cell lines. Ouabain-induced activation of Akt was not prevented by the Src inhibitor PP2. In contrast, ERK1/2 were not activated by ouabain in SYF cells but were stimulated in Src++ cells; this was prevented by PP2. In isolated adult mouse cardiac myocytes, where ouabain induces hypertrophic growth, PP2 also did not prevent ouabain-induced activation of Akt and the resulting hypertrophy. Ouabain-induced increases in the levels of co-immunoprecipitation of the α-subunit of Na+/K+-ATPase with the p85 subunit of PI3K1A were noted in SYF cells, Src++ cells, and adult cardiac myocytes. In conjunction with previous findings, the results presented here indicate that (a) if there is a preformed complex of Src and Na+/K+-ATPase, it is irrelevant to ouabain-induced activation of the PI3K1A/Akt pathway through Na+/K+-ATPase and (b) a more likely, but not established, mechanism of linkage of Na+/K+-ATPase to PI3K1A is the ouabain-induced interaction of a proline-rich domain of the α-subunit of Na+/K+-ATPase with the SH3 domain of the p85 subunit of PI3K1A. PMID:24266852

Fractional distillation as a strategy for reducing the genotoxic potential of SRC-II coal liquids: a status report

Energy Technology Data Exchange (ETDEWEB)

Pelroy, R.A.; Wilson, B.W.

1981-09-01

This report presents results of studies on the effects of fractional distillation on the genotoxic potential of Solvent Refined Coal (SRC-II) liquids. SRC-II source materials and distilled liquids were provided by Pittsburg and Midway Coal Mining Co. Fractional distillations were conducted on products from the P-99 process development unit operating under conditions approximating those anticipated at the SRC-II demonstration facility. Distillation cuts were subjected to chemical fractionation, in vitro bioassay and initial chemical analysis. Findings are discussed as they relate to the temperature at which various distillate cuts were produced. This document is the first of two status reports scheduled for 1981 describing these studies.

Endothelial cell-derived matrix promotes the metabolic functional maturation of hepatocyte via integrin-Src signalling.

Science.gov (United States)

Guo, Xinyue; Li, Weihong; Ma, Minghui; Lu, Xin; Zhang, Haiyan

2017-11-01

The extracellular matrix (ECM) microenvironment is involved in the regulation of hepatocyte phenotype and function. Recently, the cell-derived extracellular matrix has been proposed to represent the bioactive and biocompatible materials of the native ECM. Here, we show that the endothelial cell-derived matrix (EC matrix) promotes the metabolic maturation of human adipose stem cell-derived hepatocyte-like cells (hASC-HLCs) through the activation of the transcription factor forkhead box protein A2 (FOXA2) and the nuclear receptors hepatocyte nuclear factor 4 alpha (HNF4α) and pregnane X receptor (PXR). Reducing the fibronectin content in the EC matrix or silencing the expression of α5 integrin in the hASC-HLCs inhibited the effect of the EC matrix on Src phosphorylation and hepatocyte maturation. The inhibition of Src phosphorylation using the inhibitor PP2 or silencing the expression of Src in hASC-HLCs also attenuated the up-regulation of the metabolic function of hASC-HLCs in a nuclear receptor-dependent manner. These data elucidate integrin-Src signalling linking the extrinsic EC matrix signals and metabolic functional maturation of hepatocyte. This study provides a model for studying the interaction between hepatocytes and non-parenchymal cell-derived matrix. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

77 FR 4578 - Alaska Region's Subsistence Resource Commission (SRC) Program

Science.gov (United States)

2012-01-30

... DEPARTMENT OF THE INTERIOR National Park Service [NPS-AKR-ANIA; 9924-PYS] Alaska Region's... public meeting for the National Park Service (NPS) Alaska Region's Subsistence Resource Commission (SRC..., Alaska Region. [FR Doc. 2012-1860 Filed 1-27-12; 8:45 am] BILLING CODE 4310-HE-P ...

Duox, Flotillin-2, and Src42A are required to activate or delimit the spread of the transcriptional response to epidermal wounds in Drosophila.

Directory of Open Access Journals (Sweden)

Michelle T Juarez

2011-12-01

Full Text Available The epidermis is the largest organ of the body for most animals, and the first line of defense against invading pathogens. A breach in the epidermal cell layer triggers a variety of localized responses that in favorable circumstances result in the repair of the wound. Many cellular and genetic responses must be limited to epidermal cells that are close to wounds, but how this is regulated is still poorly understood. The order and hierarchy of epidermal wound signaling factors are also still obscure. The Drosophila embryonic epidermis provides an excellent system to study genes that regulate wound healing processes. We have developed a variety of fluorescent reporters that provide a visible readout of wound-dependent transcriptional activation near epidermal wound sites. A large screen for mutants that alter the activity of these wound reporters has identified seven new genes required to activate or delimit wound-induced transcriptional responses to a narrow zone of cells surrounding wound sites. Among the genes required to delimit the spread of wound responses are Drosophila Flotillin-2 and Src42A, both of which are transcriptionally activated around wound sites. Flotillin-2 and constitutively active Src42A are also sufficient, when overexpressed at high levels, to inhibit wound-induced transcription in epidermal cells. One gene required to activate epidermal wound reporters encodes Dual oxidase, an enzyme that produces hydrogen peroxide. We also find that four biochemical treatments (a serine protease, a Src kinase inhibitor, methyl-ß-cyclodextrin, and hydrogen peroxide are sufficient to globally activate epidermal wound response genes in Drosophila embryos. We explore the epistatic relationships among the factors that induce or delimit the spread of epidermal wound signals. Our results define new genetic functions that interact to instruct only a limited number of cells around puncture wounds to mount a transcriptional response, mediating

Mutations in the catalytic loop HRD motif alter the activity and function of Drosophila Src64.

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Taylor C Strong

Full Text Available The catalytic loop HRD motif is found in most protein kinases and these amino acids are predicted to perform functions in catalysis, transition to, and stabilization of the active conformation of the kinase domain. We have identified mutations in a Drosophila src gene, src64, that alter the three HRD amino acids. We have analyzed the mutants for both biochemical activity and biological function during development. Mutation of the aspartate to asparagine eliminates biological function in cytoskeletal processes and severely reduces fertility, supporting the amino acid's critical role in enzymatic activity. The arginine to cysteine mutation has little to no effect on kinase activity or cytoskeletal reorganization, suggesting that the HRD arginine may not be critical for coordinating phosphotyrosine in the active conformation. The histidine to leucine mutant retains some kinase activity and biological function, suggesting that this amino acid may have a biochemical function in the active kinase that is independent of its side chain hydrogen bonding interactions in the active site. We also describe the phenotypic effects of other mutations in the SH2 and tyrosine kinase domains of src64, and we compare them to the phenotypic effects of the src64 null allele.

Development of SRC-I product analysis. Volume 3. Documentation of procedures

Energy Technology Data Exchange (ETDEWEB)

Schweighardt, F.K.; Kingsley, I.S.; Cooper, F.E.; Kamzelski, A.Z.; Parees, D.M.

1983-09-01

This section documents the BASIC computer program written to simulate Wilsonville's GC-simulated distillation (GCSD) results at APCI-CRSD Trexlertown. The GC conditions used at APCI for the Wilsonville GCSD analysis of coal-derived liquid samples were described in the SRC-I Quarterly Technical Report, April-June 1981. The approach used to simulate the Wilsonville GCSD results is also from an SRC-I Quarterly Technical Report and is reproduced in Appendix VII-A. The BASIC computer program is described in the attached Appendix VII-B. Analysis of gases produced during coal liquefaction generates key information needed to determine product yields for material balance and process control. Gas samples from the coal process development unit (CPDU) and tubing bombs are the primary samples analyzed. A Carle gas chromatographic system was used to analyze coal liquefaction gas samples. A BASIC computer program was written to calculate the gas chromatographic peak area results into mole percent results. ICRC has employed several analytical workup procedures to determine the amount of distillate, oils, asphaltenes, preasphaltenes, and residue in SRC-I process streams. The ASE procedure was developed using Conoco's liquid column fractionation (LC/F) method as a model. In developing the ASE procedure, ICRC was able to eliminate distillation, and therefore quantify the oils fraction in one extraction step. ASE results were shown to be reproducible within +- 2 wt %, and to yield acceptable material balances. Finally, the ASE method proved to be the least affected by sample composition.

Mechanism of c-Src Synergy with the EGFR in Breast Cancer

National Research Council Canada - National Science Library

1998-01-01

.... Specifically, we have shown that kinase-inactive c-Src is able to inhibit tumorigenicity of the IOT 1/2 mouse fibroblast model cells by not phosphorylating the receptor on Tyr 845 in the activation loop of the kinase...

Pro-contractile action of the Na,K-ATPase/Src-kinase signaling pathway in the vascular wall

DEFF Research Database (Denmark)

Bouzinova, Elena; Aalkjær, Christian; Matchkov, Vladimir

Aim: Na,K-ATPase is essential for maintaining the transmembrane ion gradient and might initiate various intracellular signaling. These signals possibly act through a modification of the local ion concentrations or via Src-kinase activation. It is known that inhibition of the α-2 isoform of Na......,K-ATPase by ouabain elevates blood pressure. Consequently, ouabain was shown to potentiate arterial contraction in vitro. In contrast, we have demonstrated that siRNA-induced down-regulation of the α-2 isoform Na,K-ATPase expression reduced arterial sensitivity to agonist stimulation and prevented the effect......) phosphorylation assay. Down-regulation of the α-2 isoform Na,K-ATPase prevented the inhibitory effect of Src inhibitors on arterial contraction. Conclusions: The pro-contractile action of ouabain-sensitive Na,K-ATPase inhibition is associated with Src-kinase inhibition suggesting the role of this signaling...

Drive and the Action Calculation of GetLLM, in Beta-Beat.src

CERN Document Server

Sherman, Alexander Charles

2013-01-01

The Beta-Beat.src program is used to analyze data collected by Beam Position Monitors (BPMs) in accelerators at CERN. The Beams department at CERN uses it to study the behaviour of a beam as it traverses an accelerator, and in particular the LHC. Two pieces of code in Beta-Beat.src are “drive”, a C/C++ program, and “GetLLM”, a python program. This report described the modification of the drive code to be compatible with windows and take advantage of elements of C++, as well as a change in the calculation of the action in GetLLM to reduce its relative uncertainty. The dynamic aperture is recalculated with the new action and sees a reduction in its uncertainty.

On the quantum mechanics of consciousness, with application to anomalous phenomena

Science.gov (United States)

Jahn, Robert G.; Dunne, Brenda J.

1986-08-01

Theoretical explication of a growing body of empirical data on consciousness-related anomalous phenomena is unlikely to be achieved in terms of known physical processes. Rather, it will first be necessary to formulate the basic role of consciousness in the definition of reality before such anomalous experience can adequately be represented. This paper takes the position that reality is constituted only in the interaction of consciousness with its environment, and therefore that any scheme of conceptual organization developed to represent that reality must reflect the processes of consciousness as well as those of its environment. In this spirit, the concepts and formalisms of elementary quantum mechanics, as originally proposed to explain anomalous atomic-scale physical phenomena, are appropriated via metaphor to represent the general characteristics of consciousness interacting with any environment. More specifically, if consciousness is represented by a quantum mechanical wave function, and its environment by an appropriate potential profile, Schrödinger wave mechanics defines eigenfunctions and eigenvalues that can be associated with the cognitive and emotional experiences of that consciousness in that environment. To articulate this metaphor it is necessary to associate certain aspects of the formalism, such as the coordinate system, the quantum numbers, and even the metric itself, with various impressionistic descriptors of consciousness, such as its intensity, perspective, approach/avoidance attitude, balance between cognitive and emotional activity, and receptive/assertive disposition. With these established, a number of the generic features of quantum mechanics, such as the wave/particle duality, and the uncertainty, indistinguishability, and exclusion principles, display metaphoric relevance to familiar individual and collective experiences. Similarly, such traditional quantum theoretic exercises as the central force field and atomic structure, covalent

Role of miR-222-3p in c-Src-Mediated Regulation of Osteoclastogenesis

Directory of Open Access Journals (Sweden)

Shinya Takigawa

2016-02-01

Full Text Available MicroRNAs (miRNAs are small non-coding RNAs that play a mostly post-transcriptional regulatory role in gene expression. Using RAW264.7 pre-osteoclast cells and genome-wide expression analysis, we identified a set of miRNAs that are involved in osteoclastogenesis. Based on in silico analysis, we specifically focused on miR-222-3p and evaluated its role in osteoclastogenesis. The results show that the inhibitor of miR-222-3p upregulated the mRNA levels of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1 and tartrate-resistant acid phosphatase (TRAP, while its mimicking agent downregulated their mRNA levels. Western blot analysis showed that its inhibitor increased the protein levels of TRAP and cathepsin K, while its mimicking agent decreased their levels. Genome-wide mRNA expression analysis in the presence and absence of receptor activator of nuclear factor κ-B ligand (RANKL predicted c-Src as a potential regulatory target of miR-222-3p. Live cell imaging using a fluorescence resonance energy transfer (FRET technique revealed that miR-222-3p acted as an inhibitor of c-Src activity, and a partial silencing of c-Src suppressed RANKL-induced expression of TRAP and cathepsin K, as well as the number of multi-nucleated osteoclasts and their pit formation. Collectively, the study herein demonstrates that miR-222-3p serves as an inhibitor of osteoclastogenesis and c-Src mediates its inhibition of cathepsin K and TRAP.

DRF3 as a Cholesterol-Dependent Regulator of Src in Prostate Cancer

National Research Council Canada - National Science Library

Freeman, Michael R

2007-01-01

This project focuses on the novel finding from our group that the formin protein, Drf3, is a signaling molecule positioned downstream from the EGF receptor that intersects with the tyrosine kinase Src...

Inhibition of Src by microRNA-23b increases the cisplatin sensitivity of chondrosarcoma cells.

Science.gov (United States)

Huang, Kai; Chen, Jun; Yang, Mo-Song; Tang, Yu-Jun; Pan, Feng

2017-01-01

Chondrosarcomas are malignant cartilage-forming tumors from low-grade to high-grade aggressive tumors characterized by metastasis. Cisplatin is an effective DNA-damaging anti-tumor agent for the treatment against a wide variety of solid tumors. However, chondrosarcomas are notorious for their resistance to conventional chemo- and radio- therapies. In this study, we report miR-23b acts as a tumor suppressor in chondrosarcoma. The expressions of miR-23b are down-regulated in chondrosarcoma patient samples and cell lines compared with adjacent normal tissues and human primary chondrocytes. In addition, overexpression of miR-23b suppresses chondrosarcoma cell proliferation. By comparison of the cisplatin resistant chondrosarcoma cells and parental cells, we observed miR-23b was significantly down regulated in cisplatin resistant cells. Moreover, we demonstrate here Src kinase is a direct target of miR-23b in chondrosarcoma cells. Overexpression of miR-23b suppresses Src-Akt pathway, leading to the sensitization of cisplatin resistant chondrosarcoma cells to cisplatin. This chemo-sensitivity effect by the miR-23b-mediated inhibition of Src-Akt pathway is verified with the restoration of Src kinase in miR-23b-overespressing chondrosarcoma cells, resulting in the acquirement of resistance to cisplatin. In summary, our study reveals a novel role of miR-23b in cisplatin resistance in chondrosarcoma and will contribute to the development of the microRNA-targeted anti-cancer therapeutics.

Anomalous top magnetic couplings

Indian Academy of Sciences (India)

2012-11-09

Nov 9, 2012 ... Corresponding author. E-mail: remartinezm@unal.edu.co. Abstract. The real and imaginary parts of the one-loop electroweak contributions to the left and right tensorial anomalous couplings of the tbW vertex in the Standard Model (SM) are computed. Keywords. Top; anomalous. PACS Nos 14.65.Ha; 12.15 ...

Anomalous vacuum expectation values

International Nuclear Information System (INIS)

Suzuki, H.

1986-01-01

The anomalous vacuum expectation value is defined as the expectation value of a quantity that vanishes by means of the field equations. Although this value is expected to vanish in quantum systems, regularization in general produces a finite value of this quantity. Calculation of this anomalous vacuum expectation value can be carried out in the general framework of field theory. The result is derived by subtraction of divergences and by zeta-function regularization. Various anomalies are included in these anomalous vacuum expectation values. This method is useful for deriving not only the conformal, chiral, and gravitational anomalies but also the supercurrent anomaly. The supercurrent anomaly is obtained in the case of N = 1 supersymmetric Yang-Mills theory in four, six, and ten dimensions. The original form of the energy-momentum tensor and the supercurrent have anomalies in their conservation laws. But the modification of these quantities to be equivalent to the original one on-shell causes no anomaly in their conservation laws and gives rise to anomalous traces

Potential benefits of commercial willow Short Rotation Coppice (SRC) for farm-scale plant and invertebrate communities in the agri-environment

Energy Technology Data Exchange (ETDEWEB)

Rowe, Rebecca L.; Hanley, Mick E.; Goulson, Dave; Clarke, Donna J.; Doncaster, C. Patrick; Taylor, Gail [University of Southampton, Faculty of Natural and Environmental Sciences, Life Sciences Building, Southampton, S017 1BJ (United Kingdom)

2011-01-15

The cultivation of bioenergy crops (BECs) represents a significant land-use change in agri-environments, but their deployment has raised important issues globally regarding possible impacts on biodiversity. Few studies however, have systematically examined the effect of commercial scale bioenergy plantations on biodiversity in agri-ecosystems. In this study we investigate how the abundance and diversity of two key components of farmland biodiversity (ground flora and winged invertebrates) varied between mature willow Short Rotation Coppice (SRC) and two alternative land-use options (arable crops and set-aside land). Although the abundance of winged invertebrates was similar across all land-uses, taxonomic composition varied markedly. Hymenoptera and large Hemiptera (>5 mm) were more abundant in willow SRC than in arable or set-aside. Similarly although plant species richness was greater in set-aside, our data show that willow SRC supports a different plant community to the other land-uses, being dominated by competitive perennial species such as Elytrigia repens and Urtica dioica. Our results suggest that under current management practices a mixed farming system incorporating willow SRC can benefit native farm-scale biodiversity. In particular the reduced disturbance in willow SRC allows the persistence of perennial plant species, potentially providing a stable refuge and food sources for invertebrates. In addition, increased Hymenoptera abundance in willow SRC could potentially have concomitant effects on ecosystem processes, as many members of this Order are important pollinators of crop plants or otherwise fulfil an important beneficial role as predators or parasites of crop pests. (author)

Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinases

Science.gov (United States)

Lesslie, D P; Summy, J M; Parikh, N U; Fan, F; Trevino, J G; Sawyer, T K; Metcalf, C A; Shakespeare, W C; Hicklin, D J; Ellis, L M; Gallick, G E

2006-01-01

Vascular endothelial growth factor (VEGF) is the predominant pro-angiogenic cytokine in human malignancy, and its expression correlates with disease recurrence and poor outcomes in patients with colorectal cancer. Recently, expression of vascular endothelial growth factor receptors (VEGFRs) has been observed on tumours of epithelial origin, including those arising in the colon, but the molecular mechanisms governing potential VEGF-driven biologic functioning in these tumours are not well characterised. In this report, we investigated the role of Src family kinases (SFKs) in VEGF-mediated signalling in human colorectal carcinoma (CRC) cell lines. Vascular endothelial growth factor specifically activated SFKs in HT29 and KM12L4 CRC cell lines. Further, VEGF stimulation resulted in enhanced cellular migration, which was effectively blocked by pharmacologic inhibition of VEGFR-1 or Src kinase. Correspondingly, migration studies using siRNA clones with reduced Src expression confirmed the requirement for Src in VEGF-induced migration in these cells. Furthermore, VEGF treatment enhanced VEGFR-1/SFK complex formation and increased tyrosine phosphorylation of focal adhesion kinase, p130 cas and paxillin. Finally, we demonstrate that VEGF-induced migration is not due, at least in part, to VEGF acting as a mitogen. These results suggest that VEGFR-1 promotes migration of tumour cells through a Src-dependent pathway linked to activation of focal adhesion components that regulate this process. PMID:16685275

Solvent refined coal (SRC) process: trace elements research and development report no. 53, interim report no. 34. Volume III. Pilot plant development work part 6: the fate of trace elements in the SRC process for the period, August 1, 1977 - February 28, 1979

International Nuclear Information System (INIS)

Filby, R.H.; Khalil, S.R.; Grimm, C.A.; Ekabaram, V.; Hunt, M.L.

1980-12-01

This work reports the results of neutron activation analysis determination of the fate of trace elements in the SRC II process. Six coals were studied for their behavior in material balance runs carried out at the Fort Lewis Pilot Plant. The distribution of trace elements among products and input streams was determined by thermal neutron activation analysis using thermal neutron flux of 8 x 10 12 neutrons cm -2 sec -1 followed by Ge(Li) gamma ray spectroscopy. National Bureau of Standards Standard Reference Materials (SRM) were used to evaluate the analytical precision and accuracy of the methods used. For each material balance study the trace element input stream was taken as ground coal and the output streams were vacuum bottoms, SRC II product oil, and process water. In addition to these major components, oils, sludges and waters from liquid-liquid separators, effluent waters, biosludges, and by-product sulfur were also analyzed. Concerning the distribution of trace elements in the SRC II process, it was found that the vacuum bottoms was the major sink for all trace element studied, with the exception of Hg. Much lower trace element concentrations (except for Hg) were found in the SRC II product oil relative to the vacuum bottoms or the feed coal, irrespective of coal type. The results indicate excellent balances for the elements studied, except for Hg. Except for Hg, Se, and C1, the SRC II product and process waters contributed less than 1% of the elemental balances for light oil fractions and process waters indicates that Hg, and to a lesser degree As, Se, and Sb, exhibited volatile behavior in the SRC II process but that the degree of volatility is strongly dependent on conditions or coal type

77 FR 4580 - Alaska Region's Subsistence Resource Commission (SRC) Program

Science.gov (United States)

2012-01-30

..., February 14, 2012. The meeting will start at 9 a.m. and conclude at 5 p.m. or until business is completed.... Old Business a. Subsistence Collections and Uses of Shed or Discarded Animal & Plants Environmental.... New Business 12. Public and other Agency Comments 13. SRC Work Session 14. Select Time and Location...

Src Family Kinases and p38 Mitogen-Activated Protein Kinases Regulate Pluripotent Cell Differentiation in Culture.

Directory of Open Access Journals (Sweden)

Boon Siang Nicholas Tan

Full Text Available Multiple pluripotent cell populations, which together comprise the pluripotent cell lineage, have been identified. The mechanisms that control the progression between these populations are still poorly understood. The formation of early primitive ectoderm-like (EPL cells from mouse embryonic stem (mES cells provides a model to understand how one such transition is regulated. EPL cells form from mES cells in response to l-proline uptake through the transporter Slc38a2. Using inhibitors of cell signaling we have shown that Src family kinases, p38 MAPK, ERK1/2 and GSK3β are required for the transition between mES and EPL cells. ERK1/2, c-Src and GSK3β are likely to be enforcing a receptive, primed state in mES cells, while Src family kinases and p38 MAPK are involved in the establishment of EPL cells. Inhibition of these pathways prevented the acquisition of most, but not all, features of EPL cells, suggesting that other pathways are required. L-proline activation of differentiation is mediated through metabolism and changes to intracellular metabolite levels, specifically reactive oxygen species. The implication of multiple signaling pathways in the process suggests a model in which the context of Src family kinase activation determines the outcomes of pluripotent cell differentiation.

Src Family Kinases and p38 Mitogen-Activated Protein Kinases Regulate Pluripotent Cell Differentiation in Culture

Science.gov (United States)

Tan, Boon Siang Nicholas; Kwek, Joly; Wong, Chong Kum Edwin; Saner, Nicholas J.; Yap, Charlotte; Felquer, Fernando; Morris, Michael B.; Gardner, David K.; Rathjen, Peter D.; Rathjen, Joy

2016-01-01

Multiple pluripotent cell populations, which together comprise the pluripotent cell lineage, have been identified. The mechanisms that control the progression between these populations are still poorly understood. The formation of early primitive ectoderm-like (EPL) cells from mouse embryonic stem (mES) cells provides a model to understand how one such transition is regulated. EPL cells form from mES cells in response to l-proline uptake through the transporter Slc38a2. Using inhibitors of cell signaling we have shown that Src family kinases, p38 MAPK, ERK1/2 and GSK3β are required for the transition between mES and EPL cells. ERK1/2, c-Src and GSK3β are likely to be enforcing a receptive, primed state in mES cells, while Src family kinases and p38 MAPK are involved in the establishment of EPL cells. Inhibition of these pathways prevented the acquisition of most, but not all, features of EPL cells, suggesting that other pathways are required. L-proline activation of differentiation is mediated through metabolism and changes to intracellular metabolite levels, specifically reactive oxygen species. The implication of multiple signaling pathways in the process suggests a model in which the context of Src family kinase activation determines the outcomes of pluripotent cell differentiation. PMID:27723793

The Diaphanous-related Formin FHOD1 associates with ROCK1 and promotes Src-dependent plasma membrane blebbing.

Science.gov (United States)

Hannemann, Sebastian; Madrid, Ricardo; Stastna, Jana; Kitzing, Thomas; Gasteier, Judith; Schönichen, André; Bouchet, Jerome; Jimenez, Alberto; Geyer, Matthias; Grosse, Robert; Benichou, Serge; Fackler, Oliver T

2008-10-10

Diaphanous-related formins (DRFs) mediate GTPase-triggered actin rearrangements to regulate central cellular processes, such as cell motility and cytokinesis. The DRF FHOD1 interacts with the Rho-GTPase Rac1 and mediates formation of actin stress fibers in its deregulated form; the physiologically relevant activities and molecular mechanisms of endogenous FHOD1, however, are still unknown. Here we report that FHOD1 physically associates via the N-terminal part of its FH2 domain with the central domain of ROCK1. Although FHOD1 does not affect the kinase activity of ROCK1, the DRF is an efficient substrate for phosphorylation by ROCK1. Co-expression of FHOD1 and ROCK1 results in the generation of nonapoptotic plasma membrane (PM) blebs, to which the DRF is efficiently recruited. Blebbing induced by FHOD1 and ROCK1 depends on F-actin integrity, the Rho-ROCK cascade, and Src activity and is reminiscent of the recently described PM blebs triggered by expression of Src homology 4 (SH4) domain PM targeting signals. Consistently, endogenous FHOD1 is required in SH4 domain expressing cells for efficient PM blebbing and rounded cell morphology in two-dimensional cultures or three-dimensional matrices, respectively. Efficient association of FHOD1 with ROCK1, as well as recruitment of the DRF to blebs, depends on Src activity, suggesting that the functional interaction between both proteins is regulated by Src. These results define a role for endogenous FHOD1 in SH4 domain-induced blebbing and suggest that its activity is regulated by ROCK1 in a Src-dependent manner.

Tyrosine Kinase Inhibition in HPV-related Squamous Cell Carcinoma Reveals Beneficial Expression of cKIT and Src.

Science.gov (United States)

Kramer, Benedikt; Kneissle, Marcel; Birk, Richard; Rotter, Nicole; Aderhold, Christoph

2018-05-01

Therapeutic options of locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC) are limited. Src and cKIT are key protein regulators for local tumor progression. The aim of the study was to investigate the therapeutic potential of targeted therapies in human squamous cell carcinoma (HNSCC) in vitro. Therefore, the influence of the selective tyrosine kinase inhibitors niotinib, dasatinib, erlotinib, gefitinib and afatinib on Src and cKIT expression in Human papilloma virus (HPV)-positive and HPV-negative squamous cancer cells (SCC) was analyzed in vitro. ELISA was performed to evaluate the expression of Src and cKIT under the influence of nilotinib, dasatinib, erlotinib, gefitinib and afatinib (10 μmol/l) in HPV-negative and HPV-positive SCC (24-96 h of incubation). Gefitinib significantly increased cKIT expression in HPV-positive and HPV-negative cells whereas nilotinib and afatinib decreased cKIT expression in HPV-positive SCC. The influence of tyrosine kinase inhibitors in HPV-negative SCC was marginal. Surprisingly, Src expression was significantly increased by all tested tyrosine kinase inhibitors in HPV-positive SCC. The results revealed beneficial and unexpected information concerning the interaction of selective tyrosine kinase inhibitors and the tumor biology of HNSCC. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Anomalous x-ray scattering

International Nuclear Information System (INIS)

Wendin, G.

1979-01-01

The availability of tunable synchrotron radiation has made it possible systematically to perform x-ray diffraction studies in regions of anomalous scattering near absorption edges, e.g. in order to derive phase information for crystal structure determination. An overview is given of recent experimental and theoretical work and discuss the properties of the anomalous atomic scattering factor, with emphasis on threshold resonances and damping effects. The results are applied to a discussion of the very strong anomalous dispersion recently observed near the L 3 edge in a cesium complex. Also given is an overview of elements and levels where similar behavior can be expected. Finally, the influence of solid state and chemical effects on the absorption edge structure is discussed. 64 references

Diffusion coefficient for anomalous transport

International Nuclear Information System (INIS)

1986-01-01

A report on the progress towards the goal of estimating the diffusion coefficient for anomalous transport is given. The gyrokinetic theory is used to identify different time and length scale inherent to the characteristics of plasmas which exhibit anomalous transport

DP97, a DEAD box DNA/RNA helicase, is a target gene-selective co-regulator of the constitutive androstane receptor

International Nuclear Information System (INIS)

Kanno, Yuichiro; Serikawa, Takafumi; Inajima, Jun; Inouye, Yoshio

2012-01-01

Highlights: ► DP97 interacts with nuclear receptor CAR. ► DP97 enhances CAR-mediated transcriptional activation. ► DP97 synergistically enhances transactivity of CAR by the co-expression of SRC-1 or PGC1α. ► DP97 is a gene-selective co-activator for hCAR. -- Abstract: The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that DP97, a member of the DEAD box DNA/RNA helicase protein family, is a novel CAR-interacting protein. Using HepG2 cells expressing human CAR in the presence of tetracycline, we showed that knockdown of DP97 with small interfering RNAs suppressed tetracycline-inducible mRNA expression of CYP2B6 and UGT1A1 but not CYP3A4. Thus, DP97 was found to be a gene (or promoter)-selective co-activator for hCAR. DP97-mediated CAR transactivation was synergistically enhanced by the co-expression of SRC-1 or PGC1α, therefore it might act as mediator between hCAR and appropriate co-activators.

The spatiotemporal pattern of Src activation at lipid rafts revealed by diffusion-corrected FRET imaging.

Directory of Open Access Journals (Sweden)

Shaoying Lu

2008-07-01

Full Text Available Genetically encoded biosensors based on fluorescence resonance energy transfer (FRET have been widely applied to visualize the molecular activity in live cells with high spatiotemporal resolution. However, the rapid diffusion of biosensor proteins hinders a precise reconstruction of the actual molecular activation map. Based on fluorescence recovery after photobleaching (FRAP experiments, we have developed a finite element (FE method to analyze, simulate, and subtract the diffusion effect of mobile biosensors. This method has been applied to analyze the mobility of Src FRET biosensors engineered to reside at different subcompartments in live cells. The results indicate that the Src biosensor located in the cytoplasm moves 4-8 folds faster (0.93+/-0.06 microm(2/sec than those anchored on different compartments in plasma membrane (at lipid raft: 0.11+/-0.01 microm(2/sec and outside: 0.18+/-0.02 microm(2/sec. The mobility of biosensor at lipid rafts is slower than that outside of lipid rafts and is dominated by two-dimensional diffusion. When this diffusion effect was subtracted from the FRET ratio images, high Src activity at lipid rafts was observed at clustered regions proximal to the cell periphery, which remained relatively stationary upon epidermal growth factor (EGF stimulation. This result suggests that EGF induced a Src activation at lipid rafts with well-coordinated spatiotemporal patterns. Our FE-based method also provides an integrated platform of image analysis for studying molecular mobility and reconstructing the spatiotemporal activation maps of signaling molecules in live cells.

The role of c-Src in the invasion and metastasis of hepatocellular carcinoma cells induced by association of cell surface GRP78 with activated α2M

International Nuclear Information System (INIS)

Zhao, Song; Li, Hongdan; Wang, Qingjun; Su, Chang; Wang, Guan; Song, Huijuan; Zhao, Liang; Luan, Zhidong; Su, Rongjian

2015-01-01

Emerging data have suggested that cell surface GRP78 is a multifunctional receptor and has been linked to proliferative and antiapoptotic signaling cascades. Activated α 2− macroglobin (α 2 M*) is a natural circulating ligand of cell surface GRP78. Association of cell surface GRP78 with α 2 M* is involved in the regulation of cell proliferation, survival and apoptosis in human cancers. The invasion and metastasis of HCC cells were examined using transwell and wound healing assay; Cell surface expression of GRP78 was detected by in cell western assay. Translocation of GRP78 from cytosol to cell surface was observed by transfection of GRP78-EGFP plus TRIRC-WGA staining. The levels of Src, phosphor-Src, FAK, phospho-FAK, EGFR, phospho-EGFR, phospho-Cortactin, phospho-Paxillin were determined by western blot. Cell surface expression of GRP78 in HCC tissue samples was observed by immunofluorescence. The distribution of Paxillin and Cortactin in HCC cells was also observed by immunofluorescence. The interaction between GRP78 and Src were detected by far-western blot, co-immunoprecipitation and GST pulldown. GRP78 mRNA was detected by RT-PCR. In the current study, we showed that association of cell surface GRP78 with α 2 M* stimulated the invasion and metastasis of HCC. Cell surface GRP78 could interact directly with c-Src, promoted the phosphorylation of c-Src at Y416. Inhibition of the tyrosine kinase activity of c-Src with PP2 reverted the stimulatory effect caused by association of cell surface GRP78 with α 2 M*. Moreover, association of cell surface GRP78 with α 2 M* facilitates the interaction between EGFR and c-Src and consequently phosphorylated EGFR at Y1101 and Y845, promoting the invasion and metastasis of HCCs. However, inhibition of the tyrosine kinase of c-Src do not affect the interaction between EGFR and Src. c-Src plays a critical role in the invasion and metastasis of HCC induced by association of cell surface GRP78 with α 2 M*. Cell surface GRP

Anomalous carbon nuclei

International Nuclear Information System (INIS)

Gasparian, A.P.

1984-01-01

Results are presented from a bubble chamber experiment to search for anomalous mean free path (MFP) phenomena for secondary multicharged fragments (Zsub(f)=5 and 6) of the beam carbon nucleus at 4.2 GeV/c per nucleon. A total of 50000 primary interactions of carbon with propane (C 3 H 8 ) were created. Approximately 6000 beam tragments with charges Zsub(f)=5 and 6 were analyzed in detail to find out an anomalous decrease of MFP. The anomaly is observed only for secondary 12 C nuclei

Dendritic cells sensitize TCRs through self-MHC-mediated Src family kinase activation

Czech Academy of Sciences Publication Activity Database

Meraner, P.; Hořejší, Václav; Wolpl, A.; Fischer, G.F.; Stingl, G.; Maurer, D.

2007-01-01

Roč. 178, č. 4 (2007), s. 2262-2271 ISSN 0022-1767 Institutional research plan: CEZ:AV0Z50520514 Keywords : TCR * dendritic cells * Src kinases Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.068, year: 2007

A dynamically coupled allosteric network underlies binding cooperativity in Src kinase.

Science.gov (United States)

Foda, Zachariah H; Shan, Yibing; Kim, Eric T; Shaw, David E; Seeliger, Markus A

2015-01-20

Protein tyrosine kinases are attractive drug targets because many human diseases are associated with the deregulation of kinase activity. However, how the catalytic kinase domain integrates different signals and switches from an active to an inactive conformation remains incompletely understood. Here we identify an allosteric network of dynamically coupled amino acids in Src kinase that connects regulatory sites to the ATP- and substrate-binding sites. Surprisingly, reactants (ATP and peptide substrates) bind with negative cooperativity to Src kinase while products (ADP and phosphopeptide) bind with positive cooperativity. We confirm the molecular details of the signal relay through the allosteric network by biochemical studies. Experiments on two additional protein tyrosine kinases indicate that the allosteric network may be largely conserved among these enzymes. Our work provides new insights into the regulation of protein tyrosine kinases and establishes a potential conduit by which resistance mutations to ATP-competitive kinase inhibitors can affect their activity.

Solvent-refined-coal (SRC) process. Volume II. Sections V-XIV. Final report

Energy Technology Data Exchange (ETDEWEB)

1982-05-01

This report documents the completion of development work on the Solvent Refined Coal Process by The Pittsburgh and Midway Coal Mining Co. The work was initiated in 1966 under Office of Coal Research, US Department of Interior, Contract No. 14-01-0001-496 and completed under US Department of Energy Contract No. DE-AC05-79ET10104. This report discusses work leading to the development of the SRC-I and SRC-II processes, construction of the Fort Lewis Pilot Plant for the successful development of these processes, and results from the operation of this pilot plant. Process design data generated on a 1 ton-per-day Process Development Unit, bench-scale units and through numerous research projects in support of the design of major demonstration plants are also discussed in summary form and fully referenced in this report.

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

Directory of Open Access Journals (Sweden)

Dhawan Gunjan

2012-07-01

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

Global phosphotyrosine proteomics identifies PKCδ as a marker of responsiveness to Src inhibition in colorectal cancer.

Directory of Open Access Journals (Sweden)

Eliot T McKinley

Full Text Available Sensitive and specific biomarkers of protein kinase inhibition can be leveraged to accelerate drug development studies in oncology by associating early molecular responses with target inhibition. In this study, we utilized unbiased shotgun phosphotyrosine (pY proteomics to discover novel biomarkers of response to dasatinib, a small molecule Src-selective inhibitor, in preclinical models of colorectal cancer (CRC. We performed unbiased mass spectrometry shotgun pY proteomics to reveal the pY proteome of cultured HCT-116 colonic carcinoma cells, and then extended this analysis to HCT-116 xenograft tumors to identify pY biomarkers of dasatinib-responsiveness in vivo. Major dasatinib-responsive pY sites in xenograft tumors included sites on delta-type protein kinase C (PKCδ, CUB-domain-containing protein 1 (CDCP1, Type-II SH2-domain-containing inositol 5-phosphatase (SHIP2, and receptor protein-tyrosine phosphatase alpha (RPTPα. The pY313 site PKCδ was further supported as a relevant biomarker of dasatinib-mediated Src inhibition in HCT-116 xenografts by immunohistochemistry and immunoblotting with a phosphospecific antibody. Reduction of PKCδ pY313 was further correlated with dasatinib-mediated inhibition of Src and diminished growth as spheroids of a panel of human CRC cell lines. These studies reveal PKCδ pY313 as a promising readout of Src inhibition in CRC and potentially other solid tumors and may reflect responsiveness to dasatinib in a subset of colorectal cancers.

Ice Ih anomalies: Thermal contraction, anomalous volume isotope effect, and pressure-induced amorphization

Science.gov (United States)

Salim, Michael A.; Willow, Soohaeng Yoo; Hirata, So

2016-05-01

Ice Ih displays several anomalous thermodynamic properties such as thermal contraction at low temperatures, an anomalous volume isotope effect (VIE) rendering the volume of D2O ice greater than that of H2O ice, and a pressure-induced transition to the high-density amorphous (HDA) phase. Furthermore, the anomalous VIE increases with temperature, despite its quantum-mechanical origin. Here, embedded-fragment ab initio second-order many-body perturbation (MP2) theory in the quasiharmonic approximation (QHA) is applied to the Gibbs energy of an infinite, proton-disordered crystal of ice Ih at wide ranges of temperatures and pressures. The quantum effect of nuclei moving in anharmonic potentials is taken into account from first principles without any empirical or nonsystematic approximation to either the electronic or vibrational Hamiltonian. MP2 predicts quantitatively correctly the thermal contraction at low temperatures, which is confirmed to originate from the volume-contracting hydrogen-bond bending modes (acoustic phonons). It qualitatively reproduces (but underestimates) the thermal expansion at higher temperatures, caused by the volume-expanding hydrogen-bond stretching (and to a lesser extent librational) modes. The anomalous VIE is found to be the result of subtle cancellations among closely competing isotope effects on volume from all modes. Consequently, even ab initio MP2 with the aug-cc-pVDZ and aug-cc-pVTZ basis sets has difficulty reproducing this anomaly, yielding qualitatively varied predictions of the sign of the VIE depending on such computational details as the choice of the embedding field. However, the temperature growth of the anomalous VIE is reproduced robustly and is ascribed to the librational modes. These solid-state MP2 calculations, as well as MP2 Born-Oppenheimer molecular dynamics, find a volume collapse and a loss of symmetry and long-range order in ice Ih upon pressure loading of 2.35 GPa or higher. Concomitantly, rapid softening of

Ice Ih anomalies: Thermal contraction, anomalous volume isotope effect, and pressure-induced amorphization

Energy Technology Data Exchange (ETDEWEB)

Salim, Michael A.; Willow, Soohaeng Yoo; Hirata, So, E-mail: sohirata@illinois.edu [Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801 (United States)

2016-05-28

Ice Ih displays several anomalous thermodynamic properties such as thermal contraction at low temperatures, an anomalous volume isotope effect (VIE) rendering the volume of D{sub 2}O ice greater than that of H{sub 2}O ice, and a pressure-induced transition to the high-density amorphous (HDA) phase. Furthermore, the anomalous VIE increases with temperature, despite its quantum-mechanical origin. Here, embedded-fragment ab initio second-order many-body perturbation (MP2) theory in the quasiharmonic approximation (QHA) is applied to the Gibbs energy of an infinite, proton-disordered crystal of ice Ih at wide ranges of temperatures and pressures. The quantum effect of nuclei moving in anharmonic potentials is taken into account from first principles without any empirical or nonsystematic approximation to either the electronic or vibrational Hamiltonian. MP2 predicts quantitatively correctly the thermal contraction at low temperatures, which is confirmed to originate from the volume-contracting hydrogen-bond bending modes (acoustic phonons). It qualitatively reproduces (but underestimates) the thermal expansion at higher temperatures, caused by the volume-expanding hydrogen-bond stretching (and to a lesser extent librational) modes. The anomalous VIE is found to be the result of subtle cancellations among closely competing isotope effects on volume from all modes. Consequently, even ab initio MP2 with the aug-cc-pVDZ and aug-cc-pVTZ basis sets has difficulty reproducing this anomaly, yielding qualitatively varied predictions of the sign of the VIE depending on such computational details as the choice of the embedding field. However, the temperature growth of the anomalous VIE is reproduced robustly and is ascribed to the librational modes. These solid-state MP2 calculations, as well as MP2 Born–Oppenheimer molecular dynamics, find a volume collapse and a loss of symmetry and long-range order in ice Ih upon pressure loading of 2.35 GPa or higher. Concomitantly, rapid

Valsartan regulates the interaction of angiotensin II type 1 receptor and endothelial nitric oxide synthase via Src/PI3K/Akt signalling.

Science.gov (United States)

Su, Kuo-Hui; Tsai, Jin-Yi; Kou, Yu Ru; Chiang, An-Na; Hsiao, Sheng-Huang; Wu, Yuh-Lin; Hou, Hsin-Han; Pan, Ching-Chian; Shyue, Song-Kun; Lee, Tzong-Shyuan

2009-06-01

Valsartan, a selective angiotensin II type 1 receptor (AT1R) blocker, has beneficial effects in the cardiovascular system in part by its increase of nitric oxide (NO) bioavailability, yet the mechanisms are unclear. We investigated the molecular mechanisms underlying this effect in endothelial cells (ECs). NO production was examined by Griess reagent assay, DAF-2 DA fluorescence staining and cGMP ELISA kits. Protein interaction was determined by western blotting and immunoprecipitation. Treating bovine or human aortic ECs with valsartan increased NO production, as evidenced by elevated level of stable NO metabolites and intracellular cGMP. Valsartan increased the phosphorylation but not the protein level of endothelial NO synthase (eNOS). Inhibition of phosphoinositide-3 kinase (PI3K)/Akt and Src pathways by specific inhibitors suppressed valsartan-induced NO release. In addition, valsartan increased the tyrosine residue phosphorylation of AT1R, which was attenuated by inhibition of Src but not PI3K activities. Valsartan also suppressed the interaction of eNOS and AT1R, which was blocked by Src or PI3K inhibition. Valsartan-induced NO production in ECs is mediated through Src/PI3K/Akt-dependent phosphorylation of eNOS. Valsartan-induced AT1R phosphorylation depends on Src but not PI3K, whereas valsartan-induced suppression of AT1R-eNOS interaction depends on Src/PI3K/Akt signalling. These results indicate a novel vasoprotective mechanism of valsartan in upregulating NO production in ECs.

Anomalous Dimensions of Conformal Baryons

DEFF Research Database (Denmark)

Pica, Claudio; Sannino, Francesco

2016-01-01

We determine the anomalous dimensions of baryon operators for the three color theory as function of the number of massless flavours within the conformal window to the maximum known order in perturbation theory. We show that the anomalous dimension of the baryon is controllably small, within...

Physical and functional interactions between SH2 and SH3 domains of the Src family protein tyrosine kinase p59fyn

NARCIS (Netherlands)

Panchamoorthy, G.; Fukazawa, T.; Stolz, L.; Payne, G.; Reedquist, K.; Shoelson, S.; Songyang, Z.; Cantley, L.; Walsh, C.; Band, H.

1994-01-01

The Src family protein tyrosine kinases participate in signalling through cell surface receptors that lack intrinsic tyrosine kinase domains. All nine members of this family possess adjacent Src homology (SH2 and SH3) domains, both of which are essential for repression of the enzymatic activity. The

Can I solve my structure by SAD phasing? Planning an experiment, scaling data and evaluating the useful anomalous correlation and anomalous signal.

Science.gov (United States)

Terwilliger, Thomas C; Bunkóczi, Gábor; Hung, Li Wei; Zwart, Peter H; Smith, Janet L; Akey, David L; Adams, Paul D

2016-03-01

A key challenge in the SAD phasing method is solving a structure when the anomalous signal-to-noise ratio is low. Here, algorithms and tools for evaluating and optimizing the useful anomalous correlation and the anomalous signal in a SAD experiment are described. A simple theoretical framework [Terwilliger et al. (2016), Acta Cryst. D72, 346-358] is used to develop methods for planning a SAD experiment, scaling SAD data sets and estimating the useful anomalous correlation and anomalous signal in a SAD data set. The phenix.plan_sad_experiment tool uses a database of solved and unsolved SAD data sets and the expected characteristics of a SAD data set to estimate the probability that the anomalous substructure will be found in the SAD experiment and the expected map quality that would be obtained if the substructure were found. The phenix.scale_and_merge tool scales unmerged SAD data from one or more crystals using local scaling and optimizes the anomalous signal by identifying the systematic differences among data sets, and the phenix.anomalous_signal tool estimates the useful anomalous correlation and anomalous signal after collecting SAD data and estimates the probability that the data set can be solved and the likely figure of merit of phasing.

CMOS-based active RC sinusoidal oscillator with four-phase quadrature outputs and single-resistance-controlled (SRC) tuning laws

OpenAIRE

Lahiri, Abhirup; Herencsár, Norbert

2012-01-01

This paper proposes a very compact CMOS realization of active RC sinusoidal oscillator capable of generating four quadrature voltage outputs. The oscillator is based on the cascade of lossless and lossy integrators in loop. The governing laws for the condition of oscillation (CO) and the frequency of oscillation (FO) are single-resistance-controlled (SRC) and which allow independent FO tuning. Unlike previously reported SRC-based sinusoidal oscillators based on the active building block (ABB)...

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

Science.gov (United States)

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

2015-01-01

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

Sustained expression of steroid receptor coactivator SRC-2/TIF-2 is associated with better prognosis in malignant pleural mesothelioma.

LENUS (Irish Health Repository)

Jennings, Cormac J

2012-02-01

INTRODUCTION: Estrogen receptor beta (ERbeta) overexpression by malignant pleural mesothelioma (MPM) tumor cells correlates with enhanced patient survival. ER-regulated transcription is mediated by the p160 family of steroid receptor coactivators (SRCs), and SRC isoform overexpression is associated with worse prognosis in many steroid-related malignancies. The aim of this study was to establish whether SRC isoform expression varied between individual MPM tumors with positive or negative prognostic significance. METHODS: Immunohistochemical analysis of tumor biopsies from 89 subjects with confirmed histological diagnosis of MPM and biopsies from 3 normal control subjects was performed to detect the expression of SRC-1, SRC-2 (TIF-2), SRC-3 (AIB-1), and ERbeta. Allred scores for expression of ERbeta and each of the SRCs were determined, and Kaplan-Meier survival curves were calculated to correlate biomarker expression, gender, and histology type with postdiagnosis survival. RESULTS: ERbeta and all the SRCs were expressed at high levels in normal pleural mesothelium, and expression of each biomarker was reduced or lost in a subset of the MPM subjects; however, postdiagnosis survival only significantly correlated with TIF-2 expression. Low or intermediate expression of TIF-2 correlated with reduced median postdiagnosis survival (9 months) compared with those subjects whose tumors highly expressed TIF-2 (20 months) (p = 0.036, log-rank test). CONCLUSIONS: Maintained high expression of TIF-2 in tumor cells is a positive prognostic indicator for postdiagnosis survival in patients with confirmed MPM. This is the first clinical study to correlate high TIF-2 expression with improved patient prognosis in any malignancy.

Membrane microdomain-associated uroplakin IIIa contributes to Src-dependent mechanisms of anti-apoptotic proliferation in human bladder carcinoma cells

Directory of Open Access Journals (Sweden)

Shigeru Kihira

2012-08-01

Our previous study demonstrated that tyrosine phosphorylation of p145met/β-subunit of hepatocyte growth factor receptor by epidermal growth factor receptor and Src contributes to the anti-apoptotic growth of human bladder carcinoma cell 5637 under serum-starved conditions. Here, we show that some other cell lines of human bladder carcinoma, but not other types of human cancer cells, also exhibit Src-dependent, anti-apoptotic proliferation under serum-starved conditions, and that low-density, detergent-insoluble membrane microdomains (MD serve as a structural platform for signaling events involving p145met, EGFR, and Src. As an MD-associated molecule that may contribute to bladder carcinoma-specific cellular function, we identified uroplakin IIIa (UPIIIa, an urothelium-specific protein. Results obtained so far revealed: 1 UPIIIa undergoes partial proteolysis in serum-starved cells; 2 a specific antibody to the extracellular domain of UPIIIa inhibits the proteolysis of UPIIIa and the activation of Src, and promotes apoptosis in serum-starved cells; and 3 knockdown of UPIIIa by short interfering RNA also promotes apoptosis in serum-starved cells. GM6001, a potent inhibitor of matrix metalloproteinase (MMP, inhibits the proteolysis of UPIIIa and promotes apoptosis in serum-starved cells. Furthermore, serum starvation promotes expression and secretion of the heparin-binding EGF-like growth factor in a manner that depends on the functions of MMP, Src, and UPIIIa. These results highlight a hitherto unknown signaling network involving a subset of MD-associated molecules in the anti-apoptotic mechanisms of human bladder carcinoma cells.

KAI1 suppresses HIF-1α and VEGF expression by blocking CDCP1-enhanced Src activation in prostate cancer

Directory of Open Access Journals (Sweden)

Park Jung-Jin

2012-03-01

Full Text Available Abstract Background KAI1 was initially identified as a metastasis-suppressor gene in prostate cancer. It is a member of the tetraspan transmembrane superfamily (TM4SF of membrane glycoproteins. As part of a tetraspanin-enriched microdomain (TEM, KAI1 inhibits tumor metastasis by negative regulation of Src. However, the underlying regulatory mechanism has not yet been fully elucidated. CUB-domain-containing protein 1 (CDCP1, which was previously known as tetraspanin-interacting protein in TEM, promoted metastasis via enhancement of Src activity. To better understand how KAI1 is involved in the negative regulation of Src, we here examined the function of KAI1 in CDCP1-mediated Src kinase activation and the consequences of this process, focusing on HIF-1 α and VEGF expression. Methods We used the human prostate cancer cell line PC3 which was devoid of KAI1 expression. Vector-transfected cells (PC3-GFP clone #8 and KAI1-expressing PC3 clones (PC3-KAI1 clone #5 and #6 were picked after stable transfection with KAI1 cDNA and selection in 800 μg/ml G418. Protein levels were assessed by immunoblotting and VEGF reporter gene activity was measured by assaying luciferase activitiy. We followed tumor growth in vivo and immunohistochemistry was performed for detection of HIF-1, CDCP1, and VHL protein level. Results We demonstrated that Hypoxia-inducible factor 1α (HIF-1α and VEGF expression were significantly inhibited by restoration of KAI1 in PC3 cells. In response to KAI1 expression, CDCP1-enhanced Src activation was down-regulated and the level of von Hippel-Lindau (VHL protein was significantly increased. In an in vivo xenograft model, KAI1 inhibited the expression of CDCP1 and HIF-1α. Conclusions These novel observations may indicate that KAI1 exerts profound metastasis-suppressor activity in the tumor malignancy process via inhibition of CDCP1-mediated Src activation, followed by VHL-induced HIF-1α degradation and, ultimately, decreased VEGF

76 FR 21404 - National Park Service Alaska Region's Subsistence Resource Commission (SRC) Program

Science.gov (United States)

2011-04-15

... National Park SRC will meet at the Shungnak Public School, 907-437-2151, in Shungnak, Alaska on Wednesday... changed, a notice will be published in local newspapers and announced on local radio stations prior to the...

Anomalous Hall effect in polycrystalline Ni films

KAUST Repository

Guo, Zaibing

2012-02-01

We systematically studied the anomalous Hall effect in a series of polycrystalline Ni films with thickness ranging from 4 to 200 nm. It is found that both the longitudinal and anomalous Hall resistivity increased greatly as film thickness decreased. This enhancement should be related to the surface scattering. In the ultrathin films (46 nm thick), weak localization corrections to anomalous Hall conductivity were studied. The granular model, taking into account the dominated intergranular tunneling, has been employed to explain this phenomenon, which can explain the weak dependence of anomalous Hall resistivity on longitudinal resistivity as well. © 2011 Elsevier Ltd. All rights reserved.

Protein arginine methyltransferase 5 (PRMT5) is a novel coactivator of constitutive androstane receptor (CAR)

International Nuclear Information System (INIS)

Kanno, Yuichiro; Inajima, Jun; Kato, Sayaka; Matsumoto, Maika; Tokumoto, Chikako; Kure, Yuki; Inouye, Yoshio

2015-01-01

The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that protein arginine methyltransferase 5 (PRMT5) is a novel CAR-interacting protein. Furthermore, the PRMT-dependent induction of a CAR reporter gene, which was independent of methyltransferase activity, was enhanced in the presence of steroid receptor coactivator 1 (SRC1), peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) or DEAD box DNA/RNA helicase DP97. Using tetracycline inducible-hCAR system in HepG2 cells, we showed that knockdown of PRMT5 with small interfering RNA suppressed tetracycline -induced mRNA expression of CYP2B6 but not of CYP2C9 or CYP3A4. PRMT5 enhanced phenobarbital-mediated transactivation of a phenobarbital-responsive enhancer module (PBREM)-driven reporter gene in co-operation with PGC-1α in rat primary hepatocytes. Based on these findings, we suggest PRMT5 to be a gene (or promoter)-selective coactivator of CAR by mediating the formation of complexes between hCAR and appropriate coactivators. - Highlights: • Nuclear receptor CAR interact with PRMT5. • PRMT5 enhances transcriptional activity of CAR. • PRMT5 synergistically enhances transactivity of CAR by the co-expression of SRC-1, DP97 or PGC1α. • PRMT5 is a gene-selective co-activator for hCAR

Protein arginine methyltransferase 5 (PRMT5) is a novel coactivator of constitutive androstane receptor (CAR)

Energy Technology Data Exchange (ETDEWEB)

Kanno, Yuichiro, E-mail: ykanno@phar.toho-u.ac.jp; Inajima, Jun; Kato, Sayaka; Matsumoto, Maika; Tokumoto, Chikako; Kure, Yuki; Inouye, Yoshio

2015-03-27

The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that protein arginine methyltransferase 5 (PRMT5) is a novel CAR-interacting protein. Furthermore, the PRMT-dependent induction of a CAR reporter gene, which was independent of methyltransferase activity, was enhanced in the presence of steroid receptor coactivator 1 (SRC1), peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) or DEAD box DNA/RNA helicase DP97. Using tetracycline inducible-hCAR system in HepG2 cells, we showed that knockdown of PRMT5 with small interfering RNA suppressed tetracycline -induced mRNA expression of CYP2B6 but not of CYP2C9 or CYP3A4. PRMT5 enhanced phenobarbital-mediated transactivation of a phenobarbital-responsive enhancer module (PBREM)-driven reporter gene in co-operation with PGC-1α in rat primary hepatocytes. Based on these findings, we suggest PRMT5 to be a gene (or promoter)-selective coactivator of CAR by mediating the formation of complexes between hCAR and appropriate coactivators. - Highlights: • Nuclear receptor CAR interact with PRMT5. • PRMT5 enhances transcriptional activity of CAR. • PRMT5 synergistically enhances transactivity of CAR by the co-expression of SRC-1, DP97 or PGC1α. • PRMT5 is a gene-selective co-activator for hCAR.

Regulation of Discrete Functional Responses by Syk and Src Family Tyrosine Kinases in Human Neutrophils

Directory of Open Access Journals (Sweden)

Thornin Ear

2017-01-01

Full Text Available Neutrophils play a critical role in innate immunity and also influence adaptive immune responses. This occurs in good part through their production of inflammatory and immunomodulatory cytokines, in conjunction with their prolonged survival at inflamed foci. While a picture of the signaling machinery underlying these neutrophil responses is now emerging, much remains to be uncovered. In this study, we report that neutrophils constitutively express various Src family isoforms (STKs, as well as Syk, and that inhibition of these protein tyrosine kinases selectively hinders inflammatory cytokine generation by acting posttranscriptionally. Accordingly, STK or Syk inhibition decreases the phosphorylation of signaling intermediates (e.g., eIF-4E, S6K, and MNK1 involved in translational control. By contrast, delayed apoptosis appears to be independent of either STKs or Syk. Our data therefore significantly extend our understanding of which neutrophil responses are governed by STKs and Syk and pinpoint some signaling intermediates that are likely involved. In view of the foremost role of neutrophils in several chronic inflammatory conditions, our findings identify potential molecular targets that could be exploited for future therapeutic intervention.

Lipopolysaccharide induces VCAM-1 expression and neutrophil adhesion to human tracheal smooth muscle cells: Involvement of Src/EGFR/PI3-K/Akt pathway

International Nuclear Information System (INIS)

Lin, W.-N.; Luo, S.-F.; Wu, C.-B.; Lin, C.-C.; Yang, C.-M.

2008-01-01

In our previous study, LPS has been shown to induce vascular cell adhesion molecule-1(VCAM-1) expression through MAPKs and NF-κB in human tracheal smooth muscle cells (HTSMCs). In addition to these pathways, the non-receptor tyrosine kinases (Src), EGF receptor (EGFR), and phosphatidylinositol 3-kinase (PI3K) have been shown to be implicated in the expression of several inflammatory target proteins. Here, we reported that LPS-induced up-regulation of VCAM-1 enhanced the adhesion of neutrophils onto HTSMC monolayer, which was inhibited by LY294002 and wortmannin. LPS stimulated phosphorylation of protein tyrosine kinases including Src, PYK2, and EGFR, which were further confirmed using specific anti-phospho-Src, PYK2, or EGFR Ab, respectively, revealed by Western blotting. LPS-stimulated Src, PYK2, EGFR, and Akt phosphorylation and VCAM-1 expression were attenuated by the inhibitors of Src (PP1), EGFR (AG1478), PI3-K (LY294002 and wortmannin), and Akt (SH-5), respectively, or transfection with siRNAs of Src or Akt and shRNA of p110. LPS-induced VCAM-1 expression was also blocked by pretreatment with curcumin (a p300 inhibitor) or transfection with p300 siRNA. LPS-stimulated Akt activation translocated into nucleus and associated with p300 and VCAM-1 promoter region was further confirmed by immunofluorescence, immunoprecipitation, and chromatin immunoprecipitation assays. This association of Akt and p300 to VCAM-1 promoter was inhibited by pretreatment with PP1, AG1478, wortmannin, and SH-5. LPS-induced p300 activation enhanced VCAM-1 promoter activity and VCAM-1 mRNA expression. These results suggested that in HTSMCs, Akt phosphorylation mediated through transactivation of Src/PYK2/EGFR promoted the transcriptional p300 activity and eventually led to VCAM-1 expression induced by LPS

Role of c-Src inhibitor in the regulation of hepatocarcinoma cell ...

African Journals Online (AJOL)

SAM

2014-03-19

Mar 19, 2014 ... BEL-7402 cell line was used as HCC cell model for investigating the regulation of cell migration upon c-. Src inhibitors (PP2 and .... PDGF-BB were purchased from Enzo Life Sciences International,. USA; SU6656 Sigma (USA). .... Statistical analysis was done with Student's t-test for comparison of two ...

SRC-I solvent refined coal demonstration facility, Daviess County, Kentucky

Energy Technology Data Exchange (ETDEWEB)

1980-08-01

This volume of the Environmental Information Document on SRC-I contains appendices I-P. Information is provided for the preparation of the Environmental Impact Statement. Title listings of the appendices are: meteorology and air quality reports, December 1978 and March 1979; sound; economic, social, and cultural features; historical/architectural survey; archeological reports, 1979 and 1980; potential for burial and preservation of fossils; and alternate sites.

Modeling the anomalous flow behavior of Ni3Al intermetallic single crystals

International Nuclear Information System (INIS)

Choi, Y.S.; Parthasarathy, T.A.; Dimiduk, D.M.; Uchic, M.D.

2004-01-01

In this study we present a new constitutive model for Ni3Al and Ni3(Al, X) alloys that was developed to represent many of the unusual plastic flow behavior found in L12 intermetallics while maintaining consistency with the experimentally-observed evolution of dislocation substructure. In particular, we sought to develop a model that would not only predict the anomalous increase of the yield strength with increasing temperature, but would also capture other important flow characteristics such as extremely high work-hardening rates that change anomalously with temperature, and a flow stress that is partially to fully reversible with temperature. For this model, we have treated work-hardening as arising from two different sources. Thermally-reversible work hardening is accounted for using the description of screw dislocation motion proposed by Caillard, which involves exhaustion of mobile dislocations by cross-slip locking of the dislocation core and athermal unlocking. Thermally-irreversible work hardening is accounted for using an approach consistent with the theoretical framework proposed by Ezz and Hirsch, which involves both the multiplication of Frank-Reed sources and the interaction of edge-dislocation segments with cross-slip locking events and the dislocation forest. Both work-hardening contributions were incorporated into the rate formulation for thermally-activated plastic flow proposed by Kocks, Argon and Ashby. We will show simulation results for the flow response of Ni3(Al, X) crystals over a wide range of temperatures in the anomalous flow regime, and we will compare these findings with experimental data

syk kinase activation by a src kinase-initiated activation loop phosphorylation chain reaction

Science.gov (United States)

El-Hillal, O.; Kurosaki, T.; Yamamura, H.; Kinet, J.-P.; Scharenberg, A. M.

1997-01-01

Activation of the syk tyrosine kinase occurs almost immediately following engagement of many types of antigen receptors, including Fc receptors, but the mechanism through which syk is activated is currently unclear. Here we demonstrate that Fc receptor-induced syk activation occurs as the result of phosphorylation of the syk activation loop by both src family kinases and other molecules of activated syk, suggesting that syk activation occurs as the result of a src kinase-initiated activation loop phosphorylation chain reaction. This type of activation mechanism predicts that syk activation would exhibit exponential kinetics, providing a potential explanation for its rapid and robust activation by even weak antigen receptor stimuli. We propose that a similar mechanism may be responsible for generating rapid activation of other cytoplasmic tyrosine kinases, such as those of the Bruton tyrosine kinase/tec family, as well. PMID:9050880

Identification of a New Interaction Mode between the Src Homology 2 Domain of C-terminal Src Kinase (Csk) and Csk-binding Protein/Phosphoprotein Associated with Glycosphingolipid Microdomains♦

Science.gov (United States)

Tanaka, Hiroaki; Akagi, Ken-ichi; Oneyama, Chitose; Tanaka, Masakazu; Sasaki, Yuichi; Kanou, Takashi; Lee, Young-Ho; Yokogawa, Daisuke; Dobenecker, Marc-Werner; Nakagawa, Atsushi; Okada, Masato; Ikegami, Takahisa

2013-01-01

Proteins with Src homology 2 (SH2) domains play major roles in tyrosine kinase signaling. Structures of many SH2 domains have been studied, and the regions involved in their interactions with ligands have been elucidated. However, these analyses have been performed using short peptides consisting of phosphotyrosine followed by a few amino acids, which are described as the canonical recognition sites. Here, we report the solution structure of the SH2 domain of C-terminal Src kinase (Csk) in complex with a longer phosphopeptide from the Csk-binding protein (Cbp). This structure, together with biochemical experiments, revealed the existence of a novel binding region in addition to the canonical phosphotyrosine 314-binding site of Cbp. Mutational analysis of this second region in cells showed that both canonical and novel binding sites are required for tumor suppression through the Cbp-Csk interaction. Furthermore, the data indicate an allosteric connection between Cbp binding and Csk activation that arises from residues in the βB/βC loop of the SH2 domain. PMID:23548896

Fcγ-receptor IIa-mediated Src Signaling Pathway Is Essential for the Antibody-Dependent Enhancement of Ebola Virus Infection.

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Wakako Furuyama

2016-12-01

Full Text Available Antibody-dependent enhancement (ADE of Ebola virus (EBOV infection has been demonstrated in vitro, raising concerns about the detrimental potential of some anti-EBOV antibodies. ADE has been described for many viruses and mostly depends on the cross-linking of virus-antibody complexes to cell surface Fc receptors, leading to enhanced infection. However, little is known about the molecular mechanisms underlying this phenomenon. Here we show that Fcγ-receptor IIa (FcγRIIa-mediated intracellular signaling through Src family protein tyrosine kinases (PTKs is required for ADE of EBOV infection. We found that deletion of the FcγRIIa cytoplasmic tail abolished EBOV ADE due to decreased virus uptake into cellular endosomes. Furthermore, EBOV ADE, but not non-ADE infection, was significantly reduced by inhibition of the Src family protein PTK pathway, which was also found to be important to promote phagocytosis/macropinocytosis for viral uptake into endosomes. We further confirmed a significant increase of the Src phosphorylation mediated by ADE. These data suggest that antibody-EBOV complexes bound to the cell surface FcγRIIa activate the Src signaling pathway that leads to enhanced viral entry into cells, providing a novel perspective for the general understanding of ADE of virus infection.

c-SRC mediates neurite outgrowth through recruitment of Crk to the scaffolding protein Sin/Efs without altering the kinetics of ERK activation

DEFF Research Database (Denmark)

Yang, Liang-Tung; Alexandropoulos, Konstantina; Sap, Jan

2002-01-01

moderate activation of endogenous SRC by receptor-protein-tyrosine phosphatase alpha (a physiological SRC activator). We show that such a qualitative change in the response to EGF is not accompanied by changes in the extent or kinetics of ERK induction in response to this factor. Instead, the pathway...

DP97, a DEAD box DNA/RNA helicase, is a target gene-selective co-regulator of the constitutive androstane receptor

Energy Technology Data Exchange (ETDEWEB)

Kanno, Yuichiro, E-mail: ykanno@phar.toho-u.ac.jp [Faculty of Pharmaceutical Sciences, Toho University, Chiba (Japan); Serikawa, Takafumi; Inajima, Jun; Inouye, Yoshio [Faculty of Pharmaceutical Sciences, Toho University, Chiba (Japan)

2012-09-14

Highlights: Black-Right-Pointing-Pointer DP97 interacts with nuclear receptor CAR. Black-Right-Pointing-Pointer DP97 enhances CAR-mediated transcriptional activation. Black-Right-Pointing-Pointer DP97 synergistically enhances transactivity of CAR by the co-expression of SRC-1 or PGC1{alpha}. Black-Right-Pointing-Pointer DP97 is a gene-selective co-activator for hCAR. -- Abstract: The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that DP97, a member of the DEAD box DNA/RNA helicase protein family, is a novel CAR-interacting protein. Using HepG2 cells expressing human CAR in the presence of tetracycline, we showed that knockdown of DP97 with small interfering RNAs suppressed tetracycline-inducible mRNA expression of CYP2B6 and UGT1A1 but not CYP3A4. Thus, DP97 was found to be a gene (or promoter)-selective co-activator for hCAR. DP97-mediated CAR transactivation was synergistically enhanced by the co-expression of SRC-1 or PGC1{alpha}, therefore it might act as mediator between hCAR and appropriate co-activators.

EFFECT OF COMMERCIALLY MANUFACTURED KAPPA SEMI-REFINED CARRAGEENAN (SRC WITH DIFFERENT PHOSPHATE SALTS ON YIELD, TEXTURAL AND SENSORY PROPERTIES OF BEEF MEAT

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Marimuthu Murugesan

2016-06-01

Full Text Available The phosphate salts such as SDP, TSP, SHMP, DSP, TPPP, TKPP and STPP were blended with semi-refined kappa carrageenan (SRC individually and their aqueous solution was injected into the fresh beef meat. The highest weight gain (24% in fresh meat was obtained from injection of blend made with SRC and STPP as compared to other blends and control sample after forzen storage. Similarly, it also showed low cooking loss (24% with good testural and sensory proerties as compared to other blends. It can be concluded from the presnt study that blend of SRC and STPP can be used in beef meat for yield and quality improvement.

Inhibiting Src family tyrosine kinase activity blocks glutamate signalling to ERK1/2 and Akt/PKB but not JNK in cultured striatal neurones.

Science.gov (United States)

Crossthwaite, Andrew J; Valli, Haseeb; Williams, Robert J

2004-03-01

Glutamate receptor activation of mitogen-activated protein (MAP) kinase signalling cascades has been implicated in diverse neuronal functions such as synaptic plasticity, development and excitotoxicity. We have previously shown that Ca2+-influx through NMDA receptors in cultured striatal neurones mediates the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt/protein kinase B (PKB) through a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathway. Exposing neurones to the Src family tyrosine kinase inhibitor PP2, but not the inactive analogue PP3, inhibited NMDA receptor-induced phosphorylation of ERK1/2 and Akt/PKB in a concentration-dependent manner, and reduced cAMP response element-binding protein (CREB) phosphorylation. To establish a link between Src family tyrosine kinase-mediated phosphorylation and PI 3-kinase signalling, affinity precipitation experiments were performed with the SH2 domains of the PI 3-kinase regulatory subunit p85. This revealed a Src-dependent phosphorylation of a focal adhesion kinase (FAK)-p85 complex on glutamate stimulation. Demonstrating that PI3-kinase is not ubiquitously involved in NMDA receptor signal transduction, the PI 3-kinase inhibitors wortmannin and LY294002 did not prevent NMDA receptor Ca2+-dependent phosphorylation of c-Jun N-terminal kinase 1/2 (JNK1/2). Further, inhibiting Src family kinases increased NMDA receptor-dependent JNK1/2 phosphorylation, suggesting that Src family kinase-dependent cascades may physiologically limit signalling to JNK. These results demonstrate that Src family tyrosine kinases and PI3-kinase are pivotal regulators of NMDA receptor signalling to ERK/Akt and JNK in striatal neurones.

Rapid activation of Rac GTPase in living cells by force is independent of Src.

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Yeh-Chuin Poh

2009-11-01

Full Text Available It is well known that mechanical forces are crucial in regulating functions of every tissue and organ in a human body. However, it remains unclear how mechanical forces are transduced into biochemical activities and biological responses at the cellular and molecular level. Using the magnetic twisting cytometry technique, we applied local mechanical stresses to living human airway smooth muscle cells with a magnetic bead bound to the cell surface via transmembrane adhesion molecule integrins. The temporal and spatial activation of Rac, a small guanosine triphosphatase, was quantified using a fluorescent resonance energy transfer (FRET method that measures changes in Rac activity in response to mechanical stresses by quantifying intensity ratios of ECFP (enhanced cyan fluorescent protein as a donor and YPet (a variant yellow fluorescent protein as an acceptor of the Rac biosensor. The applied stress induced rapid activation (less than 300 ms of Rac at the cell periphery. In contrast, platelet derived growth factor (PDGF induced Rac activation at a much later time (>30 sec. There was no stress-induced Rac activation when a mutant form of the Rac biosensor (RacN17 was transfected or when the magnetic bead was coated with transferrin or with poly-L-lysine. It is known that PDGF-induced Rac activation depends on Src activity. Surprisingly, pre-treatment of the cells with specific Src inhibitor PP1 or knocking-out Src gene had no effects on stress-induced Rac activation. In addition, eliminating lipid rafts through extraction of cholesterol from the plasma membrane did not prevent stress-induced Rac activation, suggesting a raft-independent mechanism in governing the Rac activation upon mechanical stimulation. Further evidence indicates that Rac activation by stress depends on the magnitudes of the applied stress and cytoskeletal integrity. Our results suggest that Rac activation by mechanical forces is rapid, direct and does not depend on Src

Tunneling Anomalous and Spin Hall Effects.

Science.gov (United States)

Matos-Abiague, A; Fabian, J

2015-07-31

We predict, theoretically, the existence of the anomalous Hall effect when a tunneling current flows through a tunnel junction in which only one of the electrodes is magnetic. The interfacial spin-orbit coupling present in the barrier region induces a spin-dependent momentum filtering in the directions perpendicular to the tunneling current, resulting in a skew tunneling even in the absence of impurities. This produces an anomalous Hall conductance and spin Hall currents in the nonmagnetic electrode when a bias voltage is applied across the tunneling heterojunction. If the barrier is composed of a noncentrosymmetric material, the anomalous Hall conductance and spin Hall currents become anisotropic with respect to both the magnetization and crystallographic directions, allowing us to separate this interfacial phenomenon from the bulk anomalous and spin Hall contributions. The proposed effect should be useful for proving and quantifying the interfacial spin-orbit fields in metallic and metal-semiconductor systems.

Fisetin suppresses malignant proliferation in human oral squamous cell carcinoma through inhibition of Met/Src signaling pathways.

Science.gov (United States)

Li, Yan-Shu; Qin, Xing-Jun; Dai, Wei

2017-01-01

Fisetin (3,7,3',4'-tetrahydroxyflavone) is a dietary flavonoid and has been indicated as a novel anti-cancer agent in several types of cancer cells. However, the mechanisms underlying the effect of fisetin in human oral squamous cell carcinoma (OSCC) remain unclear. Here, we report that fisetin significantly inhibits tumor cell proliferation and induces apoptosis in OSCC (UM-SCC-23 and Tca-8113) cancer cell lines. Further analysis demonstrates that fisetin also inhibits Met/Src signaling pathways using the PathScan ® receptor tyrosine kinases (RTK) Signaling Antibody Array Kit. Fisetin resulted in decreased basal expression of Met and Src protein in UM-SCC-23 cancer cell lines, which validated by western blot. A student's t -test (two-tailed) was used to compare differences between groups. Furthermore, fisetin significantly inhibited the expression of a disintegrin and metalloproteinase 9 (ADAM9) protein in OSCC cells. Taken together, these results provide novel insights into the mechanism of fisetin and suggest potential therapeutic strategies for human OSCC by blocking the Met/Src signaling pathways.

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

Science.gov (United States)

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

2015-03-01

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

Anomalous dispersion enhanced Cerenkov phase-matching

Energy Technology Data Exchange (ETDEWEB)

Kowalczyk, T.C.; Singer, K.D. [Case Western Reserve Univ., Cleveland, OH (United States). Dept. of Physics; Cahill, P.A. [Sandia National Labs., Albuquerque, NM (United States)

1993-11-01

The authors report on a scheme for phase-matching second harmonic generation in polymer waveguides based on the use of anomalous dispersion to optimize Cerenkov phase matching. They have used the theoretical results of Hashizume et al. and Onda and Ito to design an optimum structure for phase-matched conversion. They have found that the use of anomalous dispersion in the design results in a 100-fold enhancement in the calculated conversion efficiency. This technique also overcomes the limitation of anomalous dispersion phase-matching which results from absorption at the second harmonic. Experiments are in progress to demonstrate these results.

Anomalous diffusion in chaotic scattering

International Nuclear Information System (INIS)

Srokowski, T.; Ploszajczak, M.

1994-01-01

The anomalous diffusion is found for peripheral collision of atomic nuclei described in the framework of the molecular dynamics. Similarly as for chaotic billiards, the long free paths are the source of the long-time correlations and the anomalous diffusion. Consequences of this finding for the energy dissipation in deep-inelastic collisions and the dynamics of fission in hot nuclei are discussed (authors). 30 refs., 2 figs

Anomalous x-ray radiation of beam plasma

International Nuclear Information System (INIS)

Dimitrov, S.K.; Zavyalov, M.A.; Mikhin, S.G.; Tarasenkov, V.A.; Telkovskij, V.G.; Khrabrov, V.A.

1985-01-01

The properties of non-equilibrium stationary plasma under the conditions of the planned plasma-chemical reactors based on beam-plasma discharge were investigated. The x-ray spectrum of the beam-plasma was measured and anomalous spectral properties were analyzed. Starting with some critical pressure the anomalous radiation was added to the classical bremsstrahlung spectrum. The occurrence of anomalous radiation can be used to diagnose the condition of beam transportation in such systems. (D.Gy.)

Anomalous osmosis resulting from preferential absorption

NARCIS (Netherlands)

Staverman, A.J.; Kruissink, C.A.; Pals, D.T.F.

1965-01-01

An explanation of the anomalous osmosis described in the preceding paper is given in terms of friction coefficients in the glass membrane. It is shown that anomalous osmosis may be expected when the friction coefficients are constant and positive provided that the membrane absorbs solute strongly

Development and experimental test of support vector machines virtual screening method for searching Src inhibitors from large compound libraries

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Han Bucong

2012-11-01

Full Text Available Abstract Background Src plays various roles in tumour progression, invasion, metastasis, angiogenesis and survival. It is one of the multiple targets of multi-target kinase inhibitors in clinical uses and trials for the treatment of leukemia and other cancers. These successes and appearances of drug resistance in some patients have raised significant interest and efforts in discovering new Src inhibitors. Various in-silico methods have been used in some of these efforts. It is desirable to explore additional in-silico methods, particularly those capable of searching large compound libraries at high yields and reduced false-hit rates. Results We evaluated support vector machines (SVM as virtual screening tools for searching Src inhibitors from large compound libraries. SVM trained and tested by 1,703 inhibitors and 63,318 putative non-inhibitors correctly identified 93.53%~ 95.01% inhibitors and 99.81%~ 99.90% non-inhibitors in 5-fold cross validation studies. SVM trained by 1,703 inhibitors reported before 2011 and 63,318 putative non-inhibitors correctly identified 70.45% of the 44 inhibitors reported since 2011, and predicted as inhibitors 44,843 (0.33% of 13.56M PubChem, 1,496 (0.89% of 168 K MDDR, and 719 (7.73% of 9,305 MDDR compounds similar to the known inhibitors. Conclusions SVM showed comparable yield and reduced false hit rates in searching large compound libraries compared to the similarity-based and other machine-learning VS methods developed from the same set of training compounds and molecular descriptors. We tested three virtual hits of the same novel scaffold from in-house chemical libraries not reported as Src inhibitor, one of which showed moderate activity. SVM may be potentially explored for searching Src inhibitors from large compound libraries at low false-hit rates.

Development and experimental test of support vector machines virtual screening method for searching Src inhibitors from large compound libraries.

Science.gov (United States)

Han, Bucong; Ma, Xiaohua; Zhao, Ruiying; Zhang, Jingxian; Wei, Xiaona; Liu, Xianghui; Liu, Xin; Zhang, Cunlong; Tan, Chunyan; Jiang, Yuyang; Chen, Yuzong

2012-11-23

Src plays various roles in tumour progression, invasion, metastasis, angiogenesis and survival. It is one of the multiple targets of multi-target kinase inhibitors in clinical uses and trials for the treatment of leukemia and other cancers. These successes and appearances of drug resistance in some patients have raised significant interest and efforts in discovering new Src inhibitors. Various in-silico methods have been used in some of these efforts. It is desirable to explore additional in-silico methods, particularly those capable of searching large compound libraries at high yields and reduced false-hit rates. We evaluated support vector machines (SVM) as virtual screening tools for searching Src inhibitors from large compound libraries. SVM trained and tested by 1,703 inhibitors and 63,318 putative non-inhibitors correctly identified 93.53%~ 95.01% inhibitors and 99.81%~ 99.90% non-inhibitors in 5-fold cross validation studies. SVM trained by 1,703 inhibitors reported before 2011 and 63,318 putative non-inhibitors correctly identified 70.45% of the 44 inhibitors reported since 2011, and predicted as inhibitors 44,843 (0.33%) of 13.56M PubChem, 1,496 (0.89%) of 168 K MDDR, and 719 (7.73%) of 9,305 MDDR compounds similar to the known inhibitors. SVM showed comparable yield and reduced false hit rates in searching large compound libraries compared to the similarity-based and other machine-learning VS methods developed from the same set of training compounds and molecular descriptors. We tested three virtual hits of the same novel scaffold from in-house chemical libraries not reported as Src inhibitor, one of which showed moderate activity. SVM may be potentially explored for searching Src inhibitors from large compound libraries at low false-hit rates.

Integrin αβ1, αvβ, α6β effectors p130Cas, Src and talin regulate carcinoma invasion and chemoresistance

International Nuclear Information System (INIS)

Sansing, Hope A.; Sarkeshik, Ali; Yates, John R.; Patel, Vyomesh; Gutkind, J. Silvio; Yamada, Kenneth M.; Berrier, Allison L.

2011-01-01

Research highlights: → Proteomics of clustered integrin αβ1, α v β, α 6 β receptors in oral carcinoma. → p130Cas, Dek, Src and talin regulate oral carcinoma invasion. → p130Cas, talin, Src and zyxin regulate oral carcinoma resistance to cisplatin. -- Abstract: Ligand engagement by integrins induces receptor clustering and formation of complexes at the integrin cytoplasmic face that controls cell signaling and cytoskeletal dynamics critical for adhesion-dependent processes. This study searches for a subset of integrin effectors that coordinates both tumor cell invasion and resistance to the chemotherapeutic drug cisplatin in oral carcinomas. Candidate integrin effectors were identified in a proteomics screen of proteins recruited to clustered integrin αβ1, α v β or α 6 β receptors in oral carcinomas. Proteins with diverse functions including microtubule and actin binding proteins, and factors involved in trafficking, transcription and translation were identified in oral carcinoma integrin complexes. Knockdown of effectors in the oral carcinoma HN12 cells revealed that p130Cas, Dek, Src and talin were required for invasion through Matrigel. Disruption of talin or p130Cas by RNA interference increased resistance to cisplatin, whereas targeting Dek, Src or zyxin reduced HN12 resistance to cisplatin. Analysis of the spreading of HN12 cells on collagen I and laminin I revealed that a decrease in p130Cas or talin expression inhibited spreading on both matrices. Interestingly, a reduction in zyxin expression enhanced spreading on laminin I and inhibited spreading on collagen I. Reduction of Dek, Src, talin or zyxin expression reduced HN12 proliferation by 30%. Proliferation was not affected by a reduction in p130Cas expression. We conclude that p130Cas, Src and talin function in both oral carcinoma invasion and resistance to cisplatin.

Characterization of cortactin as an in vivo protein kinase D substrate: interdependence of sites and potentiation by Src.

Science.gov (United States)

De Kimpe, Line; Janssens, Katrien; Derua, Rita; Armacki, Milena; Goicoechea, Silvia; Otey, Carol; Waelkens, Etienne; Vandoninck, Sandy; Vandenheede, Jackie R; Seufferlein, Thomas; Van Lint, Johan

2009-02-01

Protein Kinase D (PKD) has been implicated in the regulation of actin turnover at the leading edge, invasion and migration. In particular, a complex between cortactin, paxillin and PKD in the invadopodia of invasive breast cancer cells has been described earlier, but so far this complex remained ill defined. Here we have investigated the possible role of PKD as a cortactin kinase. Using a mass spectrometric approach, we found that PKD phosphorylates cortactin on Ser 298 in the 6th cortactin repeat region and on Ser 348, right before the helical-proline rich domain of cortactin. We developed phosphospecific antibodies against these phosphorylated sequences, and used them as tools to follow the in vivo phosphorylation of cortactin by PKD. Examination of cortactin phosphorylation kinetics revealed that Ser 298 serves as a priming site for subsequent phosphorylation of Ser 348. Src, a well-known cortactin kinase, strongly potentiated the in vivo PKD mediated cortactin phosphorylation. This Src effect is neither mediated by pre-phosphorylation of cortactin nor by activation of PKD by Src. Phosphorylation of cortactin by PKD does not affect its subcellular localization, nor does it affect its translocation to podosomes or membrane ruffles. Moreover, there was no effect of PKD mediated cortactin phosphorylation on EGF receptor degradation and LPA induced migration. Taken together, these data establish cortactin as a novel PKD substrate and reveal a novel connection between Src and PKD.

Anomalous magnetoresistance in amorphous metals

International Nuclear Information System (INIS)

Kuz'menko, V.M.; Vladychkin, A.N.; Mel'nikov, V.I.; Sudovtsev, A.I.

1984-01-01

The magnetoresistance of amorphous Bi, Ca, V and Yb films is investigated in fields up to 4 T at low temperatures. For all metals the magnetoresistance is positive, sharply decreases with growth of temperature and depends anomalously on the magnetic field strength. For amorphous superconductors the results agree satisfactorily with the theory of anomalous magnetoresistance in which allowance is made for scattering of electrons by the superconducting fluctuations

Inactivation of Src-to-Ezrin Pathway: A Possible Mechanism in the Ouabain-Mediated Inhibition of A549 Cell Migration

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Hye Kyoung Shin

2015-01-01

Full Text Available Ouabain, a cardiac glycoside found in plants, is primarily used in the treatment of congestive heart failure and arrhythmia because of its ability to inhibit Na+/K+-ATPase pump. Recently ouabain has been shown to exert anticancer effects but the underlying mechanism is not clear. Here, we explored the molecular mechanism by which ouabain exerts anticancer effects in human lung adenocarcinoma. Employing proteomic techniques, we found 7 proteins downregulated by ouabain in A549 including p-ezrin, a protein associated with pulmonary cancer metastasis in a dose-dependent manner. In addition, when the relative phosphorylation levels of 39 intracellular proteins were compared between control and ouabain-treated A549 cells, p-Src (Y416 was also found to be downregulated by ouabain. Furthermore, western blot revealed the ouabain-mediated downregulation of p-FAK (Y925, p-paxillin (Y118, p130CAS, and Na+/K+-ATPase subunits that have been shown to be involved in the migration of cancer cells. The inhibitory effect of ouabain and Src inhibitor PP2 on the migration of A549 cells was confirmed by Boyden chamber assay. Anticancer effects of ouabain in A549 cells appear to be related to its ability to regulate and inactivate Src-to-ezrin signaling, and proteins involved in focal adhesion such as Src, FAK, and p130CAS axis are proposed here.

Barium promotes anchorage-independent growth and invasion of human HaCaT keratinocytes via activation of c-SRC kinase.

Science.gov (United States)

Thang, Nguyen Dinh; Yajima, Ichiro; Kumasaka, Mayuko Y; Ohnuma, Shoko; Yanagishita, Takeshi; Hayashi, Rumiko; Shekhar, Hossain U; Watanabe, Daisuke; Kato, Masashi

2011-01-01

Explosive increases in skin cancers have been reported in more than 36 million patients with arsenicosis caused by drinking arsenic-polluted well water. This study and previous studies showed high levels of barium as well as arsenic in the well water. However, there have been no reports showing a correlation between barium and cancer. In this study, we examined whether barium (BaCl(2)) may independently have cancer-related effects on human precancerous keratinocytes (HaCaT). Barium (5-50 µM) biologically promoted anchorage-independent growth and invasion of HaCaT cells in vitro. Barium (5 µM) biochemically enhanced activities of c-SRC, FAK, ERK and MT1-MMP molecules, which regulate anchorage-independent growth and/or invasion. A SRC kinase specific inhibitor, protein phosphatase 2 (PP2), blocked barium-mediated promotion of anchorage-independent growth and invasion with decreased c-SRC kinase activity. Barium (2.5-5 µM) also promoted anchorage-independent growth and invasion of fibroblasts (NIH3T3) and immortalized nontumorigenic melanocytes (melan-a), but not transformed cutaneous squamous cell carcinoma (HSC5 and A431) and malignant melanoma (Mel-ret) cells, with activation of c-SRC kinase. Taken together, our biological and biochemical findings newly suggest that the levels of barium shown in drinking well water independently has the cancer-promoting effects on precancerous keratinocytes, fibroblast and melanocytes in vitro.

Conformational determinants of phosphotyrosine peptides complexed with the Src SH2 domain.

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Joseph Nachman

2010-06-01

Full Text Available The inhibition of specific SH2 domain mediated protein-protein interactions as an effective chemotherapeutic approach in the treatment of diseases remains a challenge. That different conformations of peptide-ligands are preferred by different SH2 domains is an underappreciated observation from the structural analysis of phosphotyrosine peptide binding to SH2 domains that may aid in future drug design. To explore the nature of ligand binding, we use simulated annealing (SA to sample the conformational space of phosphotyrosine-containing peptides complexed with the Src SH2 domain. While in good agreement with the crystallographic and NMR studies of high-affinity phosphopeptide-SH2 domain complexes, the results suggest that the structural basis for phopsphopeptide- Src SH2 interactions is more complex than the "two-pronged plug two-hole socket" model. A systematic study of peptides of type pYEEX, where pY is phosphotyrosine and X is a hydrophobic residue, indicates that these peptides can assume two conformations, one extended and one helical, representing the balance between the interaction of residue X with the hydrophobic hole on the surface of the Src SH2 domain, and its contribution to the inherent tendency of the two glutamic acids to form an alpha-helix. In contrast, a beta-turn conformation, almost identical to that observed in the crystal structure of pYVNV bound to the Grb2 SH2 domain, predominates for pYXNX peptides, even in the presence of isoleucine at the third position. While peptide binding affinities, as measured by fluorescence polarization, correlate with the relative proportion of extended peptide conformation, these results suggest a model where all three residues C-terminal to the phosphotyrosine determine the conformation of the bound phosphopeptide. The information obtained in this work can be used in the design of specific SH2 domain inhibitors.

DRF3 as a Cholesterol Dependent Regulator of Src in Prostate Cancer

Science.gov (United States)

2009-01-01

blebbing ( Hannemann et al., 2008). Human DRF3 is not well studied, although analyses of the mouse homolog Drf3, and the close mouse paralog, Drf1/mDia1... Hannemann S, Madrid R, Stastna J, et al. The diaphanous related formin FHOD1 associates with ROCK1 and promotes Src-dependent plasma membrane blebbing

Residue-specific description of non-native transient structures in the ensemble of acid-denatured structures of the all-beta protein c-src SH3

DEFF Research Database (Denmark)

Rösner, Heike I; Poulsen, Flemming Martin

2010-01-01

-src loop to the third beta-strand, exhibited an apparent helicity of nearly 45%. Furthermore, the RT loop and the diverging turn appeared to adopt non-native-like helical conformations. Interestingly, none of the residues found in transient helical conformations exhibited significant varphi-values [Riddle......Secondary chemical shift analysis has been used to characterize the unfolded state of acid-denatured c-src SH3. Even though native c-src SH3 adopts an all-beta fold, we found evidence of transient helicity in regions corresponding to native loops. In particular, residues 40-46, connecting the n...

PI3K/Akt signaling is involved in the disruption of gap junctional communication caused by v-Src and TNF-α.

Science.gov (United States)

Ito, Satoko; Hyodo, Toshinori; Hasegawa, Hitoki; Yuan, Hong; Hamaguchi, Michinari; Senga, Takeshi

2010-09-17

Gap junctional communication, which is mediated by the connexin protein family, is essential for the maintenance of normal tissue function and homeostasis. Loss of intercellular communication results in a failure to coordinately regulate cellular functions, and it can facilitate tumorigenesis. Expression of oncogenes and stimulation with cytokines has been shown to suppress intercellular communication; however, the exact mechanism by which intercellular communication is disrupted by these factors remains uncertain. In this report, we show that Akt is essential for the disruption of gap junctional communication in v-Src-transformed cells. In addition, inhibition of Akt restores gap junctional communication after it is suppressed by TNF-α signaling. Furthermore, we demonstrate that the expression of a constitutively active form of Akt1, but not of Akt2 or Akt3, is sufficient to suppress gap junctional communication. Our results clearly define Akt1 as one of the critical regulators of gap junctional communication. Copyright © 2010 Elsevier Inc. All rights reserved.

Estrogen Receptor Folding Modulates cSrc Kinase SH2 Interaction via a Helical Binding Mode.

Science.gov (United States)

Nieto, Lidia; Tharun, Inga M; Balk, Mark; Wienk, Hans; Boelens, Rolf; Ottmann, Christian; Milroy, Lech-Gustav; Brunsveld, Luc

2015-11-20

The estrogen receptors (ERs) feature, next to their transcriptional role, important nongenomic signaling actions, with emerging clinical relevance. The Src Homology 2 (SH2) domain mediated interaction between cSrc kinase and ER plays a key role in this; however the molecular determinants of this interaction have not been elucidated. Here, we used phosphorylated ER peptide and semisynthetic protein constructs in a combined biochemical and structural study to, for the first time, provide a quantitative and structural characterization of the cSrc SH2-ER interaction. Fluorescence polarization experiments delineated the SH2 binding motif in the ER sequence. Chemical shift perturbation analysis by nuclear magnetic resonance (NMR) together with molecular dynamics (MD) simulations allowed us to put forward a 3D model of the ER-SH2 interaction. The structural basis of this protein-protein interaction has been compared with that of the high affinity SH2 binding sequence GpYEEI. The ER features a different binding mode from that of the "two-pronged plug two-hole socket" model in the so-called specificity determining region. This alternative binding mode is modulated via the folding of ER helix 12, a structural element directly C-terminal of the key phosphorylated tyrosine. The present findings provide novel molecular entries for understanding nongenomic ER signaling and targeting the corresponding disease states.

Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance

Science.gov (United States)

Azam, Mohammad; Nardi, Valentina; Shakespeare, William C.; Metcalf, Chester A.; Bohacek, Regine S.; Wang, Yihan; Sundaramoorthi, Raji; Sliz, Piotr; Veach, Darren R.; Bornmann, William G.; Clarkson, Bayard; Dalgarno, David C.; Sawyer, Tomi K.; Daley, George Q.

2006-01-01

Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukemia. Many mutations favor active kinase conformations that preclude imatinib binding. Because the active forms of ABL and SRC resemble one another, we tested two dual SRC-ABL kinase inhibitors, AP23464 and PD166326, against 58 imatinib-resistant (IMR) BCR/ABL kinase variants. Both compounds potently inhibit most IMR variants, and in vitro drug selection demonstrates that active (AP23464) and open (PD166326) conformation-specific compounds are less susceptible to resistance than imatinib. Combinations of inhibitors suppressed essentially all resistance mutations, with the notable exception of T315I. Guided by mutagenesis studies and molecular modeling, we designed a series of AP23464 analogues to target T315I. The analogue AP23846 inhibited both native and T315I variants of BCR/ABL with submicromolar potency but showed nonspecific cellular toxicity. Our data illustrate how conformational dynamics of the ABL kinase accounts for the activity of dual SRC-ABL inhibitors against IMR-mutants and provides a rationale for combining conformation specific inhibitors to suppress resistance. PMID:16754879

Na,K-ATPase activity modulates Src activation: A role for ATP/ADP ratio.

NARCIS (Netherlands)

Weigand, K.M.; Swarts, H.G.P.; Fedosova, N.U.; Russel, F.G.M.; Koenderink, J.B.

2012-01-01

Digitalis-like compounds (DLCs), specific inhibitors of Na,K-ATPase, are implicated in cellular signaling. Exposure of cell cultures to ouabain, a well-known DLC, leads to up- or down regulation of various processes and involves activation of Src kinase. Since Na,K-ATPase is the only known target

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.

Neoclassical and anomalous transport in axisymmetric toroidal plasmas with electrostatic turbulence

International Nuclear Information System (INIS)

Sugama, H.; Horton, W.

1995-01-01

Neoclassical and anomalous transport fluxes are determined for axisymmetric toroidal plasmas with weak electrostatic fluctuations. The neoclassical and anomalous fluxes are defined based on the ensemble-averaged kinetic equation with the statistically averaged nonlinear term. The anomalous forces derived from that quasilinear term induce the anomalous particle and heat fluxes. The neoclassical banana-plateau particle and heat fluxes and the bootstrap current are also affected by the fluctuations through the parallel anomalous forces and the modified parallel viscosities. The quasilinear term, the anomalous forces, and the anomalous particle and heat fluxes are evaluated from the fluctuating part of the drift kinetic equation. The averaged drift kinetic equation with the quasilinear term is solved for the plateau regime to derive the parallel viscosities modified by the fluctuations. The entropy production rate due to the anomalous transport processes is formulated and used to identify conjugate pairs of the anomalous fluxes and forces, which are connected by the matrix with the Onsager symmetry. copyright 1995 American Institute of Physics

Neoclassical and anomalous transport in axisymmetric toroidal plasmas with electrostatic turbulence

International Nuclear Information System (INIS)

Sugama, H.; Horton, W.

1995-05-01

Neoclassical and anomalous transport fluxes are determined for axisymmetric toroidal plasmas with weak electrostatic fluctuations. The neoclassical and anomalous fluxes are defined based on the ensemble-averaged kinetic equation with the statistically averaged nonlinear term. The anomalous forces derived from that quasilinear term induce the anomalous particle and heat fluxes. The neoclassical banana-plateau particle and heat fluxes and the bootstrap current are also affected by the fluctuations through the parallel anomalous forces and the modified parallel viscosities. The quasilinear term, the anomalous forces, and the anomalous particle and heat fluxes are evaluated from the fluctuating part of the drift kinetic equation. The averaged drift kinetic equation with the quasilinear term is solved for the plateau regime to derive the parallel viscosities modified by the fluctuations. The entropy production rate due to the anomalous transport processes is formulated and used to identify conjugate pairs of the anomalous fluxes and forces, which are connected by the matrix with the Onsager symmetry. (author)

FAK/src-family dependent activation of the Ste20-like kinase SLK is required for microtubule-dependent focal adhesion turnover and cell migration.

Directory of Open Access Journals (Sweden)

Simona Wagner

2008-04-01

Full Text Available Cell migration involves a multitude of signals that converge on cytoskeletal reorganization, essential for development, immune responses and tissue repair. Using knockdown and dominant negative approaches, we show that the microtubule-associated Ste20-like kinase SLK is required for focal adhesion turnover and cell migration downstream of the FAK/c-src complex. Our results show that SLK co-localizes with paxillin, Rac1 and the microtubules at the leading edge of migrating cells and is activated by scratch wounding. SLK activation is dependent on FAK/c-src/MAPK signaling, whereas SLK recruitment to the leading edge is src-dependent but FAK independent. Our results show that SLK represents a novel focal adhesion disassembly signal.

Contemporary Use of Anomalous Diffraction in Biomolecular Structure Analysis

Energy Technology Data Exchange (ETDEWEB)

Liu Q.; Hendrickson, W.

2017-01-01

The normal elastic X-ray scattering that depends only on electron density can be modulated by an ?anomalous? component due to resonance between X-rays and electronic orbitals. Anomalous scattering thereby precisely identifies atomic species, since orbitals distinguish atomic elements, which enables the multi- and single-wavelength anomalous diffraction (MAD and SAD) methods. SAD now predominates in de novo structure determination of biological macromolecules, and we focus here on the prevailing SAD method. We describe the anomalous phasing theory and the periodic table of phasing elements that are available for SAD experiments, differentiating between those readily accessible for at-resonance experiments and those that can be effective away from an edge. We describe procedures for present-day SAD phasing experiments and we discuss optimization of anomalous signals for challenging applications. We also describe methods for using anomalous signals as molecular markers for tracing and element identification. Emerging developments and perspectives are discussed in brief.

Symmetrized local co-registration optimization for anomalous change detection

Energy Technology Data Exchange (ETDEWEB)

Wohlberg, Brendt E [Los Alamos National Laboratory; Theiler, James P [Los Alamos National Laboratory

2009-01-01

The goal of anomalous change detection (ACD) is to identify what unusual changes have occurred in a scene, based on two images of the scene taken at different times and under different conditions. The actual anomalous changes need to be distinguished from the incidental differences that occur throughout the imagery, and one of the most common and confounding of these incidental differences is due to the misregistration of the images, due to limitations of the registration pre-processing applied to the image pair. We propose a general method to compensate for residual misregistration in any ACD algorithm which constructs an estimate of the degree of 'anomalousness' for every pixel in the image pair. The method computes a modified misregistration-insensitive anomalousness by making local re-registration adjustments to minimize the local anomalousness. In this paper we describe a symmetrized version of our initial algorithm, and find significant performance improvements in the anomalous change detection ROC curves for a number of real and synthetic data sets.

Effects of Src Kinase Inhibition on Expression of Protein Tyrosine Phosphatase 1B after Brain Hypoxia in a Piglet Animal Model

Directory of Open Access Journals (Sweden)

Dimitrios Angelis

2017-01-01

Full Text Available Background. Protein tyrosine phosphatases (PTPs in conjunction with protein tyrosine kinases (PTKs regulate cellular processes by posttranslational modifications of signal transduction proteins. PTP nonreceptor type 1B (PTP-1B is an enzyme of the PTP family. We have previously shown that hypoxia induces an increase in activation of a class of nonreceptor PTK, the Src kinases. In the present study, we investigated the changes that occur in the expression of PTP-1B in the cytosolic component of the brain of newborn piglets acutely after hypoxia as well as long term for up to 2 weeks. Methods. Newborn piglets were divided into groups: normoxia, hypoxia, hypoxia followed by 1 day and 15 days in FiO2 0.21, and hypoxia pretreated with Src kinase inhibitor PP2, prior to hypoxia followed by 1 day and 15 days. Hypoxia was achieved by providing 7% FiO2 for 1 hour and PTP-1B expression was measured via immunoblotting. Results. PTP-1B increased posthypoxia by about 30% and persisted for 2 weeks while Src kinase inhibition attenuated the expected PTP-1B-increased expression. Conclusions. Our study suggests that Src kinase mediates a hypoxia-induced increased PTP-1B expression.

Anomalous magnon Nernst effect of topological magnonic materials

Science.gov (United States)

Wang, X. S.; Wang, X. R.

2018-05-01

The magnon transport driven by a thermal gradient in a perpendicularly magnetized honeycomb lattice is studied. The system with the nearest-neighbor pseudodipolar interaction and the next-nearest-neighbor Dzyaloshinskii–Moriya interaction has various topologically nontrivial phases. When an in-plane thermal gradient is applied, a transverse in-plane magnon current is generated. This phenomenon is termed as the anomalous magnon Nernst effect that closely resembles the anomalous Nernst effect for an electronic system. The anomalous magnon Nernst coefficient and its sign are determined by the magnon Berry curvature distributions in the momentum space and magnon populations in the magnon bands. We predict a temperature-induced sign reversal in anomalous magnon Nernst effect under certain conditions.

Constitutional changes and the dilemmas of constitutionalism

Directory of Open Access Journals (Sweden)

Arsen Bačić

2009-01-01

Full Text Available The need to develop constitutional mechanisms whose aim is to resolve fundamental relations in society demands the widest possible inclusion of all of society’s active participants in the discussion on the need to adopt or revise the Constitution. The opening of every new round of constitutional changes is of great importance because it always unlocks certain new and important questions. The answers to those questions should be offered by state authority (policy and civil society including science and its disciplines. In this paper, the author mentions several topics which are of interest in the current discussion on the significance of current constitutional changes for the future of the development of constitutionalism and democracy in the Republic of Croatia. These are above all topics of political and legal constitutionalism and suggestions linked to strengthening the independence of judicial powers. The author advocates consistent application of constitutional control and check mechanisms which exclude all insularity of judicial powers in relation to democratic control.

Anomalous Hall effect

Czech Academy of Sciences Publication Activity Database

Nagaosa, N.; Sinova, Jairo; Onoda, S.; MacDonald, A. H.; Ong, N. P.

2010-01-01

Roč. 82, č. 2 (2010), s. 1539-1592 ISSN 0034-6861 Institutional research plan: CEZ:AV0Z10100521 Keywords : anomalous Hall effect * spintronics Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 51.695, year: 2010

STEP activation by Gαq coupled GPCRs opposes Src regulation of NMDA receptors containing the GluN2A subunit

Science.gov (United States)

Tian, Meng; Xu, Jian; Lei, Gang; Lombroso, Paul J.; Jackson, Michael F.; MacDonald, John F.

2016-01-01

N-methyl-D-aspartate receptors (NMDARs) are necessary for the induction of synaptic plasticity and for the consolidation of learning and memory. NMDAR function is tightly regulated by functionally opposed families of kinases and phosphatases. Herein we show that the striatal-enriched protein tyrosine phosphatase (STEP) is recruited by Gαq-coupled receptors, including the M1 muscarinic acetylcholine receptor (M1R), and opposes the Src tyrosine kinase-mediated increase in the function of NMDARs composed of GluN2A. STEP activation by M1R stimulation requires IP3Rs and can depress NMDA-evoked currents with modest intracellular Ca2+ buffering. Src recruitment by M1R stimulation requires coincident NMDAR activation and can augment NMDA-evoked currents with high intracellular Ca2+ buffering. Our findings suggest that Src and STEP recruitment is contingent on differing intracellular Ca2+ dynamics that dictate whether NMDAR function is augmented or depressed following M1R stimulation. PMID:27857196

Monte Carlo investigation of anomalous transport in presence of a discontinuity and of an advection field

Science.gov (United States)

Marseguerra, M.; Zoia, A.

2007-04-01

Anomalous diffusion has recently turned out to be almost ubiquitous in transport problems. When the physical properties of the medium where the transport process takes place are stationary and constant at each spatial location, anomalous transport has been successfully analysed within the Continuous Time Random Walk (CTRW) model. In this paper, within a Monte Carlo approach to CTRW, we focus on the particle transport through two regions characterized by different physical properties, in presence of an external driving action constituted by an additional advective field, modelled within both the Galilei invariant and Galilei variant schemes. Particular attention is paid to the interplay between the distributions of space and time across the discontinuity. The resident concentration and the flux of the particles are finally evaluated and it is shown that at the interface between the two regions the flux is continuous as required by mass conservation, while the concentration may reveal a neat discontinuity. This result could open the route to the Monte Carlo investigation of the effectiveness of a physical discontinuity acting as a filter on particle concentration.

A Prospect and Challenges for Adopting Constitutional Complaint and Constitutional Question in the Indonesian Constitutional Court

OpenAIRE

Faiz, Pan Mohamad

2016-01-01

A jurisdiction of the Indonesian Constitutional Court concerning constitutional adjudication is only limited to review the constitutionality of national law. There is no mechanism for challenging any decision or action made by public authorities that violate fundamental rights enshrined in the Indonesian Constitution. This article argues that constitutional complaint and constitutional question might be adopted as new jurisdictions of the Indonesian Constitutional Court in order to strengthen...

Integrin {alpha}{beta}1, {alpha}{sub v}{beta}, {alpha}{sub 6}{beta} effectors p130Cas, Src and talin regulate carcinoma invasion and chemoresistance

Energy Technology Data Exchange (ETDEWEB)

Sansing, Hope A. [Department of Oral and Craniofacial Biology, Louisiana State University Health Sciences Center-New Orleans, School of Dentistry, New Orleans, LA (United States); Sarkeshik, Ali; Yates, John R. [Department of Chemical Physiology, Scripps Research Institute, La Jolla, CA (United States); Patel, Vyomesh; Gutkind, J. Silvio [Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Yamada, Kenneth M. [Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Berrier, Allison L., E-mail: allison.berrier@gmail.com [Department of Oral and Craniofacial Biology, Louisiana State University Health Sciences Center-New Orleans, School of Dentistry, New Orleans, LA (United States)

2011-03-11

Research highlights: {yields} Proteomics of clustered integrin {alpha}{beta}1, {alpha}{sub v}{beta}, {alpha}{sub 6}{beta} receptors in oral carcinoma. {yields} p130Cas, Dek, Src and talin regulate oral carcinoma invasion. {yields} p130Cas, talin, Src and zyxin regulate oral carcinoma resistance to cisplatin. -- Abstract: Ligand engagement by integrins induces receptor clustering and formation of complexes at the integrin cytoplasmic face that controls cell signaling and cytoskeletal dynamics critical for adhesion-dependent processes. This study searches for a subset of integrin effectors that coordinates both tumor cell invasion and resistance to the chemotherapeutic drug cisplatin in oral carcinomas. Candidate integrin effectors were identified in a proteomics screen of proteins recruited to clustered integrin {alpha}{beta}1, {alpha}{sub v}{beta} or {alpha}{sub 6}{beta} receptors in oral carcinomas. Proteins with diverse functions including microtubule and actin binding proteins, and factors involved in trafficking, transcription and translation were identified in oral carcinoma integrin complexes. Knockdown of effectors in the oral carcinoma HN12 cells revealed that p130Cas, Dek, Src and talin were required for invasion through Matrigel. Disruption of talin or p130Cas by RNA interference increased resistance to cisplatin, whereas targeting Dek, Src or zyxin reduced HN12 resistance to cisplatin. Analysis of the spreading of HN12 cells on collagen I and laminin I revealed that a decrease in p130Cas or talin expression inhibited spreading on both matrices. Interestingly, a reduction in zyxin expression enhanced spreading on laminin I and inhibited spreading on collagen I. Reduction of Dek, Src, talin or zyxin expression reduced HN12 proliferation by 30%. Proliferation was not affected by a reduction in p130Cas expression. We conclude that p130Cas, Src and talin function in both oral carcinoma invasion and resistance to cisplatin.

Src family kinases in chronic kidney disease.

Science.gov (United States)

Wang, Jun; Zhuang, Shougang

2017-09-01

Src family kinases (SFKs) belong to nonreceptor protein tyrosine kinases and have been implicated in the regulation of numerous cellular processes, including cell proliferation, differentiation, migration and invasion, and angiogenesis. The role and mechanisms of SFKs in tumorgenesis have been extensively investigated, and some SFK inhibitors are currently under clinical trials for tumor treatment. Recent studies have also demonstrated the importance of SFKs in regulating the development of various fibrosis-related chronic diseases (e.g., idiopathic pulmonary fibrosis, liver fibrosis, renal fibrosis, and systemic sclerosis). In this article, we summarize the roles of SFKs in various chronic kidney diseases, including glomerulonephritis, diabetic nephropathy, human immunodeficiency virus-associated nephropathy, autosomal dominant form of polycystic kidney disease, and obesity-associated kidney disease, and discuss the mechanisms involved. Copyright © 2017 the American Physiological Society.

Connection between recurrence time statistics and anomalous transport

International Nuclear Information System (INIS)

Zaslavsky, G.M.; Tippett, M.K.

1991-01-01

For a model stationary flow with hexagonal symmetry, the recurrence time statistics are studied. The model has been shown to have a sharp transition from normal to anomalous transport. Here it is shown that this transition is accompanied by a correspondent change of the recurrence time statistics from normal to anomalous. The latter one displays the existence of a power tail. Recurrence time statistics provide a local measurement of anomalous transport that is of practical interest

Inclusive anomalous muon production in e+e- annihilation

International Nuclear Information System (INIS)

Feldman, G.J.; Bulos, F.; Lueke, D.; Abrams, G.S.; Alam, M.S.; Boyarski, A.M.; Breidenbach, M.; Dorfan, J.; Friedberg, C.E.; Fryberger, D.; Goldhaber, G.; Hanson, G.; Heile, F.B.; Jaros, J.A.; Kadyk, J.A.; Larsen, R.R.; Litke, A.M.; Lueth, V.; Madaras, R.J.; Morehouse, C.C.; Nguyen, H.K.; Paterson, J.M.; Perl, M.L.; Peruzzi, I.; Piccolo, M.; Pierre, F.M.; Pun, T.P.; Rapidis, P.; Richter, B.; Sadoulet, B.; Schwitters, R.F.; Tanenbaum, W.; Trilling, G.H.; Vannucci, F.; Whitaker, J.S.; Wiss, J.E.

1977-01-01

We present measurements of inclusive anomalous muon production in e + e - annihilations in three energy ranges. In all three ranges we observe a large anomalous muon production rate in two-prong events which is compatible with the expected decays of pairs of heavy leptons. In the highest energy range there is also appreciable anomalous muon production in multiprong events which, due to its magnitude and momentum dependence, must come in part from a source other than a heavy lepton

Systematic Serendipity: A Method to Discover the Anomalous

Science.gov (United States)

Giles, Daniel; Walkowicz, Lucianne

2018-01-01

One of the challenges in the era of big data astronomical surveys is identifying anomalous data, data that exhibits as-of-yet unobserved behavior. These data may result from systematic errors, extreme (or rare) forms of known phenomena, or, most interestingly, truly novel phenomena that has historically required a trained eye and often fortuitous circumstance to identify. We describe a method that uses machine clustering techniques to discover anomalous data in Kepler lightcurves, as a step towards systematizing the detection of novel phenomena in the era of LSST. As a proof of concept, we apply our anomaly detection method to Kepler data including Boyajian's Star (KIC 8462852). We examine quarters 4, 8, 11, and 16 of the Kepler data which contain Boyajian’s Star acting normally (quarters 4 and 11) and anomalously (quarters 8 and 16). We demonstrate that our method is capable of identifying Boyajian’s Star’s anomalous behavior in quarters of interest, and we further identify other anomalous light curves that exhibit a range of interesting variability.

Anomalous couplings at LEP2

International Nuclear Information System (INIS)

Fayolle, D.

2002-01-01

In its second phase, LEP has allowed to study four fermion processes never observed before. Results are presented on the charged triple gauge boson couplings (TGC) from the W-pair, Single W and Single γ production. The anomalous quartic gauge couplings (QGC) are constrained using production of WWγ, νν-barγγ and Z γγ final states. Finally, limits on the neutral anomalous gauge couplings (NGC) using the Z γ and ZZ production processes are also reported. All results are consistent with the Standard Model expectations. (authors)

Computer simulations of anomalous transport

International Nuclear Information System (INIS)

Lee, W.W.; Okuda, H.

1980-07-01

Numerical plasma simulations have been carried out to study: (1) the turbulent spectrum and anomalous plasma transport associated with a steady state electrostatic drift turbulence; and (2) the anomalous energy transport of electrons due to shear-Alfven waves in a finite-β plasma. For the simulation of the steady state drift turbulence, it is observed that, in the absence of magnetic shear, the turbulence is quenched to a low level when the rotational transform is a rational number, while the turbulent level remains high for an irrational rotational transform

Anomalous N=2 superconformal Ward identities

International Nuclear Information System (INIS)

Ketov, Sergei V.

2000-01-01

The N=2 superconformal Ward identities and their anomalies are discussed in N=2 superspace (including N=2 harmonic superspace), at the level of the low-energy effective action (LEEA) in four-dimensional N=2 supersymmetric field theories. The (first) chiral N=2 supergravity compensator is related to the known N=2 anomalous Ward identity in the N=2 (abelian) vector mulitplet sector. As regards the hypermultiplet LEEA given by the N=2 non-linear sigma-model (NLSM), a new anomalous N=2 superconformal Ward identity is found, whose existence is related to the (second) analytic compensator in N=2 supergravity. The celebrated solution of Seiberg and Witten is known to obey the (first) anomalous Ward identity in the Coulomb branch. We find a few solutions to the new anomalous Ward identity, after making certain assumptions about unbroken internal symmetries. Amongst the N=2 NLSM target space metrics governing the hypermultiplet LEEA are the SU(2)-Yang-Mills-Higgs monopole moduli-space metrics that can be encoded in terms of the spectral curves (Riemann surfaces), similarly to the Seiberg-Witten-type solutions. After a dimensional reduction to three spacetime dimensions (3d), our results support the mirror symmetry between the Coulomb and Higgs branches in 3d, N=4 gauge theories

Fractional diffusion equations and anomalous diffusion

CERN Document Server

Evangelista, Luiz Roberto

2018-01-01

Anomalous diffusion has been detected in a wide variety of scenarios, from fractal media, systems with memory, transport processes in porous media, to fluctuations of financial markets, tumour growth, and complex fluids. Providing a contemporary treatment of this process, this book examines the recent literature on anomalous diffusion and covers a rich class of problems in which surface effects are important, offering detailed mathematical tools of usual and fractional calculus for a wide audience of scientists and graduate students in physics, mathematics, chemistry and engineering. Including the basic mathematical tools needed to understand the rules for operating with the fractional derivatives and fractional differential equations, this self-contained text presents the possibility of using fractional diffusion equations with anomalous diffusion phenomena to propose powerful mathematical models for a large variety of fundamental and practical problems in a fast-growing field of research.

Anomalous nuclear fragments

International Nuclear Information System (INIS)

Karmanov, V.A.

1983-01-01

Experimental data are given, the status of anomalon problem is discussed, theoretical approaches to this problem are outlined. Anomalons are exotic objects formed following fragmentation of nuclei-targets under the effect of nuclei - a beam at the energy of several GeV/nucleon. These nuclear fragments have an anomalously large cross section of interaction and respectively, small free path, considerably shorter than primary nuclei have. The experimental daa are obtained in accelerators following irradiation of nuclear emulsions by 16 O, 56 Fe, 40 Ar beams, as well as propane by 12 C beams. The experimental data testify to dependence of fragment free path on the distance L from the point of the fragment formation. A decrease in the fragment free path is established more reliably than its dependence on L. The problem of the anomalon existence cannot be yet considered resolved. Theoretical models suggested for explanation of anomalously large cross sections of nuclear fragment interaction are variable and rather speculative

HIV-1 Nef interaction influences the ATP-binding site of the Src-family kinase, Hck

Directory of Open Access Journals (Sweden)

Pene-Dumitrescu Teodora

2012-03-01

Full Text Available Abstract Background Nef is an HIV-1 accessory protein essential for viral replication and AIDS progression. Nef interacts with a multitude of host cell signaling partners, including members of the Src kinase family. Nef preferentially activates Hck, a Src-family kinase (SFK strongly expressed in macrophages and other HIV target cells, by binding to its regulatory SH3 domain. Recently, we identified a series of kinase inhibitors that preferentially inhibit Hck in the presence of Nef. These compounds also block Nef-dependent HIV replication, validating the Nef-SFK signaling pathway as an antiretroviral drug target. Our findings also suggested that by binding to the Hck SH3 domain, Nef indirectly affects the conformation of the kinase active site to favor inhibitor association. Results To test this hypothesis, we engineered a "gatekeeper" mutant of Hck with enhanced sensitivity to the pyrazolopyrimidine tyrosine kinase inhibitor, NaPP1. We also modified the RT loop of the Hck SH3 domain to enhance interaction of the kinase with Nef. This modification stabilized Nef:Hck interaction in solution-based kinase assays, as a way to mimic the more stable association that likely occurs at cellular membranes. Introduction of the modified RT loop rendered Hck remarkably more sensitive to activation by Nef, and led to a significant decrease in the Km for ATP as well as enhanced inhibitor potency. Conclusions These observations suggest that stable interaction with Nef may induce Src-family kinase active site conformations amenable to selective inhibitor targeting.

Can I solve my structure by SAD phasing? Anomalous signal in SAD phasing.

Science.gov (United States)

Terwilliger, Thomas C; Bunkóczi, Gábor; Hung, Li Wei; Zwart, Peter H; Smith, Janet L; Akey, David L; Adams, Paul D

2016-03-01

A key challenge in the SAD phasing method is solving a structure when the anomalous signal-to-noise ratio is low. A simple theoretical framework for describing measurements of anomalous differences and the resulting useful anomalous correlation and anomalous signal in a SAD experiment is presented. Here, the useful anomalous correlation is defined as the correlation of anomalous differences with ideal anomalous differences from the anomalous substructure. The useful anomalous correlation reflects the accuracy of the data and the absence of minor sites. The useful anomalous correlation also reflects the information available for estimating crystallographic phases once the substructure has been determined. In contrast, the anomalous signal (the peak height in a model-phased anomalous difference Fourier at the coordinates of atoms in the anomalous substructure) reflects the information available about each site in the substructure and is related to the ability to find the substructure. A theoretical analysis shows that the expected value of the anomalous signal is the product of the useful anomalous correlation, the square root of the ratio of the number of unique reflections in the data set to the number of sites in the substructure, and a function that decreases with increasing values of the atomic displacement factor for the atoms in the substructure. This means that the ability to find the substructure in a SAD experiment is increased by high data quality and by a high ratio of reflections to sites in the substructure, and is decreased by high atomic displacement factors for the substructure.

Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms

International Nuclear Information System (INIS)

Nakaya, Y; Shide, K; Niwa, T; Homan, J; Sugahara, S; Horio, T; Kuramoto, K; Kotera, T; Shibayama, H; Hori, K; Naito, H; Shimoda, K

2011-01-01

Aberrant activation of Janus kinase 2 (JAK2) caused by somatic mutation of JAK2 (JAK2V617F) or the thrombopoietin receptor (MPLW515L) plays an essential role in the pathogenesis of myeloproliferative neoplasms (MPNs), suggesting that inhibition of aberrant JAK2 activation would have a therapeutic benefit. Our novel JAK2 inhibitor, NS-018, was highly active against JAK2 with a 50% inhibition (IC 50 ) of <1 n, and had 30–50-fold greater selectivity for JAK2 over other JAK-family kinases, such as JAK1, JAK3 and tyrosine kinase 2. In addition to JAK2, NS-018 inhibited Src-family kinases. NS-018 showed potent antiproliferative activity against cell lines expressing a constitutively activated JAK2 (the JAK2V617F or MPLW515L mutations or the TEL–JAK2 fusion gene; IC 50 =11–120 n), but showed only minimal cytotoxicity against most other hematopoietic cell lines without a constitutively activated JAK2. Furthermore, NS-018 preferentially suppressed in vitro erythropoietin-independent endogenous colony formation from polycythemia vera patients. NS-018 also markedly reduced splenomegaly and prolonged the survival of mice inoculated with Ba/F3 cells harboring JAK2V617F. In addition, NS-018 significantly reduced leukocytosis, hepatosplenomegaly and extramedullary hematopoiesis, improved nutritional status, and prolonged survival in JAK2V617F transgenic mice. These results suggest that NS-018 will be a promising candidate for the treatment of MPNs

Anomalous transport from holography. Pt. II

Energy Technology Data Exchange (ETDEWEB)

Bu, Yanyan; Sharon, Amir [Ben-Gurion University of the Negev, Department of Physics, Beersheba (Israel); Lublinsky, Michael [Ben-Gurion University of the Negev, Department of Physics, Beersheba (Israel); University of Connecticut, Physics Department, Storrs, CT (United States)

2017-03-15

This is a second study of chiral anomaly-induced transport within a holographic model consisting of anomalous U(1){sub V} x U(1){sub A} Maxwell theory in Schwarzschild-AdS{sub 5} spacetime. In the first part, chiral magnetic/separation effects (CME/CSE) are considered in the presence of a static spatially inhomogeneous external magnetic field. Gradient corrections to CME/CSE are analytically evaluated up to third order in the derivative expansion. Some of the third order gradient corrections lead to an anomaly-induced negative B{sup 2}-correction to the diffusion constant. We also find modifications to the chiral magnetic wave nonlinear in B. In the second part, we focus on the experimentally interesting case of the axial chemical potential being induced dynamically by a constant magnetic and time-dependent electric fields. Constitutive relations for the vector/axial currents are computed employing two different approximations: (a) derivative expansion (up to third order) but fully nonlinear in the external fields, and (b) weak electric field limit but resuming all orders in the derivative expansion. A non-vanishing nonlinear axial current (CSE) is found in the first case. The dependence on magnetic field and frequency of linear transport coefficient functions is explored in the second. (orig.)

Anomalous transport from holography. Pt. II

International Nuclear Information System (INIS)

Bu, Yanyan; Sharon, Amir; Lublinsky, Michael

2017-01-01

This is a second study of chiral anomaly-induced transport within a holographic model consisting of anomalous U(1)_V x U(1)_A Maxwell theory in Schwarzschild-AdS_5 spacetime. In the first part, chiral magnetic/separation effects (CME/CSE) are considered in the presence of a static spatially inhomogeneous external magnetic field. Gradient corrections to CME/CSE are analytically evaluated up to third order in the derivative expansion. Some of the third order gradient corrections lead to an anomaly-induced negative B"2-correction to the diffusion constant. We also find modifications to the chiral magnetic wave nonlinear in B. In the second part, we focus on the experimentally interesting case of the axial chemical potential being induced dynamically by a constant magnetic and time-dependent electric fields. Constitutive relations for the vector/axial currents are computed employing two different approximations: (a) derivative expansion (up to third order) but fully nonlinear in the external fields, and (b) weak electric field limit but resuming all orders in the derivative expansion. A non-vanishing nonlinear axial current (CSE) is found in the first case. The dependence on magnetic field and frequency of linear transport coefficient functions is explored in the second. (orig.)

Comparison of the anomalous and non-anomalous generalized Schwinger models via functional formalism

International Nuclear Information System (INIS)

Souza Dutra, A. de.

1992-01-01

The Green functions of the two versions of the two versions of the generalized Schwinger model, the anomalous and the non-anomalous one, in their higher order Lagrangian density form are calculated. Furthermore it is shown through a sequence of transformations that the bosonized Lagrangian density is equivalent to the former, at least for the bosonic correlation functions. The introduction of the sources from the beginning, leading to a gauge-invariant source term is also considered. It is verified that the two models have the same correlation functions only of the gauge-invariant sector is taken into account. Finally it is presented a generalization of the Wess-Zumino term, and its physical consequences are studied, in particular the appearance of gauge-dependent massive excitations. (author)

Constitutional judges (guarantee of the Constitution and responsibility

Directory of Open Access Journals (Sweden)

Francisco Javier Ansuátegui Roig

2012-06-01

Full Text Available My aim in this paper is to propose a reflection on the position and the importance that the constitutional judge has in the legal systems of contemporary constitutionalism. The figure of the judge responsible of protecting the Constitution is a key institution, without which we cannot understand the laws of constitutional democracies, their current lines of development, and the guarantee of rights and freedoms that constitute the normative core of these systems. Moreover, the reflection on the exercise of the powers of the judge, its scope and its justification is an important part of contemporary legal discussion, still relevant, albeit not exclusively - in the field of legal philosophy. The object of attention of my reflection is the judge who has the power of judicial review, in a scheme of defense of the Constitution, regardless the specific ways of this defense.

The anomalous self-diffusion in α-Zr

International Nuclear Information System (INIS)

Hood, G.M.

1985-01-01

In a very recent publication, Horvath, Dyment and Mehrer, henceforth HDM, presented measurements of the self-diffusion coefficient Dsub(m) 0 for α-Zr as a function of temperature. The results of that study, done on a single crystal sample, were anomalous in the sense that a plot of log Dsub(m) 0 vs. 1/T(K -1 ) was not only non-linear, but exhibited two regions of downward curvature with increasing 1/T. HDM indicated that they were unable to see any explanation of their anomalous self-diffusion results. It is the purpose of this letter to indicate a means whereby these anomalous results may be ''explained'' and to suggest some experiments which might be undertaken to test the proposal. (orig./RK)

Src-independent ERK signaling through the rat α3 isoform of Na/K-ATPase.

Science.gov (United States)

Madan, Namrata; Xu, Yunhui; Duan, Qiming; Banerjee, Moumita; Larre, Isabel; Pierre, Sandrine V; Xie, Zijian

2017-03-01

The Na/K-ATPase α1 polypeptide supports both ion-pumping and signaling functions. The Na/K-ATPase α3 polypeptide differs from α1 in both its primary structure and its tissue distribution. The expression of α3 seems particularly important in neurons, and recent clinical evidence supports a unique role of this isoform in normal brain function. The nature of this specific role of α3 has remained elusive, because the ubiquitous presence of α1 has hindered efforts to characterize α3-specific functions in mammalian cell systems. Using Na/K-ATPase α1 knockdown pig kidney cells (PY-17), we generated the first stable mammalian cell line expressing a ouabain-resistant form of rat Na/K-ATPase α3 in the absence of endogenous pig α1 detectable by Western blotting. In these cells, Na/K-ATPase α3 formed a functional ion-pumping enzyme and rescued the expression of Na/K-ATPase β1 and caveolin-1 to levels comparable with those observed in PY-17 cells rescued with a rat Na/K-ATPase α1 (AAC-19). The α3-containing enzymes had lower Na + affinity and lower ouabain-sensitive transport activity than their α1-containing counterparts under basal conditions, but showed a greater capacity to be activated when intracellular Na + was increased. In contrast to Na/K-ATPase α1, α3 could not regulate Src. Upon exposure to ouabain, Src activation did not occur, yet ERK was activated through Src-independent pathways involving PI3K and PKC. Hence, α3 expression confers signaling and pumping properties that are clearly distinct from that of cells expressing Na/K-ATPase α1. Copyright © 2017 the American Physiological Society.

v-src induction of the TIS10/PGS2 prostaglandin synthase gene is mediated by an ATF/CRE transcription response element.

OpenAIRE

Xie, W; Fletcher, B S; Andersen, R D; Herschman, H R

1994-01-01

We recently reported the cloning of a mitogen-inducible prostaglandin synthase gene, TIS10/PGS2. In addition to growth factors and tumor promoters, the v-src oncogene induces TIS10/PGS2 expression in 3T3 cells. Deletion analysis, using luciferase reporters, identifies a region between -80 and -40 nucleotides 5' of the TIS10/PGS2 transcription start site that mediates pp60v-src induction in 3T3 cells. This region contains the sequence CGTCACGTG, which includes overlapping ATF/CRE (CGTCA) and E...

SRC Inhibition Reduces NR2B Surface Expression and Synaptic Plasticity in the Amygdala

Science.gov (United States)

Sinai, Laleh; Duffy, Steven; Roder, John C.

2010-01-01

The Src protein tyrosine kinase plays a central role in the regulation of N-methyl-d-aspartate receptor (NMDAR) activity by regulating NMDAR subunit 2B (NR2B) surface expression. In the amygdala, NMDA-dependent synaptic plasticity resulting from convergent somatosensory and auditory inputs contributes to emotional memory; however, the role of Src…

Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion.

Directory of Open Access Journals (Sweden)

Deborah Huveldt

Full Text Available Anti-VEGF antibody therapy with bevacizumab provides significant clinical benefit in patients with recurrent glioblastoma multiforme (GBM. Unfortunately, progression on bevacizumab therapy is often associated with a diffuse disease recurrence pattern, which limits subsequent therapeutic options. Therefore, there is an urgent need to understand bevacizumab's influence on glioma biology and block it's actions towards cell invasion. To explore the mechanism(s of GBM cell invasion we have examined a panel of serially transplanted human GBM lines grown either in short-term culture, as xenografts in mouse flank, or injected orthotopically in mouse brain. Using an orthotopic xenograft model that exhibits increased invasiveness upon bevacizumab treatment, we also tested the effect of dasatinib, a broad spectrum SFK inhibitor, on bevacizumab-induced invasion.We show that 1 activation of Src family kinases (SFKs is common in GBM, 2 the relative invasiveness of 17 serially transplanted GBM xenografts correlates strongly with p120 catenin phosphorylation at Y228, a Src kinase site, and 3 SFK activation assessed immunohistochemically in orthotopic xenografts, as well as the phosphorylation of downstream substrates occurs specifically at the invasive tumor edge. Further, we show that SFK signaling is markedly elevated at the invasive tumor front upon bevacizumab administration, and that dasatinib treatment effectively blocked the increased invasion induced by bevacizumab.Our data are consistent with the hypothesis that the increased invasiveness associated with anti-VEGF therapy is due to increased SFK signaling, and support testing the combination of dasatinib with bevacizumab in the clinic.

Anomalous and resonance small-angle scattering

International Nuclear Information System (INIS)

Epperson, J.E.; Thiyagarajan, P.

1988-01-01

Significant changes in the small-angle scattered intensity can be induced by making measurements with radiation close to an absorption edge of an appropriate atomic species contained in the sample. These changes can be related quantitatively to the real and imaginary anomalous-dispersion terms for the scattering factor (X-rays) or scattering length (neutrons). The physics inherent in these anomalous-dispersion terms is first discussed before consideration of how they enter the relevant scattering theory. Two major areas of anomalous-scattering research have emerged; macromolecules in solution and unmixing of metallic alloys. Research in each area is reviewed, illustrating both the feasibility and potential of these techniques. All the experimental results reported to date have been obtained with X-rays. However, it is pointed out that the formalism is the same for the analog experiment with neutrons, and a number of suitable isotopes exist which exhibit resonance in an accessible range of energy. Potential applications of resonance small-angle neutron scattering are discussed. (orig.)

Diallyl disulfide suppresses SRC/Ras/ERK signaling-mediated proliferation and metastasis in human breast cancer by up-regulating miR-34a.

Directory of Open Access Journals (Sweden)

Xiangsheng Xiao

Full Text Available Diallyl disulfide (DADS is one of the major volatile components of garlic oil. DADS has various biological properties, including anticancer, antiangiogenic, and antioxidant effects. However, the anticancer mechanisms of DADS in human breast cancer have not been elucidated, particularly in vivo. In this study, we demonstrated that the expression of miR-34a was up-regulated in DADS-treated MDA-MB-231 cells. miR-34a not only inhibited breast cancer growth but also enhanced the antitumor effect of DADS, both in vitro and in vivo. Furthermore, Src was identified as a target of miR-34a, with miR-34a inhibiting SRC expression and consequently triggering the suppression of the SRC/Ras/ERK pathway. These results suggest that DADS could be a promising anticancer agent for breast cancer. miR-34a may also demonstrate a potential gene therapy agent that could enhance the antitumor effects of DADS.

SRC-I demonstration plant analytical laboratory methods manual. Final technical report

Energy Technology Data Exchange (ETDEWEB)

Klusaritz, M.L.; Tewari, K.C.; Tiedge, W.F.; Skinner, R.W.; Znaimer, S.

1983-03-01

This manual is a compilation of analytical procedures required for operation of a Solvent-Refined Coal (SRC-I) demonstration or commercial plant. Each method reproduced in full includes a detailed procedure, a list of equipment and reagents, safety precautions, and, where possible, a precision statement. Procedures for the laboratory's environmental and industrial hygiene modules are not included. Required American Society for Testing and Materials (ASTM) methods are cited, and ICRC's suggested modifications to these methods for handling coal-derived products are provided.

Harvester development for new high yielding SRC crops and markets

International Nuclear Information System (INIS)

2005-12-01

Details are given of a project to develop a harvesting system that can produce fuel economically in a single pass to a required specification at a cost that is profitable for the grower while minimising the cost of the product. The project objectives listed include the development of a harvester drive chain and feeding systems to allow harvesting of the higher yielding crops now produced in the UK, determination of the most economic harvesting cycle for SRC crops, and production of fuels suitable for co-firing with coal in pulverised fuel systems or for gasification. The work programme and project conclusions are discussed

HBx induced AFP receptor expressed to activate PI3K/AKT signal to promote expression of Src in liver cells and hepatoma cells

International Nuclear Information System (INIS)

Zhu, Mingyue; Guo, Junli; Li, Wei; Xia, Hua; Lu, Yan; Dong, Xu; Chen, Yi; Xie, Xieju; Fu, Shigan; Li, Mengsen

2015-01-01

Hepatitis B virus (HBV)-X protein(HBx) is a transactivator of host several cellular genes including alpha-fetoprotein(AFP) and AFP receptor(AFPR) which contributes to HBV-associated tumor development. The expression of AFP/AFPR are correlated with hepatocellular carcinoma(HCC)-initial cells. But the role of AFP and AFPR in promoting occurrence of HBV-related HCC were still unclear. A total of 71 clinical patients’ liver specimens, normal human liver cells L-02 and HCC cell lines, PLC/PRF/5 were selected for analyzing the effects of HBx on expression of AFP, AFPR and Src. The expression of goal proteins were detected by Immunohistochemical stained and Western blotting; HBx-expressed vectors were constructed and transfected into L-02 cells, laser confocal microscopy was applied to observe expression and location of AFP, AFPR and Src in the normal liver cells and HCC cells, soft agar colony formation assay was used to observe colonies formed of the cells. We confirmed HBx gives preference to promote the expression of AFP and AFPR; HBx priors to up-regulate the expression of AFPR and AFP in L-02 cells and in normal liver specimens; AFPR signal been able to stimulate Src expression. The results also indicated that phosphatidylinositol 3-kinase(PI3K) inhibitors Ly294002 and GDC0941 effectively suppress AFPR mediated up-regulation expression of Src in AFPR positive HCC lines. HBx priors to drive the expression of AFP and AFPR to promote expression of Src in normal liver cells and hepatoma cells; AFP and AFPR maybe play pivotal role in HBV-related hepatocarcinogenesis; Targeting AFPR is an available therapeutic strategy of HCC. The online version of this article (doi:10.1186/s12885-015-1384-9) contains supplementary material, which is available to authorized users

Multisite tyrosine phosphorylation of the N-terminus of Mint1/X11α by Src kinase regulates the trafficking of amyloid precursor protein.

Science.gov (United States)

Dunning, Christopher J R; Black, Hannah L; Andrews, Katie L; Davenport, Elizabeth C; Conboy, Michael; Chawla, Sangeeta; Dowle, Adam A; Ashford, David; Thomas, Jerry R; Evans, Gareth J O

2016-05-01

Mint/X11 is one of the four neuronal trafficking adaptors that interact with amyloid precursor protein (APP) and are linked with its cleavage to generate β-amyloid peptide, a key player in the pathology of Alzheimer's disease. How APP switches between adaptors at different stages of the secretory pathway is poorly understood. Here, we show that tyrosine phosphorylation of Mint1 regulates the destination of APP. A canonical SH2-binding motif ((202) YEEI) was identified in the N-terminus of Mint1 that is phosphorylated on tyrosine by C-Src and recruits the active kinase for sequential phosphorylation of further tyrosines (Y191 and Y187). A single Y202F mutation in the Mint1 N-terminus inhibits C-Src binding and tyrosine phosphorylation. Previous studies observed that co-expression of wild-type Mint1 and APP causes accumulation of APP in the trans-Golgi. Unphosphorylatable Mint1 (Y202F) or pharmacological inhibition of Src reduced the accumulation of APP in the trans-Golgi of heterologous cells. A similar result was observed in cultured rat hippocampal neurons where Mint1(Y202F) permitted the trafficking of APP to more distal neurites than the wild-type protein. These data underline the importance of the tyrosine phosphorylation of Mint1 as a critical switch for determining the destination of APP. The regulation of amyloid precursor protein (APP) trafficking is poorly understood. We have discovered that the APP adapter, Mint1, is phosphorylated by C-Src kinase. Mint1 causes APP accumulation in the trans-Golgi network, whereas inhibition of Src or mutation of Mint1-Y202 permits APP recycling. The phosphorylation status of Mint1 could impact on the pathological trafficking of APP in Alzheimer's disease. © 2016 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.

Presentation: 3D magnetic inversion by planting anomalous densities

OpenAIRE

Uieda, Leonardo; Barbosa, Valeria C. F.

2013-01-01

Slides for the presentation "3D magnetic inversion by planting anomalous densities" given at the 2013 AGU Meeting of the Americas in Cancun, Mexico.   Note: There was an error in the title of the talk. The correct title should be "3D magnetic inversion by planting anomalous magnetization"   Abstract: We present a new 3D magnetic inversion algorithm based on the computationally efficient method of planting anomalous densities. The algorithm consists of an iterative growth of the an...

Anomalous high-frequency resistivity of a plasma

International Nuclear Information System (INIS)

Kruer, W.L.; Dawson, J.M.

1971-06-01

In one- and two-dimensional computer simulations we investigate anomalous high-frequency resistivity in a plasma driven by a large electric field oscillating near the electron plasma frequency. The large field excites the oscillating two-stream and the ion-acoustic decay instabilities in agreement with the linear theory. When the ion and electron fluctuations saturate, a strong anomalous heating of the plasma sets in. This strong heating is due to an efficient coupling of the externally imposed large electric field to the plasma by ion fluctuations. We determine the anomalous collision frequency and the saturation fluctuation amplitudes as a function of the external field amplitude and frequency, and the electron-ion mass ratio. A simple nonlinear theory gives results in reasonable agreement with simulations. 24 refs., 10 figs

ε-iron nitrides: Intrinsic anomalous Hall ferromagnets

Directory of Open Access Journals (Sweden)

Guo-Ke Li

2015-02-01

Full Text Available The anomalous Hall effect in ε-iron nitrides (ε-Fe3-xN, 0 ≤ x ≤ 1 has been systematically investigated taking advantage of the fact that the exchange splitting of ε-Fe3-xN can be continuously tuned through the nitrogen concentration. It has been found that the anomalous Hall conductivity, σ x y A H , is proportional to the saturation magnetization MS, i.e., σ x y A H = S H M S , across significant variations in the saturation magnetization (96–1146 emu/cc. This relationship is in excellent agreement with the intrinsic mechanism as well as with the unified theory of AHE. Our results also demonstrate that the anomalous Hall conductivity is sensitive to the exchange splitting of the band structure.

National constitutional courts in the European Constitutional Democracy

DEFF Research Database (Denmark)

Komárek, Jan

2014-01-01

This article critically assesses the transformation of national constitutional courts’ place in the law and politics of the EU and its member states. This process eliminates the difference between constitutional and ordinary national courts, which is crucial for the institutional implementation...... of the discourse theory of law and democracy. It also disrupts the symbiotic relationship between national constitutional democracies established after World War II and European integration. The article argues that maintaining the special place of national constitutional courts is in the vital interest of both...... the EU and its member states, understood together as the European Constitutional Democracy—the central notion developed in this article in order to support an argument that should speak to both EU lawyers and national constitutionalists....

Src inhibitor herbimycin A prevents 132.7 kDa tyrosine phosphatase activity in Ramos Burkitt's lymphoma B cell line

International Nuclear Information System (INIS)

Hristov, K.; Mitev, V.; Knox, K.

2006-01-01

Reversible tyrosine phosphorylation, regulation of expression and proteolytic cleavage control tyrosine phosphatase contribution for the signalling pathways of B-cell antigen receptor (BCR), and CD40 during B cell selection. We used Ramos-BL B cell line to determine whether BCR and CD40 stimulation, or inhibition of the Src - tyrosine kinase, tyrosine phosphatase and caspase activity have an effect on the tyrosine phosphatase activities determined on in-gel phosphatase assay. The tyrosine phosphatase activities present in whole cell lysates of Ramos-BL B cells following treatment with 20 μg/ml anti-IgM, 1 μg/ml anti-CD40, 10 μM herbimycin A, 178 μM vanadate,100 μM phenylarsine oxide and 10 μM zVAD-fmk were detected with an in-gel phosphatase assay. Seven major tyrosine phosphatase activities with approximate molecular weight of 132.7, 63.9, 60.3, 54.2, 49.7, 44.6, and 39 kDa are present in whole cell lysates of Ramos-BL B cells. Treatment with Src-PTK inhibitor herbimycin A prevents 132.7 kDa tyrosine phosphatase activity. We conclude that the catalytic activity of Src-PTK in Ramos-BL B cells is critical for the presence of this 132.7 kDa tyrosine phosphatase activity. (authors)

Hydrogen Sulfide Recruits Macrophage Migration by Integrin β1-Src-FAK/Pyk2-Rac Pathway in Myocardial Infarction

Science.gov (United States)

Miao, Lei; Xin, Xiaoming; Xin, Hong; Shen, Xiaoyan; Zhu, Yi-Zhun

2016-03-01

Myocardial infarction (MI) triggers an inflammatory reaction, in which macrophages are of key importance for tissue repairing. Infiltration and/or migration of macrophages into the infarct area early after MI is critical for infarct healing, vascularization, and cardiac function. Hydrogen sulfide (H2S) has been demonstrated to possess cardioprotective effects post MI and during the progress of cardiac remodeling. However, the specific molecular and cellular mechanisms involved in macrophage recruitment by H2S remain to be identified. In this study, the NaHS (exogenous sources of H2S) treatment exerted an increased infiltration of macrophages into the infarcted myocardium at early stage of MI cardiac tissues in both wild type (WT) and cystathionine-γ-lyase-knockout (CSE-KO) mice. And NaHS accelerated the migration of macrophage cells in vitro. While, the inhibitors not only significantly diminished the migratory ability in response to NaHS, but also blocked the activation of phospho-Src, -Pyk2, -FAK397, and -FAK925. Furthermore, NaHS induced the internalization of integrin β1 on macrophage surface, but, integrin β1 silencing inhibited macrophage migration and Src signaling activation. These results indicate that H2S may have the potential as an anti-infarct of MI by governing macrophage migration, which was achieved by accelerating internalization of integrin β1 and activating downstream Src-FAK/Pyk2-Rac pathway.

The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain

DEFF Research Database (Denmark)

Appel, Camilla Kristine; Gallego-Pedersen, Simone; Andersen, Line

2017-01-01

Pain is a severe and debilitating complication of metastatic bone cancer. Current analgesics do not provide sufficient pain relief for all patients, creating a great need for new treatment options. The Src kinase, a non-receptor protein tyrosine kinase, is implicated in processes involved in cancer......-induced bone pain, including cancer growth, osteoclastic bone degradation and nociceptive signalling. Here we investigate the role of dasatinib, an oral Src kinase family and Bcr-Abl tyrosine kinase inhibitor, in an animal model of cancer-induced bone pain. Daily administration of dasatinib (15 mg/kg, p...

'Complexity' and anomalous transport in space plasmas

International Nuclear Information System (INIS)

Chang, Tom; Wu Chengchin

2002-01-01

'Complexity' has become a hot topic in nearly every field of modern physics. Space plasma is of no exception. In this paper, it is demonstrated that the sporadic and localized interactions of magnetic coherent structures are the origin of 'complexity' in space plasmas. The intermittent localized interactions, which generate the anomalous diffusion, transport, and evolution of the macroscopic state variables of the overall dynamical system, may be modeled by a triggered (fast) localized chaotic growth equation of a set of relevant order parameters. Such processes would generally pave the way for the global system to evolve into a 'complex' state of long-ranged interactions of fluctuations, displaying the phenomenon of forced and/or self-organized criticality. An example of such type of anomalous transport and evolution in a sheared magnetic field is provided via two-dimensional magnetohydrodynamic simulations. The coarse-grained dissipation due to the intermittent triggered interactions among the magnetic coherent structures induces a 'fluctuation-induced nonlinear instability' that reconfigures the sheared magnetic field into an X-point magnetic geometry (in the mean field sense), leading to the anomalous acceleration of the magnetic coherent structures. A phenomenon akin to such type of anomalous transport and acceleration, the so-called bursty bulk flows, has been commonly observed in the plasma sheet of the Earth's magnetotail

Anomalous magnetohydrodynamics in the extreme relativistic domain

CERN Document Server

Giovannini, Massimo

2016-01-01

The evolution equations of anomalous magnetohydrodynamics are derived in the extreme relativistic regime and contrasted with the treatment of hydromagnetic nonlinearities pioneered by Lichnerowicz in the absence of anomalous currents. In particular we explore the situation where the conventional vector currents are complemented by the axial-vector currents arising either from the pseudo Nambu-Goldstone bosons of a spontaneously broken symmetry or because of finite fermionic density effects. After expanding the generally covariant equations in inverse powers of the conductivity, the relativistic analog of the magnetic diffusivity equation is derived in the presence of vortical and magnetic currents. While the anomalous contributions are generally suppressed by the diffusivity, they are shown to disappear in the perfectly conducting limit. When the flow is irrotational, boost-invariant and with vanishing four-acceleration the corresponding evolution equations are explicitly integrated so that the various physic...

Total least squares for anomalous change detection

Science.gov (United States)

Theiler, James; Matsekh, Anna M.

2010-04-01

A family of subtraction-based anomalous change detection algorithms is derived from a total least squares (TLSQ) framework. This provides an alternative to the well-known chronochrome algorithm, which is derived from ordinary least squares. In both cases, the most anomalous changes are identified with the pixels that exhibit the largest residuals with respect to the regression of the two images against each other. The family of TLSQbased anomalous change detectors is shown to be equivalent to the subspace RX formulation for straight anomaly detection, but applied to the stacked space. However, this family is not invariant to linear coordinate transforms. On the other hand, whitened TLSQ is coordinate invariant, and special cases of it are equivalent to canonical correlation analysis and optimized covariance equalization. What whitened TLSQ offers is a generalization of these algorithms with the potential for better performance.

chi2 analyses of data on relativistic anomalous projectile fragments

International Nuclear Information System (INIS)

MacGregor, M.H.

1983-01-01

Nuclear emulsion data from four experimental groups are now available on the interactions of p relativistic anomalous projectile fragments. In the present paper we systematically combine these data together to form several different data sets, which are used to carry out a series of chi 2 parameter studies. The anomalous particle fragment component in the relativistic nuclear beam has been characterized previously in terms of the parameters f and lambda, where f is the anomalous particle fragment fraction in the secondary beam and lambda is the average anomalous particle fragment mean free path in the emulsion. We extend this result here by setting lambda = lambda 0 (2Z)/sup -beta/, where Z is the nuclear charge of the anomalous particle fragment, so that we can investigate the Z dependence of lambda. We also investigate isotopic effects in the equations used to describe ''normal'' secondary beam nuclei, and we examine the problem of optimizing the bin sizes used to represent the data. A series of (f,lambda 0 ,#betta#) parameter studies leads to the conclusion that the ''anomalous particle fragment effect'' exists for all Z values in the range Z = 3--26 included in the chi 2 analyses. These chi 2 analyses also indicate that #betta#>0, so that the anomalous particle fragment lambda's are Z dependent, but the data are not sufficient to pin down a definite value of #betta#. In order to assess the physical content of these results, we define a domain within which nuclear mean free paths can be accounted for by conventional nuclear forces (but not necessarily by conventional nuclear structure). The Z-dependent anomalous particle fragment mean free paths lie approximately on the boundary of this domain

Fully interferometric controllable anomalous refraction efficiency using cross modulation with plasmonic metasurfaces.

Science.gov (United States)

Liu, Zhaocheng; Chen, Shuqi; Li, Jianxiong; Cheng, Hua; Li, Zhancheng; Liu, Wenwei; Yu, Ping; Xia, Ji; Tian, Jianguo

2014-12-01

We present a method of fully interferometric, controllable anomalous refraction efficiency by introducing cross-modulated incident light based on plasmonic metasurfaces. Theoretical analyses and numerical simulations indicate that the anomalous and ordinary refracted beams generated from two opposite-helicity incident beams and following the generalized Snell's law will have a superposition for certain incident angles, and the anomalous refraction efficiency can be dynamically controlled by changing the relative phase of the incident sources. As the incident wavelength nears the resonant wavelength of the plasmonic metasurfaces, two equal-amplitude incident beams with opposite helicity can be used to control the anomalous refraction efficiency. Otherwise, two unequal-amplitude incident beams with opposite helicity can be used to fully control the anomalous refraction efficiency. This Letter may offer a further step in the development of controllable anomalous refraction.

Four-fermi anomalous dimension with adjoint fermions

CERN Document Server

Del Debbio, Luigi; Ruano, Carlos Pena

2014-01-01

The four-fermi interaction can play an important role in models of strong dynamical EW sym- metry breaking if the anomalous dimensions of the four-fermi operators become large in the IR. We discuss a number of issues that are relevant for the nonperturbative computation of the four- fermi anomalous dimensions for the SU(2) gauge theory with two flavors of Dirac fermions in the adjoint representation, using a Schrödinger functional formalism.

Quantum anomalous Bloch-Siegert shift in Weyl semimetal

Science.gov (United States)

Kumar, Upendra; Kumar, Vipin; Enamullah, Setlur, Girish S.

2018-05-01

A periodic exchange of energy between the light field and two level system is known as Rabi oscillations. The Bloch-Siegert shift (BSS) is a shift in Rabi oscillation resonance condition, when the driving field is sufficiently strong. There are new type of oscillations exhibit in Weyl semimetal at far from resonance, known as anomalous Rabi oscillation. In this work, we study the phenomenon of the Bloch-Siegert shift in Weyl semimetal at far from resonance called anomalous Bloch-Siegert shift (ABSS) by purely quantum mechanical treatment and describe it's anisotropic nature. A fully numerical solution of the Floquet-Bloch equations unequivocally establishes the presence of not only anomalous Rabi oscillations in these systems but also their massless character.

Partial anomalous pulmonary venous return in patients with pulmonary hypertension

International Nuclear Information System (INIS)

Sung, Won-kyung; Au, Virginia; Rose, Anand

2012-01-01

Anomalous pulmonary venous return is an uncommon congenital malformation, and may be partial or total. Partial anomalous pulmonary venous return (PAPVR) is more common than total anomalous pulmonary venous return, and is often associated with other congenital cardiac anomalies. Whilst many patients with PAPVR remain asymptomatic, some may present in later age with symptoms related to left-to-right shunt, right heart failure and pulmonary hypertension. We report two cases of PAPVR detected on Computed Tomography Pulmonary Angiogram (CTPA) for the work up of pulmonary hypertension. The cases demonstrate that, although uncommon, partial anomalous pulmonary venous return can be a contributing factor to pulmonary hypertension and pulmonary veins should be carefully examined when reading a CTPA study.

Src Kinase Dependent Rapid Non-genomic Modulation of Hippocampal Spinogenesis Induced by Androgen and Estrogen

Directory of Open Access Journals (Sweden)

Mika Soma

2018-05-01

Full Text Available Dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from an axon terminal at the synapse. Memories are stored in synapses which consist of spines and presynapses. Rapid modulations of dendritic spines induced by hippocampal sex steroids, including dihydrotestosterone (DHT, testosterone (T, and estradiol (E2, are essential for synaptic plasticity. Molecular mechanisms underlying the rapid non-genomic modulation through synaptic receptors of androgen (AR and estrogen (ER as well as its downstream kinase signaling, however, have not been well understood. We investigated the possible involvement of Src tyrosine kinase in rapid changes of dendritic spines in response to androgen and estrogen, including DHT, T, and E2, using hippocampal slices from adult male rats. We found that the treatments with DHT (10 nM, T (10 nM, and E2 (1 nM increased the total density of spines by ~1.22 to 1.26-fold within 2 h using super resolution confocal imaging of Lucifer Yellow-injected CA1 pyramidal neurons. We examined also morphological changes of spines in order to clarify differences between three sex steroids. From spine head diameter analysis, DHT increased middle- and large-head spines, whereas T increased small- and middle-head spines, and E2 increased small-head spines. Upon application of Src tyrosine kinase inhibitor, the spine increases induced through DHT, T, and E2 treatments were completely blocked. These results imply that Src kinase is essentially involved in sex steroid-induced non-genomic modulation of the spine density and morphology. These results also suggest that rapid effects of exogenously applied androgen and estrogen can occur in steroid-depleted conditions, including “acute” hippocampal slices and the hippocampus of gonadectomized animals.

Rationality of the anomalous dimensions in N=4 SYM theory

International Nuclear Information System (INIS)

Genovese, Luigi; Stanev, Yassen S.

2005-01-01

We reconsider the general constraints on the perturbative anomalous dimensions in conformal invariant QFT and in particular in N=4 SYM with gauge group SU(N). We show that all the perturbative corrections to the anomalous dimension of a renormalized gauge invariant local operator can be written as polynomials in its one loop anomalous dimension. In the N=4 SYM theory the coefficients of these polynomials are rational functions of the number of colours N

Optimized bacterial expression and purification of the c-Src catalytic domain for solution NMR studies

International Nuclear Information System (INIS)

Piserchio, Andrea; Ghose, Ranajeet; Cowburn, David

2009-01-01

Progression of a host of human cancers is associated with elevated levels of expression and catalytic activity of the Src family of tyrosine kinases (SFKs), making them key therapeutic targets. Even with the availability of multiple crystal structures of active and inactive forms of the SFK catalytic domain (CD), a complete understanding of its catalytic regulation is unavailable. Also unavailable are atomic or near-atomic resolution information about their interactions, often weak or transient, with regulating phosphatases and downstream targets. Solution NMR, the biophysical method best suited to tackle this problem, was previously hindered by difficulties in bacterial expression and purification of sufficient quantities of soluble, properly folded protein for economically viable labeling with NMR-active isotopes. Through a choice of optimal constructs, co-expression with chaperones and optimization of the purification protocol, we have achieved the ability to bacterially produce large quantities of the isotopically-labeled CD of c-Src, the prototypical SFK, and of its activating Tyr-phosphorylated form. All constructs produce excellent spectra allowing solution NMR studies of this family in an efficient manner

Epithelial membrane protein-2 promotes endometrial tumor formation through activation of FAK and Src.

Directory of Open Access Journals (Sweden)

Maoyong Fu

Full Text Available Endometrial cancer is the most common gynecologic malignancy diagnosed among women in developed countries. One recent biomarker strongly associated with disease progression and survival is epithelial membrane protein-2 (EMP2, a tetraspan protein known to associate with and modify surface expression of certain integrin isoforms. In this study, we show using a xenograft model system that EMP2 expression is necessary for efficient endometrial tumor formation, and we have started to characterize the mechanism by which EMP2 contributes to this malignant phenotype. In endometrial cancer cells, the focal adhesion kinase (FAK/Src pathway appears to regulate migration as measured through wound healing assays. Manipulation of EMP2 levels in endometrial cancer cells regulates the phosphorylation of FAK and Src, and promotes their distribution into lipid raft domains. Notably, cells with low levels of EMP2 fail to migrate and poorly form tumors in vivo. These findings reveal the pivotal role of EMP2 in endometrial cancer carcinogenesis, and suggest that the association of elevated EMP2 levels with endometrial cancer prognosis may be causally linked to its effect on integrin-mediated signaling.

The vector meson with anomalous magnetic moment

International Nuclear Information System (INIS)

Boyarkin, O.M.

1976-01-01

The possibility of introducing an anomalous magnetic moment into the Stuckelberg version of the charged vector meson theory is considered. It is shown that the interference of states with spins equal to one and zero is absent in the presence of an anomalous magnetic moment of a particle. The differential cross section of scattering on the Coulomb field of a nucleus is calculated, and so are the differential and integral cross sections of meson pair production on annihilation of two gamma quanta. The two-photon mechanism of production of a meson pair in colliding electron-positron beams is considered. It is shown that with any value of the anomalous magnetic moment the cross section of the esup(+)esup(-) → esup(+)esup(-)γsup(*)γsup(*) → esup(+)esup(-)Wsup(+)Wsup(-) reaction exceeds that of the esup(+)esup(-) → γsup(*) → Wsup(+)Wsup(-) at sufficiently high energies

Ion anomalous transport and feedback control. Final technical report, September 1, 1987 - August 31, 1997

International Nuclear Information System (INIS)

Sen, A.K.

1998-01-01

This final report is comprised of the following six progress reports: Ion Temperature Gradient Instability and Anomalous Transport, July 1989; Ion Temperature Gradient Instability and Anomalous Transport, August 1991; Ion Temperature Gradient Instability and Anomalous Transport, July 1993; Ion Anomalous Transport and Feedback Control, May 1994; Ion Anomalous Transport and Feedback Control, April 1995; and Ion Anomalous Transport and Feedback Control, December 1997

Anomalous spreading behaviour of polyethyleneglycoldistearate ...

Indian Academy of Sciences (India)

Unknown

Anomalous behaviour; polythyleneglycoldistearate; air/water interface; ... distinguished these monolayer states in terms of molecular ordering, including the .... It has been found that the compressibilities of the materials in the condensed phase.

ROS mediates interferon gamma induced phosphorylation of Src, through the Raf/ERK pathway, in MCF-7 human breast cancer cell line.

Science.gov (United States)

Zibara, Kazem; Zeidan, Asad; Bjeije, Hassan; Kassem, Nouhad; Badran, Bassam; El-Zein, Nabil

2017-03-01

Interferon gamma (IFN-ɣ) is a pleiotropic cytokine which plays dual contrasting roles in cancer. Although IFN-ɣ has been clinically used to treat various malignancies, it was recently shown to have protumorigenic activities. Reactive oxygen species (ROS) are overproduced in cancer cells, mainly due to NADPH oxidase activity, which results into several changes in signaling pathways. In this study, we examined IFN-ɣ effect on the phosphorylation levels of key signaling proteins, through ROS production, in the human breast cancer cell line MCF-7. After treatment by IFN-ɣ, results showed a significant increase in the phosphorylation of STAT1, Src, raf, AKT, ERK1/2 and p38 signaling molecules, in a time specific manner. Src and Raf were found to be involved in early stages of IFN-ɣ signaling since their phosphorylation increased very rapidly. Selective inhibition of Src-family kinases resulted in an immediate significant decrease in the phosphorylation status of Raf and ERK1/2, but not p38 and AKT. On the other hand, IFN-ɣ resulted in ROS generation, through H 2 O 2 production, whereas pre-treatment with the ROS inhibitor NAC caused ROS inhibition and a significant decrease in the phosphorylation levels of AKT, ERK1/2, p38 and STAT1. Moreover, pretreatment with a selective NOX1 inhibitor resulted in a significant decrease of AKT phosphorylation. Finally, no direct relationship was found between ROS production and calcium mobilization. In summary, IFN-ɣ signaling in MCF-7 cell line is ROS-dependent and follows the Src/Raf/ERK pathway whereas its signaling through the AKT pathway is highly dependent on NOX1.

Evidence for in vivo phosphorylation of the Grb2 SH2-domain binding site on focal adhesion kinase by Src-family protein-tyrosine kinases.

OpenAIRE

Schlaepfer, D D; Hunter, T

1996-01-01

Focal adhesion kinase (FAK) is a nonreceptor protein-tyrosine kinase (PTK) that associates with integrin receptors and participates in extracellular matrix-mediated signal transduction events. We showed previously that the c-Src nonreceptor PTK and the Grb2 SH2/SH3 adaptor protein bound directly to FAK after fibronectin stimulation (D. D. Schlaepfer, S.K. Hanks, T. Hunter, and P. van der Geer, Nature [London] 372:786-791, 1994). Here, we present evidence that c-Src association with FAK is req...

Neoclassical and anomalous transport in toroidal plasmas with drift-ordered turbulence

International Nuclear Information System (INIS)

Sugama, H.; Horton, W.

1996-01-01

Neoclassical and anomalous transport fluxes are determined for axisymmetric toroidal plasmas with weak electromagnetic drift wave fluctuations. The neoclassical and anomalous fluxes are defined based on the ensemble-averaged kinetic equation with the statistically averaged nonlinear wave-particle interactions. The anomalous forces derived from that quasilinear term induce the anomalous particle and heat fluxes. For the microscale fluctuations k perpendicular ρ i ∼ 1 the parallel neoclassical fluxes remain invariant. For mesoscale fluctuations the mixing length fluctuation level with broken symmetry from (weak) shear flows the neoclassical banana-plateau fluxes are affected by the fluctuations through the parallel anomalous forces and the modified parallel viscosities. The entropy production rate due to the anomalous transport processes is formulated and used to identify conjugate pairs of the anomalous fluxes and forces, which are connected by the matrix with the Onsager symmetry. The proof of the Onsager symmetry is carried out by splitting the response function up into the even and odd parts under the (t, B) → (-t,-B) transformation and using the self-adjointness of the linearized Landau collision operator and the quasilinear formalism. An explicit calculation of the symmetric transport coefficients is possible when the Krook collision model replaces the Landau collision operator. The importance of low aspect ratio tokamaks and helical systems for experimental investigations of the Onsager symmetries is emphasized

Anomalous transport in tokamaks

International Nuclear Information System (INIS)

Wootton, A.J.

1989-01-01

A review is presented of what is known about anomalous transport in tokamaks. It is generally thought that this anomalous transport is the result of fluctuations in various plasma parameters. In the plasma edge detailed measurements of the quantities required to directly determine the fluctuation driven fluxes are available. The total flux of particles is well explained by the measured electrostatic fluctuation driven flux. However, a satisfactory model to explain the origin of the fluctuations has not been identified. The processes responsible for determining the edge energy flux are less clear, but electrostatic convection plays an important part. In the confinement region experimental observations are presently restricted to measurements of density and potential fluctuations and their correlations. The characteristics of the measured fluctuations are discussed and compared with the predictions of various models. Comparisons between measured particle, electron heat and ion heat fluxes, and those fluxes predicted to result from the measured fluctuations, are made. Magnetic fluctuations is discussed

The Src SH2 domain interacts dynamically with the focal adhesion kinase binding site as demonstrated by paramagnetic NMR spectroscopy.

Science.gov (United States)

Lindfors, Hanna E; Drijfhout, Jan Wouter; Ubbink, Marcellus

2012-06-01

The interaction between the tyrosine kinases Src and focal adhesion kinase (FAK) is a key step in signaling processes from focal adhesions. The phosphorylated tyrosine residue 397 in FAK is able to bind the Src SH2 domain. To establish the extent of the FAK binding motif, the binding affinity of the SH2 domain for phosphorylated and unphosphorylated FAK-derived peptides of increasing length was determined and compared with that of the internal Src SH2 binding site. It is shown that the FAK peptides have higher affinity than the internal binding site and that seven negative residues adjacent to the core SH2 binding motif increase the binding constant 30-fold. A rigid spin-label incorporated in the FAK peptides was used to establish on the basis of paramagnetic relaxation enhancement whether the peptide-protein complex is well defined. A large spread of the paramagnetic effects on the surface of the SH2 domain suggests that the peptide-protein complex exhibits dynamics, despite the high affinity of the peptide. The strong electrostatic interaction between the positive side of the SH2 domain and the negative peptide results in a high affinity but may also favor a dynamic interaction. Copyright © 2012 Wiley Periodicals, Inc.

Anomalous Magnetic and Electric Dipole Moments of the $\\tau$

CERN Document Server

Taylor, L

1998-01-01

This paper reviews the theoretical predictions for and the experimental measurements of the anomalous magnetic and electric dipole moments of the tau lepton. In particular, recent analyses of the e/sup +/e/sup -/ to tau /sup +/ tau /sup -/ gamma process from the L3 and OPAL collaborations are described. The most precise results, from L3, for the anomalous magnetic and electric dipole moments respectively are: a/sub tau /=0.004+or-0.027+or-0.023 and d /sub tau /=(0.0+or-1.5+or-1.3)*10/sup -16/ e.cm. (22 refs). This paper reviews the theoretical predictions for and the experimental measurements of the anomalous magnetic and electric dipole moments of the tau lepton. In particular, recent analyses of the $\\eettg$ process from the L3 and OPAL collaborations are described. The most precise results, from L3, for the anomalous magnetic and electric dipole moments respectively are: $\\atau = 0.004 10^{-16}{e{\\cdot}\\mathrm{cm}}$.

No need to replace an "anomalous" primate (Primates) with an "anomalous" bear (Carnivora, Ursidae).

Science.gov (United States)

Gutiérrez, Eliécer E; Pine, Ronald H

2015-01-01

By means of mitochondrial 12S rRNA sequencing of putative "yeti", "bigfoot", and other "anomalous primate" hair samples, a recent study concluded that two samples, presented as from the Himalayas, do not belong to an "anomalous primate", but to an unknown, anomalous type of ursid. That is, that they match 12S rRNA sequences of a fossil Polar Bear (Ursusmaritimus), but neither of modern Polar Bears, nor of Brown Bears (Ursusarctos), the closest relative of Polar Bears, and one that occurs today in the Himalayas. We have undertaken direct comparison of sequences; replication of the original comparative study; inference of phylogenetic relationships of the two samples with respect to those from all extant species of Ursidae (except for the Giant Panda, Ailuropodamelanoleuca) and two extinct Pleistocene species; and application of a non-tree-based population aggregation approach for species diagnosis and identification. Our results demonstrate that the very short fragment of the 12S rRNA gene sequenced by Sykes et al. is not sufficiently informative to support the hypotheses provided by these authors with respect to the taxonomic identity of the individuals from which these sequences were obtained. We have concluded that there is no reason to believe that the two samples came from anything other than Brown Bears. These analyses afforded an opportunity to test the monophyly of morphologically defined species and to comment on both their phylogenetic relationships and future efforts necessary to advance our understanding of ursid systematics.

Navigation by anomalous random walks on complex networks.

Science.gov (United States)

Weng, Tongfeng; Zhang, Jie; Khajehnejad, Moein; Small, Michael; Zheng, Rui; Hui, Pan

2016-11-23

Anomalous random walks having long-range jumps are a critical branch of dynamical processes on networks, which can model a number of search and transport processes. However, traditional measurements based on mean first passage time are not useful as they fail to characterize the cost associated with each jump. Here we introduce a new concept of mean first traverse distance (MFTD) to characterize anomalous random walks that represents the expected traverse distance taken by walkers searching from source node to target node, and we provide a procedure for calculating the MFTD between two nodes. We use Lévy walks on networks as an example, and demonstrate that the proposed approach can unravel the interplay between diffusion dynamics of Lévy walks and the underlying network structure. Moreover, applying our framework to the famous PageRank search, we show how to inform the optimality of the PageRank search. The framework for analyzing anomalous random walks on complex networks offers a useful new paradigm to understand the dynamics of anomalous diffusion processes, and provides a unified scheme to characterize search and transport processes on networks.

Navigation by anomalous random walks on complex networks

Science.gov (United States)

Weng, Tongfeng; Zhang, Jie; Khajehnejad, Moein; Small, Michael; Zheng, Rui; Hui, Pan

2016-11-01

Anomalous random walks having long-range jumps are a critical branch of dynamical processes on networks, which can model a number of search and transport processes. However, traditional measurements based on mean first passage time are not useful as they fail to characterize the cost associated with each jump. Here we introduce a new concept of mean first traverse distance (MFTD) to characterize anomalous random walks that represents the expected traverse distance taken by walkers searching from source node to target node, and we provide a procedure for calculating the MFTD between two nodes. We use Lévy walks on networks as an example, and demonstrate that the proposed approach can unravel the interplay between diffusion dynamics of Lévy walks and the underlying network structure. Moreover, applying our framework to the famous PageRank search, we show how to inform the optimality of the PageRank search. The framework for analyzing anomalous random walks on complex networks offers a useful new paradigm to understand the dynamics of anomalous diffusion processes, and provides a unified scheme to characterize search and transport processes on networks.

Partial anomalous pulmonary venous return in Turner syndrome.

Science.gov (United States)

van den Hoven, Allard T; Chelu, Raluca G; Duijnhouwer, Anthonie L; Demulier, Laurent; Devos, Daniel; Nieman, Koen; Witsenburg, Maarten; van den Bosch, Annemien E; Loeys, Bart L; van Hagen, Iris M; Roos-Hesselink, Jolien W

2017-10-01

The aim of this study is to describe the prevalence, anatomy, associations and clinical impact of partial anomalous pulmonary venous return in patients with Turner syndrome. All Turner patients who presented at our Turner clinic, between January 2007 and October 2015 were included in this study and underwent ECG, echocardiography and advanced imaging such as cardiac magnetic resonance or computed tomography as part of their regular clinical workup. All imaging was re-evaluated and detailed anatomy was described. Partial anomalous pulmonary venous return was diagnosed in 24 (25%) out of 96 Turner patients included and 14 (58%) of these 24 partial anomalous pulmonary venous return had not been reported previously. Right atrial or ventricular dilatation was present in 11 (46%) of 24 partial anomalous pulmonary venous return patients. When studied with advanced imaging modalities and looked for with specific attention, PAPVR is found in 1 out of 4 Turner patients. Half of these patients had right atrial and/or ventricular dilatation. Evaluation of pulmonary venous return should be included in the standard protocol in all Turner patients. Copyright © 2017. Published by Elsevier B.V.

Temperature dependent anomalous statistics

International Nuclear Information System (INIS)

Das, A.; Panda, S.

1991-07-01

We show that the anomalous statistics which arises in 2 + 1 dimensional Chern-Simons gauge theories can become temperature dependent in the most natural way. We analyze and show that a statistic's changing phase transition can happen in these theories only as T → ∞. (author). 14 refs

Allosteric Inhibition of Bcr-Abl Kinase by High Affinity Monobody Inhibitors Directed to the Src Homology 2 (SH2)-Kinase Interface*

Science.gov (United States)

Wojcik, John; Lamontanara, Allan Joaquim; Grabe, Grzegorz; Koide, Akiko; Akin, Louesa; Gerig, Barbara; Hantschel, Oliver; Koide, Shohei

2016-01-01

Bcr-Abl is a constitutively active kinase that causes chronic myelogenous leukemia. We have shown that a tandem fusion of two designed binding proteins, termed monobodies, directed to the interaction interface between the Src homology 2 (SH2) and kinase domains and to the phosphotyrosine-binding site of the SH2 domain, respectively, inhibits the Bcr-Abl kinase activity. Because the latter monobody inhibits processive phosphorylation by Bcr-Abl and the SH2-kinase interface is occluded in the active kinase, it remained undetermined whether targeting the SH2-kinase interface alone was sufficient for Bcr-Abl inhibition. To address this question, we generated new, higher affinity monobodies with single nanomolar KD values targeting the kinase-binding surface of SH2. Structural and mutagenesis studies revealed the molecular underpinnings of the monobody-SH2 interactions. Importantly, the new monobodies inhibited Bcr-Abl kinase activity in vitro and in cells, and they potently induced cell death in chronic myelogenous leukemia cell lines. This work provides strong evidence for the SH2-kinase interface as a pharmacologically tractable site for allosteric inhibition of Bcr-Abl. PMID:26912659

Allosteric Inhibition of Bcr-Abl Kinase by High Affinity Monobody Inhibitors Directed to the Src Homology 2 (SH2)-Kinase Interface.

Science.gov (United States)

Wojcik, John; Lamontanara, Allan Joaquim; Grabe, Grzegorz; Koide, Akiko; Akin, Louesa; Gerig, Barbara; Hantschel, Oliver; Koide, Shohei

2016-04-15

Bcr-Abl is a constitutively active kinase that causes chronic myelogenous leukemia. We have shown that a tandem fusion of two designed binding proteins, termed monobodies, directed to the interaction interface between the Src homology 2 (SH2) and kinase domains and to the phosphotyrosine-binding site of the SH2 domain, respectively, inhibits the Bcr-Abl kinase activity. Because the latter monobody inhibits processive phosphorylation by Bcr-Abl and the SH2-kinase interface is occluded in the active kinase, it remained undetermined whether targeting the SH2-kinase interface alone was sufficient for Bcr-Abl inhibition. To address this question, we generated new, higher affinity monobodies with single nanomolar KD values targeting the kinase-binding surface of SH2. Structural and mutagenesis studies revealed the molecular underpinnings of the monobody-SH2 interactions. Importantly, the new monobodies inhibited Bcr-Abl kinase activity in vitro and in cells, and they potently induced cell death in chronic myelogenous leukemia cell lines. This work provides strong evidence for the SH2-kinase interface as a pharmacologically tractable site for allosteric inhibition of Bcr-Abl. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

The anomalous magnetic moment of the muon

CERN Document Server

Jegerlehner, Friedrich

2017-01-01

This research monograph covers extensively the theory of the muon anomalous magnetic moment and provides estimates of the theoretical uncertainties. The muon anomalous magnetic moment is one of the most precisely measured quantities in elementary particle physics and provides one of the most stringent tests of relativistic quantum field theory as a fundamental theoretical framework. It allows for an extremely precise check of the standard model of elementary particles and of its limitations. This book reviews the present state of knowledge of the anomalous magnetic moment a=(g-2)/2 of the muon. Recent experiments at the Brookhaven National Laboratory now reach the unbelievable precision of 0.5 parts per million, improving the accuracy of previous g-2 experiments at CERN by a factor of 14. In addition, quantum electrodynamics and electroweak and hadronic effects are reviewed. Since non-perturbative hadronic effects play a key role for the precision test, their evaluation is described in detail. Perspectives fo...

The Anomalous Magnetic Moment of the Muon

CERN Document Server

Jegerlehner, Friedrich

2008-01-01

This book reviews the present state of knowledge of the anomalous magnetic moment a=(g-2)/2 of the muon. The muon anomalous magnetic moment amy is one of the most precisely measured quantities in elementary particle physics and provides one of the most stringent tests of relativistic quantum field theory as a fundamental theoretical framework. It allows for an extremely precise check of the standard model of elementary particles and of its limitations. Recent experiments at the Brookhaven National Laboratory now reach the unbelievable precision of 0.5 parts per million, improving the accuracy of previous g-2 experiments at CERN by a factor of 14. A major part of the book is devoted to the theory of the anomalous magnetic moment and to estimates of the theoretical uncertainties. Quantum electrodynamics and electroweak and hadronic effects are reviewed. Since non-perturbative hadronic effects play a key role for the precision test, their evaluation is described in detail. After the overview of theory, the exper...

All-loop anomalous dimensions in integrable λ-deformed σ-models

Directory of Open Access Journals (Sweden)

George Georgiou

2015-12-01

Full Text Available We calculate the all-loop anomalous dimensions of current operators in λ-deformed σ-models. For the isotropic integrable deformation and for a semi-simple group G we compute the anomalous dimensions using two different methods. In the first we use the all-loop effective action and in the second we employ perturbation theory along with the Callan–Symanzik equation and in conjunction with a duality-type symmetry shared by these models. Furthermore, using CFT techniques we compute the all-loop anomalous dimension of bilinear currents for the isotropic deformation case and a general G. Finally we work out the anomalous dimension matrix for the cases of anisotropic SU(2 and the two couplings, corresponding to the symmetric coset G/H and a subgroup H, splitting of a group G.

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

International Nuclear Information System (INIS)

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

2004-01-01

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

Statistical analysis of anomalous transport in resistive interchange turbulence

International Nuclear Information System (INIS)

Sugama, Hideo; Wakatani, Masahiro.

1992-01-01

A new anomalous transport model for resistive interchange turbulence is derived from statistical analysis applying two-scale direct-interaction approximation to resistive magnetohydrodynamic equations with a gravity term. Our model is similar to the K-ε model for eddy viscosity of turbulent shear flows in that anomalous transport coefficients are expressed in terms of by the turbulent kinetic energy K and its dissipation rate ε while K and ε are determined by transport equations. This anomalous transport model can describe some nonlocal effects such as those from boundary conditions which cannot be treated by conventional models based on the transport coefficients represented by locally determined plasma parameters. (author)

Development of anomalous detection using movie prediction

International Nuclear Information System (INIS)

Sakakibara, Yoji; Demachi, Kazuyuki; Kawai, Masaki; Chhatluli, Ritu; Kamiaka, Kazuma

2012-01-01

In this research, the new method to predict the near-future of the movie images captured by video camera based on the combination of the Principle Component Analysis (PCA) and the Singular Spectral Analysis (SSA). In the normal condition of machines, the real-time captured movie is supposed to correspond to the predicted one. If the error between the both becomes significantly large, it may suggest some anomalous motion of the machines. So the movie prediction method has a possibility of the sensitive anomalous detection system. (author)

Anomalous Nernst Effects of [CoSiB/Pt] Multilayer Films

OpenAIRE

Kelekci, O.; Lee, H. N.; Kim, T. W.; Noh, H.

2013-01-01

We report a measurement for the anomalous Nernst effects induced by a temperature gradient in [CoSiB/Pt] multilayer films with perpendicular magnetic anisotropy. The Nernst voltage shows a characteristic hysteresis which reflects the magnetization of the film as in the case of the anomalous Hall effects. With a local heating geometry, we also measure the dependence of the anomalous Nernst voltage on the distance d from the heating element. It is roughly proportional to 1/d^1.3, which can be c...

Syk/Src Pathway-Targeted Inhibition of Skin Inflammatory Responses by Carnosic Acid

Directory of Open Access Journals (Sweden)

Jueun Oh

2012-01-01

Full Text Available Carnosic acid (CA is a diterpene compound exhibiting antioxidative, anticancer, anti-angiogenic, anti-inflammatory, anti-metabolic disorder, and hepatoprotective and neuroprotective activities. In this study, the effect of CA on various skin inflammatory responses and its inhibitory mechanism were examined. CA strongly suppressed the production of IL-6, IL-8, and MCP-1 from keratinocyte HaCaT cells stimulated with sodium lauryl sulfate (SLS and retinoic acid (RA. In addition, CA blocked the release of nitric oxide (NO, tumor necrosis factor (TNF-α, and prostaglandin E2 (PGE2 from RAW264.7 cells activated by the toll-like receptor (TLR-2 ligands, Gram-positive bacterium-derived peptidoglycan (PGN and pam3CSK, and the TLR4 ligand, Gram-negative bacterium-derived lipopolysaccharide (LPS. CA arrested the growth of dermatitis-inducing Gram-positive and Gram-negative microorganisms such Propionibacterium acnes, Pseudomonas aeruginosa, and Staphylococcus aureus. CA also blocked the nuclear translocation of nuclear factor (NF-κB and its upstream signaling including Syk/Src, phosphoinositide 3-kinase (PI3K, Akt, inhibitor of κBα (IκBα kinase (IKK, and IκBα for NF-κB activation. Kinase assays revealed that Syk could be direct enzymatic target of CA in its anti-inflammatory action. Therefore, our data strongly suggest the potential of CA as an anti-inflammatory drug against skin inflammatory responses with Src/NF-κB inhibitory properties.

General PFG signal attenuation expressions for anisotropic anomalous diffusion by modified-Bloch equations

Science.gov (United States)

Lin, Guoxing

2018-05-01

Anomalous diffusion exists widely in polymer and biological systems. Pulsed-field gradient (PFG) anomalous diffusion is complicated, especially in the anisotropic case where limited research has been reported. A general PFG signal attenuation expression, including the finite gradient pulse (FGPW) effect for free general anisotropic fractional diffusion { 0 integral modified-Bloch equation, were extended to obtain general PFG signal attenuation expressions for anisotropic anomalous diffusion. Various cases of PFG anisotropic anomalous diffusion were investigated, including coupled and uncoupled anisotropic anomalous diffusion. The continuous-time random walk (CTRW) simulation was also carried out to support the theoretical results. The theory and the CTRW simulation agree with each other. The obtained signal attenuation expressions and the three-dimensional fractional modified-Bloch equations are important for analyzing PFG anisotropic anomalous diffusion in NMR and MRI.

Anomalous magnon Nernst effect of topological magnonic materials

OpenAIRE

Wang, X. S.; Wang, X. R.

2017-01-01

The magnon transport driven by thermal gradient in a perpendicularly magnetized honeycomb lattice is studied. The system with the nearest-neighbor pseudodipolar interaction and the next-nearest-neighbor Dzyaloshinskii-Moriya interaction (DMI) has various topologically nontrivial phases. When an in-plane thermal gradient is applied, a transverse in-plane magnon current is generated. This phenomenon is termed as the anomalous magnon Nernst effect that closely resembles the anomalous Nernst effe...

Particle diffusion from resonance islands in Aladdin at SRC

International Nuclear Information System (INIS)

Liu, J.; Crosbie, E.; Teng, L.; Bridges, J.; Ciarlette, D.; Kustom, R.; Voss, D.; Mills, F.; Borland, M.; Symon, K.

1993-01-01

The dynamics of the beam in the resonance islands was studied on the electron storage ring Aladdin at the Synchrotron Radiation Center (SRC). The authors especially studied the horizontal third- and fourth-integral resonances driven by sextupole fields in the first and second order. A fast kicker was fired to kick the beam into one of the outboard stable islands. The beam took on a quasi-Gaussian distribution and slowly diffused out of the island. The diffusion rate and its dependence on the strengths of the driving sextupoles and the chromaticity sextupoles were measured by tracing the resonance peak of the betatron oscillation on the spectrum analyzer. Beam positions were also recorded through the data acquisition device which was locked by a pulse-delay circuitry. Interesting results are shown and compared with numerical calculations

Particle diffusion from resonance islands in Aladdin at SRC

International Nuclear Information System (INIS)

Liu, J.; Crosbie, E.; Teng, L.; Bridges, J.; Ciarlette, D.; Kustom, R.; Voss, D.; Mills, F.; Borland, M.; Symon, K.

1993-01-01

The dynamics of the beam in the resonance islands was studied on the electron storage ring Aladdin at the Synchrotron Radiation Center (SRC). The authors especially studied the horizontal third- and fourth-integral resonances driven by sextupole fields in the first and second order. A fast kicker was fired to kick the beam into one of the outboard stable islands. The beam took on a quasi-Gaussian distribution and slowly diffused out of the island. The diffusion rate and its dependence on the strengths of the driving sextupoles and the chromaticity sextupoles were measured by tracing the resonance peak of the betatron oscillation on the spectrum analyzer. Beam positions were also recorded through the data acquisition device which was clocked by a pulse-delay circuitry. Interesting results are shown and compared with numerical calculations

Activation of AMPA receptor promotes TNF-α release via the ROS-cSrc-NFκB signaling cascade in RAW264.7 macrophages

Energy Technology Data Exchange (ETDEWEB)

Cheng, Xiu-Li [Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing (China); Ding, Fan [Office of Scientific R& D, Tsinghua University, Beijing (China); Li, Hui; Tan, Xiao-Qiu [Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing (China); Liu, Xiao [Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing (China); Cao, Ji-Min, E-mail: caojimin@126.com [Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing (China); Gao, Xue, E-mail: longlongnose@163.com [Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing (China)

2015-05-29

The relationship between glutamate signaling and inflammation has not been well defined. This study aimed to investigate the role of AMPA receptor (AMPAR) in the expression and release of tumor necrosis factor-alpha (TNF-α) from macrophages and the underlying mechanisms. A series of approaches, including confocal microscopy, immunofluorescency, flow cytometry, ELISA and Western blotting, were used to estimate the expression of AMPAR and downstream signaling molecules, TNF-α release and reactive oxygen species (ROS) generation in the macrophage-like RAW264.7 cells. The results demonstrated that AMPAR was expressed in RAW264.7 cells. AMPA significantly enhanced TNF-α release from RAW264.7 cells, and this effect was abolished by CNQX (AMPAR antagonist). AMPA also induced elevation of ROS production, phosphorylation of c-Src and activation of nuclear factor (NF)-κB in RAW264.7 cells. Blocking c-Src by PP2, scavenging ROS by glutathione (GSH) or inhibiting NF-κB activation by pyrrolidine dithiocarbamate (PDTC) decreased TNF-α production from RAW264.7 cells. We concluded that AMPA promotes TNF-α release in RAW264.7 macrophages likely through the following signaling cascade: AMPAR activation → ROS generation → c-Src phosphorylation → NF-κB activation → TNF-α elevation. The study suggests that AMPAR may participate in macrophage activation and inflammation. - Highlights: • AMPAR is expressed in RAW264.7 macrophages and is upregulated by AMPA stimulation. • Activation of AMPAR stimulates TNF-α release in macrophages through the ROS-cSrc-NFκB signaling cascade. • Macrophage AMPAR signaling may play an important role in inflammation.

Anomalous magnetic torque in the heavy-fermion superconductor UBe13

International Nuclear Information System (INIS)

Schmiedeshoff, G.M.; Fisk, Z.; Smith, J.L.

1994-01-01

Measurements of the magnetic torque acting upon a single crystal of the heavy-fermion superconductor UBe 13 have been made at temperatures from 0.5 K to 30.0 K and in magnetic fields to 23 T using a capacitive magnetometer. We find that a large, anomalous contribution to the magnetic torque appears in at low temperatures and in high fields. The anomalous torque coexists with the superconducting state at low temperature. We propose that the anomalous torque reflects the existence of a field-induced magnetic phase transition. (orig.)

Search for Anomalous Couplings in the Higgs Sector at LEP

CERN Document Server

Achard, P; Aguilar-Benítez, M; Alcaraz, J; Alemanni, G; Allaby, James V; Aloisio, A; Alviggi, M G; Anderhub, H; Andreev, V P; Anselmo, F; Arefev, A; Azemoon, T; Aziz, T; Bagnaia, P; Bajo, A; Baksay, G; Baksay, L; Baldew, S V; Banerjee, S; Banerjee, Sw; Barczyk, A; Barillère, R; Bartalini, P; Basile, M; Batalova, N; Battiston, R; Bay, A; Becattini, F; Becker, U; Behner, F; Bellucci, L; Berbeco, R; Berdugo, J; Berges, P; Bertucci, B; Betev, B L; Biasini, M; Biglietti, M; Biland, A; Blaising, J J; Blyth, S C; Bobbink, Gerjan J; Böhm, A; Boldizsar, L; Borgia, B; Bottai, S; Bourilkov, D; Bourquin, Maurice; Braccini, S; Branson, J G; Brochu, F; Burger, J D; Burger, W J; Cai, X D; Capell, M; Cara Romeo, G; Carlino, G; Cartacci, A M; Casaus, J; Cavallari, F; Cavallo, N; Cecchi, C; Cerrada, M; Chamizo-Llatas, M; Chang, Y H; Chemarin, M; Chen, A; Chen, G; Chen, G M; Chen, H F; Chen, H S; Chiefari, G; Cifarelli, Luisa; Cindolo, F; Clare, I; Clare, R; Coignet, G; Colino, N; Costantini, S; de la Cruz, B; Cucciarelli, S; van Dalen, J A; De Asmundis, R; Déglon, P L; Debreczeni, J; Degré, A; Dehmelt, K; Deiters, K; Della Volpe, D; Delmeire, E; Denes, P; De Notaristefani, F; De Salvo, A; Diemoz, M; Dierckxsens, M; Dionisi, C; Dittmar, M; Doria, A; Dova, M T; Duchesneau, D; Duda, M; Echenard, B; Eline, A; El-Hage, A; El-Mamouni, H; Engler, A; Eppling, F J; Extermann, P; Falagán, M A; Falciano, S; Favara, A; Fay, J; Fedin, O; Felcini, M; Ferguson, T; Fesefeldt, H S; Fiandrini, E; Field, J H; Filthaut, F; Fisher, P H; Fisher, W; Fisk, I; Forconi, G; Freudenreich, Klaus; Furetta, C; Galaktionov, Yu; Ganguli, S N; García-Abia, P; Gataullin, M; Gentile, S; Giagu, S; Gong, Z F; Grenier, G; Grimm, O; Grünewald, M W; Guida, M; van Gulik, R; Gupta, V K; Gurtu, A; Gutay, L J; Haas, D; Hatzifotiadou, D; Hebbeker, T; Hervé, A; Hirschfelder, J; Hofer, H; Hohlmann, M; Holzner, G; Hou, S R; Hu, Y; Jin, B N; Jones, L W; de Jong, P; Josa-Mutuberria, I; Kaur, M; Kienzle-Focacci, M N; Kim, J K; Kirkby, Jasper; Kittel, E W; Klimentov, A; König, A C; Kopal, M; Koutsenko, V F; Kräber, M H; Krämer, R W; Krüger, A; Kunin, A; Ladrón de Guevara, P; Laktineh, I; Landi, G; Lebeau, M; Lebedev, A; Lebrun, P; Lecomte, P; Lecoq, P; Le Coultre, P; Le Goff, J M; Leiste, R; Levtchenko, M; Levchenko, P M; Li, C; Likhoded, S; Lin, C H; Lin, W T; Linde, Frank L; Lista, L; Liu, Z A; Lohmann, W; Longo, E; Lü, Y S; Luci, C; Luminari, L; Lustermann, W; Ma Wen Gan; Malgeri, L; Malinin, A; Maña, C; Mans, J; Martin, J P; Marzano, F; Mazumdar, K; McNeil, R R; Mele, S; Merola, L; Meschini, M; Metzger, W J; Mihul, A; Milcent, H; Mirabelli, G; Mnich, J; Mohanty, G B; Muanza, G S; Muijs, A J M; Musicar, B; Musy, M; Nagy, S; Natale, S; Napolitano, M; Nessi-Tedaldi, F; Newman, H; Nisati, A; Novák, T; Nowak, H; Ofierzynski, R A; Organtini, G; Pal, I; Palomares, C; Paolucci, P; Paramatti, R; Passaleva, G; Patricelli, S; Paul, T; Pauluzzi, M; Paus, C; Pauss, Felicitas; Pedace, M; Pensotti, S; Perret-Gallix, D; Petersen, B; Piccolo, D; Pierella, F; Pioppi, M; Piroué, P A; Pistolesi, E; Plyaskin, V; Pohl, M; Pozhidaev, V; Pothier, J; Prokofev, D; Prokofiev, D O; Quartieri, J; Rahal-Callot, G; Rahaman, M A; Raics, P; Raja, N; Ramelli, R; Rancoita, P G; Ranieri, R; Raspereza, A V; Razis, P A; Ren, D; Rescigno, M; Reucroft, S; Riemann, S; Riles, K; Roe, B P; Romero, L; Rosca, A; Rosemann, C; Rosenbleck, C; Rosier-Lees, S; Roth, S; Rubio, J A; Ruggiero, G; Rykaczewski, H; Sakharov, A; Saremi, S; Sarkar, S; Salicio, J; Sánchez, E; Schäfer, C; Shchegelskii, V; Schopper, Herwig Franz; Schotanus, D J; Sciacca, C; Servoli, L; Shevchenko, S; Shivarov, N; Shoutko, V; Shumilov, E; Shvorob, A V; Son, D; Souga, C; Spillantini, P; Steuer, M; Stickland, D P; Stoyanov, B; Strässner, A; Sudhakar, K; Sultanov, G G; Sun, L Z; Sushkov, S; Suter, H; Swain, J D; Szillási, Z; Tang, X W; Tarjan, P; Tauscher, Ludwig; Taylor, L; Tellili, B; Teyssier, D; Timmermans, C; Ting, Samuel C C; Ting, S M; Tonwar, S C; Tóth, J; Tully, C; Tung, K L; Ulbricht, J; Valente, E; Van de Walle, R T; Vásquez, R; Veszpremi, V; Vesztergombi, G; Vetlitskii, I; Vicinanza, D; Viertel, Gert M; Villa, S; Vivargent, M; Vlachos, S; Vodopyanov, I; Vogel, H; Vogt, H; Vorobev, I; Vorobyov, A A; Wadhwa, M; Wang, Q; Wang, X L; Wang, Z M; Weber, M; Wilkens, H; Wynhoff, S; Xia, L; Xu, Z Z; Yamamoto, J; Yang, B Z; Yang, C G; Yang, H J; Yang, M; Yeh, S C; Zalite, A; Zalite, Yu; Zhang, Z P; Zhao, J; Zhu, G Y; Zhu, R Y; Zhuang, H L; Zichichi, A; Zimmermann, B; Zöller, M

2004-01-01

Anomalous couplings of the Higgs boson are searched for through the processes e^+ e^- -> H gamma, e^+ e^- -> e^+ e^- H and e^+ e^- -> HZ. The mass range 70 GeV ffbar, H -> gamma gamma, H -> Z\\gamma and H -> WW^(*) are considered and no evidence is found for anomalous Higgs production or decay. Limits on the anomalous couplings d, db, Delta(g1z), Delta(kappa_gamma) and xi^2 are derived as well as limits on the H -> gamma gamma and H -> Z gamma decay rates.

Solvent refined coal (SRC) process. Quarterly technical progress report, January 1980-March 1980. [In process streams

Energy Technology Data Exchange (ETDEWEB)

1981-01-01

This report summarizes the progress of the Solvent Refined Coal (SRC) project at the SRC Pilot Plant in Fort Lewis, Wahsington, and the Process Development Unit (P-99) in Harmarville, Pennsylvania. After the remaining runs of the slurry preheater survey test program were completed January 14, the Fort Lewis Pilot Plant was shut down to inspect Slurry Preheater B and to insulate the coil for future testing at higher rates of heat flux. Radiographic inspection of the coil showed that the welds at the pressure taps and the immersion thermowells did not meet design specifications. Slurry Preheater A was used during the first 12 days of February while weld repairs and modifications to Slurry Preheater B were completed. Two attempts to complete a material balance run on Powhatan No. 6 Mine coal were attempted but neither was successful. Slurry Preheater B was in service the remainder of the quarter. The start of a series of runs at higher heat flux was delayed because of plugging in both the slurry and the hydrogen flow metering systems. Three baseline runs and three slurry runs of the high heat flux program were completed before the plant was shut down March 12 for repair of the Inert Gas Unit. Attempts to complete a fourth slurry run at high heat flux were unsuccessful because of problems with the coal feed handling and the vortex mix systems. Process Development Unit (P-99) completed three of the four runs designed to study the effect of dissolver L/D ratio. The fourth was under way at the end of the period. SRC yield correlations have been developed that include coal properties as independent variables. A preliminary ranking of coals according to their reactivity in PDU P-99 has been made. Techniques for studying coking phenomenona are now in place.

Role of pp60(c-src) and p(44/42) MAPK in ANG II-induced contraction of rat tonic gastrointestinal smooth muscles.

Science.gov (United States)

Puri, Rajinder N; Fan, Ya-Ping; Rattan, Satish

2002-08-01

We examined the role of mitogen-activated protein kinase (p(44/42) MAPK) in ANG II-induced contraction of lower esophageal sphincter (LES) and internal anal sphincter (IAS) smooth muscles. Studies were performed in the isolated smooth muscles and cells (SMC). ANG II-induced changes in the levels of phosphorylation of different signal transduction and effector proteins were determined before and after selective inhibitors. ANG II-induced contraction of the rat LES and IAS SMC was inhibited by genistein, PD-98059 [a specific inhibitor of MAPK kinases (MEK 1/2)], herbimycin A (a pp60(c-src) inhibitor), and antibodies to pp60(c-src) and p(120) ras GTPase-activating protein (p(120) rasGAP). ANG II-induced contraction of the tonic smooth muscles was accompanied by an increase in tyrosine phosphorylation of p(120) rasGAP. These were attenuated by genistein but not by PD-98059. ANG II-induced increase in phosphorylations of p(44/42) MAPKs and caldesmon was attenuated by both genistein and PD-98059. We conclude that pp60(c-src) and p(44/42) MAPKs play an important role in ANG II-induced contraction of LES and IAS smooth muscles.

Faraday anomalous dispersion optical tuners

Science.gov (United States)

Wanninger, P.; Valdez, E. C.; Shay, T. M.

1992-01-01

Common methods for frequency stabilizing diode lasers systems employ gratings, etalons, optical electric double feedback, atomic resonance, and a Faraday cell with low magnetic field. Our method, the Faraday Anomalous Dispersion Optical Transmitter (FADOT) laser locking, is much simpler than other schemes. The FADOT uses commercial laser diodes with no antireflection coatings, an atomic Faraday cell with a single polarizer, and an output coupler to form a compound cavity. This method is vibration insensitive, thermal expansion effects are minimal, and the system has a frequency pull in range of 443.2 GHz (9A). Our technique is based on the Faraday anomalous dispersion optical filter. This method has potential applications in optical communication, remote sensing, and pumping laser excited optical filters. We present the first theoretical model for the FADOT and compare the calculations to our experimental results.

Anomalous Hall effect and Nernst effect in itinerant ferromagnets

International Nuclear Information System (INIS)

Asamitsu, A.; Miyasato, T.; Abe, N.; Fujii, T.; Onose, Y.; Onoda, S.; Nagaosa, N.; Tokura, Y.

2007-01-01

Anomalous Hall effect (AHE) and anomalous Nernst effect (ANE) in many ferromagnetic metals including pure metals, oxides, and calcogenides, are studied to obtain unified understandings of their origins. We show the universal behavior of anomalous Hall conductivity σ xy as a function of longitudinal conductivity σ xx over six orders of magnitude, which is well reproduced by rigorous unified theory assuming both intrinsic and extrinsic contributions to the AHE. ANE is closely related with AHE and gives us further information about the electronic state in the ground state of ferromagnets. The temperature dependence of transverse Peltier coefficient α xy shows almost similar behavior among various ferromagnets and this behavior is expected from a conventional Boltzmann transport theory

Anomalous Hall effect and Nernst effect in itinerant ferromagnets

International Nuclear Information System (INIS)

Miyasato, T.; Abe, N.; Fujii, T.; Asamitsu, A.; Onose, Y.; Onoda, S.; Nagaosa, N.; Tokura, Y.

2007-01-01

Anomalous Hall effect (AHE) and anomalous Nernst effect (ANE) in many ferromagnetic metals including pure metals, oxides, and chalcogenides, are studied to obtain unified understandings of their origins. We show the universal behavior of anomalous Hall conductivity σ xy as a function of longitudinal conductivity σ xx over six orders of magnitude, which is well reproduced by a recent theory assuming both the intrinsic and extrinsic contributions to the AHE. ANE is closely related with AHE and gives us further information about the electronic state in the ground state of ferromagnets. The temperature dependence of transverse Peltier coefficient α xy shows almost similar behavior among various ferromagnets, and this behavior is expected from a conventional Boltzmann transport theory

Area 3, SRC-II coal slurry preheater studies report for the technical data analysis program

Energy Technology Data Exchange (ETDEWEB)

1984-08-01

This report reviews the raw data gathered from the Preheater B test runs at Ft. Lewis, and also the Preheater B results presented in the Solvent Refined Coal (SRC) Process Final Report, Volumes 1 and 2 of Slurry Preheater Design, SRC-II Process and the Ft. Lewis Slurry Preheater Data Analysis, 1 1/2 Inch Coil by Gulf Science and Technology Corporation of Pittsburgh, Pennsylvania. attempts were made to correlate several variables not previously considered with slurry viscosity and thermal conductivity. Only partial success was realized. However, in the process of attempting to correlate these variables an understanding of why some variables could not be correlated was achieved. An attempt was also made, using multiple linear regression, to correlate coal slurry viscosity and thermal conductivity with several independent variables among which were temperature, coal concentration, total solids, coal type, slurry residence time, shear rate, and unit size. The final correlations included some, but not all, of these independent variables. This report is not a stand alone document and should be considered a supplement to work already done. It should be read in conjunction with the reports referenced above.

Fractional charge and anomalous commutators

International Nuclear Information System (INIS)

Frishman, Y.; Gepner, D.

1983-06-01

Non-integer charges on topological objects in the presence of fermions are further investigated. The connection with anomalous commutators is discussed. The reason for the identical results in two-dimensional solutions and four-dimensional monopoles is pointed out. (author)

Anomalous enthalpy relaxation in vitreous silica

DEFF Research Database (Denmark)

Yue, Yuanzheng

2015-01-01

scans. It is known that the liquid fragility (i.e., the speed of the viscous slow-down of a supercooled liquid at its Tg during cooling) has impact on enthalpy relaxation in glass. Here, we find that vitreous silica (as a strong system) exhibits striking anomalies in both glass transition and enthalpy...... relaxation compared to fragile oxide systems. The anomalous enthalpy relaxation of vitreous silica is discovered by performing the hyperquenching-annealing-calorimetry experiments. We argue that the strong systems like vitreous silica and vitreous Germania relax in a structurally cooperative manner, whereas...... the fragile ones do in a structurally independent fashion. We discuss the origin of the anomalous enthalpy relaxation in the HQ vitreous silica....

Anomalous photoconductivity of ferrocene

Energy Technology Data Exchange (ETDEWEB)

Chakraborty, A K [Indian Association for the Cultivation of Science, Calcutta (India). Dept. of Spectroscopy; Mallik, B [Indian Association for the Cultivation of Science, Calcutta (India). Dept. of Spectroscopy

1995-08-15

Photoconductivity behaviour of ferrocene, a very useful metallo-organic sandwich compound, has been investigated at different constant temperatures using powdery material in a sandwich type of cell configuration and with the exposure of a polychromatic light source (mercury lamp of 125 W). Measurements with a constant d.c. bias voltage (27 V) across the sample cell and a fixed intensity of the exciting light source have shown a drastic change in the photocurrent versus time profile with the increase in temperature. Anomalous changes have been observed in the plot of the photocurrent versus reciprocal of temperature. Such changes are completely absent in the corresponding dark current behaviour. The photoinduced changes have been observed to be almost reversible in the entire temperature range. In a particular temperature range the reversibility of photocurrent is accompanied by fluctuations in equilibrium current obtained after switching off the light source. The observed anomalous changes in photocurrent have been explained by photoinduced phase transition in ferrocene. The possible origin and implications of this photoinduced phase transition are discussed. (orig.)

Combustion quality of poplar and willow clones grown as SRC at four sites in Brandenburg, Germany

DEFF Research Database (Denmark)

Liu, Na; Ugilt Larsen, Søren; Jørgensen, Uffe

2017-01-01

The fuel quality was assessed for nine poplar clones (AF2, Androscoggin, Max1, Max3, Max4, Monviso, Muhle-Larsen, NE42, Weser6) and one willow clone (Inger) grown as short rotation coppice (SRC) on four sites in the Brandenburg area in Germany. Fuel quality was analysed in 3-year old shoots in te...

Rare associations of tetralogy of Fallot with anomalous left coronary artery from pulmonary artery and totally anomalous pulmonary venous connection.

Science.gov (United States)

Sen, Supratim; Rao, Suresh G; Kulkarni, Snehal

2016-06-01

We describe the cases of two patients with tetralogy of Fallot, aged 4 years and 8 months, who were incidentally detected to have concomitant anomalous left coronary artery from pulmonary artery and total anomalous pulmonary venous connection, respectively, on preoperative imaging. They underwent surgical correction with good mid-term outcomes. In this study, we discuss the embryological basis, physiological effects, and review the literature of these two unusual associations. Awareness of these rare associations will avoid missed diagnoses and consequent surgical surprises.

Examination of anomalous self-experience

DEFF Research Database (Denmark)

Raballo, Andrea; Parnas, Josef

2012-01-01

. Here, we present the initial normative data and psychometric properties of a newly developed instrument (Examination of Anomalous Self-experience [EASE]), specifically designed to support the psychopathological exploration of SDs in both research and "real world" clinical settings. Our results support...

Degree-strength correlation reveals anomalous trading behavior.

Science.gov (United States)

Sun, Xiao-Qian; Shen, Hua-Wei; Cheng, Xue-Qi; Wang, Zhao-Yang

2012-01-01

Manipulation is an important issue for both developed and emerging stock markets. Many efforts have been made to detect manipulation in stock markets. However, it is still an open problem to identify the fraudulent traders, especially when they collude with each other. In this paper, we focus on the problem of identifying the anomalous traders using the transaction data of eight manipulated stocks and forty-four non-manipulated stocks during a one-year period. By analyzing the trading networks of stocks, we find that the trading networks of manipulated stocks exhibit significantly higher degree-strength correlation than the trading networks of non-manipulated stocks and the randomized trading networks. We further propose a method to detect anomalous traders of manipulated stocks based on statistical significance analysis of degree-strength correlation. Experimental results demonstrate that our method is effective at distinguishing the manipulated stocks from non-manipulated ones. Our method outperforms the traditional weight-threshold method at identifying the anomalous traders in manipulated stocks. More importantly, our method is difficult to be fooled by colluded traders.

Degree-strength correlation reveals anomalous trading behavior.

Directory of Open Access Journals (Sweden)

Xiao-Qian Sun

Full Text Available Manipulation is an important issue for both developed and emerging stock markets. Many efforts have been made to detect manipulation in stock markets. However, it is still an open problem to identify the fraudulent traders, especially when they collude with each other. In this paper, we focus on the problem of identifying the anomalous traders using the transaction data of eight manipulated stocks and forty-four non-manipulated stocks during a one-year period. By analyzing the trading networks of stocks, we find that the trading networks of manipulated stocks exhibit significantly higher degree-strength correlation than the trading networks of non-manipulated stocks and the randomized trading networks. We further propose a method to detect anomalous traders of manipulated stocks based on statistical significance analysis of degree-strength correlation. Experimental results demonstrate that our method is effective at distinguishing the manipulated stocks from non-manipulated ones. Our method outperforms the traditional weight-threshold method at identifying the anomalous traders in manipulated stocks. More importantly, our method is difficult to be fooled by colluded traders.

Fractal diffusion equations: Microscopic models with anomalous diffusion and its generalizations

International Nuclear Information System (INIS)

Arkhincheev, V.E.

2001-04-01

To describe the ''anomalous'' diffusion the generalized diffusion equations of fractal order are deduced from microscopic models with anomalous diffusion as Comb model and Levy flights. It is shown that two types of equations are possible: with fractional temporal and fractional spatial derivatives. The solutions of these equations are obtained and the physical sense of these fractional equations is discussed. The relation between diffusion and conductivity is studied and the well-known Einstein relation is generalized for the anomalous diffusion case. It is shown that for Levy flight diffusion the Ohm's law is not applied and the current depends on electric field in a nonlinear way due to the anomalous character of Levy flights. The results of numerical simulations, which confirmed this conclusion, are also presented. (author)

Formation of anomalous eutectic in Ni-Sn alloy by laser cladding

Science.gov (United States)

Wang, Zhitai; Lin, Xin; Cao, Yongqing; Liu, Fencheng; Huang, Weidong

2018-02-01

Ni-Sn anomalous eutectic is obtained by single track laser cladding with the scanning velocity from 1 mm/s to 10 mm/s using the Ni-32.5 wt.%Sn eutectic powders. The microstructure of the cladding layer and the grain orientations of anomalous eutectic were investigated. It is found that the microstructure is transformed from primary α-Ni dendrites and the interdendritic (α-Ni + Ni3Sn) eutectic at the bottom of the cladding layer to α-Ni and β-Ni3Sn anomalous eutectic at the top of the cladding layer, whether for single layer or multilayer laser cladding. The EBSD maps and pole figures indicate that the spatially structure of α-Ni phase is discontinuous and the Ni3Sn phase is continuous in anomalous eutectic. The transformation from epitaxial growth columnar at bottom of cladding layer to free nucleation equiaxed at the top occurs, i.e., the columnar to equiaxed transition (CET) at the top of cladding layer during laser cladding processing leads to the generation of anomalous eutectic.

Microinstability-based model for anomalous thermal confinement in tokamaks

International Nuclear Information System (INIS)

Tang, W.M.

1986-03-01

This paper deals with the formulation of microinstability-based thermal transport coefficients (chi/sub j/) for the purpose of modelling anomalous energy confinement properties in tokamak plasmas. Attention is primarily focused on ohmically heated discharges and the associated anomalous electron thermal transport. An appropriate expression for chi/sub e/ is developed which is consistent with reasonable global constraints on the current and electron temperature profiles as well as with the key properties of the kinetic instabilities most likely to be present. Comparisons of confinement scaling trends predicted by this model with the empirical ohmic data base indicate quite favorable agreement. The subject of anomalous ion thermal transport and its implications for high density ohmic discharges and for auxiliary-heated plasmas is also addressed

HCV NS5A protein containing potential ligands for both Src homology 2 and 3 domains enhances autophosphorylation of Src family kinase Fyn in B cells.

Science.gov (United States)

Nakashima, Kenji; Takeuchi, Kenji; Chihara, Kazuyasu; Horiguchi, Tomoko; Sun, Xuedong; Deng, Lin; Shoji, Ikuo; Hotta, Hak; Sada, Kiyonao

2012-01-01

Hepatitis C virus (HCV) infects B lymphocytes and induces mixed cryoglobulinemia and B cell non-Hodgkin's lymphoma. The molecular mechanism for the pathogenesis of HCV infection-mediated B cell disorders remains obscure. To identify the possible role for HCV nonstructural 5A (NS5A) protein in B cells, we generated the stable B cell lines expressing Myc-His tagged NS5A. Immunoprecipitation study in the presence or absence of pervanadate (PV) implied that NS5A was tyrosine phosphorylated by pervanadate (PV) treatment of the cells. Therefore we examined pull-down assay by using glutathione S-transferase (GST)-fusion proteins of various Src homology 2 (SH2) domains, which associates with phosphotyrosine within a specific amino acid sequence. The results showed that NS5A specifically bound to SH2 domain of Fyn from PV-treated B cells in addition to Src homology 3 (SH3) domain. Substitution of Arg(176) to Lys in the SH2 domain of Fyn abrogated this interaction. Deletion mutational analysis demonstrated that N-terminal region of NS5A was not required for the interaction with the SH2 domain of Fyn. Tyr(334) was identified as a tyrosine phosphorylation site in NS5A. Far-western analysis revealed that SH2 domain of Fyn directly bound to NS5A. Fyn and NS5A were colocalized in the lipid raft. These results suggest that NS5A directly binds to the SH2 domain of Fyn in a tyrosine phosphorylation-dependent manner. Lastly, we showed that the expression of NS5A in B cells increased phosphorylation of activation loop tyrosine in the kinase domain of Fyn. NS5A containing ligand for both SH2 and SH3 domains enhances an aberrant autophosphorylation and kinase activity of Fyn in B cells.

HCV NS5A protein containing potential ligands for both Src homology 2 and 3 domains enhances autophosphorylation of Src family kinase Fyn in B cells.

Directory of Open Access Journals (Sweden)

Kenji Nakashima

Full Text Available Hepatitis C virus (HCV infects B lymphocytes and induces mixed cryoglobulinemia and B cell non-Hodgkin's lymphoma. The molecular mechanism for the pathogenesis of HCV infection-mediated B cell disorders remains obscure. To identify the possible role for HCV nonstructural 5A (NS5A protein in B cells, we generated the stable B cell lines expressing Myc-His tagged NS5A. Immunoprecipitation study in the presence or absence of pervanadate (PV implied that NS5A was tyrosine phosphorylated by pervanadate (PV treatment of the cells. Therefore we examined pull-down assay by using glutathione S-transferase (GST-fusion proteins of various Src homology 2 (SH2 domains, which associates with phosphotyrosine within a specific amino acid sequence. The results showed that NS5A specifically bound to SH2 domain of Fyn from PV-treated B cells in addition to Src homology 3 (SH3 domain. Substitution of Arg(176 to Lys in the SH2 domain of Fyn abrogated this interaction. Deletion mutational analysis demonstrated that N-terminal region of NS5A was not required for the interaction with the SH2 domain of Fyn. Tyr(334 was identified as a tyrosine phosphorylation site in NS5A. Far-western analysis revealed that SH2 domain of Fyn directly bound to NS5A. Fyn and NS5A were colocalized in the lipid raft. These results suggest that NS5A directly binds to the SH2 domain of Fyn in a tyrosine phosphorylation-dependent manner. Lastly, we showed that the expression of NS5A in B cells increased phosphorylation of activation loop tyrosine in the kinase domain of Fyn. NS5A containing ligand for both SH2 and SH3 domains enhances an aberrant autophosphorylation and kinase activity of Fyn in B cells.

Spacetime dependence of the anomalous exponent of electric transport in the disorder model

International Nuclear Information System (INIS)

Egami, Takeshi; Suzuki, Koshiro; Watanabe, Katsuhiro

2012-01-01

Spacetime dependence of the anomalous exponent of electric transport in the disorder model is investigated. We show that the anomalous exponent evolves with time, according to the time evolution of the number of the effective neighbouring sites. Transition from subdiffusive to normal transport is recovered at macroscopic timescales. Plateaus appear in the history of the anomalous exponent due to the discreteness of the hopping sites, which is compatible with the conventional treatment to regard the anomalous exponent as a constant. We also show that, among various microscopic spatial structures, the number of the effective neighbouring sites is the only element which determines the anomalous exponent. This is compatible with the mesoscopic model of Scher–Montroll. These findings are verified by means of Monte Carlo simulation. The well-known expression of the anomalous exponent in the conventional multiple trapping model is derived by deducing it as a special case of the disorder model. (paper)

Evaluation of right coronary anomalous origin with mulpi-slice spiral CT

International Nuclear Information System (INIS)

Shi Heshui; Han Ping; Kong Xiangquan; Feng Hansheng; Brambs, H.-J.; Hoffmann, M.H.K.

2006-01-01

Objective: To evaluate the role of 16-slice spiral computed tomography angiography (MSCTA) to identify the anomalous origin and anatomic course of the right coronary artery (RCA) with conventional X-ray coronary angiography (CAG) serving as standard of reference. Methods: MSCTA data in 8 patients with anomalous RCA were retrospectively analyzed for the study, 7 of them had also undergone CAG examinations. MSCTA and CAG images were analyzed in blinded fashion for accuracy of anomalous artery origin and path detection. Results were compared in a secondary consensus evaluation. Virtual endoscopy (VE) was used to evaluate the orifice of the anomalous arteries and its relationship with the adjacent ostia of normal arteries. Multi-planar reconstruction (MPR), curved MPR, thin-slab maximum intensity projection (MIP), volume rendering (VR) or slab VR (cut-plane VR) were used to assess the aberrant path of the RCA and its relationship with the adjacent large vessels. At least two views of the RCA were analyzed on CAG. Results: The anomalous RCA for all 8 patients were correctly displayed on MSCTA. RCA originated from the left sinus of Valsalva in 6 patients, one RCA from the end of left main coronary artery, another RCA arose from the posterior sinus of Valsalva. The anomalous ostia showed no stenosis. All of them passed between the aortic root and the pulmonary artery. For 7 patients with CAG alone correct identification of the abnormality was achieved in only 71%. Conclusion: MSCTA was superior to show the anomalous orifice and path of the RCA, it should be considered as a prime non-invasive imaging tool for suspected coronary anomalies. (authors)

Vacuum field energy and spontaneous emission in anomalously dispersive cavities

International Nuclear Information System (INIS)

Bradshaw, Douglas H.; Di Rosa, Michael D.

2011-01-01

Anomalously dispersive cavities, particularly white-light cavities, may have larger bandwidth to finesse ratios than their normally dispersive counterparts. Partly for this reason, they have been proposed for use in laser interferometer gravitational-wave observatory (LIGO)-like gravity-wave detectors and in ring-laser gyroscopes. In this paper we analyze the quantum noise associated with anomalously dispersive cavity modes. The vacuum field energy associated with a particular cavity mode is proportional to the cavity-averaged group velocity of that mode. For anomalously dispersive cavities with group index values between 1 and 0, this means that the total vacuum field energy associated with a particular cavity mode must exceed (ℎ/2π)ω/2. For white-light cavities in particular, the group index approaches zero and the vacuum field energy of a particular spatial mode may be significantly enhanced. We predict enhanced spontaneous emission rates into anomalously dispersive cavity modes and broadened laser linewidths when the linewidth of intracavity emitters is broader than the cavity linewidth.

TGFbeta Induces Binucleation/Polyploidization in Hepatocytes through a Src-Dependent Cytokinesis Failure.

Science.gov (United States)

De Santis Puzzonia, Marco; Cozzolino, Angela Maria; Grassi, Germana; Bisceglia, Francesca; Strippoli, Raffaele; Guarguaglini, Giulia; Citarella, Franca; Sacchetti, Benedetto; Tripodi, Marco; Marchetti, Alessandra; Amicone, Laura

2016-01-01

In all mammals, the adult liver shows binucleated as well as mononucleated polyploid hepatocytes. The hepatic polyploidization starts after birth with an extensive hepatocyte binucleation and generates hepatocytes of several ploidy classes. While the functional significance of hepatocyte polyploidy is becoming clearer, how it is triggered and maintained needs to be clarified. Aim of this study was to identify a major inducer of hepatocyte binucleation/polyploidization and the cellular and molecular mechanisms involved. We found that, among several cytokines analyzed, known to be involved in early liver development and/or mass control, TGFbeta1 was capable to induce, together with the expected morphological changes, binucleation in hepatocytes in culture. Most importantly, the pharmacological inhibition of TGFbeta signaling in healthy mice during weaning, when the physiological binucleation occurs, induced a significant decrease of hepatocyte binucleation rate, without affecting cell proliferation and hepatic index. The TGFbeta-induced hepatocyte binucleation resulted from a cytokinesis failure, as assessed by video microscopy, and is associated with a delocalization of the cytokinesis regulator RhoA-GTPase from the mid-body of dividing cells. The use of specific chemical inhibitors demonstrated that the observed events are Src-dependent. Finally, the restoration of a fully epithelial phenotype by TGFbeta withdrawal gave rise to a cell progeny capable to maintain the polyploid state. In conclusion, we identified TGFbeta as a major inducer of hepatocyte binucleation both in vitro and in vivo, thus ascribing a novel role to this pleiotropic cytokine. The production of binucleated/tetraploid hepatocytes is due to a cytokinesis failure controlled by the molecular axis TGFbeta/Src/RhoA.

The comparative constitutional law on national constitutional system: with regard to the IX World Congress of Constitutional Law

OpenAIRE

Landa Arroyo, César

2015-01-01

From  the  process  of  globalization  of  law,  the  comparative constitutional law has gained a leading role for a better understanding and solving old and new constitutional national and international challenges. Therefore, some assumptions and considerations to take into account are presented for the development of the national constitutional order within the framework of the comparative constitutional law, such as universality and relativism of human rights; the concept of power and cons...

Astrocyte-to-neuron communication through integrin-engaged Thy-1/CBP/Csk/Src complex triggers neurite retraction via the RhoA/ROCK pathway.

Science.gov (United States)

Maldonado, H; Calderon, C; Burgos-Bravo, F; Kobler, O; Zuschratter, W; Ramirez, O; Härtel, S; Schneider, P; Quest, A F G; Herrera-Molina, R; Leyton, L

2017-02-01

Two key proteins for cellular communication between astrocytes and neurons are αvβ3 integrin and the receptor Thy-1. Binding of these molecules in the same (cis) or on adjacent (trans) cellular membranes induces Thy-1 clustering, triggering actin cytoskeleton remodeling. Molecular events that could explain how the Thy-1-αvβ3 integrin interaction signals have only been studied separately in different cell types, and the detailed transcellular communication and signal transduction pathways involved in neuronal cytoskeleton remodeling remain unresolved. Using biochemical and genetic approaches, single-molecule tracking, and high-resolution nanoscopy, we provide evidence that upon binding to αvβ3 integrin, Thy-1 mobility decreased while Thy-1 nanocluster size increased. This occurred concomitantly with inactivation and exclusion of the non-receptor tyrosine kinase Src from the Thy-1/C-terminal Src kinase (Csk)-binding protein (CBP)/Csk complex. The Src inactivation decreased the p190Rho GTPase activating protein phosphorylation, promoting RhoA activation, cofilin, and myosin light chain II phosphorylation and, consequently, neurite shortening. Finally, silencing the adaptor CBP demonstrated that this protein was a key transducer in the Thy-1 signaling cascade. In conclusion, these data support the hypothesis that the Thy-1-CBP-Csk-Src-RhoA-ROCK axis transmitted signals from astrocytic integrin-engaged Thy-1 (trans) to the neuronal actin cytoskeleton. Importantly, the β3 integrin in neurons (cis) was not found to be crucial for neurite shortening. This is the first study to detail the signaling pathway triggered by αvβ3, the endogenous Thy-1 ligand, highlighting the role of membrane-bound integrins as trans acting ligands in astrocyte-neuron communication. Copyright © 2016 Elsevier B.V. All rights reserved.

Autocrine VEGF and IL-8 Promote Migration via Src/Vav2/Rac1/PAK1 Signaling in Human Umbilical Vein Endothelial Cells.

Science.gov (United States)

Ju, Li; Zhou, Zhiwen; Jiang, Bo; Lou, Yue; Guo, Xirong

2017-01-01

Pro-angiogenic factors VEGF and IL-8 play a major role in modulating the migratory potential of endothelial cells. The goal of this study was to investigate the effect of autocrine VEGF and IL-8 in the form of self-conditioned medium (CM) on human umbilical vein endothelial cells (HUVECs). Enzyme-linked immunosorbent assay (ELISA) examined the automatic secretion of VEGF and IL-8 protein by HUVECs. Western blot, small interfering RNA (siRNA), pulldown and Transwell assays were used to explore the role and the mechanism of autocrine VEGF and IL-8 in migration of HUVECs. Neutralizing VEGF and IL-8 in CM significantly abrogated CM-induced migration of HUVECs. Autocrine VEGF and IL-8 increased Src phosphorylation, Rac1 activity and PAK1 phosphorylation in a time dependent manner. Additionally, blocking Rac1 activity with Rac1 siRNA largely abolished autocrine VEGF and IL-8-induced cell migration. Vav2 siRNA suppressed autocrine VEGF and IL-8-induced Rac1 activation and cell migration. Furthermore, blocking Src signaling with PP2, a specific inhibitor for Src, markedly prevented autocrine VEGF and IL-8-induced Vav2 and Rac1 activation as well as consequently cell migration. PAK1 siRNA also significantly abolished autocrine VEGF and IL-8-induced cell migration. We demonstrated for the first time that autocrine VEGF and IL-8 promoted endothelial cell migration via the Src/Vav2/Rac1/PAK1 signaling pathway. This finding reveals the molecular mechanism in the increase of endothelial cell migration induced by autocrine growth factors and cytokines, which is expected to provide a novel therapeutic target in vascular diseases. © 2017 The Author(s)Published by S. Karger AG, Basel.

Crystal structure of the Src family kinase Hck SH3-SH2 linker regulatory region supports an SH3-dominant activation mechanism.

Science.gov (United States)

Alvarado, John J; Betts, Laurie; Moroco, Jamie A; Smithgall, Thomas E; Yeh, Joanne I

2010-11-12

Most mammalian cell types depend on multiple Src family kinases (SFKs) to regulate diverse signaling pathways. Strict control of SFK activity is essential for normal cellular function, and loss of kinase regulation contributes to several forms of cancer and other diseases. Previous x-ray crystal structures of the SFKs c-Src and Hck revealed that intramolecular association of their Src homology (SH) 3 domains and SH2 kinase linker regions has a key role in down-regulation of kinase activity. However, the amino acid sequence of the Hck linker represents a suboptimal ligand for the isolated SH3 domain, suggesting that it may form the polyproline type II helical conformation required for SH3 docking only in the context of the intact structure. To test this hypothesis directly, we determined the crystal structure of a truncated Hck protein consisting of the SH2 and SH3 domains plus the linker. Despite the absence of the kinase domain, the structures and relative orientations of the SH2 and SH3 domains in this shorter protein were very similar to those observed in near full-length, down-regulated Hck. However, the SH2 kinase linker adopted a modified topology and failed to engage the SH3 domain. This new structure supports the idea that these noncatalytic regions work together as a "conformational switch" that modulates kinase activity in a manner unique to the SH3 domain and linker topologies present in the intact Hck protein. Our results also provide fresh structural insight into the facile induction of Hck activity by HIV-1 Nef and other Hck SH3 domain binding proteins and implicate the existence of innate conformational states unique to individual Src family members that "fine-tune" their sensitivities to activation by SH3-based ligands.

Contribution of MRI in supracardiac total anomalous pulmonary venous drainage

International Nuclear Information System (INIS)

Kastler, B.; Germain, P.; Gangi, A.; Klinkert, A.; Dietemann, J.L.; Wackenheim, A.; Livolsi, A.; Willard, D.

1992-01-01

A case of supracardiac total anomalous pulmonary venous drainage (TAPVD) in an infant aged 2 1/2 months is presented. Diagnosis was established non invasively by magnetic resonance image (MRI). Not only did MRI precisely depict the anomalous venous pathway but it moreover securely excluded pulmonary venous obstruction. (orig.)

Electrostatic effects in the folding of the SH3 domain of the c-Src tyrosine kinase: pH-dependence in 3D-domain swapping and amyloid formation.

Directory of Open Access Journals (Sweden)

Julio Bacarizo

Full Text Available The SH3 domain of the c-Src tyrosine kinase (c-Src-SH3 aggregates to form intertwined dimers and amyloid fibrils at mild acid pHs. In this work, we show that a single mutation of residue Gln128 of this SH3 domain has a significant effect on: (i its thermal stability; and (ii its propensity to form amyloid fibrils. The Gln128Glu mutant forms amyloid fibrils at neutral pH but not at mild acid pH, while Gln128Lys and Gln128Arg mutants do not form these aggregates under any of the conditions assayed. We have also solved the crystallographic structures of the wild-type (WT and Gln128Glu, Gln128Lys and Gln128Arg mutants from crystals obtained at different pHs. At pH 5.0, crystals belong to the hexagonal space group P6₅22 and the asymmetric unit is formed by one chain of the protomer of the c-Src-SH3 domain in an open conformation. At pH 7.0, crystals belong to the orthorhombic space group P2₁2₁2₁, with two molecules at the asymmetric unit showing the characteristic fold of the SH3 domain. Analysis of these crystallographic structures shows that the residue at position 128 is connected to Glu106 at the diverging β-turn through a cluster of water molecules. Changes in this hydrogen-bond network lead to the displacement of the c-Src-SH3 distal loop, resulting also in conformational changes of Leu100 that might be related to the binding of proline rich motifs. Our findings show that electrostatic interactions and solvation of residues close to the folding nucleation site of the c-Src-SH3 domain might play an important role during the folding reaction and the amyloid fibril formation.

Anomalous CO2 Emissions in Different Ecosystems Around the World

Science.gov (United States)

Sanchez-Canete, E. P.; Moya Jiménez, M. R.; Kowalski, A. S.; Serrano-Ortiz, P.; López-Ballesteros, A.; Oyonarte, C.; Domingo, F.

2016-12-01

As an important tool for understanding and monitoring ecosystem dynamics at ecosystem level, the eddy covariance (EC) technique allows the assessment of the diurnal and seasonal variation of the net ecosystem exchange (NEE). Despite the high temporal resolution data available, there are still many processes (in addition to photosynthesis and respiration) that, although they are being monitored, have been neglected. Only a few authors have studied anomalous CO2 emissions (non biological), and have related them to soil ventilation, photodegradation or geochemical processes. The aim of this study is: 1) to identify anomalous short term CO2 emissions in different ecosystems distributed around the world, 2) to determine the meteorological variables that are influencing these emissions, and 3) to explore the potential processes that can be involved. We have studied EC data together with other meteorological ancillary variables obtained from the FLUXNET database (version 2015) and have found more than 50 sites with anomalous CO2 emissions in different ecosystem types such as grasslands, croplands or savannas. Data were filtered according to the FLUXNET quality control flags (only data with quality control flag equal to 0 was used) and correlation analysis were performed with NEE and ancillary data. Preliminary results showed strong and highly significant correlations between meteorological variables and anomalous CO2 emissions. Correlation results showed clear differing behaviors between ecosystems types, which could be related to the different processes involved in the anomalous CO2 emissions. We suggest that anomalous CO2 emissions are happening globally and therefore, their contribution to the global net ecosystem carbon balance requires further investigation in order to better understand its drivers.

UNDERSTANDING INFORMAL CONSTITUTIONAL CHANGE

Directory of Open Access Journals (Sweden)

Stephen M. Griffin

2016-01-01

Full Text Available Amid much recent American work on the problem of informal constitutional change, this article stakes out a distinctive position. I argue that theories of constitutional change in the US must address the question of the relationship between the “small c” and “big C” Constitution and treat seriously the possibility of conflict between them. I stress the unavoidable role the text of the Constitution and structural doctrines of federalism and separation of powers play in this relationship and thus in constitutional change, both formal and informal. I therefore counsel against theories that rely solely on a practice-based approach or analogies between “small c” constitutional developments and British or Commonwealth traditions of the “unwritten” constitution and constitutional “conventions.” The alternative I advocate is to approach constitutional change from a historicist perspective that focuses attention on state building and the creation of new institutional capacities. This approach will allow us to make progress by highlighting that there can be multiple constitutional orders in a given historical era, thus accounting for the conflictual nature of contemporary constitutional development in the US.

Investigation of phosphotyrosine recognition by the SH2 domain of the Src kinase.

Science.gov (United States)

Bradshaw, J M; Mitaxov, V; Waksman, G

1999-11-05

The binding of tyrosine phosphorylated targets by SH2 domains is required for propagation of many cellular signals in higher eukaryotes; however, the determinants of phosphotyrosine (pTyr) recognition by SH2 domains are not well understood. In order to identify the attributes of pTyr required for high affinity interaction with SH2 domains, the binding of the SH2 domain of the Src kinase (Src SH2 domain) to a dephosphorylated peptide, a phosphoserine-containing peptide, and the amino acid pTyr was studied using titration calorimetry and compared with the binding of a high affinity tyrosyl phosphopeptide. The dephosphorylated peptide and the phosphoserine containing peptide both bind extremely weakly to the Src SH2 domain (DeltaGo (dephosphorylated)=-3.6 kcal/mol, DeltaGo (phosphoserine) >-3.7 kcal/mol); however, the DeltaGo value of pTyr binding is more favorable (-4.7 kcal/mol, or 50 % of the entire binding free energy of a high affinity tyrosyl phosphopeptide). These results indicate that both the phosphate and the tyrosine ring of the pTyr are critical determinants of high affinity binding. Alanine mutagenesis was also used to evaluate the energetic contribution to binding of ten residues located in the pTyr-binding site. Mutation of the strictly conserved Arg betaB5 resulted in a large increase in DeltaGo (DeltaDeltaGo=3.2 kcal/mol) while elimination of the other examined residues each resulted in a significantly smaller (DeltaDeltaGoSH2 domain, surprisingly increased affinity by eightfold (DeltaDeltaGo=-1.1 kcal/mol). Using a double mutant cycle analysis, it was revealed that residues of the pTyr-binding pocket are not coupled to the peptide residues C-terminal to the pTyr. In addition, comparison of each residue's DeltaDeltaGo value upon mutation with that residue's sequence conservation among SH2 domains revealed only a modest correlation between a residue's energetic contribution to pTyr recognition and its conservation throughout evolution. The results of

Transnational Constitutional Law

NARCIS (Netherlands)

Zumbansen, P (Peer); K.I. Bhatt (Kinnari)

2018-01-01

textabstractThis chapter provides an overview of the emerging field of transnational constitutional law (TCL). Whilst questions of constitutional law are typically discussed in the context of a specific domestic legal setting, a salient strategy of TCL is to understand constitutional law and its

Anomalous neutron scattering and feroelectric modes

International Nuclear Information System (INIS)

Viswanathan, K.S.

1977-01-01

It is suggested that anomalous neutron scattering could prove a powerful experimental tool in studying ferroelectric phase transition, the sublattice displacements of the soft modes as well as their symmetry characteristics. (author)

Observations of Anomalous Refraction with Co-housed Telescopes

Science.gov (United States)

Taylor, Malinda S.; McGraw, J. T.; Zimmer, P. C.

2013-01-01

Anomalous refraction is described as a low frequency, large angular scale motion of the entire image plane with respect to the celestial coordinate system as observed and defined by previous astrometric catalogs. These motions of typically several tenths of an arcsecond with timescales on the order of ten minutes are ubiquitous to drift-scan ground-based astrometric measurements regardless of location or telescopes used and have been attributed to meter scale slowly evolving coherent dynamical structures in the boundary-layer below 60 meters. The localized nature of the effect and general inconsistency of the motions seen by even closely spaced telescopes in individual domes has led to the hypothesis that the dome or other type of telescope housing may be responsible. This hypothesis is tested by observing anomalous refraction using two telescopes housed in a single roll-off roof observatory building with the expected outcome that the two telescopes will see correlated anomalous refraction induced motions.

Nonredundant roles of Src-family kinases and Syk in the initiation of B-cell antigen receptor signaling

Czech Academy of Sciences Publication Activity Database

Štěpánek, Ondřej; Dráber, Peter; Drobek, Aleš; Hořejší, Václav; Brdička, Tomáš

2013-01-01

Roč. 190, č. 4 (2013), s. 1807-1818 ISSN 0022-1767 R&D Projects: GA ČR(CZ) GBP302/12/G101; GA ČR GAP302/12/1712 Institutional support: RVO:68378050 Keywords : BCR signaling * Src family kinases * Syk Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.362, year: 2013

Regulation of Src family kinases involved in T cell receptor signaling by protein-tyrosine phosphatase CD148

Czech Academy of Sciences Publication Activity Database

Štěpánek, Ondřej; Kalina, T.; Dráber, Peter; Skopcová, Tereza; Svojgr, K.; Angelisová, Pavla; Hořejší, Václav; Weiss, A.; Brdička, Tomáš

2011-01-01

Roč. 286, č. 25 (2011), s. 22101-22112 ISSN 0021-9258 R&D Projects: GA MŠk 2B06064; GA MŠk 1M0506 Institutional research plan: CEZ:AV0Z50520514 Keywords : CD148 * tyrosine phosphatase * Src family kinases Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.773, year: 2011

Anomalous momentum transport from drift waves

International Nuclear Information System (INIS)

Dominguez, R.R.; Staebler, G.M.

1993-01-01

A sheared slab magnetic field model B = B 0 [z + (x/L s )y], with inhomogeneous flows in the y and z directions, is used to perform a fully-kinetic stability analysis of the ion temperature gradient (ITG) and dissipative trapped electron (DTE) modes. The concomitant quasilinear stress components that couple to the local perpendicular (y-component) and parallel (z-component) momentum transport are also calculated and the anomalous perpendicular and parallel viscous stresses obtained. A breakdown of the ITG-induced perpendicular viscous stress is generally observed at moderate values of the sheared perpendicular flow. The ITG-induced parallel viscous stress is generally larger and strongly dependent on the sheared flows. The DTE-induced perpendicular viscous stress may sometimes be negative, tending to cancel the ITG contributions while the DTE-induced parallel viscous stress is generally small. The effect of the perpendicular stress component in the momentum balance equations is generally small while the parallel stress component can dominate the usual neoclassical viscous stress terms. The dominant contribution to parallel viscous stress by the ITG mode suggests that bulk plasma toroidal momentum confinement, like energy confinement, is governed by an anomalous ion loss mechanism. Furthermore, the large anomalous effect suggests that the neoclassical explanation of poloidal flows in tokamaks may be incorrect. The present results are in general agreement with existing experimental observations on momentum transport in tokamaks

Gauge invariance and anomalous theories at finite fermionic density

International Nuclear Information System (INIS)

Roberge, A.

1990-01-01

We investigate the issue of stability of anomalous matter at finite fermionic density using a two-dimensional toy model. In particular, we pay careful attention to the issue of gauge invariance. We find that, contrary to some recent claims, the effective free energy (obtained by integrating out the fermions) cannot be obtained by the simple inclusion of a Chern-Simons term multiplying the fermionic chemical potential. We obtain some conditions for stability of anomalous charges when some finite density of conserved charge is present as well as for the neutral case. We also show that, under reasonable conditions, no sphaleron-type solution can exist in the toy model unless the anomalous charge density vanishes. We argue that this could be the case for more realistic models as well

ZINC-INDUCED EGF RECEPTOR SIGNALING REQUIRES SRC-MEDIATED PHOSPHORYLATION OF THE EGF RECEPTOR ON TYROSINE 845 (Y845)

Science.gov (United States)

ZINC-INDUCED EGF RECEPTOR SIGNALING REQUIRES Src-MEDIATED PHOSPHORYLATION OF THE EGF RECEPTOR ON TYROSINE 845 (Y845)Weidong Wu1, Lee M. Graves2, Gordon N. Gill3 and James M. Samet4 1Center for Environmental Medicine and Lung Biology; 2Department of Pharmacology, University o...

Effects of surface and interface scattering on anomalous Hall effect in Co/Pd multilayers

KAUST Repository

Guo, Zaibing

2012-09-27

In this paper, we report the results of surface and interface scattering on anomalous Hall effect in Co/Pd multilayers with perpendicular magnetic anisotropy. The surface scattering effect has been extracted from the total anomalous Hall effect. By scaling surface scattering contribution with ρAHs∼ργss, the exponent γ has been found to decrease with the increase of surface scattering resistivity, which could account for the thickness-dependent anomalous Hall effect. Interface diffusion induced by rapid thermal annealing modifies not only the magnetization and longitudinal resistivity but also the anomalous Hall effect; a large exponent γ ∼ 5.7 has been attributed to interface scattering-dominated anomalous Hall effect.

Paeonol Suppresses Chondrosarcoma Metastasis through Up-Regulation of miR-141 by Modulating PKCδ and c-Src Signaling Pathway

Science.gov (United States)

Horng, Chi-Ting; Shieh, Po-Chuen; Tan, Tzu-Wei; Yang, Wei-Hung; Tang, Chih-Hsin

2014-01-01

Chondrosarcoma, a primary malignant bone cancer, has potential for local invasion and distant metastasis, especially to the lungs. Patients diagnosed with it show poor prognosis. Paeonol (2'-hydroxy-4'-methoxyacetophenone), the main active compound of traditional Chinese remedy Paeonia lactiflora Pallas, exhibits anti-inflammatory and anti-tumor activity; whether paeonol regulates metastatic chondrosarcoma is largely unknown. Here, we find paeonol do not increase apoptosis. By contrast, at non-cytotoxic concentrations, paeonol suppresses migration and invasion of chondrosarcoma cells. We also demonstrate paeonol enhancing miR-141 expression and miR-141 inhibitor reversing paeonol-inhibited cell motility; paeonol also reduces protein kinase C (PKC)δ and c-Src kinase activity. Since paeonol inhibits migration and invasion of human chondrosarcoma via up-regulation of miR-141 via PKCδ and c-Src pathways, it thus might be a novel anti-metastasis agent for treatment of metastatic chondrosarcoma. PMID:24992595

Magnetic effects in anomalous dispersion

International Nuclear Information System (INIS)

Blume, M.

1992-01-01

Spectacular enhancements of magnetic x-ray scattering have been predicted and observed experimentally. These effects are the result of resonant phenomena closely related to anomalous dispersion, and they are strongest at near-edge resonances. The theory of these resonances will be developed with particular attention to the symmetry properties of the scatterer. While the phenomena to be discussed concern magnetic properties the transitions are electric dipole or electric quadrupole in character and represent a subset of the usual anomalous dispersion phenomena. The polarization dependence of the scattering is also considered, and the polarization dependence for magnetic effects is related to that for charge scattering and to Templeton type anisotropic polarization phenomena. It has been found that the strongest effects occur in rare-earths and in actinides for M shell edges. In addition to the scattering properties the theory is applicable to ''forward scattering'' properties such as the Faraday effect and circular dichroism

Right Product, Wrong Packaging: Not 'Constitution', but 'Constitutional Charter'

Directory of Open Access Journals (Sweden)

John Law

2007-05-01

Full Text Available The article seeks to locate the principal cause of Europe’s prevailing ratification crisis in the inappropriate title arrived at in the European Convention, Treaty Establishing a Constitution for Europe. This over-ambitious styling led the media to characterise the text as simply an ‘EU Constitution’. Yet, the text was not a Constitution as we traditionally understand the term, i.e. the founding document of a State: scholars are agreed that the EU is not, and will not become upon ratification, a State.In terms of substance, whilst the text certainly strengthened some emerging constitutional aspects, it was not a major departure from the status quo like the Single European Act and Treaty on European Union had been; and it remained technically a treaty like all its predecessors. Arguably, therefore, it did not require referenda to ratify. However, confusion over the scale and importance of what was proposed, stemming from ambiguity in the title, pushed politicians down this unfortunate path.The article identifies a high level of consensus among commentators as to the true nature of the text: most are happy designating it a treaty (noun with constitutional (adjective aspects. The early proposed title Constitutional Treaty for Europe was arguably, therefore, the correct one; but it is now too late to choose this option, as the terms Constitution and Constitutional Treaty have already been muddled in debate. A more distinctive change is required. One idea could be to follow the principle employed elsewhere in the text of codifying the generally accepted but presently unwritten legal concepts of the European Court of Justice, as was done for example for ‘primacy’ and ‘direct effect’. The Court has characterised the EU treaties as a ‘constitutional charter’ for over twenty years now, and on this basis a modified title could read Treaty Establishing a Constitutional Charter for Europe. Importantly, the term ‘charter’ is recognised

Anomalous diffusion in a dynamical optical lattice

Science.gov (United States)

Zheng, Wei; Cooper, Nigel R.

2018-02-01

Motivated by experimental progress in strongly coupled atom-photon systems in optical cavities, we study theoretically the quantum dynamics of atoms coupled to a one-dimensional dynamical optical lattice. The dynamical lattice is chosen to have a period that is incommensurate with that of an underlying static lattice, leading to a dynamical version of the Aubry-André model which can cause localization of single-particle wave functions. We show that atomic wave packets in this dynamical lattice generically spread via anomalous diffusion, which can be tuned between superdiffusive and subdiffusive regimes. This anomalous diffusion arises from an interplay between Anderson localization and quantum fluctuations of the cavity field.

Noncausal two-stage image filtration at presence of observations with anomalous errors

OpenAIRE

S. V. Vishnevyy; S. Ya. Zhuk; A. N. Pavliuchenkova

2013-01-01

Introduction. It is necessary to develop adaptive algorithms, which allow to detect such regions and to apply filter with respective parameters for suppression of anomalous noises for the purposes of image filtration, which consist of regions with anomalous errors. Development of adaptive algorithm for non-causal two-stage images filtration at pres-ence of observations with anomalous errors. The adaptive algorithm for noncausal two-stage filtration is developed. On the first stage the adaptiv...

2D QSAR studies of the inhibitory activity of a series of substituted purine derivatives against c-Src tyrosine kinase

Directory of Open Access Journals (Sweden)

Mukesh C. Sharma

2016-07-01

Full Text Available A series of 34 substituted purine analogues derivatives were subjected to quantitative structure-activity relationship analyses as inhibitors of c-Src tyrosine kinase. Partial least squares regression was applied to derive QSAR models, which were further validated for statistical significance by internal and external validation. The best QSAR model developed had a good predictive correlation coefficient (r2 of 0.8319, a significant cross-validated correlation coefficient (q2 of 0.7550, and an r2 for the external test set (pred_r2 of 0.7983. It was developed from the PLS method with descriptors including the SsCH3E-index, H-Donor Count, T_2_Cl_3, and negative correlation with SsOHcount. The current study provides better insight into the future design of more potent c-Src tyrosine kinase inhibitors prior to synthesis.

Resurgence of the Cusp Anomalous Dimension

International Nuclear Information System (INIS)

Dorigoni, Daniele; Hatsuda, Yasuyuki

2015-06-01

We revisit the strong coupling limit of the cusp anomalous dimension in planar N=4 super Yang-Mills theory. It is known that the strong coupling expansion is asymptotic and non-Borel summable. As a consequence, the cusp anomalous dimension receives non-perturbative corrections, and the complete strong coupling expansion should be a resurgent transseries. We reveal that the perturbative and non-perturbative parts in the transseries are closely interrelated. Solving the Beisert-Eden-Staudacher equation systematically, we analyze in detail the large order behavior in the strong coupling perturbative expansion and show that the non-perturbative information is indeed encoded there. An ambiguity of (lateral) Borel resummations of the perturbative expansion is precisely canceled by the contributions from the non-perturbative sectors, and the final result is real and unambiguous.

Resurgence of the cusp anomalous dimension

Energy Technology Data Exchange (ETDEWEB)

Dorigoni, Daniele; Hatsuda, Yasuyuki [DESY Theory Group, DESY Hamburg,Notkestrasse 85, D-22603 Hamburg (Germany)

2015-09-21

We revisit the strong coupling limit of the cusp anomalous dimension in planar N=4 super Yang-Mills theory. It is known that the strong coupling expansion is asymptotic and non-Borel summable. As a consequence, the cusp anomalous dimension receives non-perturbative corrections, and the complete strong coupling expansion should be a resurgent transseries. We reveal that the perturbative and non-perturbative parts in the transseries are closely interrelated. Solving the Beisert-Eden-Staudacher equation systematically, we analyze in detail the large order behavior in the strong coupling perturbative expansion and show that the non-perturbative information is indeed encoded there. An ambiguity of (lateral) Borel resummations of the perturbative expansion is precisely canceled by the contributions from the non-perturbative sectors, and the final result is real and unambiguous.

Resurgence of the Cusp Anomalous Dimension

Energy Technology Data Exchange (ETDEWEB)

Dorigoni, Daniele; Hatsuda, Yasuyuki [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Theory Group

2015-06-15

We revisit the strong coupling limit of the cusp anomalous dimension in planar N=4 super Yang-Mills theory. It is known that the strong coupling expansion is asymptotic and non-Borel summable. As a consequence, the cusp anomalous dimension receives non-perturbative corrections, and the complete strong coupling expansion should be a resurgent transseries. We reveal that the perturbative and non-perturbative parts in the transseries are closely interrelated. Solving the Beisert-Eden-Staudacher equation systematically, we analyze in detail the large order behavior in the strong coupling perturbative expansion and show that the non-perturbative information is indeed encoded there. An ambiguity of (lateral) Borel resummations of the perturbative expansion is precisely canceled by the contributions from the non-perturbative sectors, and the final result is real and unambiguous.

Revisiting the Anomalous rf Field Penetration into a Warm Plasma

International Nuclear Information System (INIS)

Kaganovich, Igor D.; Polomarov, Oleg V.; Theodosiou, Constantine E.

2005-01-01

Radio-frequency [rf] waves do not penetrate into a plasma and are damped within it. The electric field of the wave and plasma current are concentrated near the plasma boundary in a skin layer. Electrons can transport the plasma current away from the skin layer due to their thermal motion. As a result, the width of the skin layer increases when electron temperature effects are taken into account. This phenomenon is called anomalous skin effect. The anomalous penetration of the rf electric field occurs not only for transversely propagating to the plasma boundary wave (inductively coupled plasmas) but also for the wave propagating along the plasma boundary (capacitively coupled plasmas). Such anomalous penetration of the rf field modifies the structure of the capacitive sheath. Recent advances in the nonlinear, non-local theory of the capacitive sheath are reported. It is shown that separating the electric field profile into exponential and non-exponential parts yields an efficient qualitative and quantitative description of the anomalous skin effect in both inductively and capacitively coupled plasma

Absence of U(1) anomalous superamplitudes in N≥5 supergravities

Energy Technology Data Exchange (ETDEWEB)

Freedman, Daniel Z. [Stanford Institute for Theoretical Physics and Department of Physics, Stanford University,Stanford, CA 94305 (United States); Center for Theoretical Physics and Department of Mathematics,Massachusetts Institute of Technology,Cambridge, MA 02139 (United States); Kallosh, Renata; Murli, Divyanshu [Stanford Institute for Theoretical Physics and Department of Physics, Stanford University,Stanford, CA 94305 (United States); Proeyen, Antoine Van [KU Leuven, Institute for Theoretical Physics,Celestijnenlaan 200D, B-3001, Leuven (Belgium); Yamada, Yusuke [Stanford Institute for Theoretical Physics and Department of Physics, Stanford University,Stanford, CA 94305 (United States)

2017-05-12

We list all potential candidates for U(1) anomalous non-local 1-loop 4-point amplitudes and higher loop UV divergences in N≥5 supergravities. The relevant chiral superinvariants are constructed from linearized chiral superfields and define the corresponding superamplitudes. The anomalous amplitudes, of the kind present in N=4, are shown to be absent in N≥5. In N=6 supergravity the result is deduced from the double-copy (N=4){sub YM}×(N=2){sub YM} model, whereas in N=5,8 the result on absence of anomalous amplitudes is derived in supergravities as well as in the (N=4){sub YM}×(N−4){sub YM} double-copy models.

Hydrotreating catalyst deactivation by coke from SRC-II oil

Energy Technology Data Exchange (ETDEWEB)

Yamamoto, Y.; Kumata, F.; Massoth, F.E.

1988-10-01

Samples of a CoMo/Al/sub 2/O/sub 3/ catalyst were partially deactivated with SRC-II feed in an autoclave reactor to give coked samples of 5 to 18% C. The coked catalysts were analyzed for surface area, pore volume, coronene adsorption and diffusivity, and their catalytic activity determined for hydrodesulfurization (HDS), hydrodeoxygenation (HDO) and C-N hydrogenolysis (CNH) using model compounds. All of the above measurements decreased with increase in coke content. Property data indicate that some pores are blocked by coke and diffusivity results show narrowing of pore mouths with increasing coke content. Catalyst deactivation versus coke level was identical for HDS and HDO, but less for CNH. A simple model of coke deactivation was developed to relate activity to coke content. Coke is envisioned as forming wedge-like deposits in the catalyst pores. 11 refs., 5 figs., 3 tabs.

Analysis on anomalous degradation in silicon solar cell designed for space use

Energy Technology Data Exchange (ETDEWEB)

Ohshima, Takeshi; Morita, Yousuke; Nashiyama, Isamu [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment; Kawasaki, Osamu; Hisamatsu, Tadashi; Yamamoto, Yasunari; Matsuda, Sumio; Nakao, Tetsuya; Wakow, Yoshihito

1997-03-01

Recently, we have found the anomalous degradation of electrical performance in silicon solar cells irradiated with charged particles in a high-fluence region. This anomalous phenomenon has two typical features, which are sudden-drop-down of electrical performances in a high-fluence region and slight recovery of the short circuit current I{sub SC} just before the sudden-drop-down. These features cannot be understood by a conventional model coming from the decrease of minority-carriers life-time. We introduce this anomalous degradation of the electrical performance in Si solar cells irradiated with electrons or protons. We also report the result of simulation for the fluence dependence of the I{sub SC}, and discuss the mechanism of this anomalous phenomenon. (author)

A variable-order fractal derivative model for anomalous diffusion

Directory of Open Access Journals (Sweden)

Liu Xiaoting

2017-01-01

Full Text Available This paper pays attention to develop a variable-order fractal derivative model for anomalous diffusion. Previous investigations have indicated that the medium structure, fractal dimension or porosity may change with time or space during solute transport processes, results in time or spatial dependent anomalous diffusion phenomena. Hereby, this study makes an attempt to introduce a variable-order fractal derivative diffusion model, in which the index of fractal derivative depends on temporal moment or spatial position, to characterize the above mentioned anomalous diffusion (or transport processes. Compared with other models, the main advantages in description and the physical explanation of new model are explored by numerical simulation. Further discussions on the dissimilitude such as computational efficiency, diffusion behavior and heavy tail phenomena of the new model and variable-order fractional derivative model are also offered.

Src Is a Prime Target Inhibited by Celtis choseniana Methanol Extract in Its Anti-Inflammatory Action

Directory of Open Access Journals (Sweden)

Han Gyung Kim

2018-01-01

Full Text Available Celtis choseniana is the traditional plant used at Korea as a herbal medicine to ameliorate inflammatory responses. Although Celtis choseniana has been traditionally used as a herbal medicine at Korea, no systemic research has been conducted on its anti-inflammatory activity. Therefore, the present study explored an anti-inflammatory effect and its underlying molecular mechanism using Celtis choseniana methanol extract (Cc-ME in macrophage-mediated inflammatory responses. In vitro anti-inflammatory activity of Cc-ME was evaluated using RAW264.7 cells and peritoneal macrophages stimulated by lipopolysaccharide (LPS, pam3CSK4 (Pam3, or poly(I:C. In vivo anti-inflammatory activity of Cc-ME was investigated using acute inflammatory disease mouse models, such as LPS-induced peritonitis and HCl/EtOH-induced gastritis. The molecular mechanism of Cc-ME-mediated anti-inflammatory activity was examined by Western blot analysis and immunoprecipitation using whole cell and nuclear fraction prepared from the LPS-stimulated RAW264.7 cells and HEK293 cells. Cc-ME inhibited NO production and mRNA expression of inducible nitric oxide synthase (iNOS, cyclooxygenase (COX-2, and tumor necrosis factor-alpha (TNF-α in the RAW264.7 cells and peritoneal macrophages induced by LPS, pam3, or poly(I:C without cytotoxicity. High-performance liquid chromatography (HPLC analysis showed that Cc-ME contained anti-inflammatory flavonoids quercetin, luteolin, and kaempferol. Among those, the content of luteolin, which showed an inhibitory effect on NO production, was highest. Cc-ME suppressed the NF-κB signaling pathway by targeting Src and interrupting molecular interactions between Src and p85, its downstream kinase. Moreover, Cc-ME ameliorated the morphological finding of peritonitis and gastritis in the mouse disease models. Therefore, these results suggest that Cc-ME exerted in vitro and in vivo anti-inflammatory activity in LPS-stimulated macrophages and mouse models of

Constitutional Rights in Indonesia

OpenAIRE

Judhariksawan

2018-01-01

The constitution is fundamental to the life of the modern state as a major foothold in state governance. Includes the guarantee of constitutional rights of citizens. The The constitution is the basis of state organizers to be implemented so that the state is obliged to guarantee the fulfillment of citizens' constitutional rights. Human rights have become an important part of the modern constitution. This study will describe how human rights guarantees become part of consti...

TGFbeta Induces Binucleation/Polyploidization in Hepatocytes through a Src-Dependent Cytokinesis Failure.

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Marco De Santis Puzzonia

Full Text Available In all mammals, the adult liver shows binucleated as well as mononucleated polyploid hepatocytes. The hepatic polyploidization starts after birth with an extensive hepatocyte binucleation and generates hepatocytes of several ploidy classes. While the functional significance of hepatocyte polyploidy is becoming clearer, how it is triggered and maintained needs to be clarified. Aim of this study was to identify a major inducer of hepatocyte binucleation/polyploidization and the cellular and molecular mechanisms involved. We found that, among several cytokines analyzed, known to be involved in early liver development and/or mass control, TGFbeta1 was capable to induce, together with the expected morphological changes, binucleation in hepatocytes in culture. Most importantly, the pharmacological inhibition of TGFbeta signaling in healthy mice during weaning, when the physiological binucleation occurs, induced a significant decrease of hepatocyte binucleation rate, without affecting cell proliferation and hepatic index. The TGFbeta-induced hepatocyte binucleation resulted from a cytokinesis failure, as assessed by video microscopy, and is associated with a delocalization of the cytokinesis regulator RhoA-GTPase from the mid-body of dividing cells. The use of specific chemical inhibitors demonstrated that the observed events are Src-dependent. Finally, the restoration of a fully epithelial phenotype by TGFbeta withdrawal gave rise to a cell progeny capable to maintain the polyploid state. In conclusion, we identified TGFbeta as a major inducer of hepatocyte binucleation both in vitro and in vivo, thus ascribing a novel role to this pleiotropic cytokine. The production of binucleated/tetraploid hepatocytes is due to a cytokinesis failure controlled by the molecular axis TGFbeta/Src/RhoA.

Src-family kinases negatively regulate NFAT signaling in resting human T cells.

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Alan Baer

Full Text Available T cell signaling is required for activation of both natural and therapeutic T cells including chimeric antigen receptor (CAR T cells. Identification of novel factors and pathways regulating T cell signaling may aid in development of effective T cell therapies. In resting human T cells, the majority of Src-family of tyrosine kinases (SFKs are inactive due to phosphorylation of a conserved carboxy-terminal tyrosine residue. Recently, a pool of enzymatically active SFKs has been identified in resting T cells; however, the significance of these is incompletely understood. Here, we characterized the role of active SFKs in resting human T cells. Pharmacologic inhibition of active SFKs enhanced distal TCR signaling as measured by IL-2 release and CD25 surface expression following TCR-independent activation. Mechanistically, inhibition of the active pool of SFKs induced nuclear translocation of NFAT1, and enhanced NFAT1-dependent signaling in resting T cells. The negative regulation of NFAT1 signaling was in part mediated by the Src-kinase Lck as human T cells lacking Lck had increased levels of nuclear NFAT1 and demonstrated enhanced NFAT1-dependent gene expression. Inhibition of active SFKs in resting primary human T cells also increased nuclear NFAT1 and enhanced NFAT1-dependent signaling. Finally, the calcineurin inhibitor FK506 and Cyclosporin A reversed the effect of SFKs inhibition on NFAT1. Together, these data identified a novel role of SFKs in preventing aberrant NFAT1 activation in resting T cells, and suggest that maintaining this pool of active SFKs in therapeutic T cells may increase the efficacy of T cell therapies.

Regulation of mTORC1 signaling by Src kinase activity is Akt1-independent in RSV-transformed cells

Czech Academy of Sciences Publication Activity Database

Vojtěchová, Martina; Turečková, Jolana; Kučerová, Dana; Šloncová, Eva; Vachtenheim, J.; Tuháčková, Zdena

2008-01-01

Roč. 10, č. 2 (2008), s. 99-107 ISSN 1522-8002 R&D Projects: GA ČR GA301/04/0550 Institutional research plan: CEZ:AV0Z50520514 Keywords : Akt/PKB * mTOR C1 signaling pathway * Src Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.191, year: 2008

Anomalous Symmetry Fractionalization and Surface Topological Order

Directory of Open Access Journals (Sweden)

Xie Chen

2015-10-01

Full Text Available In addition to possessing fractional statistics, anyon excitations of a 2D topologically ordered state can realize symmetry in distinct ways, leading to a variety of symmetry-enriched topological (SET phases. While the symmetry fractionalization must be consistent with the fusion and braiding rules of the anyons, not all ostensibly consistent symmetry fractionalizations can be realized in 2D systems. Instead, certain “anomalous” SETs can only occur on the surface of a 3D symmetry-protected topological (SPT phase. In this paper, we describe a procedure for determining whether a SET of a discrete, on-site, unitary symmetry group G is anomalous or not. The basic idea is to gauge the symmetry and expose the anomaly as an obstruction to a consistent topological theory combining both the original anyons and the gauge fluxes. Utilizing a result of Etingof, Nikshych, and Ostrik, we point out that a class of obstructions is captured by the fourth cohomology group H^{4}(G,U(1, which also precisely labels the set of 3D SPT phases, with symmetry group G. An explicit procedure for calculating the cohomology data from a SET is given, with the corresponding physical intuition explained. We thus establish a general bulk-boundary correspondence between the anomalous SET and the 3D bulk SPT whose surface termination realizes it. We illustrate this idea using the chiral spin liquid [U(1_{2}] topological order with a reduced symmetry Z_{2}×Z_{2}⊂SO(3, which can act on the semion quasiparticle in an anomalous way. We construct exactly solved 3D SPT models realizing the anomalous surface terminations and demonstrate that they are nontrivial by computing three-loop braiding statistics. Possible extensions to antiunitary symmetries are also discussed.

Computational Study of Anomalous Transport in High Beta DIII-D Discharges with ITBs

Science.gov (United States)

Pankin, Alexei; Garofalo, Andrea; Grierson, Brian; Kritz, Arnold; Rafiq, Tariq

2015-11-01

The advanced tokamak scenarios require a large bootstrap current fraction and high β. These large values are often outside the range that occurs in ``conventional'' tokamak discharges. The GLF23, TGLF, and MMM transport models have been previously validated for discharges with parameters associated with ``conventional'' tokamak discharges. It has been demonstrated that the TGLF model under-predicts anomalous transport in high β DIII-D discharges [A.M. Garofalo et al. 2015 TTF Workshop]. In this research, the validity of MMM7.1 model [T. Rafiq et al. Phys. Plasmas 20 032506 (2013)] is tested for high β DIII-D discharges with low and high torque. In addition, the sensitivity of the anomalous transport to β is examined. It is shown that the MMM7.1 model over-predicts the anomalous transport in the DIII-D discharge 154406. In particular, a significant level of anomalous transport is found just outside the internal transport barrier. Differences in the anomalous transport predicted using TGLF and MMM7.1 are reviewed. Mechanisms for quenching of anomalous transport in the ITB regions of high-beta discharges are investigated. This research is supported by US Department of Energy.

Clonorchis sinensis excretory-secretory products promote the migration and invasion of cholangiocarcinoma cells by activating the integrin β4-FAK/Src signaling pathway.

Science.gov (United States)

Pak, Jhang Ho; Bashir, Qudsia; Kim, In Ki; Hong, Sung-Jong; Maeng, Sejung; Bahk, Young Yil; Kim, Tong-Soo

2017-06-01

Cholangiocarcinoma (CCA) is a slow-growing but highly metastatic cancer. Its metastatic potential largely explains its high mortality rate. A recognized risk factor for CCA development is infection with the liver flukes Opisthorchis viverrini and Clonorchis sinensis. We previously reported that the excretory-secretory products (ESPs) of C. sinensis promoted the three-dimensional aggregation and invasion of CCA cells. In the present study, a quantitative real-time PCR array of extracellular matrix (ECM) and adhesion molecules was used to examine the regulatory mechanism of ESP-mediated CCA cell migration and invasion. In particular, the expression levels of integrin α isoforms and β4 were upregulated in response to ESPs. Increased expression of integrin β4 was probably correlated with activation of focal adhesion kinase (FAK) and the steroid receptor coactivator (Src) family kinase and the subsequent activation of two downstream focal adhesion molecules, paxillin and vinculin. Moreover, inhibition of FAK/Src activation reduced paxillin and vinculin phosphorylation and attenuated ESP-induced CCA cell migration and invasion. These findings suggest that the integrin β4-FAK/Src signaling axis may play a crucial role in clonorchiasis-associated CCA metastasis during tumor progression. Copyright © 2017 Elsevier B.V. All rights reserved.

The Constitutional Amendment Process

Science.gov (United States)

Chism, Kahlil

2005-01-01

This article discusses the constitutional amendment process. Although the process is not described in great detail, Article V of the United States Constitution allows for and provides instruction on amending the Constitution. While the amendment process currently consists of six steps, the Constitution is nevertheless quite difficult to change.…

Anomalous feedback and negative domain wall resistance

International Nuclear Information System (INIS)

Cheng, Ran; Xiao, Di; Zhu, Jian-Gang

2016-01-01

Magnetic induction can be regarded as a negative feedback effect, where the motive-force opposes the change of magnetic flux that generates the motive-force. In artificial electromagnetics emerging from spintronics, however, this is not necessarily the case. By studying the current-induced domain wall dynamics in a cylindrical nanowire, we show that the spin motive-force exerting on electrons can either oppose or support the applied current that drives the domain wall. The switching into the anomalous feedback regime occurs when the strength of the dissipative torque β is about twice the value of the Gilbert damping constant α . The anomalous feedback manifests as a negative domain wall resistance, which has an analogy with the water turbine. (paper)

Constitutional Politics, Constitutional Texts and Democratic Variety in Central and Eastern Europe

OpenAIRE

Blokker, Paul

2008-01-01

In the paper, it is argued that democratization in Central and Eastern Europe involves important forms of differentiation of democracy, rather than merely convergence to a singular – liberal-democratic, constitutional - model. One way of taking up democratic differentiation in post-communist societies is by analysing the constitutional documents of the new democratic orders, and the constitutional politics leading to the foundational documents. In a first step, the paper analyses constitution...

Constraints on Anomalous Quartic Gauge Boson Couplings from $\

CERN Document Server

Abbiendi, G; Åkesson, P F; Alexander, G; Allison, J; Amaral, P; Anagnostou, G; Anderson, K J; Asai, S; Axen, D A; Azuelos, Georges; Bailey, I; Barberio, E; Barillari, T; Barlow, R J; Batley, J Richard; Bechtle, P; Behnke, T; Bell, K W; Bell, P J; Bella, G; Bellerive, A; Benelli, G; Bethke, Siegfried; Biebel, O; Boeriu, O; Bock, P; Boutemeur, M; Braibant, S; Brigliadori, L; Brown, R M; Büsser, K; Burckhart, H J; Campana, S; Carnegie, R K; Carter, A A; Carter, J R; Chang, C Y; Charlton, D G; Ciocca, C; Csilling, Akos; Cuffiani, M; Dado, S; de Roeck, A; De Wolf, E A; Desch, Klaus; Dienes, B; Donkers, M; Dubbert, J; Duchovni, E; Duckeck, G; Duerdoth, I P; Etzion, E; Fabbri, Franco Luigi; Feld, L; Ferrari, P; Fiedler, F; Fleck, I; Ford, M; Frey, A; Gagnon, P; Gary, J W; Gaycken, G; Geich-Gimbel, C; Giacomelli, G; Giacomelli, P; Giunta, M; Goldberg, J; Gross, E; Grunhaus, Jacob; Gruwé, M; Günther, P O; Sen-Gupta, A; Hajdu, C; Hamann, M; Hanson, G G; Harel, A; Hauschild, M; Hawkes, C M; Hawkings, R; Hemingway, Richard J; Herten, G; Heuer, R D; Hill, J C; Hoffman, K; Horváth, D; Igo-Kemenes, P; Ishii, K; Jeremie, H; Jovanovic, P; Junk, T R; Kanaya, N; Kanzaki, J; Karlen, Dean A; Kawagoe, K; Kawamoto, T; Keeler, Richard K; Kellogg, R G; Kennedy, B W; Kluth, S; Kobayashi, T; Kobel, M; Komamiya, S; Kramer, T; Krieger, P; Von Krogh, J; Krüger, K; Kühl, T; Kupper, M; Lafferty, G D; Landsman, Hagar Yaël; Lanske, D; Layter, J G; Lellouch, D; Letts, J; Levinson, L; Lillich, J; Lloyd, S L; Loebinger, F K; Lü, J; Ludwig, A; Ludwig, J; Mader, W; Marcellini, S; Martin, A J; Masetti, G; Mashimo, T; Mättig, P; McKenna, J A; McPherson, R A; Meijers, F; Menges, W; Merritt, F S; Mes, H; Meyer, N; Michelini, Aldo; Mihara, S; Mikenberg, G; Miller, D J; Moed, S; Mohr, W; Mori, T; Mutter, A; Nagai, K; Nakamura, I; Nanjo, H; Neal, H A; Nisius, R; O'Neale, S W; Oh, A; Oreglia, M J; Orito, S; Pahl, C; Pásztor, G; Pater, J R; Pilcher, J E; Pinfold, J L; Plane, D E; Poli, B; Pooth, O; Przybycien, M B; Quadt, A; Rabbertz, K; Rembser, C; Renkel, P; Roney, J M; Rozen, Y; Runge, K; Sachs, K; Saeki, T; Sarkisyan-Grinbaum, E; Schaile, A D; Schaile, O; Scharff-Hansen, P; Schieck, J; Schörner-Sadenius, T; Schröder, M; Schumacher, M; Scott, W G; Seuster, R; Shears, T G; Shen, B C; Sherwood, P; Skuja, A; Smith, A M; Sobie, R J; Söldner-Rembold, S; Spanó, F; Stahl, A; Strom, D; Ströhmer, R; Tarem, S; Tasevsky, M; Teuscher, R; Thomson, M A; Torrence, E; Toya, D; Tran, P; Trigger, I; Trócsányi, Z L; Tsur, E; Turner-Watson, M F; Ueda, I; Ujvári, B; Vollmer, C F; Vannerem, P; Vertesi, R; Verzocchi, M; Voss, H; Vossebeld, Joost Herman; Ward, C P; Ward, D R; Watkins, P M; Watson, A T; Watson, N K; Wells, P S; Wengler, T; Wermes, N; Wilson, G W; Wilson, J A; Wolf, G; Wyatt, T R; Yamashita, S; Zer-Zion, D; Zivkovic, L

2004-01-01

Anomalous quartic couplings between the electroweak gauge bosons may contribute to the vv gamma gamma and qq gamma gamma final states produced in e+e- collisions. This analysis uses the LEP2 OPAL data sample at centre-of-mass energies up to 209 GeV. Event selections identify vv gamma gamma and qq gamma gamma events in which the two photons are reconstructed within the detector acceptance. The cross-section for the process e+e- -> qq gamma gamma is measured. Averaging over all energies, the ratio of the observed e+e- -> qq gamma gamma cross-section to the Standard Model expectation is R(data/SM) = 0.92 +- 0.07 +- 0.04 where the errors represent the statistical and systematic uncertainties respectively. The vv gamma gamma and qq gamma gamma data are used to constrain possible anomalous W+W- gamma gamma and ZZ gamma gamma couplings. Combining with previous OPAL results from the W+W- gamma final state, the 95% confidence level limits on the anomalous coupling parameters aoz, acz, aow and acw are found to be: -0.0...

Anomalous structural changes and elastic properties of bismuth oxide superconductors

International Nuclear Information System (INIS)

He, Y.S.; Xiang, J.; Chang, F.G.; Zhang, J.C.; He, A.S.; Wang, H.; Gu, B.L.

1989-01-01

Ultrasonic measurement revealed that there are anomalous structural changes near 200 K in single 2212 or 2223 phase samples of Bi(Pb)-Sr-Ca-Cu-O. Detailed study showed such anomalous changes are isothermal-like processes and have a characteristics of second order phase transition, accompanying with increases in lattice constants. The elastic properties of these ceramics and related systems are discussed

Nonlinear trapped electron mode and anomalous heat transport in tokamaks

International Nuclear Information System (INIS)

Kaw, P.K.

1982-01-01

We take the phenomenological point of view that the anomalous electron thermal conductivity produced by the non-linear trapped electron mode should also influence the stability properties of the mode itself. Using a model equation, we show that this effect makes the mode self-stabilizing. A simple expression for the anomalous thermal conductivity is derived, and its scaling properties are discussed. (orig.)

Subdiffusive master equation with space-dependent anomalous exponent and structural instability

Science.gov (United States)

Fedotov, Sergei; Falconer, Steven

2012-03-01

We derive the fractional master equation with space-dependent anomalous exponent. We analyze the asymptotic behavior of the corresponding lattice model both analytically and by Monte Carlo simulation. We show that the subdiffusive fractional equations with constant anomalous exponent μ in a bounded domain [0,L] are not structurally stable with respect to the nonhomogeneous variations of parameter μ. In particular, the Gibbs-Boltzmann distribution is no longer the stationary solution of the fractional Fokker-Planck equation whatever the space variation of the exponent might be. We analyze the random distribution of μ in space and find that in the long-time limit, the probability distribution is highly intermediate in space and the behavior is completely dominated by very unlikely events. We show that subdiffusive fractional equations with the nonuniform random distribution of anomalous exponent is an illustration of a “Black Swan,” the low probability event of the small value of the anomalous exponent that completely dominates the long-time behavior of subdiffusive systems.

tbW anomalous couplings in the Two Higgs Doublet Model

Energy Technology Data Exchange (ETDEWEB)

Arhrib, Abdesslam; Jueid, Adil [Département de Mathématiques, Faculté des Sciences et Techniques,Université Abdelmalek Essaadi,B. 416, Tangier (Morocco)

2016-08-11

We make a complete one loop calculation of the tbW couplings in the Two Higgs Doublet Model. We evaluate both the anomalous couplings g{sub L} and g{sub R} as well as left handed and right handed component of tbW. The computation is done in the Feynman gauge using the on-shell scheme renormalization for the Standard Model wave functions and parameters. We first show that the relative corrections to these anomalous couplings are rather small in most regions of the parameter space. We then analyze the effects of these anomalous couplings on certain observables such as top quark polarization in single top production through t−channel as well as W{sup ±} boson helicity fractions in top decay.

Multislice CT imaging of anomalous coronary arteries

International Nuclear Information System (INIS)

Shi Heshui; Aschoff, Andrik J.; Brambs, Hans-Juergen; Hoffmann, Martin H.K.

2004-01-01

The purpose of the present study was to evaluate the role of 16 multislice computed tomography (MSCT) to identify the origin of anomalous coronary arteries and to confirm their anatomic course in relation to the great vessels. Accuracy of coronary artery disease (CAD) detection was a secondary aim and was tested with conventional angiograms (CA) serving as standard of reference. Two hundred and forty-two consecutive patients referred for noninvasive coronary CT imaging were reviewed for the study. Sixteen patients (6.6%) with anomalous coronary arteries were detected and included as the study group. MSCT and CA images were analyzed in a blinded fashion for accuracy of anomalous artery origin and path detection. Results were compared in a secondary consensus evaluation. Accuracy ratios to detect CAD with MSCT in all vessels were calculated. Coronary anomalies for all 16 patients were correctly displayed on MSCT. CA alone achieved correct identification of the abnormality in only 53% (P=0.016). Sensitivity and specificity of MSCT to detect significantly stenosed vessels was 90 and 92%. 16-MSCT is accurate to delineate abnormally branching coronary arteries and allows sufficiently accurate detection of obstructive coronary artery disease in distal branches. It should therefore be considered as a prime non-invasive imaging tool for suspected coronary anomalies. (orig.)

Structural Analysis of DFG-in and DFG-out Dual Src-Abl Inhibitors Sharing a Common Vinyl Purine Template

Energy Technology Data Exchange (ETDEWEB)

Zhou, Tianjun; Commodore, Lois; Huang, Wei-Sheng; Wang, Yihan; Sawyer, Tomi K.; Shakespeare, William C.; Clackson, Tim; Zhu, Xiaotian; Dalgarno, David C. (ARIAD)

2010-09-30

Bcr-Abl is the oncogenic protein tyrosine kinase responsible for chronic myeloid leukemia (CML). Treatment of the disease with imatinib (Gleevec) often results in drug resistance via kinase mutations at the advanced phases of the disease, which has necessitated the development of new mutation-resistant inhibitors, notably against the T315I gatekeeper mutation. As part of our efforts to discover such mutation resistant Abl inhibitors, we have focused on optimizing purine template kinase inhibitors, leading to the discovery of potent DFG-in and DFG-out series of Abl inhibitors that are also potent Src inhibitors. Here we present crystal structures of Abl bound by two such inhibitors, based on a common N9-arenyl purine, and that represent both DFG-in and -out binding modes. In each structure the purine template is bound deeply in the adenine pocket and the novel vinyl linker forms a non-classical hydrogen bond to the gatekeeper residue, Thr315. Specific template substitutions promote either a DFG-in or -out binding mode, with the kinase binding site adjusting to optimize molecular recognition. Bcr-Abl T315I mutant kinase is resistant to all currently marketed Abl inhibitors, and is the focus of intense drug discovery efforts. Notably, our DFG-out inhibitor, AP24163, exhibits modest activity against this mutant, illustrating that this kinase mutant can be inhibited by DFG-out class inhibitors. Furthermore our DFG-out inhibitor exhibits dual Src-Abl activity, absent from the prototypical DFG-out inhibitor, imatinib as well as its analog, nilotinib. The data presented here provides structural guidance for the further design of novel potent DFG-out class inhibitors against Src, Abl and Abl T315I mutant kinases.

P120-GAP associated with syndecan-2 to function as an active switch signal for Src upon transformation with oncogenic ras

International Nuclear Information System (INIS)

Huang, J.-W.; Chen, C.-L.; Chuang, N.-N.

2005-01-01

BALB/3T3 cells transfected with plasmids pcDNA3.1-[S-ras(Q 61 K)] of shrimp Penaeus japonicus were applied to reveal a complex of p120-GAP/syndecan-2 being highly expressed upon transformation. Of interest, most of the p120-GAP/syndecan-2 complex was localized at caveolae, a membrane microdomain enriched with caveolin-1. To confirm the molecular interaction between syndecan-2 and p120-GAP, we further purified p120-GAP protein from mouse brains by using an affinity column of HiTrap-RACK1 and expressed mouse RACK1-encoded fusion protein and mouse syndecan-2-encoded fusion protein in bacteria. We report molecular affinities exist between p120-GAP and RACK1, syndecan-2 and RACK1 as well as p120-GAP and syndecan-2. The selective affinity between p120-GAP and syndecan-2 was found to be sufficient to detach RACK1. The p120-GAP/syndecan-2 complex was demonstrated to keep Src tyrosine kinase in an activated form. On the other hand, the syndecan-2/RACK1 complex was found to have Src in an inactivated form. These data indicate that the p120-GAP/syndecan-2 complex at caveolae could provide a docking site for Src to transmit tyrosine signaling, implying that syndecan-2/p120-GAP functions as a tumor promoter upon transformation with oncogenic ras of shrimp P. japonicus

Inhibition of tumor metastasis by a growth factor receptor bound protein 2 Src homology 2 domain-binding antagonist.

Science.gov (United States)

Giubellino, Alessio; Gao, Yang; Lee, Sunmin; Lee, Min-Jung; Vasselli, James R; Medepalli, Sampath; Trepel, Jane B; Burke, Terrence R; Bottaro, Donald P

2007-07-01

Metastasis, the primary cause of death in most forms of cancer, is a multistep process whereby cells from the primary tumor spread systemically and colonize distant new sites. Blocking critical steps in this process could potentially inhibit tumor metastasis and dramatically improve cancer survival rates; however, our understanding of metastasis at the molecular level is still rudimentary. Growth factor receptor binding protein 2 (Grb2) is a widely expressed adapter protein with roles in epithelial cell growth and morphogenesis, as well as angiogenesis, making it a logical target for anticancer drug development. We have previously shown that a potent antagonist of Grb2 Src homology-2 domain-binding, C90, blocks growth factor-driven cell motility in vitro and angiogenesis in vivo. We now report that C90 inhibits metastasis in vivo in two aggressive tumor models, without affecting primary tumor growth rate. These results support the potential efficacy of this compound in reducing the metastatic spread of primary solid tumors and establish a critical role for Grb2 Src homology-2 domain-mediated interactions in this process.

UCN anomalous losses and the UCN capture cross section on material defects

International Nuclear Information System (INIS)

Serebrov, A.; Romanenko, N.; Zherebtsov, O.; Lasakov, M.; Vasiliev, A.; Fomin, A.; Geltenbort, P.; Krasnoshekova, I.; Kharitonov, A.; Varlamov, V.

2005-01-01

Experimental data shows anomalously large ultra cold neutrons (UCN) reflection losses and that the process of UCN reflection is not completely coherent. UCN anomalous losses under reflection cannot be explained in the context of neutron optics calculations. UCN losses by means of incoherent scattering on material defects are considered and cross-section values calculated. The UCN capture cross section on material defects is enhanced by a factor of 10 4 due to localization of UCN around defects. This phenomenon can explain anomalous losses of UCN

Current Driven Instabilities and Anomalous Mobility in Hall-effect Thrusters

Science.gov (United States)

Tran, Jonathan; Eckhardt, Daniel; Martin, Robert

2017-10-01

Due to the extreme cost of fully resolving the Debye length and plasma frequency, hybrid plasma simulations utilizing kinetic ions and quasi-steady state fluid electrons have long been the principle workhorse methodology for Hall-effect thruster (HET) modeling. Plasma turbulence and the resulting anomalous electron transport in HETs is a promising candidate for developing predictive models for the observed anomalous transport. In this work, we investigate the implementation of an anomalous electron cross field transport model for hybrid HET simulations such a HPHall. A theory for anomalous transport in HETs and current driven instabilities has been recently studied by Lafleur et al. This work has shown collective electron-wave scattering due to large amplitude azimuthal fluctuations of the electric field. We will further adapt the previous results for related current driven instabilities to electric propulsion relevant mass ratios and conduct a preliminary study of resolving this instability with a modified hybrid (fluid electron and kinetic ion) simulation with the hope of integration with established hybrid HET simulations. This work is supported by the Air Force Office of Scientific Research award FA9950-17RQCOR465.

Molecular characterization of c-Abl/c-Src kinase inhibitors targeted against murine tumour progenitor cells that express stem cell markers.

Directory of Open Access Journals (Sweden)

Thomas Kruewel

Full Text Available BACKGROUND: The non-receptor tyrosine kinases c-Abl and c-Src are overexpressed in various solid human tumours. Inhibition of their hyperactivity represents a molecular rationale in the combat of cancerous diseases. Here we examined the effects of a new family of pyrazolo [3,4-d] pyrimidines on a panel of 11 different murine lung tumour progenitor cell lines, that express stem cell markers, as well as on the human lung adenocarcinoma cell line A549, the human hepatoma cell line HepG2 and the human colon cancer cell line CaCo2 to obtain insight into the mode of action of these experimental drugs. METHODOLOGY/PRINCIPAL FINDINGS: Treatment with the dual kinase inhibitors blocked c-Abl and c-Src kinase activity efficiently in the nanomolar range, induced apoptosis, reduced cell viability and caused cell cycle arrest predominantly at G0/G1 phase while western blot analysis confirmed repressed protein expression of c-Abl and c-Src as well as the interacting partners p38 mitogen activated protein kinase, heterogenous ribonucleoprotein K, cyclin dependent kinase 1 and further proteins that are crucial for tumour progression. Importantly, a significant repression of the epidermal growth factor receptor was observed while whole genome gene expression analysis evidenced regulation of many cell cycle regulated genes as well integrin and focal adhesion kinase (FAK signalling to impact cytoskeleton dynamics, migration, invasion and metastasis. CONCLUSIONS/SIGNIFICANCE: Our experiments and recently published in vivo engraftment studies with various tumour cell lines revealed the dual kinase inhibitors to be efficient in their antitumour activity.

Algebraic isomorphism in two-dimensional anomalous gauge theories

International Nuclear Information System (INIS)

Carvalhaes, C.G.; Belvedere, L.V.; Filho, H.B.; Natividade, C.P.

1997-01-01

The operator solution of the anomalous chiral Schwinger model is discussed on the basis of the general principles of Wightman field theory. Some basic structural properties of the model are analyzed taking a careful control on the Hilbert space associated with the Wightman functions. The isomorphism between gauge noninvariant and gauge invariant descriptions of the anomalous theory is established in terms of the corresponding field algebras. We show that (i) the Θ-vacuum representation and (ii) the suggested equivalence of vector Schwinger model and chiral Schwinger model cannot be established in terms of the intrinsic field algebra. copyright 1997 Academic Press, Inc

Anomalous tensoelectric effects in gallium arsenide tunnel diodes

Energy Technology Data Exchange (ETDEWEB)

Alekseeva, Z.M.; Vyatkin, A.P.; Krivorotov, N.P.; Shchegol' , A.A.

1988-02-01

Anomalous tensoelectric phenomena induced in a tunnel p-n junction by a concentrated load and by hydrostatic compression were studied. The anomalous tensoelectric effects are caused by the action of concentrators of mechanical stresses in the vicinity of the p-n junction, giving rise to local microplastic strain. Under the conditions of hydrostatic compression prolate inclusions approx.100-200 A long play the role of concentrators. Analysis of irreversible changes in the current-voltage characteristics of tunnel p-n junctions made it possible to separate the energy levels of the defects produced with plastic strain of gallium arsenide.

Anomalous scaling of stochastic processes and the Moses effect.

Science.gov (United States)

Chen, Lijian; Bassler, Kevin E; McCauley, Joseph L; Gunaratne, Gemunu H

2017-04-01

The state of a stochastic process evolving over a time t is typically assumed to lie on a normal distribution whose width scales like t^{1/2}. However, processes in which the probability distribution is not normal and the scaling exponent differs from 1/2 are known. The search for possible origins of such "anomalous" scaling and approaches to quantify them are the motivations for the work reported here. In processes with stationary increments, where the stochastic process is time-independent, autocorrelations between increments and infinite variance of increments can cause anomalous scaling. These sources have been referred to as the Joseph effect and the Noah effect, respectively. If the increments are nonstationary, then scaling of increments with t can also lead to anomalous scaling, a mechanism we refer to as the Moses effect. Scaling exponents quantifying the three effects are defined and related to the Hurst exponent that characterizes the overall scaling of the stochastic process. Methods of time series analysis that enable accurate independent measurement of each exponent are presented. Simple stochastic processes are used to illustrate each effect. Intraday financial time series data are analyzed, revealing that their anomalous scaling is due only to the Moses effect. In the context of financial market data, we reiterate that the Joseph exponent, not the Hurst exponent, is the appropriate measure to test the efficient market hypothesis.

Anomalous scaling of stochastic processes and the Moses effect

Science.gov (United States)

Chen, Lijian; Bassler, Kevin E.; McCauley, Joseph L.; Gunaratne, Gemunu H.

2017-04-01

The state of a stochastic process evolving over a time t is typically assumed to lie on a normal distribution whose width scales like t1/2. However, processes in which the probability distribution is not normal and the scaling exponent differs from 1/2 are known. The search for possible origins of such "anomalous" scaling and approaches to quantify them are the motivations for the work reported here. In processes with stationary increments, where the stochastic process is time-independent, autocorrelations between increments and infinite variance of increments can cause anomalous scaling. These sources have been referred to as the Joseph effect and the Noah effect, respectively. If the increments are nonstationary, then scaling of increments with t can also lead to anomalous scaling, a mechanism we refer to as the Moses effect. Scaling exponents quantifying the three effects are defined and related to the Hurst exponent that characterizes the overall scaling of the stochastic process. Methods of time series analysis that enable accurate independent measurement of each exponent are presented. Simple stochastic processes are used to illustrate each effect. Intraday financial time series data are analyzed, revealing that their anomalous scaling is due only to the Moses effect. In the context of financial market data, we reiterate that the Joseph exponent, not the Hurst exponent, is the appropriate measure to test the efficient market hypothesis.

PDGF-induced migration of synthetic vascular smooth muscle cells through c-Src-activated L-type Ca2+ channels with full-length CaV1.2 C-terminus.

Science.gov (United States)

Guo, Xiaoguang; Kashihara, Toshihide; Nakada, Tsutomu; Aoyama, Toshifumi; Yamada, Mitsuhiko

2018-06-01

In atherosclerosis, vascular smooth muscle cells (VSMC) migrate from the media toward the intima of the arteries in response to cytokines, such as platelet-derived growth factor (PDGF). However, molecular mechanism underlying the PDGF-induced migration of VSMCs remains unclear. The migration of rat aorta-derived synthetic VSMCs, A7r5, in response to PDGF was potently inhibited by a Ca V 1.2 channel inhibitor, nifedipine, and a Src family tyrosine kinase (SFK)/Abl inhibitor, bosutinib, in a less-than-additive manner. PDGF significantly increased Ca V 1.2 channel currents without altering Ca V 1.2 protein expression levels in A7r5 cells. This reaction was inhibited by C-terminal Src kinase, a selective inhibitor of SFKs. In contractile VSMCs, the C-terminus of Ca V 1.2 is proteolytically cleaved into proximal and distal C-termini (PCT and DCT, respectively). Clipped DCT is noncovalently reassociated with PCT to autoinhibit the channel activity. Conversely, in synthetic A7r5 cells, full-length Ca V 1.2 (Ca V 1.2FL) is expressed much more abundantly than truncated Ca V 1.2. In a heterologous expression system, c-Src activated Ca V 1.2 channels composed of Ca V 1.2FL but not truncated Ca V 1.2 (Ca V 1.2Δ1763) or Ca V 1.2Δ1763 plus clipped DCT. Further, c-Src enhanced the coupling efficiency between the voltage-sensing domain and activation gate of Ca V 1.2FL channels by phosphorylating Tyr1709 and Tyr1758 in PCT. Compared with Ca V 1.2Δ1763, c-Src could more efficiently bind to and phosphorylate Ca V 1.2FL irrespective of the presence or absence of clipped DCT. Therefore, in atherosclerotic lesions, phenotypic switching of VSMCs may facilitate pro-migratory effects of PDGF on VSMCs by suppressing posttranslational Ca V 1.2 modifications.

Effect of anomalous resistivity on the dynamics of plasma switching

Energy Technology Data Exchange (ETDEWEB)

Kingsep, A [Kurchatov Institute, Moscow (Russian Federation); Munier, A [Centre d` Etudes Limeil-Vaneton, Villeneuve St. Georges (France)

1997-12-31

Some of the conditions for electron MHD are recollected, and it is shown how this leads to anomalous resistivity which may play an important role in the dynamics of POS. It has been shown that not only the order of value of the resistance of the plasma-filled diode but rather basic scalings have to be changed in the regime of essential anomalous resistivity. (author). 11 refs.

Polymeric immunoglobulin receptor-mediated invasion of Streptococcus pneumoniae into host cells requires a coordinate signaling of SRC family of protein-tyrosine kinases, ERK, and c-Jun N-terminal kinase.

Science.gov (United States)

Agarwal, Vaibhav; Asmat, Tauseef M; Dierdorf, Nina I; Hauck, Christof R; Hammerschmidt, Sven

2010-11-12

Streptococcus pneumoniae are commensals of the human nasopharynx with the capacity to invade mucosal respiratory cells. PspC, a pneumococcal surface protein, interacts with the human polymeric immunoglobulin receptor (pIgR) to promote bacterial adherence to and invasion into epithelial cells. Internalization of pneumococci requires the coordinated action of actin cytoskeleton rearrangements and the retrograde machinery of pIgR. Here, we demonstrate the involvement of Src protein-tyrosine kinases (PTKs), focal adhesion kinase (FAK), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) but not p38 mitogen-activated protein kinases (MAPK) in pneumococcal invasion via pIgR. Pharmacological inhibitors of PTKs and MAPKs and genetic interference with Src PTK and FAK functions caused a significant reduction of pIgR-mediated pneumococcal invasion but did not influence bacterial adhesion to host cells. Furthermore, pneumococcal ingestion by host cells induces activation of ERK1/2 and JNK. In agreement with activated JNK, its target molecule and DNA-binding protein c-Jun was phosphorylated. We also show that functionally active Src PTK is essential for activation of ERK1/2 upon pneumococcal infections. In conclusion, these data illustrate the importance of a coordinated signaling between Src PTKs, ERK1/2, and JNK during PspC-pIgR-mediated uptake of pneumococci by host epithelial cells.

Mobility of TOAC spin-labelled peptides binding to the Src SH3 domain studied by paramagnetic NMR

Energy Technology Data Exchange (ETDEWEB)

Lindfors, Hanna E. [Leiden University, Leiden Institute of Chemistry, Gorlaeus Laboratories (Netherlands); Koning, Peter E. de; Wouter Drijfhout, Jan [Leiden University Medical Centre, Department of Immunohematology and Blood Transfusion (Netherlands); Venezia, Brigida; Ubbink, Marcellus [Leiden University, Leiden Institute of Chemistry, Gorlaeus Laboratories (Netherlands)], E-mail: m.ubbink@chem.leidenuniv.nl

2008-07-15

Paramagnetic relaxation enhancement provides a tool for studying the dynamics as well as the structure of macromolecular complexes. The application of side-chain coupled spin-labels is limited by the mobility of the free radical. The cyclic, rigid amino acid spin-label TOAC (2,2,6,6-Tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid), which can be incorporated straightforwardly by peptide synthesis, provides an attractive alternative. In this study, TOAC was incorporated into a peptide derived from focal adhesion kinase (FAK), and the interaction of the peptide with the Src homology 3 (SH3) domain of Src kinase was studied, using paramagnetic NMR. Placing TOAC within the binding motif of the peptide has a considerable effect on the peptide-protein binding, lowering the affinity substantially. When the TOAC is positioned just outside the binding motif, the binding constant remains nearly unaffected. Although the SH3 domain binds weakly and transiently to proline-rich peptides from FAK, the interaction is not very dynamic and the relative position of the spin-label to the protein is well-defined. It is concluded that TOAC can be used to generate reliable paramagnetic NMR restraints.

Mobility of TOAC spin-labelled peptides binding to the Src SH3 domain studied by paramagnetic NMR

International Nuclear Information System (INIS)

Lindfors, Hanna E.; Koning, Peter E. de; Wouter Drijfhout, Jan; Venezia, Brigida; Ubbink, Marcellus

2008-01-01

Paramagnetic relaxation enhancement provides a tool for studying the dynamics as well as the structure of macromolecular complexes. The application of side-chain coupled spin-labels is limited by the mobility of the free radical. The cyclic, rigid amino acid spin-label TOAC (2,2,6,6-Tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid), which can be incorporated straightforwardly by peptide synthesis, provides an attractive alternative. In this study, TOAC was incorporated into a peptide derived from focal adhesion kinase (FAK), and the interaction of the peptide with the Src homology 3 (SH3) domain of Src kinase was studied, using paramagnetic NMR. Placing TOAC within the binding motif of the peptide has a considerable effect on the peptide-protein binding, lowering the affinity substantially. When the TOAC is positioned just outside the binding motif, the binding constant remains nearly unaffected. Although the SH3 domain binds weakly and transiently to proline-rich peptides from FAK, the interaction is not very dynamic and the relative position of the spin-label to the protein is well-defined. It is concluded that TOAC can be used to generate reliable paramagnetic NMR restraints

Combining biophysical methods to analyze the disulfide bond in SH2 domain of C-terminal Src kinase.

Science.gov (United States)

Liu, Dongsheng; Cowburn, David

2016-01-01

The Src Homology 2 (SH2) domain is a structurally conserved protein domain that typically binds to a phosphorylated tyrosine in a peptide motif from the target protein. The SH2 domain of C-terminal Src kinase (Csk) contains a single disulfide bond, which is unusual for most SH2 domains. Although the global motion of SH2 domain regulates Csk function, little is known about the relationship between the disulfide bond and binding of the ligand. In this study, we combined X-ray crystallography, solution NMR, and other biophysical methods to reveal the interaction network in Csk. Denaturation studies have shown that disulfide bond contributes significantly to the stability of SH2 domain, and crystal structures of the oxidized and C122S mutant showed minor conformational changes. We further investigated the binding of SH2 domain to a phosphorylated peptide from Csk-binding protein upon reduction and oxidation using both NMR and fluorescence approaches. This work employed NMR, X-ray cryptography, and other biophysical methods to study a disulfide bond in Csk SH2 domain. In addition, this work provides in-depth understanding of the structural dynamics of Csk SH2 domain.

The effect of temperature and time of extraction on the quality of Semi Refined Carrageenan (SRC

Directory of Open Access Journals (Sweden)

Heriyanto Heri

2018-01-01

Full Text Available Euchema cottonii is a good source of kappa-carrageenan and can be found cultivated in the Indonesia coastal areas in which one of them is in Banten Province. Carrageenans have many applications and are utilized in human food and pet-food industry. Carrageenans are also utilized in non-food industry such as pharmaceuticals, cosmetics, printing and textile formulations. Hence, the present study features on the cooking process cooking time and cooking temperature. The effects of these parameters on carrageenan quality such as gel viscosity and gel strength were studied. The process of extraction of carrageenan was conducted with variations temperature: 60, 70, and 80 °C and the variation of time: 1, 2, and 3 hours. Alkaline substance used was KOH with 8% concentration and the ratio of solvent to dry seaweed 8:1. From the present investigation, it was observed that SRC extraction reached the best condition at temperature 70 °C for 2 hours with the value of yield 30.20%, 5.90% moisture content, 18.34% ash content, sulfate content of 6.94%, viscosity of 190 cP, and the gel strength 714.45 g / cm2. The treatment of temperature and extraction time significantly affected the quality of the SRC yield parameter, viscosity and gel strength.

Study on Progressive Collapse Behavior of SRC Column-Steel Beam Hybrid Frame Based on Pushdown Analysis

Directory of Open Access Journals (Sweden)

Liusheng Chu

2017-01-01

Full Text Available To investigate the progressive collapse behavior of Steel Reinforced Concrete (SRC column-steel beam hybrid frame after the failure of key structural elements, a PQ-Fiber model for an 8-storey structure is established in ABAQUS program. Nonlinear dynamic and static pushdown analysis are carried out after the failure and removal of the bottom-middle and bottom-corner columns. Numerical results of both methods agree well with each other. Results show that SRC column-steel frame has good resistance to progressive collapse under dynamic instantaneous load. After sudden removal of a bottom middle column, the development of structural collapse exhibits two mechanisms, the beam mechanism and the catenary mechanism. When the structure is within small deformation range, the collapse resistance of the residual frame is provided by the beam bending moment capacity, which is beam mechanism. For large deformation situation, the collapse resistance is mainly provided by the beam tensile strength, which is catenary mechanism. However, with the removal of a bottom corner column, the residual structure only undergoes the beam mechanism even for large deformations. For future practical applications, the influence of the steel ratio, steel section size, and the vertical position of the removed key components are investigated through a detailed parametric study.

Transnational Constitutional Law

OpenAIRE

Zumbansen, P (Peer); Bhatt, Kinnari

2018-01-01

textabstractThis chapter provides an overview of the emerging field of transnational constitutional law (TCL). Whilst questions of constitutional law are typically discussed in the context of a specific domestic legal setting, a salient strategy of TCL is to understand constitutional law and its values by placing them ‘in context’ with existing and evolving cultural norms and political, social and economic discourses and struggles. Drawing on socio-legal investigations into the relationships ...

Field enhancement due to anomalous skin effect inside a target

International Nuclear Information System (INIS)

Ma, G.; Tan, W.

1996-01-01

A new method based on Fourier transformation to study the skin effects is presented. Using this method, the field amplitude in plasma is represented in terms of electric conductivity, and the normal and anomalous skin effects are described through one formula by omitting the plasma dispersion or not. The results are in agreement with other publications [e.g., J. P. Matte and K. Aguenaou, Phys. Rev. A 45, 2558 (1992)] for equivalent parameters. But for deeper positions inside a target, which have not been studied by others, it is found that the field amplitude is considerably enhanced due to an anomalous skin effect, even for constant collision frequency. In addition, the skin absorptions and some calculations on an anomalous skin effect for different collision frequencies are also presented. copyright 1996 American Institute of Physics

Anomalous thermoelectric phenomena in lattice models of multi-Weyl semimetals

Science.gov (United States)

Gorbar, E. V.; Miransky, V. A.; Shovkovy, I. A.; Sukhachov, P. O.

2017-10-01

The thermoelectric transport coefficients are calculated in a generic lattice model of multi-Weyl semimetals with a broken time-reversal symmetry by using the Kubo's linear response theory. The contributions connected with the Berry curvature-induced electromagnetic orbital and heat magnetizations are systematically taken into account. It is shown that the thermoelectric transport is profoundly affected by the nontrivial topology of multi-Weyl semimetals. In particular, the calculation reveals a number of thermal coefficients of the topological origin which describe the anomalous Nernst and thermal Hall effects in the absence of background magnetic fields. Similarly to the anomalous Hall effect, all anomalous thermoelectric coefficients are proportional to the integer topological charge of the Weyl nodes. The dependence of the thermoelectric coefficients on the chemical potential and temperature is also studied.

CAN THE MUSLIM WORLD BORROW FROM INDONESIAN CONSTITUTIONAL REFORM? A Comparative Constitutional Approach

Directory of Open Access Journals (Sweden)

Nadirsyah Hosen

2007-06-01

Full Text Available This paper attempts to analytically examine the possibility of constitutional borrowing for the Muslim world regardless the differences in history, system, culture, language, and cha­racteristics. It discusses this issue by looking at the arguments put forth by the oppo­nents of comparative cons­titutional interpre­tation and their counter arguments. It will consider materials from Canada, USA, South Africa, Singapore, Malaysia, and Hungary, taking the position that constitutional borrowing can be justified. The paper argues that the 1999-2002 Indonesian constitutional reform should be taken into account by other Muslim countries in undertaking their constitutional reform. The substantive approach of the Shari‘ah that has been used in Indonesia has shown that Muslim world can reform its constitutions without the “assistance” of Western foreign policy. Indo­nesian constitutional reform has demonstrated that Islamic constitutionalism comes from within Islamic teaching and the Islamic community itself; it is a home grown product.

Anomalous Hall conductivity: Local orbitals approach

Czech Academy of Sciences Publication Activity Database

Středa, Pavel

2010-01-01

Roč. 82, č. 4 (2010), 045115/1-045115/9 ISSN 1098-0121 Institutional research plan: CEZ:AV0Z10100521 Keywords : anomalous Hall effect * Berry phase correction * orbital polarization momentum Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 3.772, year: 2010

A classical picture of anomalous effects in a tokamak

International Nuclear Information System (INIS)

Hirano, K.

1984-01-01

It is demonstrated that the atomic collisions between plasma ions and a very small amount of neutral particles remaining in a hot plasma plays a very important role for plasma transports and may be an origin of anomalous effects observed in a tokamak such as the diffusion coefficient independent of the field strength, a rapid plasma density increase during gas puffing and current penetration with anomalously high speed in the start-up phase. The Ohm's law derived by Cowling is used for the analysis. (author)

Anomalous incident-angle and elliptical-polarization rotation of an elastically refracted P-wave

Science.gov (United States)

Fa, Lin; Fa, Yuxiao; Zhang, Yandong; Ding, Pengfei; Gong, Jiamin; Li, Guohui; Li, Lijun; Tang, Shaojie; Zhao, Meishan

2015-08-01

We report a newly discovered anomalous incident-angle of an elastically refracted P-wave, arising from a P-wave impinging on an interface between two VTI media with strong anisotropy. This anomalous incident-angle is found to be located in the post-critical incident-angle region corresponding to a refracted P-wave. Invoking Snell’s law for a refracted P-wave provides two distinctive solutions before and after the anomalous incident-angle. For an inhomogeneously refracted and elliptically polarized P-wave at the anomalous incident-angle, its rotational direction experiences an acute variation, from left-hand elliptical to right-hand elliptical polarization. The new findings provide us an enhanced understanding of acoustical-wave scattering and lead potentially to widespread and novel applications.

Sampling and Characterization of 618-2 Anomalous Material

International Nuclear Information System (INIS)

Zacharias, A.E.

2006-01-01

This as low as reasonably achievable (ALARA) Level II review documents radiological engineering and administrative controls necessary for the sampling and characterization of anomalous materials discovered during the remediation of the 618-2 solid waste burial ground. The goals of these engineering and administrative controls are to keep personnel exposure ALARA, control contamination levels, and minimize potential for airborne contamination. Excavation of the 618-2 Burial Ground has produced many items of anomalous waste. Prior to temporary packaging and/or storage, these items have been characterized in the field to identify radiological and industrial safety conditions. Further sampling and characterization of these items, as well as those remaining from an excavated combination safe, is the subject of this ALARA Level II review. An ALARA in-progress review will also be performed prior to sampling and characterization of 618-2 anomalous materials offering risks of differing natures. General categories of anomalies requiring further characterization include the following: (1) Containers of unknown liquids and/or solids and powders (excluding transuranics); (2) Drums containing unknown liquids and/or solids; (3) Metal containers with unknown contents; and (4) Known or suspected transuranic material.

Constitutional Issues--Watergate and the Constitution. Teaching with Documents.

Science.gov (United States)

National Archives and Records Administration, Washington, DC.

When U.S. President Richard Nixon resigned in 1974 in the wake of the Watergate scandal, it was only the second time that impeachment of a president had been considered. Although the U.S. Constitution has provisions for a person removed from office to be indicted, there are no guidelines in the Constitution about a President who has resigned. The…

Anomalous dissolution of metals and chemical corrosion

Directory of Open Access Journals (Sweden)

DRAGUTIN M. DRAZIC

2005-03-01

Full Text Available An overview is given of the anomalous behavior of some metals, in particular Fe and Cr, in acidic aqueous solutions during anodic dissolution. The anomaly is recognizable by the fact that during anodic dissolutionmore material dissolves than would be expected from the Faraday law with the use of the expected valence of the formed ions. Mechanical disintegration, gas bubble blocking, hydrogen embrittlement, passive layer cracking and other possible reasons for such behavior have been discussed. It was shown, as suggested by Kolotyrkin and coworkers, that the reason can be, also, the chemical reaction in which H2O molecules with the metal form metal ions and gaseous H2 in a potential independent process. It occurs simultaneously with the electrochemical corrosion process, but the electrochemical process controls the corrosion potential. On the example of Cr in acid solution itwas shown that the reason for the anomalous behavior is dominantly chemical dissolution, which is considerably faster than the electrochemical corrosion, and that the increasing temperature favors chemical reaction, while the other possible reasons for the anomalous behavior are of negligible effect. This effect is much smaller in the case of Fe, but exists. The possible role of the chemical dissolution reacton and hydrogen evolution during pitting of steels and Al and stress corrosion cracking or corrosion fatigue are discussed.

Combination Therapy with c-Met and Src Inhibitors Induces Caspase-Dependent Apoptosis of Merlin-Deficient Schwann Cells and Suppresses Growth of Schwannoma Cells.

Science.gov (United States)

Fuse, Marisa A; Plati, Stephani Klingeman; Burns, Sarah S; Dinh, Christine T; Bracho, Olena; Yan, Denise; Mittal, Rahul; Shen, Rulong; Soulakova, Julia N; Copik, Alicja J; Liu, Xue Zhong; Telischi, Fred F; Chang, Long-Sheng; Franco, Maria Clara; Fernandez-Valle, Cristina

2017-11-01

Neurofibromatosis type 2 (NF2) is a nervous system tumor disorder caused by inactivation of the merlin tumor suppressor encoded by the NF2 gene. Bilateral vestibular schwannomas are a diagnostic hallmark of NF2. Mainstream treatment options for NF2-associated tumors have been limited to surgery and radiotherapy; however, off-label uses of targeted molecular therapies are becoming increasingly common. Here, we investigated drugs targeting two kinases activated in NF2-associated schwannomas, c-Met and Src. We demonstrated that merlin-deficient mouse Schwann cells (MD-MSC) treated with the c-Met inhibitor, cabozantinib, or the Src kinase inhibitors, dasatinib and saracatinib, underwent a G 1 cell-cycle arrest. However, when MD-MSCs were treated with a combination of cabozantinib and saracatinib, they exhibited caspase-dependent apoptosis. The combination therapy also significantly reduced growth of MD-MSCs in an orthotopic allograft mouse model by greater than 80% of vehicle. Moreover, human vestibular schwannoma cells with NF2 mutations had a 40% decrease in cell viability when treated with cabozantinib and saracatinib together compared with the vehicle control. This study demonstrates that simultaneous inhibition of c-Met and Src signaling in MD-MSCs triggers apoptosis and reveals vulnerable pathways that could be exploited to develop NF2 therapies. Mol Cancer Ther; 16(11); 2387-98. ©2017 AACR . ©2017 American Association for Cancer Research.

Vector boson scattering, triple gauge-boson final states and limits on anomalous quartic gauge couplings with the ATLAS detector

CERN Document Server

Li, Bing; The ATLAS collaboration

2018-01-01

Measurements of the cross sections of the production of three electroweak gauge bosons and of vector-boson scattering processes at the LHC constitute stringent tests of the electroweak sector of the Standard Model and provide a model-independent means to search for new physics at the TeV scale. The ATLAS collaboration has recently searched for the production of three W bosons or of a W boson and a photon together with a Z or W boson at a center of mass energy of 8 TeV. We also present searches for the electroweak production of a Z boson and a photon together with two jets. The results are compared to state-of-the art theory predictions and have been used to constrain anomalous quartic gauge couplings.

Vector boson scattering, triple gauge-boson final states and limits on anomalous quartic gauge couplings with the ATLAS detector

CERN Document Server

Li, Bing; The ATLAS collaboration

2017-01-01

Measurements of the cross sections of the production of three electroweak gauge bosons and of vector-boson scattering processes at the LHC constitute stringent tests of the electroweak sector of the Standard Model and provide a model-independent means to search for new physics at the TeV scale. The ATLAS collaboration has recently searched for the production of three $W$ bosons or of a $W$ boson and a photon together with a $Z$ or $W$ boson at a center of mass energy of 8 TeV. We also present searches for the electroweak production of a $Z$ boson and a photon together with two jets. The results are compared to state-of-the art theory predictions and have been used to constrain anomalous quartic gauge couplings.

Vector boson scattering, triple gauge-boson final states and limits on anomalous quartic gauge couplings with the ATLAS detector

CERN Document Server

Li, Bing; The ATLAS collaboration

2017-01-01

Measurements of the cross sections of the production of three electroweak gauge bosons and of vector-boson scattering processes at the LHC constitute stringent tests of the electroweak sector of the Standard Model and provide a model-independent means to search for new physics at the TeV scale. The ATLAS collaboration has recently searched for the production of three W bosons or of a W boson and a photon together with a Z or W boson at a center of mass energy of 8 TeV. We also present searches for the electroweak production of a Z boson and a photon together with two jets. The results are compared to state-of-the art theory predictions and have been used to constrain anomalous quartic gauge couplings.

Vector boson scattering, triple gauge-boson final states and limits on anomalous quartic gauge couplings with the ATLAS detector

CERN Document Server

Nitta, Tatsumi; The ATLAS collaboration

2018-01-01

Measurements of the cross sections of the production of three electroweak gauge bosons and of vector-boson scattering processes at the LHC constitute stringent tests of the electroweak sector of the Standard Model and provide a model-independent means to search for new physics at the TeV scale. The ATLAS collaboration searched for the production of three $W$ bosons or of a $W$ boson and a photon together with a $Z$ or $W$ boson at a center of mass energy of 8 TeV. ATLAS has also searched for the electroweak production of a heavy boson and a photon together with two jets. All results have been used to constrain anomalous quartic gauge couplings and have been compared to the latest theory predictions.

Anomalous decay and scattering processes of the meson

Science.gov (United States)

Kubis, Bastian; Plenter, Judith

2015-06-01

We amend a recent dispersive analysis of the anomalous decay process by the effects of the tensor meson, the lowest-lying resonance that can contribute in the system. While the net effects on the measured decay spectrum are small, they may be more pronounced for the analogous decay. There are nonnegligible consequences for the transition form factor, which is an important quantity for the hadronic light-by-light scattering contribution to the muon's anomalous magnetic moment. We predict total and differential cross sections, as well as a marked forward-backward asymmetry, for the crossed process , which could be measured in Primakoff reactions in the future.

Top quark amplitudes with an anomalous magnetic moment

International Nuclear Information System (INIS)

Larkoski, Andrew J.; Peskin, Michael E.

2011-01-01

The anomalous magnetic moment of the top quark may be measured during the first run of the LHC at 7 TeV. For these measurements, it will be useful to have available tree amplitudes with tt and arbitrarily many photons and gluons, including both QED and color anomalous magnetic moments. In this paper, we present a method for computing these amplitudes using the Britto-Cachazo-Feng-Witten recursion formula. Because we deal with an effective theory with higher-dimension couplings, there are roadblocks to a direct computation with the Britto-Cachazo-Feng-Witten method. We evade these by using an auxiliary scalar theory to compute a subset of the amplitudes.

Five-loop anomalous dimension of twist-two operators

Energy Technology Data Exchange (ETDEWEB)

Lukowski, T. [Institute of Physics, Jagellonian University, ul. Reymonta 4, 30-059 Krakow (Poland); Rej, A. [Blackett Laboratory, Imperial College, London SW7 2AZ (United Kingdom); Velizhanin, V.N., E-mail: velizh@mail.desy.d [Theoretical Physics Department, Petersburg Nuclear Physics Institute, Orlova Roscha, Gatchina, 188300 St. Petersburg (Russian Federation)

2010-05-21

In this article we calculate the five-loop anomalous dimension of twist-two operators in the planar N=4 SYM theory. Firstly, using reciprocity, we derive the contribution of the asymptotic Bethe ansatz. Subsequently, we employ the first finite-size correction for the AdS{sub 5}xS{sup 5} sigma model to determine the wrapping correction. The anomalous dimension found in this way passes all known tests provided by the NLO BFKL equation and double-logarithmic constraints. This result thus furnishes an infinite number of experimental data for testing the veracity of the recently proposed spectral equations for planar AdS/CFT correspondence.

Essential Medicines in National Constitutions

Science.gov (United States)

Toebes, Brigit; Hogerzeil, Hans

2016-01-01

Abstract A constitutional guarantee of access to essential medicines has been identified as an important indicator of government commitment to the progressive realization of the right to the highest attainable standard of health. The objective of this study was to evaluate provisions on access to essential medicines in national constitutions, to identify comprehensive examples of constitutional text on medicines that can be used as a model for other countries, and to evaluate the evolution of constitutional medicines-related rights since 2008. Relevant articles were selected from an inventory of constitutional texts from WHO member states. References to states’ legal obligations under international human rights law were evaluated. Twenty-two constitutions worldwide now oblige governments to protect and/or to fulfill accessibility of, availability of, and/or quality of medicines. Since 2008, state responsibilities to fulfill access to essential medicines have expanded in five constitutions, been maintained in four constitutions, and have regressed in one constitution. Government commitments to essential medicines are an important foundation of health system equity and are included increasingly in state constitutions. PMID:27781006

Anomalous Threshold Voltage Variability of Nitride Based Charge Storage Nonvolatile Memory Devices

Directory of Open Access Journals (Sweden)

Meng Chuan Lee

2013-01-01

Full Text Available Conventional technology scaling is implemented to meet the insatiable demand of high memory density and low cost per bit of charge storage nonvolatile memory (NVM devices. In this study, effect of technology scaling to anomalous threshold voltage ( variability is investigated thoroughly on postcycled and baked nitride based charge storage NVM devices. After long annealing bake of high temperature, cell’s variability of each subsequent bake increases within stable distribution and found exacerbate by technology scaling. Apparent activation energy of this anomalous variability was derived through Arrhenius plots. Apparent activation energy (Eaa of this anomalous variability is 0.67 eV at sub-40 nm devices which is a reduction of approximately 2 times from 110 nm devices. Technology scaling clearly aggravates this anomalous variability, and this poses reliability challenges to applications that demand strict control, for example, reference cells that govern fundamental program, erase, and verify operations of NVM devices. Based on critical evidence, this anomalous variability is attributed to lateral displacement of trapped charges in nitride storage layer. Reliability implications of this study are elucidated. Moreover, potential mitigation methods are proposed to complement technology scaling to prolong the front-runner role of nitride based charge storage NVM in semiconductor flash memory market.

The Causes of Failure of the European Constitution From the Perspective of the Constitution-Making Process

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Robert Podolnjak

2006-01-01

Full Text Available The basic argument of the article is that the main causes of failure of the European Constitution stem from an inadequate preparation and implementation of a complex procedure of constitution-making for a federation of countries on a continental scale. This process includes the issues of temporal aspects of constitutionmaking, the subject of constitution-making, the text of the constitution, the strategy of constitutional ratifi cation and the constitution-makers themselves. The principal causes of failure of the European Constitution will be presented in the form of certain preliminary assumptions, which will then be examined in the light of certain comparative experiences of constitution-making in two federal systems – the American and the Swiss system. The primary mistakes of the European constitution-making are refl ected in the lack of an appropriate moment for making the constitution, in the vagueness of the document in terms of its constitutional or contractual quality, in the creation of a text of the Constitution which is completely incomprehensible to the average citizen, in the making of the Constitution without a vision or ambition, in the complete lack of any strategy of ratifi cation of the Constitution, in the insistence on the direct participation of the people in the adoption of the Constitution, which is legally and politically considered primarily an international treaty, and in badly managed media presentation and defence of the Constitution before the European public. The most important mistakes, crucial to the failure of the Constitution, are the ambivalent approach of the European constitutionmakers to the mode of ratifi cation of the Constitution, and their disregard of the constitution-making experience of other federal countries.

Anomalous Micellization of Pluronic Block Copolymers

Science.gov (United States)

Leonardi, Amanda; Ryu, Chang Y.

2014-03-01

Poly(ethylene oxide) - poly(propylene oxide) - poly(ethylene oxide) (PEO-PPO-PEO) block copolymers, commercially known as Pluronics, are a unique family of amphiphilic triblock polymers, which self-assemble into micelles in aqueous solution. These copolymers have shown promise in therapeutic, biomedical, cosmetic, and nanotech applications. As-received samples of Pluronics contain low molecular weight impurities (introduced during the manufacturing and processing), that are ignored in most applications. It has been observed, however, that in semi-dilute aqueous solutions, at concentrations above 1 wt%, the temperature dependent micellization behavior of the Pluronics is altered. Anomalous behavior includes a shift of the critical micellization temperature and formation of large aggregates at intermediate temperatures before stable sized micelles form. We attribute this behavior to the low molecular weight impurities that are inherent to the Pluronics which interfere with the micellization process. Through the use of Dynamic Light Scattering and HPLC, we compared the anomalous behavior of different Pluronics of different impurity levels to their purified counterparts.

Revisit to diffraction anomalous fine structure

International Nuclear Information System (INIS)

Kawaguchi, T.; Fukuda, K.; Tokuda, K.; Shimada, K.; Ichitsubo, T.; Oishi, M.; Mizuki, J.; Matsubara, E.

2014-01-01

The diffraction anomalous fine structure method has been revisited by applying this measurement technique to polycrystalline samples and using an analytical method with the logarithmic dispersion relation. The diffraction anomalous fine structure (DAFS) method that is a spectroscopic analysis combined with resonant X-ray diffraction enables the determination of the valence state and local structure of a selected element at a specific crystalline site and/or phase. This method has been improved by using a polycrystalline sample, channel-cut monochromator optics with an undulator synchrotron radiation source, an area detector and direct determination of resonant terms with a logarithmic dispersion relation. This study makes the DAFS method more convenient and saves a large amount of measurement time in comparison with the conventional DAFS method with a single crystal. The improved DAFS method has been applied to some model samples, Ni foil and Fe 3 O 4 powder, to demonstrate the validity of the measurement and the analysis of the present DAFS method

Chemical and biological effects of heavy distillate recycle in the SRC-II process

Energy Technology Data Exchange (ETDEWEB)

Wilson, B.W.; Pelroy, R.A.; Anderson, R.P.; Freel, J.

1983-12-01

Recent work from the Merriam Laboratory continuous coal liquefaction units shows that heavy distillate from the SRC-II process can be recycled to extinction, and hence a distillate product boiling entirely below 310/sup 0/C (590/sup 0/F) (or other selected boiling points) is feasible. In these runs distillate yield was not reduced; gas make was unaffected; and hydrogen consumption was increased only slightly, in keeping with the generally higher hydrogen content of lighter end products. Total distillate yield (C/sub 5/-590/sup 0/F) was 56 wt %, MAF coal in runs with subbituminous coal from the Amax Belle Ayr mine. Product endpoint is well below 371/sup 0/C (700/sup 0/F), the temperature above which coal distillates appear to become genotoxic; and the product was shown to be free of mutagenic activity in the Ames test. Chemical analyses showed both the < 270/sup 0/C (< 518/sup 0/F) and the < 310/sup 0/C (< 590/sup 0/F) distillates to be essentially devoid of several reference polycyclic compounds known to be carcinogenic in laboratory animals. Tests for tumorigenic or carcinogenic activity were not carried out on these materials. However, a comparison of chemical data from the Merriam heavy distillate samples with data on the other SRC-II distillates where carcinogenesis or tumorigenesis data is available leads to the expectation that < 371/sup 0/C (< 700/sup 0/F) materials from the Merriam Laboratory will have greatly reduced tumorigenic and carcinogenic activity in skin painting tests. Other studies suggest the product should be more readily upgraded than full-range (C/sub 5/-900/sup 0/F) distillate.

Fickian dispersion is anomalous

Science.gov (United States)

Cushman, John H.; O'Malley, Dan

2015-12-01

The thesis put forward here is that the occurrence of Fickian dispersion in geophysical settings is a rare event and consequently should be labeled as anomalous. What people classically call anomalous is really the norm. In a Lagrangian setting, a process with mean square displacement which is proportional to time is generally labeled as Fickian dispersion. With a number of counter examples we show why this definition is fraught with difficulty. In a related discussion, we show an infinite second moment does not necessarily imply the process is super dispersive. By employing a rigorous mathematical definition of Fickian dispersion we illustrate why it is so hard to find a Fickian process. We go on to employ a number of renormalization group approaches to classify non-Fickian dispersive behavior. Scaling laws for the probability density function for a dispersive process, the distribution for the first passage times, the mean first passage time, and the finite-size Lyapunov exponent are presented for fixed points of both deterministic and stochastic renormalization group operators. The fixed points of the renormalization group operators are p-self-similar processes. A generalized renormalization group operator is introduced whose fixed points form a set of generalized self-similar processes. Power-law clocks are introduced to examine multi-scaling behavior. Several examples of these ideas are presented and discussed.

Suppressed invasive and migratory behaviors of SW1353 chondrosarcoma cells through the regulation of Src, Rac1 GTPase, and MMP13.

Science.gov (United States)

Xu, Wenxiao; Wan, Qiaoqiao; Na, Sungsoo; Yokota, Hiroki; Yan, Jing-Long; Hamamura, Kazunori

2015-12-01

Chondrosarcoma is the second frequent type of primary bone cancer. In response to stress to the endoplasmic reticulum, activation of eIF2α-mediated signaling is reported to induce apoptosis. However, its effects on invasive and migratory behaviors of chondrosarcoma have not been understood. Focusing on potential roles of Src kinase, Rac1 GTPase, and MMP13, we investigated eIF2α-driven regulation of SW1353 chondrosarcoma cells. In particular, we employed two chemical agents (salubrinal, Sal; and guanabenz, Gu) that elevate the level of eIF2α phosphorylation. The result revealed that both Sal and Gu reduced invasion and motility of SW1353 chondrosarcoma cells in a dose dependent manner. Live imaging using a fluorescent resonance energy transfer (FRET) technique showed that Sal and Gu downregulated activities of Src kinase as well as Rac1 GTPase in an eIF2α dependent manner. RNA interference experiments supported an eIF2α-mediated regulatory network in the inhibitory role of Sal and Gu. Partial silencing of MMP13 also suppressed malignant phenotypes of SW1353 chondrosarcoma cells. However, MMP13 was not regulated via eIF2α since administration of Sal but not Gu reduced expression of MMP13. In summary, we demonstrate that eIF2α dependent and independent pathways regulate invasion and motility of SW1353 chondrosarcoma cells, and inactivation of Src, Rac1, and MMP13 by Sal could provide a potential adjuvant therapy for combating metastatic chondrosarcoma cells. Copyright © 2015 Elsevier Inc. All rights reserved.

ECHR and national constitutional courts

Directory of Open Access Journals (Sweden)

Nastić Maja

2015-01-01

Full Text Available Comprising fundamental rights and freedoms and establishing the effective control system, the European Convention on Human Rights (ECHR encroaches upon the area that is traditional reserved for constitutional law. Although built on the doctrine reserved for international treaty law, the Convention goes beyond the traditional boundaries that exist between international and constitutional law. It has gradually infiltrated into the national legal systems. Constitutional courts have had the crucial role in this process. This paper will focus on the applicability of the ECHR in proceedings before national constitutional courts. Having in mind the jurisdiction of the national constitutional court, the ECHR may be applied in two ways: first, in the process of constitutional review by national constitutional courts and, second, in the process of deciding on constitutional complaints.

Anomalous variations of lithosphere magnetic field before several earthquakes

Science.gov (United States)

Ni, Z.; Chen, B.

2015-12-01

Based on the geomagnetic vector data measured each year since 2011 at more than 500 sites with a mean spatial interval of ~70km.we observed anomalous variations of lithospheric magnetic field before and after over 15 earthquakes having magnitude > 5. We find that the field in near proximity (about 50km) to the epicenter of large earthquakes shows high spatial and temporal gradients before the earthquake. Due to the low frequency of repeat measurements it is unclear when these variations occurred and how do them evolve. We point out anomalous magnetic filed using some circles with radius of 50km usually in June of each year, and then we would check whether quake will locat in our circles during one year after that time (June to next June). Now we caught 10 earthquakes of 15 main shocks having magnitude > 5, most of them located at less than10km away from our circles and some of them were in our circles. Most results show that the variations of lithosphere magnetic filed at the epicenter are different with surrending backgroud usually. When we figure out horizontal variations (vector) of lithosphere magnetic field and epicenter during one year after each June, we found half of them show that the earthquakes will locat at "the inlands in a flowing river", that means earthquakes may occur at "quiet"regions while the backgroud show character as"flow" as liquid. When we compared with GPS results, it appears that these variations of lithospere magnetic field may also correlate with displacement of earth's surface. However we do not compared with GPS results for each earthquake, we are not clear whether these anomalous variations of lithospere magnetic field may also correlate with anomalous displacement of earth's surface. Future work will include developing an automated method for identifying this type of anomalous field behavior and trying to short repeat measurement period to 6 month to try to find when these variations occur.

Anomalous magnetic moment with heavy virtual leptons

Energy Technology Data Exchange (ETDEWEB)

Kurz, Alexander [Karlsruher Institut fuer Technologie (Germany). Inst. fuer Theoretische Teilchenphysik; Deutsches Elektronen-Synchrotron (DESY), Zeuthen (Germany); Liu, Tao; Steinhauser, Matthias [Karlsruher Institut fuer Technologie (Germany). Inst. fuer Theoretische Teilchenphysik; Marquard, Peter [Deutsches Elektronen-Synchrotron (DESY), Zeuthen (Germany)

2013-11-15

We compute the contributions to the electron and muon anomalous magnetic moment induced by heavy leptons up to four-loop order. Asymptotic expansion is applied to obtain three analytic expansion terms which show rapid convergence.

Kinetic studies of anomalous transport

International Nuclear Information System (INIS)

Tang, W.M.

1990-11-01

Progress in achieving a physics-based understanding of anomalous transport in toroidal systems has come in large part from investigations based on the proposition that low frequency electrostatic microinstabilities are dominant in the bulk (''confinement'') region of these plasmas. Although the presence here of drift-type modes dependent on trapped particle and ion temperature gradient driven effects appears to be consistent with a number of important observed confinement trends, conventional estimates for these instabilities cannot account for the strong current (I p ) and /or q-scaling frequently found in empirically deduced global energy confinement times for auxiliary-heated discharges. The present paper deals with both linear and nonlinear physics features, ignored in simpler estimates, which could introduce an appreciable local dependence on current. It is also pointed out that while the thermal flux characteristics of drift modes have justifiably been the focus of experimental studies assessing their relevance, other transport properties associated with these microinstabilities should additionally be examined. Accordingly, the present paper provides estimates and discusses the significance of anomalous energy exchange between ions and electrons when fluctuations are present. 19 refs., 3 figs

Anomalous transport in toroidal plasmas

International Nuclear Information System (INIS)

Punjabi, A.

1991-01-01

We have developed a Monte Carlo method to estimate the transport of different groups of particles for plasmas in toroidal geometries. This method can determine the important transport mechanisms driving the anomalous transport by comparing the numerical results with the experimental data. The important groups of particles whose transport can be estimated by this method include runaway electrons, thermal electrons, both passing and trapped diagnostic beam ions etc. The three basic mechanisms driving the anomalous transport are: spatial variation of magnetic field strength, spatial variation of electrostatic potential within the flux surfaces, and the loss of flux surfaces. The equation of motion are obtained from the drift hamiltonian. The equations of motion are developed in the canonical and in the non-canonical, practical co-ordinates as well. The effects of collisions are represented by appropriate stochastic changes in the constants of motion at each time-step. Here we present the results of application of this method to three cases: superathermal alphas in the rippled field of tokamaks, motion in the magnetic turbulence of takapole II, and transport in the stochastic fields of ZT40. This work is supported by DOE OFE and ORAU HBCU program

Echocardiographic diagnosis of transposition of the great arteries associated with anomalous pulmonary venous connection

Directory of Open Access Journals (Sweden)

Lilian Maria Lopes

2001-07-01

Full Text Available We report 2 cases of transposition of the great arteries associated with anomalous pulmonary venous connection emphasizing the clinical findings, the diagnosis, and the evolution of the association. One of the patients had the anomalous pulmonary venous connection in its total infradiaphragmatic form, in the portal system, and the other patient had a partial form, in which an anomalous connection of the left superior lobar vein with the innominate vein existed. At the time of hospital admission, the patients had cyanosis and respiratory distress with clinical findings suggesting transposition of the great arteries. The diagnosis in 1 of the cases, in which the anomalous connection was partial, was established only with echocardiography, without invasive procedures that would represent risk for the patient; in the other case, in which the anomalous connection was total, the malformation was only evidenced with catheterization. The patients underwent surgery for anatomical correction of the heart disease. Only 1 patient had a good outcome.

Anomalous evolution of Ar metastable density with electron density in high density Ar discharge

International Nuclear Information System (INIS)

Park, Min; Chang, Hong-Young; You, Shin-Jae; Kim, Jung-Hyung; Shin, Yong-Hyeon

2011-01-01

Recently, an anomalous evolution of argon metastable density with plasma discharge power (electron density) was reported [A. M. Daltrini, S. A. Moshkalev, T. J. Morgan, R. B. Piejak, and W. G. Graham, Appl. Phys. Lett. 92, 061504 (2008)]. Although the importance of the metastable atom and its density has been reported in a lot of literature, however, a basic physics behind the anomalous evolution of metastable density has not been clearly understood yet. In this study, we investigated a simple global model to elucidate the underlying physics of the anomalous evolution of argon metastable density with the electron density. On the basis of the proposed simple model, we reproduced the anomalous evolution of the metastable density and disclosed the detailed physics for the anomalous result. Drastic changes of dominant mechanisms for the population and depopulation processes of Ar metastable atoms with electron density, which take place even in relatively low electron density regime, is the clue to understand the result.

Institute of constitutional revision in the Constitution of the Republic of Albania, comparative view

Directory of Open Access Journals (Sweden)

Makbule Çeço

2014-07-01

Full Text Available In its very dynamic essence, a democratic society bears the need for continuous reformation and perfection, and that is why the application of reforms represents an inseparable feature for this type of society. The consolidation of the rule of law, the institutional independence, and the cause of justice itself comprise, inter alia, the need for constitutional revision. This study puts forward a theoretical-historical comparative view of the relevant and dynamic issue of the institute of constitutional revision in the framework of the Constitution of the Republic of Albania, as a complex process accompanied by limitations on constitutional revision. The historical evolution of constitutional drafting, modern constitutions, relevant issues, political and social circumstances as well as drafting and adoption procedures, dynamism of constitutions to cope with the course of time achieved by revisions for the purpose of their stability as well as consolidation of the role of constitutions as a factor that facilitates and precedes social development, comprise the pillar of this study addressed in a comparative point of view.

Anomalous relaxation in binary mixtures: a dynamic facilitation picture

International Nuclear Information System (INIS)

Moreno, A J; Colmenero, J

2007-01-01

Recent computational investigations of polymeric and non-polymeric binary mixtures have reported anomalous relaxation features when both components exhibit very different mobilities. Anomalous relaxation is characterized by sublinear power-law behaviour for mean-squared displacements, logarithmic decay in dynamic correlators, and a striking concave-to-convex crossover in the latter by tuning the relevant control parameter, in analogy with predictions of the mode-coupling theory for state points close to higher-order transitions. We present Monte Carlo simulations on a coarse-grained model for relaxation in binary mixtures. The liquid structure is substituted by a three-dimensional array of cells. A spin variable is assigned to each cell, representing unexcited and excited local states of a mobility field. Changes in local mobility (spin flip) are permitted according to kinetic constraints determined by the mobilities of the neighbouring cells. We introduce two types of cell ('fast' and 'slow') with very different rates for spin flip. This coarse-grained model qualitatively reproduces the mentioned anomalous relaxation features observed for real binary mixtures

Schwinger Model Mass Anomalous Dimension

CERN Document Server

Keegan, Liam

2016-06-20

The mass anomalous dimension for several gauge theories with an infrared fixed point has recently been determined using the mode number of the Dirac operator. In order to better understand the sources of systematic error in this method, we apply it to a simpler model, the massive Schwinger model with two flavours of fermions, where analytical results are available for comparison with the lattice data.

Faraday anomalous dispersion optical filters

Science.gov (United States)

Shay, T. M.; Yin, B.; Alvarez, L. S.

1993-01-01

The effect of Faraday anomalous dispersion optical filters on infrared and blue transitions of some alkali atoms is calculated. A composite system is designed to further increase the background noise rejection. The measured results of the solar background rejection and image quality through the filter are presented. The results show that the filter may provide high transmission and high background noise rejection with excellent image quality.

Electrical control of the anomalous valley Hall effect in antiferrovalley bilayers

Science.gov (United States)

Tong, Wen-Yi; Duan, Chun-Gang

2017-08-01

In analogy to all-electric spintronics, all-electric valleytronics, i.e., valley manipulation via electric means, becomes an exciting new frontier as it may bring revolutions in the field of data storage with ultra-high speed and ultra-low power consumption. The existence of the anomalous valley Hall effect in ferrovalley materials demonstrates the possibility of electrical detection for valley polarization. However, in previously proposed valley-polarized monolayers, the anomalous valley Hall effect is controlled by external magnetic fields. Here, through elaborate structural design, we propose the antiferrovally bilayer as an ideal candidate for realizing all-electric valleytronic devices. Using the minimal k.p model, we show that the energy degeneracy between valley indexes in such system can be lifted by electric approaches. Subsequently, the anomalous valley Hall effect strongly depends on the electric field as well. Taking the bilayer VSe2 as an example, all-electric tuning and detecting of anomalous valley Hall effect is confirmed by density-functional theory calculations, indicating that the valley information in such antiferrovalley bilayer can be reversed by an electric field perpendicular to the plane of the system and easily probed through the sign of the Hall voltage.

Anomalous periodic disruptions in tokamak plasma

International Nuclear Information System (INIS)

Montvai, A.; Tegze, M.; Valyi, I.

1982-09-01

Anomalously strong, periodic instabilities were observed in the MT-1 tokamak. Characteristics of these instabilities were partly similar to those of internal disruptions, but there were features making them different from the normal relaxational oscillations. Basic characteristics of the phenomenon were studied with the aid of generally used diagnostics. (author)

Influence of anomalous transport phenomena on onset of Neoclassical Tearing Modes in tokamaks

International Nuclear Information System (INIS)

Konovalov, S.V.; Mikhailovskii, A.B.; Shirokov, M.S.; Ozeki, T.; Takizuka, T.; Hayashi, N.

2005-01-01

Influence of anomalous perpendicular heat transport and anomalous ion perpendicular viscosity on conditions of Neoclassical Tearing Mode (NTM) onset is studied theoretically. Series of various parallel transport mechanisms competitive to anomalous cross-island heat transport in formation of the perturbed electron and ion temperature profiles within the island are considered. Analytical solutions to respective heat balance equations were found and perturbed temperature profiles were calculated rigorously. The partial contributions from the plasma electron and ion temperature perturbations in the bootstrap drive of the mode and magnetic curvature effect were then accounted in construction of a generalized transport threshold model of NTMs. Taking into account the curvature effect weakening in the generalized transport threshold model predicts notable improvement of NTM stability. The anomalous perpendicular ion viscosity was shown to modify collisionality dependence of polarization current effect reducing it to the low collisionality limit. The bootstrap drive of NTM in the presence of anomalous perpendicular ion viscosity was found to be dependent on the island rotation frequency and direction. For island rotating in direction of the electron diamagnetic drift viscosity effect was shown to be stabilizing. The role of viscosity effect grows rapidly with rise of the plasma ion temperature. (author)

Probing anomalous quartic gauge-boson couplings via e+e-→4 fermions +γ

International Nuclear Information System (INIS)

Denner, A.; Dittmaier, S.; Roth, M.; Wackeroth, D.

2001-01-01

All lowest-order amplitudes for e + e - →4fγ are calculated including five anomalous quartic gauge-boson couplings that are allowed by electromagnetic gauge invariance and the custodial SU(2) c symmetry. Three of these anomalous couplings correspond to the operators L 0 ,L c , and L n that have been constrained by the LEP collaborations in WWγ production. The anomalous couplings are incorporated in the Monte Carlo generator RacoonWW(RacoonWW fellow of the Deutsche Forschungsgemeinschaft). Moreover, for the processes e + e - →4fγ RacoonWW is improved upon including leading universal electroweak corrections such as initial-state radiation. The discussion of numerical results illustrates the size of the leading corrections as well as the impact of the anomalous quartic couplings for LEP2 energies and at 500 GeV. (orig.)

SAD phasing with in-house cu Ka radiation using barium as anomalous scatterer.

Science.gov (United States)

Dhanasekaran, V; Velmurugan, D

2011-12-01

Phasing of lysozyme crystals using co-crystallized barium ions was performed using single-wavelength anomalous diffraction (SAD) method using Cu Ka radiation with in-house source of data collection. As the ion binding sites vary with respect to the pH of the buffer during crystallization, the highly isomorphic forms of lysozyme crystals grown at acidic and alkaline pH were used for the study. Intrinsic sulphur anomalous signal was also utilized with anomalous signal from lower occupancy ions for phasing. The study showed that to solve the structure by SAD technique, 2.8-fold data redundancy was sufficient when barium was used as an anomalous marker in the in-house copper X-ray radiation source for data collection. Therefore, co-crystallization of proteins with barium containing salt can be a powerful tool for structure determination using lab source.

The Emerging and Diverse Roles of Src-Like Adaptor Proteins in Health and Disease

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Nikolett Marton

2015-01-01

Full Text Available Although Src-like adaptor proteins (SLAP-1 and SLAP-2 were mainly studied in lymphocytes, where they act as negative regulators and provide fine control of receptor signaling, recently, several other functions of these proteins were discovered. In addition to the well-characterized immunoregulatory functions, SLAP proteins appear to have an essential role in the pathogenesis of type I hypersensitivity, osteoporosis, and numerous malignant diseases. Both adaptor proteins are expressed in a wide variety of tissues, where they have mostly inhibitory effects on multiple intracellular signaling pathways. In this review, we summarize the diverse effects of SLAP proteins.

Anomalous vibrational modes in acetanilide as studied by inelastic neutron scattering

Science.gov (United States)

Barthes, Mariette; Eckert, Juegen; Johnson, Susanna W.; Moret, Jacques; Swanson, Basil I.; Unkefer, Clifford J.

1992-10-01

A study of the anomalous modes in acetanilide and five deuterated derivatives by incoherent inelastic neutron scattering is reported. These data show that the dynamics of the amide and methyl groups influence each other. In addition, the anomalous temperature behaviour of the NH out-of-plane bending mode is confirmed. These observations suggest that the self-trapping mechanism in ACN may be more complex than hitherto assumed.

On the importance of a funneled energy landscape for the assembly and regulation of multidomain Src tyrosine kinases.

Science.gov (United States)

Faraldo-Gómez, José D; Roux, Benoît

2007-08-21

Regulation of signaling pathways in the cell often involves multidomain allosteric enzymes that are able to adopt alternate active or inactive conformations in response to specific stimuli. It is therefore of great interest to elucidate the energetic and structural determinants that govern the conformational plasticity of these proteins. In this study, free-energy computations have been used to address this fundamental question, focusing on one important family of signaling enzymes, the Src tyrosine kinases. Inactivation of these enzymes depends on the formation of an assembly comprising a tandem of SH3 and SH2 modules alongside a catalytic domain. Activation results from the release of the SH3 and SH2 domains, which are then believed to be structurally uncoupled by virtue of a flexible peptide link. In contrast to this view, this analysis shows that inactivation depends critically on the intrinsic propensity of the SH3-SH2 tandem to adopt conformations that are conducive to the assembled inactive state, even when no interactions with the rest of the kinase are possible. This funneling of the available conformational space is encoded within the SH3-SH2 connector, which appears to have evolved to modulate the flexibility of the tandem in solution. To further substantiate this notion, we show how constitutively activating mutations in the SH3-SH2 connector shift the assembly equilibrium toward the disassembled, active state. Based on a similar analysis of several constructs of the kinase complex, we propose that assembly is characterized by the progressive optimization of the protein's conformational energy, with little or no energetic frustration.

The Possibility of Vice-Presidents’ Authority Arrangement in the 1945 Constitution through Constitutional Amendment

Directory of Open Access Journals (Sweden)

Fajar L. Suroso

2016-04-01

Full Text Available The debate over the vice-presidents’ authority reappeared in the administration of President Jokowi after the “authority expansion of the Chief of Presidency Staff” and the case of “Rizal Ramli vs Jusuf Kalla”. This article is intended to provide arguments for the idea of some parties to organize more explicit and detailed the authority of vice-president in the 1945 Constitution. The idea arises from the absence of further arrangement on the authority of vice-president in the 1945 Constitution. This article is systematized into 3 (three sub-theme; 1 the arrangement of the vice-presidents’ authority in the constitution for several countries; 2 The authority of the vice-president according to the 1945 Constitution, and 3 New resultant and the possibility of 1945 Constitution amendment. The result revealed a number of interesting things; 1 the constitutions of other countries do not specify the authority of the vice-president and put the vice-president as a “spare tire” when the president is absent; 2 no new resultant about the position and authority of the vice-president so that theoretically is not reason enough to regulate in detail the authority of the vice-president through the 1945 Constitution amendment; 3 arrangement in detail in the authority of vice-president in the 1945 Constitution holds the potential to confuse the presidential system design as the 1945 Constitution. Therefore, the possibility of vice-presidents’ authority arrangement in the 1945 Constitution through amendment is very small, both in terms of momentum and the substance of issues.

Anomalous refraction of light colors by a metamaterial prism.

Science.gov (United States)

Silveirinha, Mário G

2009-05-15

A prism of glass separates white light into its spectral components in such a manner that colors associated with shorter wavelengths are more refracted than the colors associated with longer wavelengths. Here, we demonstrate that this property is not universal, and that a lossless metamaterial prism with a suitable microstructure may enable a broadband regime of anomalous dispersion, where the spectral components of light are separated in an unconventional way, so that "violet light" is less refracted than "red light." This phenomenon is fundamentally different from conventional anomalous dispersion effects, which are invariably accompanied by significant loss and are typically very narrow band.

Requirement of ERα and basal activities of EGFR and Src kinase in Cd-induced activation of MAPK/ERK pathway in human breast cancer MCF-7 cells

Energy Technology Data Exchange (ETDEWEB)

Song, Xiulong, E-mail: songxiulong@hotmail.com; Wei, Zhengxi; Shaikh, Zahir A., E-mail: zshaikh@uri.edu

2015-08-15

Cadmium (Cd) is a common environmental toxicant and an established carcinogen. Epidemiological studies implicate Cd with human breast cancer. Low micromolar concentrations of Cd promote proliferation of human breast cancer cells in vitro. The growth promotion of breast cancer cells is associated with the activation of MAPK/ERK pathway. This study explores the mechanism of Cd-induced activation of MAPK/ERK pathway. Specifically, the role of cell surface receptors ERα, EGFR, and Src kinase was evaluated in human breast cancer MCF-7 cells treated with 1–3 μM Cd. The activation of ERK was studied using a serum response element (SRE) luciferase reporter assay. Receptor phosphorylation was detected by Western blot analyses. Cd treatment increased both the SRE reporter activity and ERK1/2 phosphorylation in a concentration-dependent manner. Cd treatment had no effect on reactive oxygen species (ROS) generation. Also, blocking the entry of Cd into the cells with manganese did not diminish Cd-induced activation of MAPK/ERK. These results suggest that the effect of Cd was likely not caused by intracellular ROS generation, but through interaction with the membrane receptors. While Cd did not appear to activate either EGFR or Src kinase, their inhibition completely blocked the Cd-induced activation of ERK as well as cell proliferation. Similarly, silencing ERα with siRNA or use of ERα antagonist blocked the effects of Cd. Based on these results, it is concluded that not only ERα, but also basal activities of EGFR and Src kinase are essential for Cd-induced signal transduction and activation of MAPK/ERK pathway for breast cancer cell proliferation. - Highlights: • Low micromolar concentrations of Cd rapidly activate ERK1/2 in MCF-7 cells. • Signal transduction and resulting cell proliferation require EGFR, ERα, and Src. • These findings implicate Cd in promotion of breast cancer.

Constitutional Fundamentals of Conscription and Some Aspects of the Ordinary Legal Regulation of Constitutionality

Directory of Open Access Journals (Sweden)

Kenstavičienė Kristina

2015-12-01

Full Text Available Article 139 of the Constitution of the Republic of Lithuania is one of the constitutional fundamentals of state defense and stipulates the defense of the state as the right of citizens on the one hand and the duty on the other. This article of the Constitution gives the legislative power the right of discretion to detail by law the order of the implementation of citizens’ duty to perform military or alternative country defense service. Due to the reorganization of the armed forces into a professional and volunteer army, the issue of some ordinary regulation rules concerning the constitutionality of nationwide conscription, though at present suspended but not abolished, is becoming urgent. Though the Constitutional Court of the Republic of Lithuania presented their ruling on the constitutionality of the suspension of military conscription, it does not mean that all problems related to conscription have been settled. The aim of this article is to analyze the constitutional basis of nationwide conscription as well as the constitutionality of some ordinary regulation provisions related to nationwide conscription. Therefore, the issue to be analyzed is whether nationwide conscription, if it were to be implemented, complies with the constitutional principles of human equality and military justice1. Consequently, the question is posed how the constitutional objective of ensuring the defense of the state determines conscription. Because of the growing employment of the army abroad, yet the dwindling demand for conscripts, it should be explored whether the suspension of the nationwide conscription as a part of the defense reform is further feasible in order to guarantee the defense of the state. In answering the raised questions, the author will analyze the abundant and long-lasting constitutional doctrine of Germany which provides clarifications of the Basic Law, as the legal act of the establishing power, which can doubtless be of assistance in

Anomalous Hall effect in disordered multiband metals

Czech Academy of Sciences Publication Activity Database

Kovalev, A.A.; Sinova, Jairo; Tserkovnyak, Y.

2010-01-01

Roč. 105, č. 3 (2010), 036601/1-036601/4 ISSN 0031-9007 Institutional research plan: CEZ:AV0Z10100521 Keywords : anomalous Hall effect * spintronics Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 7.621, year: 2010

Bunburra Rockhole: A New Anomalous Achondrite

Czech Academy of Sciences Publication Activity Database

Bland, P.A.; Spurný, Pavel; Greenwood, R.C.; Towner, M.C.; Bevan, A.W.R.; Bottke jr., W.F.; Shrbený, Lukáš; McClafferty, T.; Vaughan, D.; Benedix, G.K.; Franchi, I.A.; Hough, R.M.

2009-01-01

Roč. 72, Supplement (2009), A34-A34 ISSN 1086-9379. [Annual Meeting of the Meteoritical Society /72./. Nancy, 13.06.2009-18.06.2009] Institutional research plan: CEZ:AV0Z10030501 Keywords : Bunburra Rockhole * anomalous achondrite Subject RIV: BN - Astronomy, Celestial Mechanics, Astrophysics Impact factor: 3.253, year: 2009

Structural and Biochemical Characterization of SrcA, a Multi-cargo Type III Secretion Chaperone in Salmonella Required for Pathogenic Association with a Host

Energy Technology Data Exchange (ETDEWEB)

Cooper, C.; Zhang, K; Andres, S; Fnag, Y; Kaniuk, N; Hannemann, M; Brumell, J; Foster, L; Junop, M; Coombes, B

2010-01-01

Many Gram-negative bacteria colonize and exploit host niches using a protein apparatus called a type III secretion system (T3SS) that translocates bacterial effector proteins into host cells where their functions are essential for pathogenesis. A suite of T3SS-associated chaperone proteins bind cargo in the bacterial cytosol, establishing protein interaction networks needed for effector translocation into host cells. In Salmonella enterica serovar Typhimurium, a T3SS encoded in a large genomic island (SPI-2) is required for intracellular infection, but the chaperone complement required for effector translocation by this system is not known. Using a reverse genetics approach, we identified a multi-cargo secretion chaperone that is functionally integrated with the SPI-2-encoded T3SS and required for systemic infection in mice. Crystallographic analysis of SrcA at a resolution of 2.5 {angstrom} revealed a dimer similar to the CesT chaperone from enteropathogenic E. coli but lacking a 17-amino acid extension at the carboxyl terminus. Further biochemical and quantitative proteomics data revealed three protein interactions with SrcA, including two effector cargos (SseL and PipB2) and the type III-associated ATPase, SsaN, that increases the efficiency of effector translocation. Using competitive infections in mice we show that SrcA increases bacterial fitness during host infection, highlighting the in vivo importance of effector chaperones for the SPI-2 T3SS.

Structural and biochemical characterization of SrcA, a multi-cargo type III secretion chaperone in Salmonella required for pathogenic association with a host.

Directory of Open Access Journals (Sweden)

Colin A Cooper

2010-02-01

Full Text Available Many Gram-negative bacteria colonize and exploit host niches using a protein apparatus called a type III secretion system (T3SS that translocates bacterial effector proteins into host cells where their functions are essential for pathogenesis. A suite of T3SS-associated chaperone proteins bind cargo in the bacterial cytosol, establishing protein interaction networks needed for effector translocation into host cells. In Salmonella enterica serovar Typhimurium, a T3SS encoded in a large genomic island (SPI-2 is required for intracellular infection, but the chaperone complement required for effector translocation by this system is not known. Using a reverse genetics approach, we identified a multi-cargo secretion chaperone that is functionally integrated with the SPI-2-encoded T3SS and required for systemic infection in mice. Crystallographic analysis of SrcA at a resolution of 2.5 A revealed a dimer similar to the CesT chaperone from enteropathogenic E. coli but lacking a 17-amino acid extension at the carboxyl terminus. Further biochemical and quantitative proteomics data revealed three protein interactions with SrcA, including two effector cargos (SseL and PipB2 and the type III-associated ATPase, SsaN, that increases the efficiency of effector translocation. Using competitive infections in mice we show that SrcA increases bacterial fitness during host infection, highlighting the in vivo importance of effector chaperones for the SPI-2 T3SS.

The hidden treasure in your data: phasing with unexpected weak anomalous scatterers from routine data sets

Energy Technology Data Exchange (ETDEWEB)

Hegde, Raghurama P.; Fedorov, Alexander A.; Sauder, J. Michael; Burley, Stephen K.; Almo, Steven C.; Ramagopal, Udupi A.

2017-03-22

Single-wavelength anomalous dispersion (SAD) utilizing anomalous signal from native S atoms, or other atoms withZ≤ 20, generally requires highly redundant data collected using relatively long-wavelength X-rays. Here, the results from two proteins are presented where the anomalous signal from serendipitously acquired surface-bound Ca atoms with an anomalous data multiplicity of around 10 was utilized to drivede novostructure determination. In both cases, the Ca atoms were acquired from the crystallization solution, and the data-collection strategy was not optimized to exploit the anomalous signal from these scatterers. The X-ray data were collected at 0.98 Å wavelength in one case and at 1.74 Å in the other (the wavelength was optimized for sulfur, but the anomalous signal from calcium was exploited for structure solution). Similarly, using a test case, it is shown that data collected at ~1.0 Å wavelength, where thef'' value for sulfur is 0.28 e, are sufficient for structure determination using intrinsic S atoms from a strongly diffracting crystal. Interestingly, it was also observed thatSHELXDwas capable of generating a substructure solution from high-exposure data with a completeness of 70% for low-resolution reflections extending to 3.5 Å resolution with relatively low anomalous multiplicity. Considering the fact that many crystallization conditions contain anomalous scatterers such as Cl, Ca, Mnetc., checking for the presence of fortuitous anomalous signal in data from well diffracting crystals could prove useful in either determining the structurede novoor in accurately assigning surface-bound atoms.

Application of new synchrotron powder diffraction techniques to anomalous scattering from glasses

International Nuclear Information System (INIS)

Beno, M.A.; Knapp, G.S.; Armand, P.; Price, D.L.; Saboungi, M.

1995-01-01

We have applied two synchrotron powder diffraction techniques to the measurement of high quality anomalous scattering diffraction data for amorphous materials. One of these methods, which uses a curved perfect crystal analyzer to simultaneously diffract multiple powder lines into a position sensitive detector has been shown to possess high resolution, low background, and very high counting rates. This data measurement technique provides excellent energy resolution while minimizing systematic errors resulting from detector nonlinearity. Anomalous scattering data for a Cesium Germanate glass collected using this technique will be presented. The second powder diffraction technique uses a flat analyzer crystal to deflect multiple diffraction lines out of the equatorial plane. Calculations show that this method possesses sufficient energy resolution for anomalous scattering experiments when a perfect crystal analyzer is used and is experimentally much simpler. Future studies will make use of a rapid sample changer allowing the scattering from the sample and a standard material (a material not containing the anomalous scatterer) to be measured alternately at each angle, reducing systematic errors due to beam instability or sample misalignment

Complexes of gamma-tubulin with nonreceptor protein tyrosine kinases Src and Fyn in differentiating P19 embryonal carcinoma cells

Czech Academy of Sciences Publication Activity Database

Kukharskyy, Vitaliy; Sulimenko, Vadym; Macůrek, Libor; Sulimenko, Tetyana; Dráberová, Eduarda; Dráber, Pavel

2004-01-01

Roč. 298, - (2004), s. 218-228 ISSN 0014-4827 R&D Projects: GA AV ČR IAA5052004; GA ČR GA304/00/0553; GA ČR GA304/04/1273; GA MŠk LN00A026 Keywords : gamma-tubulin * P19 cells * Fyn and Src kinase Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.007, year: 2004

Observation of the Zero Hall Plateau in a Quantum Anomalous Hall Insulator

Energy Technology Data Exchange (ETDEWEB)

Feng, Yang; Feng, Xiao; Ou, Yunbo; Wang, Jing; Liu, Chang; Zhang, Liguo; Zhao, Dongyang; Jiang, Gaoyuan; Zhang, Shou-Cheng; He, Ke; Ma, Xucun; Xue, Qi-Kun; Wang, Yayu

2015-09-16

We report experimental investigations on the quantum phase transition between the two opposite Hall plateaus of a quantum anomalous Hall insulator. We observe a well-defined plateau with zero Hall conductivity over a range of magnetic field around coercivity when the magnetization reverses. The features of the zero Hall plateau are shown to be closely related to that of the quantum anomalous Hall effect, but its temperature evolution exhibits a significant difference from the network model for a conventional quantum Hall plateau transition. We propose that the chiral edge states residing at the magnetic domain boundaries, which are unique to a quantum anomalous Hall insulator, are responsible for the novel features of the zero Hall plateau.

Anomalous Seebeck coefficient in boron carbides

International Nuclear Information System (INIS)

Aselage, T.L.; Emin, D.; Wood, C.; Mackinnon, I.D.R.; Howard, I.A.

1987-01-01

Boron carbides exhibit an anomalously large Seebeck coefficient with a temperature coefficient that is characteristic of polaronic hopping between inequivalent sites. The inequivalence in the sites is associated with disorder in the solid. The temperature dependence of the Seebeck coefficient for materials prepared by different techniques provides insight into the nature of the disorder

Anomalous experiences, trauma and symbolization processes at the frontier between psychoanalysis and cognitive neurosciences

Directory of Open Access Journals (Sweden)

Thomas eRabeyron

2015-12-01

Full Text Available Anomalous or exceptional experiences are uncommon experiences which are usually interpreted as being paranormal by those who report them. These experiences have long remained difficult to explain, but current progress in cognitive neuroscience and psychoanalysis sheds light on the contexts in which they emerge, as well as on their underlying processes. Following a brief description of the different types of anomalous experiences, we underline how they can be better understood at the frontiers between psychoanalysis and cognitive neurosciences. In this regard, three main lines of research are discussed and illustrated, alongside clinical cases which come from a clinical service specializing in anomalous experiences. First, we study the links between anomalous experiences and hallucinatory processes, by showing that anomalous experiences frequently occur as a specific reaction to negative life events, in which case they mainly take the form of non-pathological hallucinations. Next, we propose to analyze these experiences from the perspective of their traumatic aspects and the altered states of consciousness they often imply. Finally, these experiences are considered to be the consequence of a hypersensitivity that can be linked to an increase in psychic permeability. In conclusion, these different processes lead us to consider anomalous experiences as primary forms of symbolization and transformation of the subjective experience, especially during or after traumatic situations.

Anomalous Experiences, Trauma, and Symbolization Processes at the Frontiers between Psychoanalysis and Cognitive Neurosciences

Science.gov (United States)

Rabeyron, Thomas; Loose, Tianna

2015-01-01

Anomalous or exceptional experiences are uncommon experiences which are usually interpreted as being paranormal by those who report them. These experiences have long remained difficult to explain, but current progress in cognitive neuroscience and psychoanalysis sheds light on the contexts in which they emerge, as well as on their underlying processes. Following a brief description of the different types of anomalous experiences, we underline how they can be better understood at the frontiers between psychoanalysis and cognitive neurosciences. In this regard, three main lines of research are discussed and illustrated, alongside clinical cases which come from a clinical service specializing in anomalous experiences. First, we study the links between anomalous experiences and hallucinatory processes, by showing that anomalous experiences frequently occur as a specific reaction to negative life events, in which case they mainly take the form of non-pathological hallucinations. Next, we propose to analyze these experiences from the perspective of their traumatic aspects and the altered states of consciousness they often imply. Finally, these experiences are considered to be the consequence of a hypersensitivity that can be linked to an increase in psychic permeability. In conclusion, these different processes lead us to consider anomalous experiences as primary forms of symbolization and transformation of the subjective experience, especially during, or after traumatic situations. PMID:26732646

Magnetic resonance imaging of anomalous pulmonary venous connections

International Nuclear Information System (INIS)

Choe, Yeon Hyeon; Lee, Heung Jae; Kim, Hak Soo; Ko, Jae Kon; Kim, Ji Eun; Han, Jae Jin

1994-01-01

We evaluated the capability of MR in the diagnosis of anomalous pulmonary venous connection (APVC). The patient group consisted of 11 total APVC and 8 partial APVC diagnosed with MR. Echocardiography was performed in all cases, cardiac angiography in 12 cases and operation in 12 cases. We compared MR findings with those of operation, echocardiography and cardiac angiography. In surgically proven 12 cases, diagnostic accuracy of preoperative MR, echocardiography and cardiac angiography was 100%, 67%, and 63%, respectively. In the remaining cases, MR findings well correlated with those of echocardiography or cardiac angiography. Stenosis of common pulmonary vein or superior vena cava was identified in 4 cases. In one patient, MR duplicated associated cortriatriatum clearly. MR is an effective modally in depicting anomalous pulmonary venous connections

Is anomalous origin of the left vertebral artery indeed a rare finding ...

African Journals Online (AJOL)

We present a pictorial review of anomalous origin of the left vertebral artery observed in 5 patients imaged in our after-hours trauma radiology unit within a period of 7 days. We raise the question of whether the incidence of anomalous origin of the left vertebral artery quoted in the radiology literature as 5% is really that low, ...

Progress in analytical calculations for the anomalous magnetic moment of the muon

International Nuclear Information System (INIS)

Baikov, P.A.

2013-11-01

We present results for certain classes of diagrams contributing to the anomalous magnetic moment of the muon at five-loop order. Our method is based on first constructing an approximating function for the vacuum polarization function of the photon at four loop order which later can be numerically integrated to obtain the anomalous magnetic moment of the muon.

Progress in analytical calculations for the anomalous magnetic moment of the muon

Energy Technology Data Exchange (ETDEWEB)

Baikov, P.A. [Moscow State Univ. (Russian Federation). Skobeltsyn Inst. of Nuclear Physics; Maier, A. [Technische Univ. Muenchen (Germany). Physik Dept. T31; Marquard, P. [Deutsches Elektronen-Synchrotron (DESY), Zeuthen (Germany)

2013-11-15

We present results for certain classes of diagrams contributing to the anomalous magnetic moment of the muon at five-loop order. Our method is based on first constructing an approximating function for the vacuum polarization function of the photon at four loop order which later can be numerically integrated to obtain the anomalous magnetic moment of the muon.

MR appearance of anomalous insertion of the medial meniscus. A case report

International Nuclear Information System (INIS)

Arjun, S.; Takahashi, S.; Nakane, N.; Yonemitsu, H.; Tang, Y.

1998-01-01

We report on the MR imaging of an anomalous medial meniscus with a tear in a 41-year-old man. Anomaly of the medial meniscus is rare and difficult to diagnose clinically. The MR images contributed to the pre-arthroscopic diagnosis and arthroscopy confirmed the lesion. The anomalous meniscus was not related to the symptoms. (orig.)

On the Casimir scaling violation in the cusp anomalous dimension at small angle

Science.gov (United States)

Grozin, Andrey; Henn, Johannes; Stahlhofen, Maximilian

2017-10-01

We compute the four-loop n f contribution proportional to the quartic Casimir of the QCD cusp anomalous dimension as an expansion for small cusp angle ϕ. This piece is gauge invariant, violates Casimir scaling, and first appears at four loops. It requires the evaluation of genuine non-planar four-loop Feynman integrals. We present results up to O({φ}^4) . One motivation for our calculation is to probe a recent conjecture on the all-order structure of the cusp anomalous dimension. As a byproduct we obtain the four-loop HQET wave function anomalous dimension for this color structure.

Anomalous U(1) models in four and five dimensions and their anomaly poles

International Nuclear Information System (INIS)

Armillis, Roberta; Coriano, Claudio; Delle Rose, Luigi; Guzzi, Marco